Pediatric Dosage and Administration of Anti-C5 Antibodies for the Treatment of Complement Disorders

Abstract

A device, system, and method are provided for the clinical treatment of complement disorders (e.g., paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome) in human pediatric patients, using a subcutaneous delivery system (e.g., an on-body device and / or syringe) to administer an effective dose of a therapeutic anti-C5 antibody such as ravulizumab or its antigen-binding fragment.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and benefits of U.S. Provisional Application No. 63 / 499,599, filed on 2 May 2023, which is incorporated herein by reference in its entirety.

[0002] (Reference to electronically submitted sequence listings) This application is filed electronically in XML format and includes a sequence listing, which is incorporated herein by reference in its entirety. The XML copy, created on 17 February 2023, is named 51196-034001_Sequence_Listing_2_17_23 and is 49,397 bytes in size. [Background technology]

[0003] The complement system works in conjunction with the body's other immune systems to defend against the invasion of cells and viral pathogens. At least 25 complement proteins exist, found as a complex assembly of plasma proteins and membrane cofactors. Plasma proteins constitute approximately 10% of the globulins in vertebrate serum. Complement components achieve their immunodefense functions by interacting in a series of complex but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonin, immunomodulatory, and lytic functions. A concise summary of the biological activities associated with complement activation is provided, for example, in The Merck Manual, 16th Edition.

[0004] A properly functioning complement system provides robust defense against infectious microorganisms, but inappropriate regulation or activation of the complement pathways is involved in the etiology of various disorders, including paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Both PNH and aHUS are extremely rare disorders driven by chronic uncontrolled complement activation. The resulting inflammation and cell damage lead to the severe clinical symptoms of these diseases.

[0005] PNH is a condition in which uncontrolled complement activity leads to systemic complications mainly through intravascular hemolysis and platelet activation (see Socie G, et al., French Society of Haematology. Lancet. 1996;348(9027):573 - 577 and Brodsky, R., Blood. 2014;124(18):2804 - 2811). Persistent intravascular hemolysis can be induced by various stress factors such as infections or physical exercise, which leads to an increased risk of smooth muscle contraction (free hemoglobin), chronic anemia, and severe thromboembolism. Thromboembolism, as the most common cause of death in patients with PNH, can lead to pulmonary hypertension and end - organ damage in vital organs such as the liver, kidney, brain, and intestine (Hillmen, P., et al, Am. J. Hematol. 2010;85(8):553 - 559). Due to these harmful pathological processes, patients with PNH have a decreased quality of life (QoL), which can include debilitating fatigue, chronic pain, reduced physical function, shortness of breath, abdominal pain, erectile dysfunction, the need for anticoagulation, blood transfusions, and in some cases, the need for dialysis (Weitz, I C., et al., Thromb Res. 2012;130(3):361 - 368).

[0006] Hemolytic uremic syndrome (HUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS is classified as one of two types: diarrhea-associated (D+HUS, also known as Shiga toxin-producing E. coli (STEC)-HUS or typical HUS) and non-diarrhea or atypical HUS (aHUS). D+HUS is the most common form, accounting for over 90% of cases, and is caused by a preceding illness with Shiga-like toxin-producing bacteria, such as E. coli O157:H7.

[0007] aHUS can be hereditary, acquired, or idiopathic. The hereditary forms of aHUS may be associated with mutations in a number of human complement components, including, for example, complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C4b-binding protein (C4BP), complement factor B (CFB), and complement component 3 (C3). See, for example, Caprioli et al. (2006) Blood 108:1267-1279. Certain mutations in the gene encoding CD55 are not yet implicated in aHUS but are associated with the severity of aHUS. See, for example, Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703-712.

[0008] aHUS is rare and has a mortality rate of up to 25%. Many patients with this disease experience persistent neurological or renal impairment, and for example, at least 50% of aHUS patients progress to end-stage renal failure (ESRF). See, for example, Kavanagh et al. (2006) British Medical Bulletin 77 and 78:5-22. Until recently, treatment options for patients with aHUS were limited and often involved plasma infusion or plasmapheresis. In some cases, aHUS patients undergo unilateral or bilateral nephrectomy or kidney transplantation (see Artz et al. (2003) Transplantation 76:821-826). However, disease recurrence is common in treated patients.

[0009] Patients with PNH or aHUS are at significant risk of morbidity and mortality. Therefore, an object of the present invention is to provide an improved method for treating patients with PNH or aHUS. [Overview of the project]

[0010] This specification provides, in particular, devices, compositions, methods, and kits for treating PNH or aHUS in pediatric human patients, comprising subcutaneously administering a therapeutic anti-C5 antibody or its antigen-binding fragment to the patient, wherein the anti-C5 antibody or its antigen-binding fragment is administered or intended to be administered according to a specific clinical dosage regimen (i.e., in a specific dose and according to a specific administration schedule).

[0011] Any suitable anti-C5 antibody or its antigen-binding fragment can be used in the manner described herein. Exemplary anti-C5 antibodies are ravulizumab (also known as Ultomiris®, ALXN1210, and antibody BNJ441), or its antigen-binding fragment and variants, comprising heavy and light chains having the sequences shown in SEQ ID NOs. 14 and 11, respectively. In other embodiments, the antibody comprises complementarity determining regions (CDRs) or variable regions (VRs) of the heavy and light chains of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence shown in SEQ ID NOs. 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NOs. 8. In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences described in SEQ ID NOs. 12 and 8, respectively. In yet another embodiment, the antibody comprises the heavy chain constant region described in SEQ ID NO. 13.

[0012] In a first aspect, the present invention relates to an on-body delivery system (OBDS) configured to administer an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment to a pediatric human patient requiring treatment for atypical hemolytic uremic syndrome (aHUS) or paroxysmal nocturnal hemoglobinuria (PNH), comprising the complementarity-determining regions (CDR) 1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naïve or eculizumab-treated, and the therapeutic anti-C5 antibody or its antigen-binding fragment is (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) An on-body delivery system (OBDS) is used to deliver 490 mg subcutaneously once weekly to patients weighing 40 kg or more.

[0013] In another embodiment, the present invention relates to an OBDS configured for treating aHUS or PNH in a pediatric human patient, wherein the OBDS comprises an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naive or eculizumab-treated, and the OBDS is (i) In patients weighing 20 kg or more but less than 40 kg, 245 mg of anti-C5 antibody or its antigen-binding fragment, (ii) An OBDS comprising means for subcutaneously administering 490 mg of anti-C5 antibody or its antigen-binding fragment to a patient weighing 40 kg or more.

[0014] In another embodiment, the present invention relates to an OBDS configured for administering an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment to a pediatric human patient requiring treatment for aHUS or PNH, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a history of ravulizumab, and the therapeutic anti-C5 antibody or its antigen-binding fragment is (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) A drug characterized by OBDS, administered subcutaneously once weekly at a dose of 490 mg to patients weighing 40 kg or more.

[0015] In another embodiment, the present invention relates to an OBDS configured for treating aHUS or PNH in a pediatric human patient, wherein the OBDS comprises an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a history of ravulizumab, and the OBDS is (i) In patients weighing 20 kg or more but less than 40 kg, 245 mg of anti-C5 antibody or its antigen-binding fragment, (ii) An OBDS comprising means for subcutaneously administering 490 mg of anti-C5 antibody or its antigen-binding fragment to a patient weighing 40 kg or more.

[0016] In some embodiments of the aforementioned models, the pediatric human patient is under 21 years of age. In some embodiments, the pediatric human patient is between 2 and 18 years of age.

[0017] In some embodiments of the aforementioned aspects, the OBDS comprises a cartridge containing a therapeutic anti-C5 antibody or its antigen-binding fragment, and an on-body injector (OBI). In some embodiments, the OBDS is configured to subcutaneously administer a dose of 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment to a patient weighing between 20 kg and 40 kg using one OBDS. In some embodiments, the 245 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% by volume (w / v) sucrose, 0.05% w / v polysorbate 80 (PS80), and water for injection, pH 7.4, and at a concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

[0018] In some embodiments of the aforementioned models, the OBDS is configured to subcutaneously administer a therapeutic anti-C5 antibody or its antigen-binding fragment in a dose of 490 mg in combination with a second OBDS to patients weighing 40 kg or more. In some embodiments, the 490 mg dose of therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of therapeutic anti-C5 antibody or its antigen-binding fragment.

[0019] In some embodiments of the aforementioned models, the OBDS is a single-use electromechanical medical device comprising a syringe containing a 29-gauge needle and a cartridge containing a piston and a telescopic screw assembly. In some embodiments, the cartridge has a volume of 3.5 mL. In some embodiments, the cartridge has a volume of 10 mL. In some embodiments, the OBDS is configured to deliver a therapeutic anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes. In some embodiments, the cartridge includes the therapeutic anti-C5 antibody or its antigen-binding fragment and an opening sealed by a puncturable septum.

[0020] In some of the embodiments described above, OBDS is (i) Syringe housing and (ii) An injection needle that is translationally movable between a retracted position in which at least the tip of the injection needle is housed within the syringe housing and an injection position in which at least the tip of the injection needle protrudes from the syringe housing, (iii) A start button assembly that is movably mounted on a syringe housing and operably connected to a needle, wherein the start button assembly is translatable from a non-operating position to an operating position in order to drive the needle from its retracted position to its injection position, (iv) A cartridge door that is movablely attached to the syringe housing between an open position and a closed position, the cartridge door is open end, An internal channel having a cartridge, wherein the cartridge contains a dispensed therapeutic anti-C5 antibody or its antigen-binding fragment, and has an opening at the front end of the cartridge and a flange at the rear end, sealed by a puncturable septum, and A cartridge door includes a cartridge puncture needle, which is mounted within an internal channel and connected to a needle in fluid communication, wherein the cartridge puncture needle is configured to completely penetrate the puncturable septum of the cartridge and connect to the material inside the cartridge in fluid communication with the needle. (v) An OBI comprising a deflectable interfering member which, in a stationary position of the interfering member, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge puncture needle does not completely penetrate the septum through which it can puncture, The cartridge door is movable to its closed position when the cartridge is sealed, and the movement of the activation button assembly from the non-operated position to the operated position when the cartridge door is closed deflects the interfering element and disengages it from the rear end flange of the cartridge, thereby allowing the cartridge to advance further into the internal channel of the cartridge door to the unsealed position, allowing the cartridge puncture needle to fully penetrate the puncturable septum.

[0021] In some embodiments of the aforementioned models, the OBDS is configured for subcutaneous self-administration of a therapeutic anti-C5 antibody or its antigen-binding fragment to the patient. In some embodiments, the OBDS is configured for subcutaneous administration of a therapeutic anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh.

[0022] In another embodiment, the present invention relates to a needle syringe configured for administering an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, for use in pediatric human patients requiring treatment for aHUS or PNH, wherein the patient weighs 10 kg or more but less than 20 kg, is either complement inhibitor-naïve, has experience with eculizumab, or has experience with ravulizumab, and the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once weekly at a dose of 150 mg. In some embodiments, the antibody preparation administered by the syringe (e.g., 100 mg / ml ravulizumab) is not diluted before administration.

[0023] In yet another embodiment, the present invention relates to a needle syringe configured for treating aHUS or PNH in a pediatric human patient requiring such treatment, wherein the needle syringe is configured for subcutaneous administration and contains 150 mg of a therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a body weight of 10 kg or more but less than 20 kg, is either complement inhibitor-naïve, has received eculizumab treatment, or has received ravulizumab treatment, and the needle syringe delivers 150 mg of the anti-C5 antibody or its antigen-binding fragment subcutaneously.

[0024] In some embodiments of the aforementioned models, a 150 mg dose of therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with sodium phosphate, sucrose, L-arginine, PS80, and sterile water for injection, at pH 7.4 and a concentration of 100 mg / mL. In some embodiments, a needle syringe is configured to administer the therapeutic anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh.

[0025] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in EU numbering. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 12 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region contained in the amino acid sequence of SEQ ID NO: 13. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain variable region includes an N-terminal pyroglutamic acid residue.

[0026] In another embodiment, the present invention features a kit comprising an OBDS or a needle syringe in any of the embodiments described above, and instructions for using the OBDS or needle syringe for the treatment of PNH or aHUS.

[0027] In another embodiment, the present invention relates to a method for treating a pediatric human patient having PNH or aHUS, wherein the patient is either complement inhibitor-naïve or has experience with eculizumab, the method comprising administering to the patient an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment during a treatment cycle, the therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) Once on day 1 of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, the drug is administered intravenously at a dose of 2700 mg, and (b) Day 15 of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method characterized by subcutaneous administration of 490 mg to patients weighing 40 kg or more.

[0028] In another embodiment, the present invention relates to a therapeutic anti-C5 antibody or antigen-binding fragment thereof for use in the treatment of a pediatric human patient having PNH or aHUS, wherein the patient is either complement inhibitor-naïve or has experience with eculizumab, wherein the treatment comprises administering to the patient in an effective amount of the therapeutic anti-C5 antibody or antigen-binding fragment thereof during a treatment cycle, wherein the therapeutic anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, and the therapeutic anti-C5 antibody or antigen-binding fragment thereof (a) Once on day 1 of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, the drug is administered intravenously at a dose of 2700 mg, and (b) Day 15 of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A therapeutic anti-C5 antibody or its antigen-binding fragment, administered subcutaneously at a dose of 490 mg to patients weighing 40 kg or more.

[0029] In yet another embodiment, the present invention relates to the use of a therapeutic anti-C5 antibody or its antigen-binding fragment in the manufacture of a drug for treating aHUS or PNH in a pediatric human patient requiring such treatment, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naïve or has received eculizumab treatment, and the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) Once on day 1 of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) Administer intravenously to patients weighing 60 kg or more at a dose of 2700 mg, and (b) Day 15 of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A formulation characterized by use for subcutaneous administration at a dose of 490 mg to patients weighing 40 kg or more.

[0030] In another embodiment, the present invention relates to a method for treating a pediatric human patient having PNH or aHUS, the patient having prior experience with ravulizumab, the method comprising administering to the patient an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, during a treatment cycle, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered on day 1 of the treatment cycle and weekly thereafter. (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method characterized by subcutaneous administration of 490 mg to patients weighing 40 kg or more.

[0031] In another embodiment, the present invention relates to a therapeutic anti-C5 antibody or antigen-binding fragment thereof for use in the treatment of a pediatric human patient having PNH or aHUS, the patient having a ravulizumab experience, wherein the treatment comprises administering to the patient in an effective amount of the therapeutic anti-C5 antibody or antigen-binding fragment thereof during a treatment cycle, the therapeutic anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, the therapeutic anti-C5 antibody or antigen-binding fragment thereof (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A therapeutic anti-C5 antibody or its antigen-binding fragment, administered subcutaneously once weekly at a dose of 490 mg to patients weighing 40 kg or more.

[0032] In another embodiment, the present invention relates to the use of a therapeutic anti-C5 antibody or its antigen-binding fragment in the manufacture of a drug for treating aHUS or PNH in a pediatric human patient requiring such treatment, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a history of ravulizumab, and the therapeutic anti-C5 antibody or its antigen-binding fragment is administered on day 1 of the administration cycle and weekly thereafter. (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A formulation for use in patients weighing 40 kg or more, administered subcutaneously once weekly at a dose of 490 mg.

[0033] In some embodiments of the aforementioned models, the pediatric human patient is under 21 years of age. In some embodiments, the pediatric human patient is between 2 and 18 years of age.

[0034] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing 10 kg or more but less than 20 kg at a dose of 150 mg using a 1.5 mL syringe. In some embodiments, the 150 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with sodium phosphate, sucrose, L-arginine, PS80, and sterile water for injection, at pH 7.4 and a concentration of 100 mg / mL.

[0035] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing 20 kg or more using an OBDS. In some embodiments, the OBDS comprises a cartridge containing the therapeutic anti-C5 antibody or its antigen-binding fragment, and an OBI. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing 20 kg or more but less than 40 kg using one OBDS in a dose of 245 mg. In some embodiments, the 245 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, pH 7.4 and concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

[0036] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to a patient weighing 40 kg or more in a dose of 490 mg using two OBDSs. In some embodiments, the 490 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

[0037] In some embodiments of the aforementioned models, the OBDS is a single-use electromechanical medical device comprising a syringe containing a 29-gauge needle and a cartridge containing a piston and a telescopic screw assembly. In some embodiments, the cartridge has a volume of 3.5 mL. In some embodiments, the cartridge has a volume of 10 mL. In some embodiments, the OBDS is configured to deliver a therapeutic anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes. In some embodiments, the cartridge includes the therapeutic anti-C5 antibody or its antigen-binding fragment and an opening sealed by a puncturable septum.

[0038] In some of the embodiments described above, OBDS is (i) Syringe housing and (ii) An injection needle that is translationally movable between a retracted position in which at least the tip of the injection needle is housed within the syringe housing and an injection position in which at least the tip of the injection needle protrudes from the syringe housing, (iii) A start button assembly that is movably mounted on a syringe housing and operably connected to a needle, wherein the start button assembly is translatable from a non-operating position to an operating position in order to drive the needle from its retracted position to its injection position, (iv) A cartridge door that is movablely attached to the syringe housing between an open position and a closed position, the cartridge door is open end, An internal channel having a cartridge, wherein the cartridge contains a dispensed therapeutic anti-C5 antibody or its antigen-binding fragment, and has an opening at the front end of the cartridge and a flange at the rear end, sealed by a puncturable septum, and A cartridge door includes a cartridge puncture needle, which is mounted within an internal channel and connected to a needle in fluid communication, wherein the cartridge puncture needle is configured to completely penetrate the puncturable septum of the cartridge and connect to the material inside the cartridge in fluid communication with the needle. (v) An OBI comprising a deflectable interfering member which, in a stationary position of the interfering member, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge puncture needle does not completely penetrate the septum through which it can puncture, The cartridge door is movable to its closed position when the cartridge is sealed, and the movement of the activation button assembly from the non-operated position to the operated position when the cartridge door is closed deflects the interfering element and disengages it from the rear end flange of the cartridge, thereby allowing the cartridge to advance further into the internal channel of the cartridge door to the unsealed position, allowing the cartridge puncture needle to fully penetrate the puncturable septum.

[0039] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to the patient. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered to a site selected from the patient's arm, abdomen, and thigh. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once a week for a period of up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or for the remainder of the patient's life after the administration cycle.

[0040] In some embodiments of the aforementioned models, the patient has been previously treated with eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clobalimab, CAN106, or pozelimuab. In some embodiments, the patient has been previously treated with eculizumab or its biosimilar. In some embodiments, the biosimilar of eculizumab includes ABP 959, ELIZARIA®, SB12, ISU305, ABLYZE®, or BCD 148. In some embodiments, the administration cycle is initiated approximately two weeks after the patient's last dose of eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clobalimab, CAN106, or pozelimuab. In some embodiments, the administration cycle is initiated approximately two weeks after the patient's last dose of eculizumab or its biosimilar. In some embodiments, the patient has been treated with eculizumab or its biosimilar for at least 90 days prior to day 1 of the administration cycle. In some embodiments, (i) the patient weighs less than 20 kg and the administration cycle is initiated about 4 weeks after the patient's last dose of ravulizumab, or (ii) the patient weighs 20 kg or more and the administration cycle is initiated about 8 weeks after the patient's last dose of ravulizumab.

[0041] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in EU numbering. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain variable region comprises an N-terminal pyroglutamic acid residue.

[0042] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment has a pH of 7.4 and 25°C, with a range of 0.1 nM ≤ K D Affinity dissociation constant (K) in ≤ 1nM D ) binds to human C5. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment has a K content of 10 nM or higher at pH 6.0 and 25°C. D It then binds to human C5.

[0043] In some of the embodiments described above, the therapeutic anti-C5 antibody is ravulizumab.

[0044] In some embodiments of the aforementioned models, the patient is vaccinated against meningococcal infections from serogroups A, C, Y, W135, and B within three years prior to day 1 of the administration cycle, or for at least two weeks prior thereto, and the patient is vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b.

[0045] In some embodiments of the aforementioned models, the patient has PNH. In some embodiments, the patient has PNH confirmed by flow cytometry evaluation of red blood cells (RBCs) and white blood cells (WBCs) with a granulocyte or monocyte clone size of 5 or more. In some embodiments, the patient is complement inhibitor-naïve and has at least one of the following symptoms prior to treatment: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, a history of major adverse cardiovascular events (MAVEs) (including thrombosis), dysphagia, or erectile dysfunction, or a history of concentrated red blood cell transfusion due to PNH. In some embodiments, (i) the patient is complement inhibitor-naïve and has lactate dehydrogenase (LDH) levels of 1.5 times or more above the upper limit of normal (ULN), or (ii) has experience with eculizumab or ravulizumab and has LDH levels of 1.5 times or less above the ULN.

[0046] In some embodiments of the aforementioned models, the treatment results in (i) a change in LDH levels relative to baseline, (ii) a reduction in the incidence of breakthrough hemolysis, (iii) achievement of transfusion avoidance, (iv) achievement of stabilized hemoglobin, and / or (v) a change in baseline PNH RBC clone size. In some embodiments, the treatment results in (i) a percentage change in LDH levels relative to baseline at weeks 10 and 52, (ii) a reduction in the incidence of breakthrough hemolysis over weeks 10 and 52, (iii) achievement of transfusion avoidance over weeks 10 and 52, (iv) achievement of stabilized hemoglobin over weeks 10 and 52, and (v) a change in RBC levels relative to baseline at week 52.

[0047] In some embodiments of the aforementioned aspects, the patient has aHUS. In some embodiments, the treatment results in (i) a change in dialysis requirement, (ii) a change in observed and from baseline values ​​of estimated glomerular filtration rate (eGFR), (iii) a change in observed and from baseline values ​​of serum creatinine, and / or (iv) a change in observed and from baseline values ​​of a hematological parameter selected from (1) platelets, (2) lactate dehydrogenase (LDH), and / or (3) hemoglobin. In some embodiments, the treatment results in (i) a change in dialysis requirement relative to baseline over weeks 10 and 52, (ii) a change in observed eGFR and change from baseline over weeks 10 and 52, (iii) a change in observed serum creatinine and change from baseline over weeks 10 and 52, and / or (iv) a change in observed hematological parameters selected from (1) platelets, (2) lactate dehydrogenase (LDH), and / or (3) hemoglobin over weeks 10 and 52. In some embodiments, the patient is not administered immunosuppressive therapy selected from steroids, mammalian target of rapamycin (mTOR) inhibitors, or calcineurin inhibitors, except (a) as part of an established post-transplant anti-rejection regimen, (b) the patient has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, (c) steroids are being used to treat a condition other than aHUS, or (d) steroids have been empirically initiated before treatment and tapered off as standard treatment. In some embodiments, the mTOR inhibitor may be sirolimus or everolimus. In some embodiments, the calcineurin inhibitor may be cyclosporine or tacrolimus.In some embodiments, the patient is complement inhibitor-naïve and has evidence of thrombotic microangiopathy (TMA) prior to the administration cycle, based on: (a) a platelet count of less than 150,000 / μL, (b) LDH of 1.5 times or more above the upper limit of normal (ULN), (c) hemoglobin below the lower limit of normal (LLN) for age and sex, and (d) a serum creatinine level above the 97.5th percentile for age.

[0048] In some embodiments of the aforementioned models, the patient had prior experience with eculizumab or ravulizumab and at the time of the TMA event had: (a) increased LDH above ULN, (b) increased serum creatinine above ULN, and (c) decreased platelets below LLN. In some embodiments, the patient had prior experience with eculizumab or ravulizumab and had (a) LDH less than 1.5 times ULN, (b) platelet count greater than 150,000 / μL, and (c) 30 mL / min / 1.73 m using Schwartz's formula. 2 The patients had clinical evidence of a response to eculizumab or rabulizumab, indicated by stable TMA parameters, including an estimated glomerular filtration rate (eGFR). In some embodiments, the patients had a kidney transplant and (a) had a known history of aHUS prior to the current kidney transplant, or (b) did not have a known history of aHUS and had persistent evidence of TMA at least 4 days after modification of a mammalian-targeted immunosuppressive regimen of a calcineurin inhibitor or rapamycin inhibitor. In some embodiments, the patients developed TMA postpartum and had persistent symptoms of TMA for more than 3 days from the date of delivery. In some embodiments, the treatment resulted in (i) improvement of the patient's dialysis needs, (ii) a change in eGFR levels relative to baseline, (iii) a change in serum creatinine levels relative to baseline, and (iv) a change in hematological parameters relative to baseline, including platelet, LDH, and / or hemoglobin levels.

[0049] In some embodiments of the aforementioned aspects, the treatment maintains (a) a serum trough concentration of free C5 less than 0.5 μg / mL during the administration cycle, and / or (b) a serum concentration of therapeutic anti-C5 antibody or its antigen-binding fragment at 175 μg / mL during the administration cycle. In some embodiments, the method further includes monitoring the concentrations of (a) serum anti-C5 antibody or its antigen-binding fragment, and / or (b) serum free C5. In some embodiments, the concentrations of (a) serum anti-C5 antibody or its antigen-binding fragment, and / or (b) serum free C5 are determined from blood samples taken before and after each administration of therapeutic anti-C5 antibody or its antigen-binding fragment. In some embodiments, the blood samples are taken within 30 minutes before and within 60 minutes after each administration of therapeutic anti-C5 antibody or its antigen-binding fragment.

[0050] In some embodiments of the aforementioned aspects, the treatment results in terminal complement inhibition. In some embodiments, the treatment results in a reduction of hemolysis as assessed by LDH levels. In some embodiments, the treatment includes (a) (i) the incidence of adverse events (AEs) and serious AEs, and (ii) the incidence of adverse drug events (ADEs) and serious ADEs, (b) the results of attempts at full-dose administration via OBI and / or reported device defects or complaints and investigation of the associated device, and / or (c) monitoring the incidence, response categories, and titers of anti-drug antibodies (ADAs). In some embodiments, the treatment results in a change from baseline in patient-reported fatigue, as measured by Pediatric FACIT-Fatigue, and optionally, the patient is 8 years of age or older. In some embodiments, the treatment results in a change from baseline in the PedsQL 4.0 General Core Scale.

[0051] In another embodiment, the present invention relates to a kit for treating PNH or aHUS in a pediatric human patient who is either complement inhibitor-naïve or eculizumab-treated, the kit comprising: (a) a dose of a therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively; and (b) instructions for using the therapeutic anti-C5 antibody or its antigen-binding fragment in any of the manner described in the preceding embodiments.

[0052] In some embodiments of the aforementioned model, the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, the drug is administered intravenously at a dose of 2700 mg, and (b) (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) Patients weighing 40 kg or more are administered 490 mg subcutaneously once a week.

[0053] In some embodiments of the aforementioned model, the therapeutic anti-C5 antibody or its antigen-binding fragment is provided in a 3 mL vial containing type I borosilicate glass for (a) intravenous administration and (b) subcutaneous administration to patients weighing 10 kg or more but less than 20 kg.

[0054] In another embodiment, the present invention relates to a kit for treating PNH or aHUS in a pediatric human patient, the patient having a rabulizumab experience, the kit comprising: (a) a dose of a therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively; and (b) instructions for using the therapeutic anti-C5 antibody or its antigen-binding fragment in any of the manner described in the preceding embodiments.

[0055] In some embodiments of the aforementioned models, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once weekly at doses of (i) 150 mg to patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg to patients weighing 20 kg or more but less than 40 kg, or (iii) 490 mg to patients weighing 40 kg or more. In some embodiments, the pediatric human patient is under 21 years of age. In some embodiments, the pediatric human patient is between 2 and 18 years of age. In some embodiments, the therapeutic anti-C5 antibody or its antigen-binding fragment is administered to a site selected from the patient's arm, abdomen, and thigh.

[0056] Furthermore, this disclosure includes the possibility that any of the above embodiments may be used in any combination with any other of the above embodiments. [Brief explanation of the drawing]

[0057] [Figure 1] This is a schematic diagram illustrating the design of a Phase III clinical trial in pediatric patients with PNH or aHUS who are either complement-inhibitor-naïve or have prior eculizumab treatment. [Figure 2] This is a schematic diagram illustrating the design of a Phase III clinical trial in pediatric patients with PNH or aHUS who have a history of ravulizumab treatment. [Figure 3]This flowchart shows the criteria for classifying defects and complaints related to medical devices. Abbreviations: ADE = Device Adverse Effects, AE = Adverse Events, SADE = Serious Device Adverse Effects. [Figure 4] This flowchart shows the criteria for determining whether an adverse event, device adverse effect, serious adverse event, or significant device adverse effect has occurred. Abbreviations: AE = Adverse event, ADE = Device adverse effect, SAE = Serious adverse event, SADE = Significant device adverse effect. [Figure 5] Functional assessment of chronic disease therapy in children - showing fatigue. The prompt for the patient is as follows: This figure shows a list of reports that other people with your disease have stated are important. Circle or mark one number per line to indicate your response to apply over the past 7 days. [Figure 6A] This document presents parental reports on the Pediatric Quality of Life Inventory (PedsQL) 4.0 General Core Scale for toddlers (2-4 years old). [Figure 6B] This document presents parental reports on the Pediatric Quality of Life Inventory (PedsQL) 4.0 General Core Scale for toddlers (2-4 years old). [Figure 7A] The PedsQL 4.0 general core scale report for young children (5-7 years old) is shown. [Figure 7B] The PedsQL 4.0 general core scale report for young children (5-7 years old) is shown. [Figure 7C] The PedsQL 4.0 general core scale report for young children (5-7 years old) is shown. [Figure 8A] This paper presents parental reports on the PedsQL 4.0 General Core Scale for young children (5-7 years). [Figure 8B] This paper presents parental reports on the PedsQL 4.0 General Core Scale for young children (5-7 years). [Figure 9A] This shows the PedsQL 4.0 general core scale report for children (8-12 years old). [Figure 9B] This shows the PedsQL 4.0 general core scale report for children (8-12 years old). [Figure 10A] This paper presents parental reports on the PedsQL 4.0 General Core Scale for children (8-12 years). [Figure 10B] This paper presents parental reports on the PedsQL 4.0 General Core Scale for children (8-12 years). [Figure 11A] The PedsQL 4.0 General Core Scale for Adolescents (ages 13-18) is shown. [Figure 11B] The PedsQL 4.0 General Core Scale for Adolescents (ages 13-18) is shown. [Figure 12A] This shows parental reports for adolescents (13-18 years old) on the PedsQL 4.0 General Core Scale. [Figure 12B] This shows parental reports for adolescents (13-18 years old) on the PedsQL 4.0 General Core Scale. [Modes for carrying out the invention]

[0058] definition As used herein, the terms “subject” or “patient” mean a human patient (e.g., a patient with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS)). As used herein, the terms “subject” and “patient” are interchangeable. In some examples, a patient is a pediatric patient (e.g., a patient under 21 years of age, e.g., a patient between 2 and 18 years of age (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18)).

[0059] As used herein, the phrase "complement inhibitor-naive" includes pediatric human patients who have not received any complement inhibitor therapy (e.g., anti-C5 antibody) prior to administration of an anti-C5 antibody (e.g., ravulizumab) according to the devices, compositions, and methods described herein.

[0060] As used herein, the phrase “eculizumab experienced” includes pediatric human patients who have received therapy with an anti-C5 antibody (e.g., eculizumab, its biosimilar, or another non-ravulizumab anti-C5 antibody) prior to administration of an anti-C5 antibody according to the devices, compositions, and methods described herein. In some embodiments, a patient is considered eculizumab experienced if, prior to administration of an anti-C5 antibody (e.g., ravulizumab) according to the devices, compositions, and methods described herein, the patient has received therapy containing eculizumab or its biosimilar, or an anti-C5 antibody selected from tesidorumab, clobarimab, CAN106, or pozelimuab. In some embodiments, the biosimilar of eculizumab includes ABP 959, ELIZARIA®, SB12, ISU305, ABLYZE®, or BCD 148.

[0061] As used herein, “effective treatment” means treatment that results in a beneficial effect, for example, improvement of at least one symptom of a disease or disorder. Beneficial effects can take the form of improvement beyond baseline, i.e., improvement beyond the measurement or observation made before the commencement of treatment with this method. Effective treatment may mean relief of at least one symptom of PNH (e.g., fatigue, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction) or at least one symptom of aHUS (e.g., severe hypertension, proteinuria, uremia, malaise / fatigue, irritability, thrombocytopenia, microangiogenic hemolytic anemia, and renal dysfunction (e.g., acute renal failure)).

[0062] The term “effective dose” refers to the amount of drug that provides the desired biological, therapeutic, and / or prophylactic outcome. The outcome may be a reduction, improvement, temporary relief, reduction, delay, and / or cessation of one or more signs, symptoms, or causes of a disease, or any other desired change in the biological system. For example, the “effective dose” is the amount of anti-C5 antibody or its antigen-binding fragment clinically proven to alleviate at least one symptom of PNH (e.g., fatigue, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction) or at least one symptom of aHUS (e.g., severe hypertension, proteinuria, uremia, malaise / fatigue, irritability, thrombocytopenia, microangiogenic hemolytic anemia, and renal dysfunction (e.g., acute renal failure)). An effective dose may be administered in one or more doses.

[0063] As used herein, the terms “fixed dose,” “uniform dose,” and “uniform fixed dose” are used interchangeably and refer to the dose administered to a patient regardless of the patient’s body weight or body surface area (BSA). Therefore, the fixed dose or uniform dose is provided not as a mg / kg dose, but rather as an absolute amount of the drug (e.g., anti-C5 antibody or its antigen-binding fragment).

[0064] As used herein, the term “loading dose” refers to the initial dose administered to a patient. The loading dose may be, for example, 600 mg, 900 mg, 1200 mg, 2400 mg, or 2700 mg. The loading dose may be measured in terms of potency based on body weight.

[0065] As used herein, the term “maintenance dose” refers to the dose administered to a patient after a loading dose. For example, the maintenance dose may be 150 mg, 245 mg, or 490 mg. The maintenance dose may be quantified based on body weight.

[0066] As used herein, the terms “on-body delivery system” and “OBDS” refer to a wearable device for subcutaneous administration of a therapeutic agent (e.g., an anti-C5 antibody as described herein (e.g., ravulizumab)). In some examples, an OBDS may include an on-body syringe (OBI) and a cartridge (e.g., a pre-filled cartridge). An exemplary device is the OBDS manufactured by West Pharmaceuticals, Inc., which is currently approved in the United States for use with evolocumab (Repatha®) as a combination drug and is CE marked in the European Union as a Class IIA Medical Device. This device is a small, sterile, single-use, disposable electromechanical (battery-powered, microprocessor-controlled) clinical trial medical device having a 29-gauge integrated needle (manufactured by West Pharmaceuticals, Inc.) with a pre-filled, stoppered Crystal Zenith® cartridge having a piston and telescopic screw assembly (TSA). Exemplary OBDS devices include WestSMARTDOSE® OBDS (which may be referred to as WestSMARTDOSE® First Generation Device) and SMARTDOSE® 10 OBDS (which may be referred to as WestSMARTDOSE® Second Generation Device). Exemplary OBDS devices are described in U.S. Patent Publication 2020 / 0254185 and U.S. Patent No. 11,571,517, which are incorporated herein by reference in their entirety. In some embodiments, the cartridge has a volume of 3.5 mL. In some embodiments, the cartridge has a volume of 10 mL.

[0067] As used herein, the terms “on-body syringe” and “OBI” refer to a wearable syringe that may be a component of an OBDS as described herein. An OBI may include, for example, an injection needle configured for subcutaneous administration of a therapeutic agent (e.g., an anti-C5 antibody as described herein (e.g., ravulizumab)). An OBI may be battery-powered and may include means for receiving a cartridge (e.g., a pre-filled cartridge) containing the therapeutic agent (e.g., an anti-C5 antibody as described herein (e.g., ravulizumab)).

[0068] As used herein, the phrase "experienced with ravulizumab" includes pediatric human patients who have received therapy with ravulizumab prior to the administration of anti-C5 antibodies according to the devices, compositions, and methods described herein.

[0069] As used herein, the term “serum trough level” refers to the lowest level of a drug (e.g., an anti-C5 antibody or its antigen-binding fragment) present in the serum. In contrast, “peak serum level” refers to the highest level of a drug in the serum. “Mean serum level” refers to the average level of a drug in the serum over time.

[0070] In one embodiment, the described treatment regimen is sufficient to maintain a specific serum trough concentration of anti-C5 antibody or its antigen-binding fragment. In one embodiment, for example, the treatment is 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 2 The treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 45, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or higher. In one embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 100 μg / mL or higher. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 150 μg / mL or higher. In yet another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 200 μg / mL or higher. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 250 μg / mL or higher. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 300 μg / mL or higher. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 100 μg / mL to 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at approximately 175 μg / mL.

[0071] In another embodiment, to obtain an effective response, the anti-C5 antibody or its antigen-binding fragment is administered to the patient in an amount and frequency to maintain a desired minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody or its antigen-binding fragment is administered to the patient in an amount and frequency to maintain free C5 concentrations of 0.2 pg / mL, 0.3 pg / mL, 0.4 pg / mL, 0.5 pg / mL or less. In another embodiment, the anti-C5 antibody or its antigen-binding fragment is administered to the patient in an amount and frequency to maintain a free C5 concentration of 0.309 to 0.5 pg / mL or less. In another embodiment, the treatment described herein reduces the free C5 concentration by more than 99% throughout the entire treatment period. In another embodiment, the treatment reduces the free C5 concentration by more than 99.5% throughout the entire treatment period.

[0072] The term "antibody" describes a polypeptide containing at least one antibody-derived antigen-binding site (e.g., a VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies. Antibodies may be, for example, human antibodies, humanized antibodies, bispecific antibodies, chimeric antibodies, or camel antibodies. Antibodies may also be Fab, Fab'2, scFv, SMIP, Affibody®, nanobody, or single-domain antibodies. Antibodies may also be any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE, as well as hybrid isotypes, e.g., IgG2 / 4. Antibodies may be naturally occurring antibodies or antibodies modified by protein manipulation techniques (e.g., by mutation, deletion, substitution, or conjugation to a non-antibody portion). Antibodies may contain, for example, one or more variant amino acids (compared to naturally occurring antibodies) that alter the properties of the antibody (e.g., functional properties). Numerous such modifications affecting antibodies in patients, for example, half-life, effector function, and / or immune response, are known in the art. The term antibody also includes artificial or engineered polypeptide constructs comprising at least one antibody-derived antigen-binding site.

[0073] How to use The methods and compositions described herein are useful for treating paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), extremely rare disorders in pediatric human patients driven by chronic, uncontrolled complement activation. In each case, ongoing complement dysregulation leads to increased systemic activation of C5 with resulting terminal complement activation, resulting in severe clinical manifestations of these disorders. Patients with PNH or aHUS are at considerable risk of morbidity and mortality.

[0074] This disease begins with clonal expansion of hematopoietic stem cells that have acquired somatic mutations in the PIGA gene (Brodsky R A., Blood. 2014;124:2804-1). As a result, PNH blood cells lack glycophosphatidylinositol (GPI) anchored proteins and membrane-bound complement inhibitory proteins CD55 and CD59. In the absence of CD55, deposition of complement protein C3 cleavage products on the blood cell membrane surface increases, followed by cleavage of C5 to C5a and C5b. The pathological and clinical findings in patients with PNH are driven by uncontrolled terminal complement activation.

[0075] A significant proportion of patients with PNH experience renal dysfunction and pulmonary hypertension (Hillmen, et al., Am J Hematol. 2010;85:553-9. [erratum in Am J Hematol. 2010;85:911.], Hill, et al., Br. J Haematol. 2012;158:409-14., Hill, et al., Blood 2013;121:4985-96). Patients also experience venous or arterial thrombosis in various locations, including the abdomen or central nervous system (Brodsky R A., Blood. 2014;124:2804-1).

[0076] The pathology and clinical findings of patients with aHUS are also driven by terminal complement activation. More specifically, C5 activation and dysregulation of complement activation lead to endothelial damage, platelet consumption, and thrombotic microangiopathy (TMA) events, characterized by thrombocytopenia, mechanical intravascular hemolysis, and renal injury. Importantly, approximately 20% of patients also experience extrarenal manifestations of the disease, including involvement of the central nervous system, heart, gastrointestinal tract, distal extremities, and severe systemic organs (Loirat, et al., Orphanet. J. Rare Dis. 2011; 6:60). The symptoms of aHUS are well known to those skilled in the art of rare or renal diseases, and include, for example, severe hypertension, proteinuria, uremia, malaise / fatigue, irritability, thrombocytopenia, microangiogenic hemolytic anemia, and renal dysfunction (e.g., acute renal failure).

[0077] aHUS can be hereditary, acquired, or idiopathic. aHUS may be considered hereditary if two or more members of the same family (e.g., three, four, five, or six or more) develop the disease at least six months apart, exposure to common triggers has been ruled out, or if one or more aHUS-related gene mutations (e.g., one or more mutations in CFH, MCP / CD46, CFB, or CFI) are identified in the subject. For example, a subject may have CFH-related aHUS, CFB-related aHUS, CFI-related aHUS, or MCP-related aHUS. Up to 30% of hereditary aHUS cases are associated with CFH mutations, 12% with MCP mutations, 5-10% with CFI mutations, and less than 2% with CFB mutations. Hereditary aHUS can be multiplicative (i.e., familial, involving two or more affected family members) or simple (i.e., a single occurrence within a family). aHUS may be considered acquired if an underlying environmental factor (e.g., a drug, systemic disease, or a non-Shiga-like exotoxin-producing viral or bacterial factor) or trigger can be identified. aHUS may be considered idiopathic if no trigger (genetic or environmental) is apparent.

[0078] Laboratory tests can be performed to determine whether a human subject has thrombocytopenia, microangiogenic hemolytic anemia, or acute renal failure. Thrombocytopenia is diagnosed by a medical professional when (i) 150,000 / mm³ 3 Platelet counts less than (e.g., 60,000 / mm³) 3(i) a decrease in platelet survival time, reflecting enhanced platelet destruction in circulation; and (iii) giant platelets observed in peripheral smears, consistent with secondary activation of thrombocytosis. Microangiogenic hemolytic anemia can be diagnosed by a healthcare professional as one or more of the following: (i) hemoglobin concentration less than 10 mg / dL (e.g., less than 6.5 mg / dL); (ii) elevated serum lactate dehydrogenase (LDH) concentration (greater than 460 U / L); (iii) hyperbilirubinemia, polyretic erythrocytosis, circulating free hemoglobin, and low or undetectable haptoglobin concentration; and (iv) detection of fragmented erythrocytes (mitotic erythrocytes) with typical characteristics of Burr cells or helmet cells in peripheral blood smears, along with a negative Coombs test. For example, see Kaplan et al. (1992) "Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura," Informa Health Care (ISBN 0824786637) and Zipfel (2005) "Complement and Kidney Disease," Springer (ISBN 3764371668). Blood concentrations of C3 and C4 can also be used as measures of complement activation or dysregulation. In addition, the subject's condition can be further characterized by identifying the subject as having mutations in one or more aHUS-related genes such as CFI, CFB, CFH, or MCP (above). Preferred methods for detecting gene mutations include, for example, DNA sequencing techniques and nucleic acid array techniques. For example, see Breslin et al. (2006) Clin Am Soc Nephrol 1:88-99 and Goicoechea de Jorge et al. (2007) Proc Natl Acad Sci USA 104:240-245.

[0079] This specification provides a method for treating a pediatric human patient having PNH or aHUS, wherein the patient is either complement inhibitor-naïve or has experience with eculizumab, the method comprising the step of administering an effective amount of anti-C5 antibody or its antigen-binding fragment to the patient during a dosing cycle, wherein the anti-C5 antibody or its antigen-binding fragment is (a) Once on day 1 of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, the drug is administered intravenously at a dose of 2700 mg, and (b) Day 15 of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method is provided for subcutaneous administration of a dose of 490 mg to patients weighing 40 kg or more.

[0080] In addition, this specification provides a method for treating a pediatric human patient having PNH or aHUS, the patient having prior experience with ravulizumab, the method comprising the step of administering an effective amount of anti-C5 antibody or its antigen-binding fragment to the patient during a treatment cycle, wherein the anti-C5 antibody or its antigen-binding fragment is administered on day 1 of the treatment cycle and weekly thereafter. (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method is provided for subcutaneous administration of a dose of 490 mg to patients weighing 40 kg or more.

[0081] In some embodiments, the pediatric human patient is under 21 years of age (e.g., 20, 19, 18, 17, 16, 15, 10, 5, or 2 years). In some embodiments, the pediatric human patient is between 2 and 18 years of age (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years).

[0082] Any suitable anti-C5 antibody or antigen-binding fragment thereof, including any suitable anti-C5 antibody or antigen-binding fragment thereof disclosed herein, may be used. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in their EU numbering. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NOs. 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NOs. 8. In some embodiments, the heavy chain variable region includes an N-terminal pyroglutamic acid residue. In some embodiments, the anti-C5 antibody or its antigen-binding fragment further includes a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-C5 antibody or its antigen-binding fragment includes a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11.

[0083] In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing between 10 kg and 20 kg at a dose of 150 mg using a 1.5 mL syringe. In some embodiments, the 150 mg dose of the anti-C5 antibody or its antigen-binding fragment is formulated with sodium phosphate, sucrose, L-arginine, polysorbate 80 (PS80), and water for injection, at pH 7.4 and a concentration of 100 mg / mL.

[0084] In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing 20 kg or more using an on-body delivery system (OBDS). In some embodiments, the OBDS is a single-use electromechanical medical device comprising a syringe containing a 29-gauge needle and a cartridge containing a piston and a telescopic screw assembly. In some embodiments, the OBDS is configured to deliver the anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes. In some embodiments, the OBDS comprises a cartridge containing the anti-C5 antibody or its antigen-binding fragment and an on-body syringe (OBI). In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously using the OBDS at a dose of 245 mg to patients weighing 20 kg or more but less than 40 kg. In some embodiments, a dose of 245 mg of anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% by weight / volume (w / v) sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of anti-C5 antibody or its antigen-binding fragment.

[0085] In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to patients weighing 40 kg or more in a dose of 490 mg using two OBDSs. In some embodiments, the 490 mg dose of the anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the anti-C5 antibody or its antigen-binding fragment.

[0086] In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously by the patient. In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered to a site selected from the patient's arm, abdomen, and thigh. In some embodiments, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once a week for a long period, up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or for the remainder of the patient's life, after the administration cycle.

[0087] In some embodiments, the patient has been previously treated with eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clovalimab, CAN106, or pozelimuab. In some embodiments, the treatment cycle is initiated approximately two weeks after the patient's last dose of eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clovalimab, CAN106, or pozelimuab. In some embodiments, the patient has been previously treated with eculizumab or its biosimilar. In some embodiments, the treatment cycle is initiated approximately two weeks after the patient's last dose of eculizumab or its biosimilar. In some embodiments, the patient has been treated with eculizumab or its biosimilar for at least 90 days prior to day 1 of the treatment cycle.

[0088] In some embodiments, (i) the patient weighs less than 20 kg and the administration cycle is initiated about 4 weeks after the patient's last dose of ravulizumab, or (ii) the patient weighs 20 kg or more and the administration cycle is initiated about 8 weeks after the patient's last dose of ravulizumab. In some embodiments, the patient has been vaccinated against meningococcal infections from serogroups A, C, Y, W135, and B within 3 years prior to day 1 of the administration cycle, or at least 2 weeks prior thereto, and the patient has been vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b.

[0089] In some embodiments, the patient has PNH. In some embodiments, the patient has PNH confirmed by flow cytometry evaluation of red blood cells (RBCs) and white blood cells (WBCs) with a granulocyte or monocyte clone size of 5 or more. In some embodiments, the patient is complement inhibitor-naive and has at least one of the following symptoms prior to treatment: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, a history of major cardiovascular adverse events (MAVEs) (including thrombosis), dysphagia, or erectile dysfunction, or a history of packed red blood cell transfusion due to PNH. In some embodiments, the patient is complement inhibitor-naive and has lactate dehydrogenase (LDH) levels greater than 1.5 times the upper limit of normal (ULN). In some embodiments, the patient has experience with eculizumab or ravulizumab and has LDH levels less than or equal to 1.5 times the ULN.

[0090] In some embodiments, the patient has aHUS. In some embodiments, the patient is not administered immunosuppressive therapy selected from steroids, mammalian targeted rapamycin (mTOR) inhibitors, or calcineurin inhibitors, except (a) as part of an established post-transplant anti-rejection regimen, (b) the patient has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, (c) steroids are being used to treat a condition other than aHUS, or (d) steroids are being empirically initiated before treatment and tapered off as standard treatment. In some embodiments, the patient is complement inhibitor-naïve and has evidence of TMA prior to the administration cycle based on: (a) a platelet count of less than 150,000 / μL, (b) LDH greater than 1.5 times the upper limit of normal (ULN), (c) hemoglobin below the lower limit of normal (LLN) for age and sex, and (d) serum creatinine levels above the 97.5th percentile for age. In some embodiments, the patient has prior experience with eculizumab or ravulizumab, (a) LDH less than 1.5 times ULN, (b) platelet count greater than 150,000 / μL, and (c) 30 mL / min / 1.73 m using Schwartz formula. 2 The patients had clinical evidence of a response to eculizumab or rabulizumab, indicated by stable TMA parameters, including an estimated glomerular filtration rate (eGFR). In some embodiments, the patients had a kidney transplant and (a) had a known history of aHUS prior to the current kidney transplant, or (b) did not have a known history of aHUS and had persistent evidence of TMA at least 4 days after modification of a mammalian-targeted immunosuppressive regimen of a calcineurin inhibitor or rapamycin inhibitor. In some embodiments, the patients developed TMA postpartum and had persistent symptoms of TMA for more than 3 days from the date of delivery.

[0091] Delivery system Subcutaneous administration of an anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab) according to the methods described herein can be achieved by any preferred means. In addition, the anti-C5 antibody or its antigen-binding fragment can be administered subcutaneously by a healthcare professional or self-administered.

[0092] In one embodiment, an anti-C5 antibody or its antigen-binding fragment is administered subcutaneously using an OBDS. Any suitable OBDS may be used.

[0093] An exemplary OBDS for subcutaneous administration of anti-C5 antibodies or their antigen-binding fragments is the OBDS manufactured by West Pharmaceuticals, Inc., which is currently approved in the United States for use with evolocumab (Repatha®) as a combination drug and is CE marked in the European Union as a Class IIA Medical Device. This device is a small, sterile, single-use, disposable electromechanical (battery-powered, microprocessor-controlled) clinical trial medical device with a 29-gauge integrated needle (manufactured by West Pharmaceuticals, Inc.) designed for use with a pre-filled, stoppered Crystal Zenith® cartridge having a piston and telescopic screw assembly (TSA). Exemplary OBDS devices include the WestSMARTDOSE® OBDS (which may be referred to as the WestSMARTDOSE® First Generation Device) and the SMARTDOSE® 10 OBDS (which may be referred to as the WestSMARTDOSE® Second Generation Device). Exemplary OBDS devices are described in U.S. Patent Publication No. 2020 / 0254185 and U.S. Patent No. 11,571,517, which are incorporated herein by reference in their entirety.

[0094] The cartridge may have any preferred volume. In some embodiments, the cartridge has a volume of 3.5 mL. In some embodiments, the cartridge has a volume of 10 mL.

[0095] In some embodiments, an OBDS is provided herein, configured for administering an effective amount of anti-C5 antibody or its antigen-binding fragment to pediatric human patients requiring treatment for paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), wherein the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once weekly in doses of (a)(i) 245 mg to patients weighing 20 kg or more but less than 40 kg, or (ii) 490 mg to patients weighing 40 kg or more. In some embodiments, an OBDS is provided herein, configured for administering PNH or aHUS to pediatric human patients requiring treatment for PNH or aHUS, wherein the OBDS comprises an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, and the OBDS comprises means for subcutaneously administering 245 mg to patients weighing 20 kg or more but less than 40 kg, or 490 mg to patients weighing 40 kg or more.

[0096] In some embodiments, the patient is either new to complement inhibitor therapy or has prior experience with eculizumab. In some embodiments, the patient has prior experience with ravulizumab.

[0097] In some embodiments, the patient is under 21 years of age (e.g., 20, 19, 18, 17, 16, 15, 10, 5, or 2 years). In some embodiments, the patient is between 2 and 18 years of age (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years).

[0098] In some embodiments, the OBDS is configured to subcutaneously administer a therapeutic anti-C5 antibody or its antigen-binding fragment in a dose of 245 mg to a patient weighing between 20 kg and 40 kg using one OBDS. In some embodiments, the 245 mg dose of anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v polysorbate 80 (PS80), and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of anti-C5 antibody or its antigen-binding fragment.

[0099] In some embodiments, the OBDS is configured to subcutaneously administer an anti-C5 antibody or its antigen-binding fragment in a dose of 490 mg in combination with a second OBDS to patients weighing 40 kg or more. In some embodiments, the 490 mg dose of the anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the anti-C5 antibody or its antigen-binding fragment.

[0100] In some embodiments, the OBDS is a single-use electromechanical medical device comprising a syringe containing a 29-gauge needle and a cartridge containing a piston and a telescopic screw assembly. In some embodiments, the cartridge has a volume of 3.5 mL. In some embodiments, the OBDS is configured to deliver an anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes. In some embodiments, the cartridge comprises the anti-C5 antibody or its antigen-binding fragment and an opening sealed by a puncturable septum.

[0101] Exemplary and non-limiting OBDS devices that may be used are described in U.S. Patent No. 11,571,517 and U.S. Patent Publication No. 2020 / 0254185, which are incorporated herein by reference in their entirety.

[0102] In some embodiments, the OBDS includes an OBI. The OBI may include, for example, an injection needle configured for subcutaneous administration of a therapeutic agent (e.g., an anti-C5 antibody as described herein (e.g., ravulizumab)). The OBI may be battery-operated and may include means for receiving a cartridge (e.g., a pre-filled cartridge) containing the therapeutic agent (e.g., an anti-C5 antibody as described herein (e.g., ravulizumab)). In some embodiments, the OBI is configured to maintain the cartridge loaded inside in a sealed state until the OBDS is activated for use.

[0103] For example, this specification describes a syringe housing; a syringe needle, which is translationally movable between a retracted position in which at least the tip of the syringe needle is housed within the syringe housing and an injection position in which at least the tip of the syringe needle protrudes from the syringe housing; an activation button assembly, which is movably mounted on the syringe housing and operably connected to the syringe needle, wherein the activation button assembly is translationally movable from a non-activating position to an activating position in order to drive the syringe needle from its retracted position to its injection position; a cartridge door, which is movably mounted on the syringe housing between an open position and a closed position, wherein the cartridge door has an open end, an internal channel having a cartridge mounted inside, the cartridge having an opening at the front end of the cartridge and a flange at the rear end, the cartridge containing a substance to be dispensed and sealed by a puncturable septum; and a cartridge puncture needle, which is mounted within the internal channel and connected in fluid communication with the syringe needle, wherein the cartridge puncture needle punctures the cartridge A syringe (e.g., OBI) is provided, comprising a cartridge door, a cartridge puncture needle configured to fully penetrate a possible septum and connect to a substance in the cartridge in fluid communication with the injection needle; and a deflectable interference member, which, in a stationary position of the interference member, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge puncture needle does not fully penetrate the puncturable septum, wherein the cartridge door is movable to its closed position in the sealed position of the cartridge, and movement of the activation button assembly from the non-operated position to the activated position in the closed position of the cartridge door deflects the interference element, disengaging it from the rear end flange of the cartridge, thereby allowing further advance of the cartridge into the internal channel of the cartridge door to an unsealed position, the cartridge puncture needle fully penetrating the puncturable septum, and the substance containing an anti-C5 antibody or its antigen-binding fragment.

[0104] In some embodiments, the OBI further includes a drive assembly that is engageable with a cartridge and releases material therefrom, the drive assembly being operably engaged with an activation button assembly and configured to drive the cartridge from a sealed position to an unsealed position when the activation button assembly moves from a non-operated position to an activated position. In some embodiments, a deflectable interference member includes a cantilever arm.

[0105] In some embodiments, the cantilever arm defines a first end connected to the cartridge door and extends to a second free end adjacent to the open end of the cartridge door.

[0106] In some embodiments, the cartridge door includes a side wall, and the cantilever arm defines a deflectable portion of the cartridge door side wall.

[0107] In some embodiments, the side wall of the cartridge door defines a first inner circumference at the second free end of the cantilever arm when the cantilever arm is in its resting position, and the side wall of the cartridge door defines a second inner circumference at the second free end of the cantilever arm when the cantilever arm is deflected from its resting position, wherein the first inner circumference is smaller than the maximum outer circumference of the cartridge that can be inserted into the internal channel, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door, and the second inner circumference is larger than the maximum outer circumference of the cartridge, thereby allowing further advancement of the cartridge into the internal channel of the cartridge door.

[0108] In some embodiments, the activation button assembly includes a post extending therefrom to a tapered end, the post having a post path, along which the post moves from a non-operating position to an operating position of the activation button assembly; the cantilever arm includes a tab extending laterally therefrom toward the post path, the tab having a hooked end facing the tapered surface of the post, and the movement of the activation button assembly from the non-operating position to the operating position in the closed position of the cartridge door causes the post to engage with the tab, the tapered surface to engage with the hooked end, translating it laterally, and then deflecting the cantilever arm away from its resting position.

[0109] In some embodiments, the OBI further includes a biasing member connected to an activation button assembly and a syringe needle, the biasing member being stabilized in an energy-storage state when the activation button assembly is in a non-activating position and released in an energy-releasing state when the activation button assembly is in an activating position, driving the syringe needle from its retracted position to its injection position, the position of the activation button assembly between its non-activating position and its activating position defining a threshold point, and movement of the activation button assembly beyond the threshold point fixing the activation button assembly to the activating position and the syringe needle to the injection position.

[0110] In some embodiments, the biasing member biases the activation button assembly to its non-operating position and returns the activation button assembly to its non-operating position in response to the movement of the activation button assembly not exceeding a threshold point.

[0111] In some embodiments, the OBI further includes a needle hub movably mounted within the syringe housing, the injection needle being supported by the movable needle hub, and the needle hub and injection needle being translatable between a retracted position and an injection position.

[0112] In some embodiments, the OBI further includes an elongated first post connected to the syringe housing and projecting upward therefrom, having an upper end including a downwardly sloping surface and an undercut below the sloping surface; a deflectable second post connected to the syringe housing and projecting upward therefrom, having a flange at its upper part supporting a portion of the needle hub, thereby fixing the needle hub and the syringe needle in their retracted position; and the activation button assembly includes a downwardly projecting first arm having a flanged end that is slidable along the sloping surface of the elongated first post, the first arm being elastically deflectable from its original position, and the movement of the activation button assembly is along the sloping surface of the first post and the first arm The flanged end of the arm slides, thereby elastically deflecting the first arm away from its original position. The inclined surface and undercut of the elongated first post intersect at a vertex defining a threshold point. The movement of the activation button assembly beyond the vertex induces the first arm to retract back to its original position, hooking its flanged end onto the undercut of the elongated first post and fixing the activation button assembly in its operating position. The movement of the activation button beyond the vertex also engages the flanged end of the first arm with the second post, deflecting the second post. The deflected second post then releases the needle hub and subsequently releases the biasing member into an energy-releasing state, driving the needle hub and injection needle from their retracted position to their injection position.

[0113] In some embodiments, the syringe (e.g., OBI) may be configured to receive a cartridge containing a substance to be dispensed (e.g., as an anti-C5 antibody or its antigen-binding fragment as described herein), the cartridge having an opening sealed by a puncturable septum, and the syringe comprises a syringe housing, an activation button assembly movably mounted on the syringe housing and translatable from a non-activating position to an activated position, a needle translatable between a retracted position in which at least the tip of the needle is housed within the syringe housing and an injection position in which at least the tip of the needle protrudes from the syringe housing, and a cartridge door movably mounted on the syringe housing between an open position and a closed position, having an open end, an internal channel configured to receive the cartridge, and an internal The device comprises a cartridge door, which includes a cartridge puncture needle mounted within a channel and fluid-connected to a needle, and an interference member having a stationary position configured to limit the insertion depth of the cartridge within the internal channel of the cartridge door to a sealed position, wherein the cartridge puncture needle does not fully penetrate the puncturable septum in the sealed position, the cartridge door is movable to a closed position when the cartridge is in the sealed position, and the movement of an activation button assembly from a non-operating position to an operating position when the cartridge door is in the closed position deflects the interference member from the stationary position, thereby allowing the cartridge to advance into the internal channel of the cartridge door to an unsealed position, the cartridge puncture needle fully penetrating the puncturable septum in the unsealed position to dispense a substance (e.g., anti-C5 antibody or its antigen-binding fragment) through the needle.

[0114] In some embodiments, the syringe further includes a drive assembly that is engageable with a cartridge and releases a substance (e.g., an anti-C5 antibody or its antigen-binding fragment) therefrom, the drive assembly being operably engaged with an activation button assembly and configured to drive the cartridge from a sealed position to an unsealed position when the activation button assembly moves from a non-operated position to an activated position. In some embodiments, the internal channel defines a length greater than the length of the cartridge. In some embodiments, the interference member comprises a cantilever arm.

[0115] In some embodiments, the cantilever arm defines a first end connected to the cartridge door and extends to a second free end adjacent to the open end of the cartridge door. In some embodiments, the cartridge door includes a side wall, and the cantilever arm defines a deflectable portion of the side wall of the cartridge door. In some embodiments, the cantilever arm is formed integrally with the side wall of the cartridge door. In some embodiments, the side wall of the cartridge door defines a first inner circumference at the second free end of the cantilever arm when the cantilever arm is in its resting position, and the side wall of the cartridge door defines a second inner circumference at the second free end of the cantilever arm when the cantilever arm is deflected from its resting position, wherein the first inner circumference is smaller than the maximum outer circumference of a cartridge that can be inserted into the internal channel, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door, and the second inner circumference is larger than the maximum outer circumference of the cartridge, thereby allowing the cartridge to advance into the internal channel of the cartridge door.

[0116] In some embodiments, the activation button assembly comprises a post extending from there to a tapered end, the post having a post path, along which the post moves from a non-activating position to an operating position, and the cantilever arm comprises a tab extending laterally from there toward the post path, the tab having a hooked end facing the tapered surface of the post, and the movement of the activation button assembly from the non-activating position to the operating position in the closed position of the cartridge door engages the post with the tab, the tapered surface engages with the hooked end, translating it laterally and then deflecting the cantilever arm away from its resting position. In some embodiments, the activation button assembly is operably connected to the injection needle, so that the movement of the activation button assembly from its non-activating position to the operating position drives the injection needle from its retracted position to the injection position. In some embodiments, the cartridge door is pivotably attached to the syringe housing at the end of the cartridge door opposite its open end.

[0117] In some embodiments, the syringe (e.g., OBI) comprises a syringe housing, a needle that is translationally movable between a retracted position in which at least the tip of the needle is housed within the syringe housing and an injection position in which at least the tip of the needle protrudes from the syringe housing, an activation button assembly movably mounted on the syringe housing and operably connected to the needle, the activation button assembly being translationally movable from an inactive position to an active position to drive the needle from the retracted position to the injection position, and a cartridge door movably mounted on the syringe housing between an open position and a closed position, the internal channel having an open end, an internally mounted cartridge, the cartridge containing a substance to be dispensed (e.g., an anti-C5 antibody or its antigen-binding fragment), and the internal channel having an opening at the front end of the cartridge and a flange at the rear end of the cartridge, and internal The invention provides a cartridge door containing a cartridge puncture needle mounted within a channel and fluid-connected to a syringe needle, and an interfering member which, in the resting position of the interfering member, engages with the flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to the sealed position, so that the cartridge puncture needle does not fully penetrate the puncturable septum in the sealed position, the cartridge door being movable to a closed position in the sealed position of the cartridge, and the movement of an activation button assembly from a non-operating position to an operating position when the cartridge door is in the closed position deflects the interfering member and disengages it from the flange of the cartridge, thereby allowing the cartridge to advance into the unsealed position within the internal channel of the cartridge door, so that the cartridge puncture needle fully penetrates the puncturable septum in the unsealed position and dispenses a substance (e.g., anti-C5 antibody or its antigen-binding fragment) through the syringe needle.

[0118] In some embodiments, the interfering member comprises a cantilever arm. In some embodiments, the cantilever arm defines a first end connected to a cartridge door and extends to a second free end adjacent to the open end of the cartridge door. In some embodiments, the cartridge door comprises a side wall, and the cantilever arm defines a deflectable portion of the side wall of the cartridge door. In some embodiments, the side wall of the cartridge door defines a first inner circumference at the second free end of the cantilever arm when the cantilever arm is in its resting position, and the side wall of the cartridge door defines a second inner circumference at the second free end of the cantilever arm when the cantilever arm is deflected from its resting position, wherein the first inner circumference is smaller than the outer circumference of the rear end flange of the cartridge that can be inserted into the internal channel, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door, and the second inner circumference is larger than the outer circumference of the rear end flange of the cartridge, thereby allowing the cartridge to advance into the internal channel of the cartridge door.

[0119] In some embodiments, the activation button assembly comprises a post extending therefrom to a tapered end, the post having a post path, along which the post moves from a non-operating position to an operating position of the activation button assembly, and the cantilever arm comprises a tab extending laterally therefrom toward the post path, the tab having a hooked end facing the tapered surface of the post, and the movement of the activation button assembly from the non-operating position to the operating position in the closed position of the cartridge door engages the post with the tab, the tapered surface engages with the hooked end, translating it laterally, and then deflecting the cantilever arm away from its resting position.

[0120] In some embodiments, a syringe (e.g., OBI) is configured to receive a cartridge containing a substance to be dispensed (e.g., as an anti-C5 antibody or its antigen-binding fragment), the cartridge having an opening sealed by a puncturable septum, and the syringe comprises a syringe housing, an activation button assembly movably mounted on the syringe housing and translatable from a non-activating position to an activated position, a needle, a cartridge door movably mounted on the syringe housing between an open position and a closed position, the cartridge door including an internal channel configured to receive a cartridge and a cartridge puncture needle fluidly connected to the needle, and the cartridge The device comprises an interfering member having a position configured to limit the insertion depth of the cartridge within the internal channel of the door to a sealed position, wherein the cartridge puncture needle does not fully penetrate the puncturable septum in the sealed position, the cartridge door is movable to a closed position when the cartridge is in the sealed position, and the movement of the activation button assembly from a non-operating position to an operating position when the cartridge door is in the closed position moves the interfering member out of its position, thereby allowing the cartridge to advance to an unsealed position within the internal channel of the cartridge door, the cartridge puncture needle fully penetrating the puncturable septum in the unsealed position, and injecting a substance (e.g., an anti-C5 antibody or its antigen-binding fragment) through the injection needle.

[0121] In some embodiments, the internal channel defines a length greater than the length of the cartridge. In some embodiments, the interference member comprises a cantilever arm.

[0122] In some embodiments, the syringe (e.g., OBI) comprises a syringe housing, a needle that is translationally movable between a retracted position in which at least the tip of the needle is housed within the syringe housing and an injection position in which at least the tip of the needle protrudes from the syringe housing, an activation button assembly movably mounted on the syringe housing and operably connected to the needle, the activation button assembly being translationally movable from an inactive position to an active position to drive the needle from the retracted position to the injection position, a cartridge door movably mounted on the syringe housing between an open position and a closed position, an internal channel having an open end, an internally mounted cartridge, the cartridge having an opening at the front end of the cartridge and a flange at the rear end, which is sealed by a puncturable septum, and a component mounted within the internal channel and in fluid communication with the needle A cartridge lancet is connected to a cartridge lancet configured to fully penetrate the puncturable septum of the cartridge and to connect an antibody (e.g., anti-C5 antibody or its antigen-binding fragment) in the cartridge to the injection needle in fluid communication; and a deflectable interfering member is configured to engage with the rear end flange of the cartridge in a stationary position of the interfering member, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge lancet does not fully penetrate the puncturable septum, wherein the cartridge door is movable to a closed position at the sealed position of the cartridge, and movement of the activation button assembly from a non-operated position to an activated position at the closed position of the cartridge door deflects the interfering member and disengages it from the rear end flange of the cartridge, thereby allowing further advance of the cartridge into the internal channel of the cartridge door to an unsealed position where the cartridge lancet fully penetrates the puncturable septum.

[0123] In some embodiments, the syringe further includes a drive assembly that is engageable with a cartridge and releases an antibody (e.g., an anti-C5 antibody or its antigen-binding fragment) therefrom, the drive assembly being operably engaged with an activation button assembly and configured to drive the cartridge from a sealed position to an unsealed position when the activation button assembly moves from a non-operated position to an activated position. In some embodiments, the deflectable interference member comprises a cantilever arm. In some embodiments, the cantilever arm is connected to a cartridge door and defines a first end that extends to a second free end adjacent to the open end of the cartridge door. In some embodiments, the cartridge door comprises a side wall, and the cantilever arm defines a deflectable portion of the side wall of the cartridge door. In some embodiments, the side wall of the cartridge door defines a first inner circumference at the second free end of the cantilever arm when the cantilever arm is in a stationary position, and the side wall of the cartridge door defines a second inner circumference at the second free end of the cantilever arm when the cantilever arm is deflected from the stationary position, wherein the first inner circumference is smaller than the maximum outer circumference of the cartridge that can be inserted into the internal channel, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door, and the second inner circumference is larger than the maximum outer circumference of the cartridge, thereby allowing further advancement of the cartridge into the internal channel of the cartridge door.

[0124] In some embodiments, the activation button assembly comprises a post extending therefrom to an end having a tapered surface, the post having a post path, the post moving along it from a non-operating position to an operating position of the activation button assembly, the cantilever arm comprising a tab extending laterally therefrom toward the post path, the tab having a hooked end facing the tapered surface of the post, the movement of the activation button assembly from the non-operating position to the operating position in the closed position of the cartridge door engages the post with the tab, the tapered surface engages with the hooked end, translating it laterally, and then deflecting the cantilever arm away from its stationary position.

[0125] In some embodiments, the syringe further comprises a biasing member connected to an activation button assembly and a needle, the biasing member being stabilized in an energy-storage state when the activation button assembly is in a non-activating position and released in an energy-releasing state when the activation button assembly is in an activating position, driving the needle from a retracted position to an injection position, the position between the non-activating and activating positions of the activation button assembly defining a threshold point, and any movement of the activation button assembly beyond the threshold point fixing the activation button assembly to the activating position and the needle to the injection position. In some embodiments, the biasing member biases the activation button assembly to the non-activating position and returns the activation button assembly to the non-activating position in response to the activation button assembly not moving beyond the threshold point.

[0126] In some embodiments, the syringe further comprises a needle hub movably mounted within the syringe housing, the needle being supported by the needle hub, and the needle hub and needle being translationally movable between a retracted position and an injection position. In some embodiments, the syringe further comprises an elongated first post connected to the syringe housing and projecting upward therefrom, having an upper end including a downwardly sloping surface and an undercut below the sloping surface; and a deflectable second post connected to the syringe housing and projecting upward therefrom, having a flange at its upper part supporting a portion of the needle hub, thereby fixing the needle hub and needle in its retracted position; the activation button assembly comprises a downwardly projecting first arm having a flanged end slidable along the sloping surface of the elongated first post, the first arm being elastically deflectable from its original position, and the movement of the activation button assembly is along the sloping surface of the first post. The flanged end of the arm slides, thereby elastically deflecting the first arm away from its original position. The inclined surface and elongated undercut of the first post intersect at a vertex defining a threshold point. The movement of the activation button assembly beyond the vertex induces the first arm to retract back to its original position, thereby hooking the flanged end onto the undercut of the elongated first post and fixing the activation button assembly in its operating position. The movement of the activation button beyond the vertex also engages the flanged end of the first arm with the second post, deflecting the second post. The deflected second post then releases the needle hub, and subsequently releases the biasing member into an energy-releasing state, driving the needle hub and injection needle from the retracted position to the injection position.

[0127] In some embodiments, this specification describes a method for dispensing an antibody (e.g., an anti-C5 antibody or its antigen-binding fragment) from a syringe (e.g., OBI), wherein the syringe comprises a syringe housing, a needle movable from a retracted position in which at least the tip of the needle is housed within the syringe housing and an injection position in which at least the tip of the needle protrudes from the syringe housing, an activation button assembly movably mounted to the syringe housing and operably connected to the needle, a cartridge door movably mounted to the syringe housing between an open position and a closed position, having an open end, an internal channel, and a cartridge puncture needle mounted within the internal channel and operably connected to the needle, and a drive assembly operably engaged with the activation button assembly, wherein the method involves inserting a cartridge into the internal channel of the cartridge door in the open position of the cartridge door, wherein the cartridge contains an antibody (e.g., an anti-C5 antibody or its antigen-binding fragment) in its sealed reservoir and has a punctureable septum A method is provided comprising: inserting a sealed reservoir having an opening at the front end and a flange at the rear end of the reservoir; engaging the rear end flange of the cartridge with a deflectable interfering member of a syringe in the stationary position of the interfering member, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge puncture needle does not completely penetrate the puncturable septum; moving the activation button assembly from a non-activating position to an activated position, thereby deflecting the interfering member and disengaging it from the rear end flange of the cartridge, activating the drive assembly to advance the rear end flange of the cartridge beyond the interfering member, driving the cartridge from a sealed position to an unsealed position where the cartridge puncture needle completely penetrates the puncturable septum of the cartridge and connects the antibody (e.g., anti-C5 antibody or its antigen-binding fragment) in the cartridge in fluid communication with the injection needle; and driving the injection needle from a retracted position to an injection position and dispensing the antibody (e.g., anti-C5 antibody or its antigen-binding fragment) from there.

[0128] In some embodiments, driving the needle to the injection position includes extending at least the tip of the needle from the syringe housing and dispensing an antibody (e.g., an anti-C5 antibody or its antigen-binding fragment) from the needle. In some embodiments, the syringe further includes a sensor connected to a control assembly, and the method further includes detecting via the sensor at least one of (i) a movement of the activation button assembly from its non-activating position to an activated position, or (ii) a movement of the needle from its retracted position to an injection position, and activating the drive assembly via the control assembly upon such detection.

[0129] In some embodiments, the activation button assembly includes a post extending therefrom to a tapered end, the post having a post path, along which the post moves from a non-activating position to an activated position, and the interfering member includes a cantilever arm defining a deflectable portion of the side wall of the cartridge door, thereby the first end of the cantilever arm being connected to the side wall and extending to a second free end adjacent to the open end of the cartridge door, the cantilever arm including a tab extending laterally thereto toward the post path, the tab having a hooked end facing the tapered surface of the post, and moving the activation button assembly from a non-activating position to an activated position includes engaging the tapered surface of the post with the hooked end of the tab, translating the hooked end laterally, and then deflecting the cantilever arm to disengage it from the rear end flange of the cartridge.

[0130] In some embodiments, the syringe (e.g., OBI) comprises a syringe housing, a needle that is translationally movable between a retracted position in which at least the tip of the needle is housed within the syringe housing and an injection position in which at least the tip of the needle protrudes from the syringe housing, and a cartridge door that is movable between an open position and a closed position, wherein the cartridge door has an open end, an internally mounted cartridge, the cartridge having an opening at the front end of the cartridge and a flange at the rear end, the cartridge containing an antibody to be dispensed (e.g., anti-C5 antibody or its antigen-binding fragment) and sealed by a puncturable septum. A cartridge door comprising a cartridge puncture needle mounted within an internal channel and connected to a needle in fluid communication, wherein the cartridge puncture needle is configured to completely penetrate the puncturable septum of the cartridge and to connect the antibody (e.g., anti-C5 antibody or its antigen-binding fragment) in the cartridge to the needle in fluid communication; and a deflectable interference member which, in a stationary position, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position where the cartridge puncture needle does not completely penetrate the puncturable septum.

[0131] In some embodiments, the syringe further comprises an activation button assembly movably mounted on the syringe housing and operably connected to the injection needle, which is translatable from a non-operating position to an operating position in order to drive the injection needle from a retracted position to an injection position. In some embodiments, the syringe further comprises a drive assembly operably engaged with the activation button assembly and configured to drive the cartridge when the activation button assembly moves from a non-operating position to an operating position, which is engaged with a cartridge from which an antibody (e.g., an anti-C5 antibody or its antigen-binding fragment) is released.

[0132] In some embodiments, the deflectable buffer member comprises a cantilever arm connected to a cartridge door, defining a first end that extends to a second free end adjacent to the open end of the cartridge door. In some embodiments, the cartridge door comprises a side wall, and the cantilever arm defines a deflectable portion of the side wall of the cartridge door. In some embodiments, the side wall of the cartridge door defines a first inner circumference at the second free end of the cantilever arm when the cantilever arm is in a stationary position, and the side wall of the cartridge door defines a second inner circumference at the second free end of the cantilever arm when the cantilever arm is deflected from the stationary position, wherein the first inner circumference is smaller than the maximum outer circumference of the cartridge that can be inserted into the internal channel, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door, and the second inner circumference is larger than the maximum outer circumference of the cartridge, thereby allowing further advancement of the cartridge into the internal channel of the cartridge door.

[0133] In some embodiments, the activation button assembly comprises a post extending therefrom to an end having a tapered surface, the post having a post path, the post moving along it from a non-operating position to an operating position of the activation button assembly, the cantilever arm comprising a tab extending laterally therefrom toward the post path, the tab having a hooked end facing the tapered surface of the post, the movement of the activation button assembly from the non-operating position to the operating position in the closed position of the cartridge door engages the post with the tab, the tapered surface engages with the hooked end, translating it laterally, and then deflecting the cantilever arm away from its stationary position.

[0134] In some embodiments, the syringe further comprises a biasing member connected to an activation button assembly and a needle, the biasing member being stabilized in an energy-storage state when the activation button assembly is in a non-activating position and released in an energy-releasing state when the activation button assembly is in an activating position, driving the needle from a retracted position to an injection position, the position between the non-activating and activating positions of the activation button assembly defining a threshold point, and any movement of the activation button assembly beyond the threshold point fixing the activation button assembly to the activating position and the needle to the injection position. In some embodiments, the biasing member biases the activation button assembly to the non-activating position and returns the activation button assembly to the non-activating position in response to the activation button assembly not moving beyond the threshold point.

[0135] In some embodiments, the syringe further comprises a needle hub movably mounted within the syringe housing, the injection needle being supported by the needle hub, and the needle hub and injection needle being translationally movable between a retracted position and an injection position.

[0136] In some embodiments, the syringe further includes an elongated first post connected to the syringe housing and projecting upward therefrom, having an upper end including a downwardly sloping surface and an undercut below the sloping surface; and a deflectable second post connected to the syringe housing and projecting upward therefrom, having a flange at its upper part supporting a portion of the needle hub, thereby fixing the needle hub and the syringe needle in their retracted position; and the activation button assembly includes a downwardly projecting first arm having a flanged end that is slidable along the sloping surface of the elongated first post, the first arm being elastically deflectable from its original position, and the movement of the activation button assembly is along the sloping surface of the first post. The flanged end of the arm slides, thereby elastically deflecting the first arm away from its original position. The inclined surface and elongated undercut of the first post intersect at a vertex defining a threshold point. The movement of the activation button assembly beyond the vertex induces the first arm to retract back to its original position, thereby hooking the flanged end onto the undercut of the elongated first post and fixing the activation button assembly in its operating position. The movement of the activation button beyond the vertex also engages the flanged end of the first arm with the second post, deflecting the second post. The deflected second post then releases the needle hub, and subsequently releases the biasing member into an energy-releasing state, driving the needle hub and injection needle from the retracted position to the injection position.

[0137] In some embodiments, the cartridge has a volume of 10 mL. In some embodiments, the OBDS is configured for subcutaneous self-administration of an anti-C5 antibody or its antigen-binding fragment to a patient.

[0138] OBDS can be configured for subcutaneous delivery of an anti-C5 antibody or its antigen-binding fragment to any preferred site. In some embodiments, OBDS is configured for subcutaneous delivery of an anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh.

[0139] In addition, this specification provides a needle syringe configured for administering an effective dose of anti-C5 antibody or its antigen-binding fragment to a pediatric human patient requiring treatment for aHUS or PNH, wherein the patient weighs between 10 kg and 20 kg, is either new to complement inhibitor treatment, has experience with eculizumab, or has experience with ravulizumab, and the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once weekly at a dose of 150 mg.

[0140] Furthermore, this specification provides a needle syringe configured for treating aHUS or PNH in pediatric human patients requiring such treatment, wherein the needle syringe is configured for subcutaneous administration and contains 150 mg of anti-C5 antibody or its antigen-binding fragment, wherein the patient weighs 10 kg or more but less than 20 kg and is either new to complement inhibitor treatment, has experience with eculizumab, or has experience with ravulizumab.

[0141] In some embodiments, a 150 mg dose of anti-C5 antibody or its antigen-binding fragment is formulated with sodium phosphate, sucrose, L-arginine, PS80, and water for injection, at pH 7.4 and a concentration of 100 mg / mL. In some embodiments, a needle syringe is configured to administer the anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh. In some embodiments, the patient is under 21 years of age (e.g., 20, 19, 18, 17, 16, 15, 10, 5, or 2 years). In some embodiments, the patient is between 2 and 18 years of age (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years).

[0142] Any suitable anti-C5 antibody or antigen-binding fragment thereof, including any suitable anti-C5 antibody or antigen-binding fragment thereof disclosed herein, may be contained in the OBDS or needle syringes provided herein. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in their EU numbering. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 12 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain variable region contains an N-terminal pyroglutamic acid residue. In some embodiments, the anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11.

[0143] Anti-C5 antibody C5 complement, which forms part of the later stages of the complement pathway, is cleaved into C5a and C5b. C5a is a cell-activating molecule that mediates potent anaphylatoxin, chemotactic, and multiple pro-inflammatory and pro-thrombotic activities (Matis LA, et al., Nat. Med. 1995; 1: 839-42; Prodinger et al., Complement. In: Paul WE, editor. Fundamental immunology (4th ed). Philadelphia: Lippincott-Raven Publishers; 1999: 967-95). C5b recruits terminal complement components C6, C7, C8, and C9 to form the pro-inflammatory, pro-thrombotic, and cytolytic pore molecule C5b-9, a process that is normally blocked by CD59 on the red blood cell (RBC) membrane. However, in patients with PNH, these final steps progress unchecked, leading to hemolysis and release of free hemoglobin, as well as platelet activation (Hill, et al., Blood 2013;121:4985-96). The signs and symptoms of PNH may be due to chronic, uncontrolled complement C5 cleavage and the release of C5a and C5b-9 resulting in RBC hemolysis, which together (Hill, et al., Blood 2013;121:4985-96; Brodsky R A., Blood. 2014;124:2804-1): (1) Release of intracellular free hemoglobin and lactate dehydrogenase (LDH) into circulation as a direct result of hemolysis. (2) Irreversible binding of hemoglobin to nitric oxide (NO) and its inactivation, and inhibition of NO synthesis. (3) Vasoconstriction and tissue bed ischemia due to the absence of vasodilatory NO, and microthrombi that may manifest as abdominal pain and dysphagia. (4) Platelet activation, and (5) It leads to a pro-inflammatory and pro-thrombus formation state.

[0144] The anti-C5 antibodies described herein bind to complement component C5 (e.g., human complement C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have improved pharmacokinetic properties compared to other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab). Anti-C5 antibodies (or VH / VL domains or other antigen-binding fragments derived therefrom) suitable for use herein can be produced using methods known in the art. Anti-C5 antibodies recognized in the art can also be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 can also be used.

[0145] Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs. 10 and 11, respectively, or an antigen-binding fragment and variant thereof. Eculizumab is described in International Application US2007 / 006606 and U.S. Patent No. 9,732,149, the teachings of which are incorporated herein by reference. In one embodiment, the anti-C5 antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of eculizumab having the sequence described in SEQ ID NOs. 7, and the CDR1, CDR2, and CDR3 domains of the VL region of eculizumab having the sequence described in SEQ ID NOs. 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In another embodiment, the antibody includes VH and VL regions having the amino acid sequences described in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

[0146] Labulizumab (also known as BNJ441, ALXN1210, ULTOMIRIS®, or labulizumab-cwvz) is an anti-C5 antibody, or its antigen-binding fragment and variant, comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs. 14 and 11, respectively. Labulizumab is described in International Application US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference in their entirety. Labulizumab is a humanized monoclonal antibody structurally related to eculizumab (Soliris®). Labulizumab was induced through a minimal targeting operation of eculizumab by introducing four unique amino acid substitutions into the heavy chain, with the goal of enhancing the duration of terminal complement suppression while maintaining the key attributes of eculizumab. Rabulizumab and eculizumab share over 99% primary sequence identity and possess very similar pharmacological properties. Rabulizumab selectively binds to human complement protein C5 and inhibits its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the pro-inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving proximal or early components of complement activation (e.g., C3 and C3b) essential for microbial opsonization and immune complex clearance.

[0147] In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in their EU numbering. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NOs. 8. In some embodiments, the anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region contained in the amino acid sequence of SEQ ID NOs. 13. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide having the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 14 except that it lacks a C-terminal lysine residue, and a light chain polypeptide having the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain amino acid sequence includes an N-terminal pyroglutamic acid residue.

[0148] In some embodiments, the anti-C5 antibody is ravulizumab.

[0149] The precise boundaries of the CDR are defined differently according to different methods. In some embodiments, the location of the CDR or framework region within the light chain or heavy chain variable domain may be as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91-3242, USD Department of Health and Human Services, Bethesda, MD]. In such cases, the CDR may be referred to as "Kabat CDR" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the location of the CDR in the light chain or heavy chain variable region may be as defined by Chothia et al. (Nature, 342:877-83, 1989). Thus, these regions may be referred to as "Chothia CDR" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the locations of the CDRs in the light-chain and heavy-chain variable regions may be as defined by the Kabat-Chothia combination definition. In such embodiments, these regions can be referred to as the "combination Kabat-Chothia CDR" (Thomas, T. et al., Mol.Immunol., 33:1389-401, 1996).

[0150] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable region of the 7086 antibody (see U.S. Patents 8,241,628 and 8,883,158). In another embodiment, the antibody or its antigen-binding fragment comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 24, 25, and 26, respectively. In yet another embodiment, the antibody or its antigen-binding fragment comprises the VH region of the 7086 antibody having the sequence described in SEQ ID NOs. 27, and the VL region of the 7086 antibody having the sequence described in SEQ ID NOs. 28.

[0151] Another exemplary anti-C5 antibody is the 8110 antibody, also described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable region of the 8110 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 32, 33, and 34, respectively. In yet another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence described in SEQ ID NO. 35, and the VL region of the 8110 antibody having the sequence described in SEQ ID NO. 36.

[0152] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy chain and light chain CDR or variable region of the 305LO5 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 40, 41, and 42, respectively. In yet another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence described in SEQ ID NO. 43, and the VL region of the 305LO5 antibody having the sequence described in SEQ ID NO. 44.

[0153] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa T. et al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy chain and light chain CDR or variable region of the SKY59 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 45 and a light chain containing SEQ ID NO: 46.

[0154] Another exemplary anti-C5 antibody is the H4H12166PP antibody described in International Application US2017 / 037226 and U.S. Patent No. 10,633,434. In one embodiment, the antibody comprises the heavy chain and light chain CDR or variable region of the H4H12166PP antibody. In another embodiment, the antibody or its antigen-binding fragment comprises the VH region of the H4H12166PP antibody having the sequence described in SEQ ID NO: 47, and the VL region of the H4H12166PP antibody having the sequence described in SEQ ID NO: 48. In yet another embodiment, the antibody or its antigen-binding fragment comprises the heavy chain containing SEQ ID NO: 49, and the light chain containing SEQ ID NO: 50.

[0155] In some embodiments, the patient has been previously treated with eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clovalimab, CAN106, or pozerimab. In some embodiments, the biosimilar of eculizumab includes ABP 959, ELIZARIA®, SB12, ISU305, ABLYZE®, or BCD 148. In some embodiments, the administration cycle is initiated approximately two weeks after the patient's last dose of eculizumab. In some embodiments, the patient has been treated with eculizumab for at least 90 days prior to day 1 of the administration cycle. In some embodiments, (i) the patient weighs less than 20 kg and the administration cycle is initiated approximately four weeks after the patient's last dose of ravulizumab, or (ii) the patient weighs 20 kg or more and the administration cycle is initiated approximately eight weeks after the patient's last dose of ravulizumab.

[0156] In some embodiments, the anti-C5 antibody described herein includes a heavy chain CDR1 comprising the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibody described herein includes a heavy chain CDR2 comprising the following amino acid sequence: EILPGSHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibody described herein includes a heavy chain variable region comprising the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS(Sequence ID 12).

[0157] In some embodiments, the anti-C5 antibodies described herein include a light chain variable region comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (Sequence ID 8).

[0158] The anti-C5 antibodies described herein may, in some embodiments, include a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with a higher affinity than the native human Fc constant region from which the variant human Fc constant region originates. The Fc constant region may include one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions compared to, for example, the native human Fc constant region from which the variant human Fc constant region originates. The substitutions can increase the binding affinity of the IgG antibody containing the variant Fc constant region to FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody enhance the affinity of the Fc constant region to FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are illustrated in the examples (see, for example, International Application US2015 / 019225 and U.S. Patent No. 9,079,949, the disclosures of which, by reference, are incorporated herein by reference in their entirety).

[0159] Substitutions that enhance the binding affinity of the antibody Fc constant region to FcRn are known in the art, for example, (1) M252Y / S254T / T256E triple substitution (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q / M428L substitution (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006), and (3) N434A or T307 / E380A / N434A substitution (Petkova, S. et al. Examples include al., Int.Immunol., 18:1759-69, 2006). Further substitution pairs, such as P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), are also considered herein.

[0160] In some embodiments, the variant constant region has a substitution for valine at EU amino acid residue 255. In some embodiments, the variant constant region has a substitution for asparagine at EU amino acid residue 309. In some embodiments, the variant constant region has a substitution for isoleucine at EU amino acid residue 312. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.

[0161] In some embodiments, the variant Fc constant region includes 30 or fewer amino acid substitutions, insertions, or deletions (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) compared to the native constant region from which it is derived. In some embodiments, the variant Fc constant region includes one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region includes methionine at position 428 and asparagine at position 434, respectively, in EU numbering. In some embodiments, the variant Fc steady-state region includes, for example, a 428L / 434S double substitution as described in U.S. Patent No. 8,088,376.

[0162] In some embodiments, the precise locations of these mutations may be shifted from the location of the natural human Fc constant region due to antibody manipulation. The 428L / 434S double substitution, for example, when used in IgG2 / 4 chimeric Fc, may correspond to 429L and 435S, as found in BNJ441 (ravulizumab) and the M429L and N435S variants described in U.S. Patent No. 9,079,949, the disclosure thereof is incorporated herein by reference in its entirety.

[0163] In some embodiments, the variant constant region includes substitutions at amino acid positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 (EU numbering) compared to the natural human Fc constant region. In some embodiments, the substitutions are, all in EU numbering, methionine instead of glycine at position 237; alanine instead of proline at position 238; lysine instead of serine at position 239; isoleucine instead of lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine instead of threonine at position 250; phenylalanine, tryptophan, or tyrosine instead of methionine at position 252; threonine instead of serine at position 254; glutamic acid instead of arginine at position 255; aspartic acid, glutamic acid, or glutamine instead of threonine at position 256; and alanine, glycine, isoleucine, leucine, or methionine instead of proline at position 257. , asparagine, serine, threonine, or valine; histidine instead of glutamic acid at position 258; alanine instead of aspartic acid at position 265; phenylalanine instead of aspartic acid at position 270; alanine or glutamic acid instead of asparagine at position 286; histidine instead of threonine at position 289; alanine instead of asparagine at position 297; glycine instead of serine at position 298; alanine instead of valine at position 303; alanine instead of valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine;At position 308, alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine instead of valine; at position 309, alanine, aspartic acid, glutamic acid, proline, or arginine instead of leucine or valine; at position 311, alanine, histidine, or isoleucine instead of glutamine; at position 312, alanine or histidine instead of aspartic acid; at position 314, lysine or arginine instead of leucine; at position 315, alanine or histidine instead of asparagine; at position 317, alanine instead of lysine; at position 325, glycine instead of asparagine; at position 332, valine instead of isoleucine; at position 334, leucine instead of lysine; at position 360, histidine instead of lysine; at position 376, alanine instead of aspartic acid; at position 380, alanine instead of glutamic acid; position 382 In position 384, alanine is used instead of glutamic acid; in position 384, alanine is used instead of asparagine or serine; in position 385, aspartic acid or histidine is used instead of glycine; in position 386, proline is used instead of glutamine; in position 387, glutamic acid is used instead of proline; in position 389, alanine or serine is used instead of asparagine; in position 424, alanine is used instead of serine; in position 428, alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine is used instead of methionine; in position 433, lysine is used instead of histidine; in position 434, alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine is used instead of asparagine; and in position 436, histidine is used instead of tyrosine or phenylalanine.

[0164] Suitable anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11. Alternatively, anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.

[0165] In one embodiment, the antibody binds to C5 with an affinity dissociation constant (K D ) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM at pH 7.4 and 25°C (and otherwise under physiological conditions). In some embodiments, the K D of the anti-C5 antibody or antigen-binding fragment thereof is 1 (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 or less) nM or less.

[0166] In some embodiments, [(K D of the antibody for C5 at pH 6.0, 25°C) / (K D)] is greater than 21 (for example, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 24 (0, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or greater than 8000).

[0167] Methods for determining whether an antibody binds to a protein antigen and / or for determining the affinity of an antibody to a protein antigen are known in the art. The binding of antibodies to protein antigens can be detected and / or quantified using a variety of techniques, including, but not limited to, Western blotting, dot blotting, surface plasmon resonance (SPR) methods (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA) (see, for example, Benny KCLo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11:620-7, 1991). For example, additional methods for measuring affinity (e.g., dissociation and association constants) are described in the examples.

[0168] When used herein, "k a The term "k" refers to the rate constant for antibody association with antigen.d The term "K" refers to the rate constant for the dissociation of an antibody from an antibody / antigen complex. D The term "equilibrium dissociation constant" refers to the equilibrium dissociation constant of antibody-antigen interactions. The equilibrium dissociation constant is the ratio of the kinetic rate constants, K D =k d / k a This is estimated from the following. Such a determination is preferably measured at 25°C or 37°C. The dynamics of antibody binding to human C5 can be determined via surface plasmon resonance (SPR) on a BIAcore 3000 instrument using an anti-Fc capture method for immobilizing the antibody, for example at pH 8.0, 7.4, 7.0, 6.5, and 6.0. In one embodiment, an anti-C5 antibody or its antigen-binding fragment blocks the generation or activity of the C5a and / or C5b active fragments of the C5 protein (e.g., human C5 protein). Through this blocking effect, the antibody inhibits, for example, the pro-inflammatory effect of C5a and the generation of the C5b-9 membrane attack complex (MAC) on the cell surface.

[0169] Methods for determining whether specific antibodies described herein inhibit C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic capacity of complement in the body fluids of interest. Such reduction in the cytolytic capacity of complement present in body fluids is described, for example, in Kabat and Mayer (eds.), "Experimental Immunochemistry, 2 ndThe results can be measured by conventional hemolysis assays, such as the hemolysis assay described in "Edition," 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or by conventional modifications of such assays, such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentrations and / or physiological activities of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, a hemolysis assay or the assay for soluble C5b-9 discussed herein can be used. Other assays known in the art can also be used. These or other suitable assays can be used to screen for candidate drugs that can inhibit human complement component C5.

[0170] Immunological techniques such as ELISA can be used to measure the protein concentrations of C5 and / or its fragmented products in order to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 to a biologically active product. In some embodiments, C5a production is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect terminal complement formation.

[0171] A hemolysis assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment against complement activation. To determine the effect of an anti-C5 antibody or its antigen-binding fragment against classical complement pathway-mediated hemolysis in a serum test solution in vitro, target cells are used, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with an anti-chicken erythrocyte antibody. The percentage of lysis is normalized by considering 100% lysis, which is equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, such as the one used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of a human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescence-generating substrate, and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of anti-C5 antibody or its antigen-binding fragment. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0172] To determine the effect of an anti-C5 antibody or its antigen-binding fragment on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis, which is equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by a lipopolysaccharide molecule, such as that used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescence-generating substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum was incubated in the absence of anti-C5 antibody or its antigen-binding fragment.

[0173] In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This assay is a lysis assay that determines the amount required to yield 50% lysis (CH50) using antibody-sensitized erythrocytes as activators of the classical complement pathway and various dilutions of the test serum. The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of TCC formation, as the terminal complement complex (TCC) itself is directly involved in the hemolysis being measured. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized erythrocytes, thereby generating TCCs. The activated serum sample is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). TCCs present in the activated sample bind to a monoclonal antibody coating the surface of the microassay wells. The wells are washed, and a detection reagent that recognizes the bound TCCs, which has been detected and labeled, is added to each well. The detectable label can be, for example, fluorescent or enzymatic. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0174] Inhibition, for example, if it relates to terminal complement activity, includes a reduction of at least 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) of terminal complement activity in a hemolysis assay or CH50eq assay, compared to the effect of a control antibody (or its antigen-binding fragment) under similar conditions and at equimolar concentrations. Substantial inhibition, as used herein, refers to inhibition of at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%) of a given activity (e.g., terminal complement activity). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions compared to the CDR of eculizumab (i.e., SEQ ID NOs: 1-6), but retain at least 30% (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%) of the complement inhibitory activity of eculizumab in a hemolysis assay or CH50eq assay.

[0175] In some embodiments, the anti-C5 antibodies described herein have a serum half-life in humans of at least 20 days (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of at least 40 days. In yet another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of about 43 days. In yet another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments described herein have a serum half-life that is at least 20% (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500)% longer than the serum half-life of eculizumab, as measured in one of the mouse model systems described in the Examples (e.g., C5-deficient / NOD / scid mouse or hFcRn transgenic mouse model system).

[0176] In one embodiment, an antibody competes for and / or binds to the same C5 epitope as the antibody described herein. The term “binding to the same epitope” with respect to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether an antibody binds to the “same C5 epitope” as the antibody described herein include, for example, epitope mapping methods such as X-ray analysis of antigen:antibody complexes that provide atomic resolution and hydrogen / deuterium exchange mass spectrometry (HDX-MS) of the epitope. Other methods involve monitoring the binding of antibodies to peptide antigen fragments or variant variations of antigens, where loss of binding due to alterations of amino acid residues in the antigen sequence is often considered an indicator of the epitope component. Computer combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from a peptide library of combinatorial phage displays. Antibodies having the same VH and VL sequences, or the same CDR1, 2, and 3 sequences, are expected to bind to the same epitope.

[0177] An antibody that "competes with another antibody for binding to its target" refers to an antibody that (partially or completely) inhibits the binding of another antibody to its target. Whether two antibodies compete with each other for binding to their target, i.e., whether one antibody inhibits the binding of the other antibody to its target, and to what extent, can be determined using known competition experiments. In some embodiments, an antibody competes with another antibody for binding to its target, inhibiting it by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition may vary depending on which antibody is a "blocking antibody" (i.e., the cold antibody initially incubated with the target). Competing antibodies can bind to the same epitope, overlapping epitopes, or adjacent epitopes (as demonstrated, for example, by steric hindrance).

[0178] The anti-C5 antibodies or their antigen-binding fragments used in the methods described herein can be produced using a variety of techniques known in the art. Monoclonal antibodies can be obtained by a variety of techniques familiar to those skilled in the art. Briefly, spleen cells from animals immunized with the desired antigen are immortalized, generally by fusion with myeloma cells (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or other methods known in the art. Colonies resulting from a single immortalized cell are screened for the production of antibodies with desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by a variety of techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0179] composition This specification provides compositions comprising an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively. In yet another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 20 and 11, respectively.

[0180] For example, pharmaceutical compositions are provided that contain ravulizumab alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. The ravulizumab-containing pharmaceutical compositions provided herein are for use, for example, in the diagnosis, detection, or monitoring of disorders, the prevention, treatment, management, or improvement of disorders or one or more symptoms thereof, and / or in research. Formulations of pharmaceutical compositions, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier, are known in the art.

[0181] The composition can be formulated as a pharmaceutical solution for administration to a subject for the treatment or prevention of complement-related disorders, including PNH or aHUS. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” means, and includes, any and all physiologically compatible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, etc. The composition may also contain pharmaceutically acceptable salts, such as acid-addition salts or base-addition salts, sugars, carbohydrates, polyols, and / or tonic modifiers.

[0182] The composition can be formulated according to known methods (Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20 th Edition, Lippincott, Williams & Wilkins (ISBN:0683306472), Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727), and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rdEdition (ISBN: 091733096X). In some embodiments, the composition can be formulated, for example, as a buffer solution suitable for storage at a preferred concentration and at 2-8°C (e.g., 4°C). In some embodiments, the composition can be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage at 2-8°C (e.g., 4°C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable for storage at 2-8°C (e.g., 4°C) for at least 1 year.

[0183] Pharmaceutical compositions can exist in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions containing compositions intended for systemic or local delivery may, for example, be in the form of injectable or injectable solutions. Compositions can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). When used herein, “parenteral administration,” “administered parenterally,” and other grammatically equivalent terms refer to modes of administration other than intestinal and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intrasacral, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, carotid, and intrasternal injections and infusions. In one embodiment, the antibody is formulated for intravenous administration. In certain embodiments, the antibody is formulated for subcutaneous administration.

[0184] The exemplary and non-limiting range of therapeutic or prophylactic effective doses of the anti-C5 antibody or its antigen-binding fragment provided herein (e.g., ravulizumab) (for example, for human pediatric patients who are complement inhibitor-naive or eculizumab-treated) is: (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) The dose is 2700 mg for patients weighing 60 kg or more.

[0185] The exemplary and non-limiting range of therapeutic or prophylactic effective doses of the anti-C5 antibody or its antigen-binding fragment provided herein (e.g., ravulizumab) for human pediatric patients who are complement inhibitor-naive or eculizumab-treated is: (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) 490 mg for patients weighing 40 kg or more.

[0186] The exemplary and non-limiting range of therapeutic or prophylactic effective doses of the anti-C5 antibody or its antigen-binding fragment provided herein (e.g., ravulizumab) (e.g., for human pediatric patients with prior ravulizumab experience) is as follows: (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) 490 mg for patients weighing 40 kg or more.

[0187] It should be noted that dosage values ​​may vary depending on the type and severity of the condition being alleviated. Furthermore, it should be understood that for any particular subject, a specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the dosage ranges described herein are illustrative only and are not intended to limit the scope or practice of the claimed method.

[0188] Combination therapy The anti-C5 antibodies provided herein may also be administered together with one or more additional pharmaceuticals or therapeutic agents useful in the treatment of PNH or aHUS. The additional agents may be, for example, therapeutic agents recognized in the art as useful in treating PNH or aHUS. The combination may also include two or more further agents, for example, two or three additional agents. Subcutaneous formulations containing the anti-C5 antibodies of this disclosure may be administered together with agents that are proteins, peptides, carbohydrates, drugs, small molecules, or genetic material (e.g., DNA or RNA). In various embodiments, the agents may be one or more cholinesterase inhibitors, one or more corticosteroids, and / or one or more immunosuppressants (most commonly azathioprine (AZA), cyclosporine, and / or mycophenolate mofetil (MMF)).

[0189] Outcome This specification provides systems, devices, and methods for treating PNH in pediatric patients, comprising administering an anti-C5 antibody or its antigen-binding fragment to a patient. The symptoms of PNH in pediatric patients, in particular, are described in International Publications 2019231983 and 2022011086, including a clinical trial identified as ALXN1210-PNH-304 (NCT03406507, Pediatric PNH Study), and these disclosures are incorporated herein by reference. These include, but are not limited to, fatigue (e.g., tiredness, difficulty performing daily activities, difficulty concentrating, dizziness, weakness), pain (e.g., stomach pain, leg pain or swelling, chest pain, back pain), dark urine, shortness of breath, dysphagia, yellowing of the skin and / or eyes, erectile dysfunction, thrombosis, kidney disease, organ injury, stroke, or heart attack. Patients treated according to the methods disclosed herein preferably experience improvement in at least one sign of PNH. For example, the treatment may produce at least one therapeutic effect selected from the group consisting of relief or cessation of fatigue, abdominal pain, shortness of breath, dysphagia, chest pain, and erectile dysfunction.

[0190] Furthermore, this specification also provides a method for treating aHUS in a patient, comprising administering an anti-C5 antibody or its antigen-binding fragment to the patient. Symptoms of aHUS include, but are not limited to, severe hypertension, proteinuria, uremia, malaise / fatigue, irritability, thrombocytopenia, microangiogenic hemolytic anemia, and renal dysfunction (e.g., acute renal failure). Patients treated according to the methods disclosed herein preferably experience improvement in at least one sign of aHUS. For example, treatment may result in at least one therapeutic effect selected from the group consisting of reduction or cessation of severe hypertension, proteinuria, uremia, malaise / fatigue, irritability, thrombocytopenia, microangiogenic hemolytic anemia, and renal dysfunction (e.g., acute renal failure).

[0191] In another embodiment, the improvement is measured by terminal complement inhibition.

[0192] In other embodiments, the treatment results in a shift to normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH erythrocyte (RBC) clones, and D-dimer. In some embodiments, the treatment results in the achievement of stabilized hemoglobin. In some embodiments, the treatment results in the achievement of stabilized hemoglobin over weeks 10 and 52.

[0193] In some embodiments, the treatment results in a change from baseline in PNH erythrocyte (RBC) clone size. In some embodiments, the treatment results in a change from baseline in PNH RBC clone size at 52 weeks.

[0194] In other embodiments, the treatment results in the achievement of transfusion avoidance. In some embodiments, the treatment results in transfusion avoidance at weeks 10 and 52.

[0195] In other embodiments, the treatment results in a reduction in the incidence of breakthrough hemolysis relative to baseline. In some embodiments, the treatment results in a reduction in the incidence of breakthrough hemolysis over weeks 10 and 52. In yet another embodiment, the treatment results in the elimination of breakthrough hemolysis during the treatment period.

[0196] In other embodiments, the treatment results in a reduction of major adverse vascular events (MAVEs).

[0197] In other embodiments, treatment results in a shift to normal levels of estimated glomerular filtration rate (eGFR) and chronic disease-related biomarkers selected from the group consisting of random urine:albumin:creatinine and plasma brain natriuretic peptide (BNP). In some embodiments, treatment results in observed changes in eGFR and changes from baseline. In some embodiments, treatment results in observed changes in eGFR and changes from baseline over weeks 10 and 52.

[0198] In some embodiments, the treatment results in a change in dialysis requirement relative to baseline. In some embodiments, the treatment results in a change in dialysis requirement relative to baseline over weeks 10 and 52.

[0199] In some embodiments, the treatment results in changes in observed serum creatinine levels and changes from baseline. In some embodiments, the treatment results in changes in observed serum creatinine levels and changes from baseline over weeks 10 and 52.

[0200] In some embodiments, the treatment results in observed changes and changes from baseline in hematological parameters selected from platelets, LDH, and / or hemoglobin. In some embodiments, the treatment results in observed changes and changes from baseline in hematological parameters selected from platelets, LDH, and / or hemoglobin over weeks 10 and 52. In some embodiments, the treatment results in a reduction of hemolysis as assessed by LDH levels.

[0201] In some embodiments, the patient is not administered immunosuppressive therapy selected from steroids, mammalian targeted rapamycin (mTOR) inhibitors, or calcineurin inhibitors, except when immunosuppressive therapy is part of an established post-transplant anti-rejection regimen, when the patient has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, when steroids are being used to treat a condition other than aHUS, or when steroids have been empirically initiated before treatment and tapered off as standard care. In some embodiments, the mTOR inhibitor may be sirolimus or everolimus. In some embodiments, the calcineurin inhibitor may be cyclosporine or tacrolimus.

[0202] In some embodiments of the aforementioned aspects, the treatment maintains a serum trough concentration of less than 0.5 μg / mL of free C5 and / or a serum concentration of 175 μg / mL of anti-C5 antibody or its antigen-binding fragment during the administration cycle. In some embodiments, the method further includes monitoring the concentration of serum anti-C5 antibody or its antigen-binding fragment and / or serum free C5. In some embodiments, the concentration of serum anti-C5 antibody or its antigen-binding fragment and / or serum free C5 is determined from blood samples taken before and after each administration of the anti-C5 antibody or its antigen-binding fragment. In some embodiments, the blood samples are taken within 30 minutes before and within 60 minutes after each administration of the anti-C5 antibody or its antigen-binding fragment.

[0203] In other embodiments, treatment results in a change from baseline in quality of life, such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4 and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale. In yet another embodiment, treatment results in a change from baseline in quality of life, such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4 and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale, from the baseline score of an untreated patient. In some embodiments, treatment results in a change from baseline in patient-reported fatigue, as measured by Pediatric FACIT-Fatigue, and optionally, the patient is 8 years of age or older. In some embodiments, treatment results in a change from baseline in the PedsQL 4.0 General Core Scale.

[0204] In another embodiment, the treatment does not result in any change in quality of life (QoL) as assessed via the Functional Assessment of Chronic Disease Therapy (FACIT)-Fatigue Scale, version 4, from baseline to weeks 10 and 52. In another embodiment, the treatment results in an increase in quality of life (QoL) as assessed via the Functional Assessment of Chronic Disease Therapy (FACIT)-Fatigue Scale, version 4, from baseline to weeks 10 and 52.

[0205] In other embodiments, lactate dehydrogenase (LDH) levels are used to assess responsiveness to therapy (for example, a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels indicates improvement in at least one sign of PNH). LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414-25, 2010; Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004; Parker, C. et al., Blood, 106:3699-709, 2005). Red blood cells contain large amounts of LDH, and correlations between cell-free hemoglobin and LDH concentration have been reported in vitro (Van Lente, F. et al., Clin. Chem., 27:1453-5, 1981) and in vivo (Kato, G. et al., Blood, 107:2279-85, 2006). Hemolysis is unrelated to anemia (Hill, A. et al., Haematologica, 93(s1):359 Abs.0903, 2008; Kanakura, Y et al., Int. J. Hematol., 93:36-46, 2011). Baseline and then continuously obtained LDH concentrations throughout the treatment period are important indicators of hemolysis. Baseline levels of cell-free plasma hemoglobin are significantly elevated in patients with PNH, and LDH levels are more than 1.5 times above the upper limit of normal (LDH ≥ 1.5 × ULN), indicating a significant correlation between LDH and cell-free plasma hemoglobin (Hillmen, P. et al., N. Engl. J. Med., 355:1233-43, 2006). The normal range for LDH levels is 105–333 IU / L (International Units per Liter).

[0206] LDH levels can be measured using any suitable test or assay, such as those described in Ferri FF, ed. Ferri's Clinical Advisor 2014. Philadelphia: Pa: Elsevier Mosby; 2014: Section IV - Laboratory tests and interpretation of results. LDH concentrations can be measured in a variety of samples obtained from patients, particularly serum samples. As used herein, the term “sample” refers to the biological material from which the subject is derived. While serum LDH concentration is of interest, the sample may originate from other sources, such as single cells, multiple cells, tissues, tumors, biological fluids, biological molecules, or supernatants or extracts of any of the aforementioned. Examples include tissues removed for biopsy, tissues removed during excision, blood, urine, lymphoid tissue, lymph fluid, cerebrospinal fluid, mucus, and fecal samples. The sample used will vary depending on the assay type, detection method, and the nature of the tumor, tissue, cell, or extract being assayed. The methods for preparing the sample are known in the art and can be easily adapted to obtain a sample that is compatible with the methods used.

[0207] In one embodiment, the treatment described herein results in normalization of LDH levels. In another embodiment, a patient treated according to the disclosed method experiences a reduction in LDH levels to near normal levels, or to within 10% or 20% above what is considered normal levels (e.g., within 105–333 IU / L (International Units per Liter)). In some embodiments, the treatment results in a percentage change in LDH levels relative to baseline. In some embodiments, the treatment results in a percentage change in LDH levels relative to baseline at weeks 10 and 52. In another embodiment, the patient's LDH levels are normalized throughout the entire maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized for at least 95% of the time during the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized for at least 90%, 85%, or 80% of the time during the maintenance period of treatment. In one embodiment, the patient's LDH levels are 1.5 times or more above the upper limit of normal (LDH ≥ 1.5 × ULN) before initiating treatment. In another embodiment, the treatment results in a normalization of LDH levels by at least 24 days of treatment. In one embodiment, a patient treated according to the disclosed method experiences a reduction in LDH levels to within normal levels or within 10%, 20%, 30%, 40%, or 50% below what is considered normal levels (e.g., within 105–333 IU / L (International Units per Liter)). In one embodiment, the patient's LDH level is 1.5 times or more above the upper limit of normal (LDH ≥ 1.5 × ULN) before initiating treatment. In one embodiment, the treatment results in an LDH level of less than twice the upper limit of normal (ULN).

[0208] This specification provides systems, devices, and methods for treating aHUS in pediatric patients, comprising administering an anti-C5 antibody or its antigen-binding fragment to a patient. The symptoms of aHUS in pediatric patients, in particular, are described in International Publication No. 2019236345, including a clinical trial identified as ALXN1210-aHUS-312 (NCT03131219, Pediatric aHUS Study), which is incorporated herein by reference. These symptoms include, but are not limited to, endothelial damage caused by thrombotic microangiopathy (TMA), and include life-threatening symptoms such as renal failure and extrarenal tissue damage. See, for example, Tanaka et al. (Pediatr Nephrol. 2021;36(4):889-898), the relevant disclosures therein, which are incorporated herein by reference.

[0209] kit Furthermore, this specification provides a kit comprising a pharmaceutical composition containing an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, and a pharmaceutically acceptable carrier, in a therapeutically effective dose suitable for use in the methods described above. The kit may optionally include instructions, such as an administration schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to a patient having PNH or aHUS. The kit may also include a syringe.

[0210] The kit may optionally include multiple packages of a single-dose pharmaceutical composition, each containing an effective amount of anti-C5 antibody or its antigen-binding fragment, for single-dose administration according to the method provided above. Equipment or devices necessary for administering the pharmaceutical composition may also be included in the kit. The kit may provide one or more pre-filled syringes containing a certain amount of anti-C5 antibody or its antigen-binding fragment.

[0211] In some embodiments, a kit is provided herein comprising an on-body delivery system (OBDS) as described herein and instructions for using the OBDS for the treatment of PNH or aHUS in a pediatric human patient according to one of the methods described herein. In some embodiments, the OBDS is configured for the administration of an effective dose of anti-C5 antibody or its antigen-binding fragment. In some embodiments, the patient is either complement inhibitor-naive or has experience with eculizumab. In some embodiments, the patient has experience with ravulizumab.

[0212] In some embodiments, a kit is provided herein comprising a needle syringe as described herein and instructions for using the needle syringe for the treatment of PNH or aHUS in a pediatric human patient according to one of the methods described herein. In some embodiments, the needle syringe is configured for the administration of an effective amount of anti-C5 antibody or its antigen-binding fragment. In some embodiments, the patient has a body weight of 10 kg or more and less than 20 kg and is either complement inhibitor-naïve, has experience with eculizumab, or has experience with ravulizumab.

[0213] In some embodiments, kits are provided herein for treating PNH or aHUS in pediatric human patients who are either complement inhibitor-naïve or eculizumab-treated, the kits comprising (a) a certain dose of an anti-C5 antibody or its antigen-binding fragment, and (b) instructions for using the anti-C5 antibody or its antigen-binding fragment according to any of the methods described herein. In some embodiments of the above embodiments, the anti-C5 antibody or its antigen-binding fragment is provided in a 3 mL vial containing type I borosilicate glass for (a) intravenous administration and (b) subcutaneous administration to patients weighing 10 kg or more and less than 20 kg.

[0214] In some embodiments, kits are provided herein for treating PNH or aHUS in pediatric human patients, wherein the patient has a ravulizumab experience, the kit comprising (a) a certain dose of an anti-C5 antibody or its antigen-binding fragment, and (b) instructions for using the anti-C5 antibody or its antigen-binding fragment according to any of the methods described herein.

[0215] In some embodiments, the kit described herein may be used to provide a therapeutic anti-C5 antibody or its antigen-binding fragment, which is administered subcutaneously once weekly in doses of (i) 150 mg to patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg to patients weighing 20 kg or more but less than 40 kg, or (iii) 490 mg to patients weighing 40 kg or more. In some embodiments, the pediatric human patient is under 21 years of age. In some embodiments, the pediatric human patient is between 2 and 18 years of age. In some embodiments, the anti-C5 antibody or its antigen-binding fragment is configured for subcutaneous administration to a site selected from the patient's arm, abdomen, and thigh.

[0216] Any suitable anti-C5 antibody or antigen-binding fragment thereof, including any suitable anti-C5 antibody or antigen-binding fragment thereof disclosed herein, may be included in the kit provided herein. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof includes the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof includes a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region includes Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in their EU numbering. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof includes a heavy chain variable region containing the amino acid sequence of SEQ ID NOs. 12 and a light chain variable region containing the amino acid sequence of SEQ ID NOs. 8. In some embodiments, the heavy chain variable region includes an N-terminal pyroglutamic acid residue. In some embodiments, the anti-C5 antibody or its antigen-binding fragment further includes a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-C5 antibody or its antigen-binding fragment includes a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11.

[0217] The following embodiments are merely illustrative and should not be construed as limiting the scope of this disclosure, as many variations and equivalents will become apparent to those skilled in the art who have read this disclosure. All references, Genbank entries, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. [Examples]

[0218] Phase 3, open-label, single-group, multi-center study to evaluate the pharmacokinetics, pharmacodynamics, activity, and safety of ravulizumab administered subcutaneously in pediatric participants (2 to less than 18 years of age) with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS). This example describes a Phase 3, open-label, single-group, multi-center study to evaluate the safety and efficacy of ravulizumab administered subcutaneously in pediatric human participants (2 to less than 18 years of age) with PNH or aHUS. Study schematic diagrams are shown in Figures 1 and 2.

[0219] Background: PNH is a very rare, progressive, debilitating, and life-threatening disease characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Ravulizumab was approved as an intravenous (IV) treatment for pediatric patients with PNH based on data from controlled clinical studies in adult patients, along with additional pharmacokinetic (PK), efficacy, and safety data obtained from a specialized study (ALXN1210-PNH-304) in pediatric patients 9 to less than 18 years of age. Use in pediatric patients with PNH who are less than 9 years of age and less than 30 kg in weight was based on extrapolation of PK / pharmacodynamic (PD), efficacy, and safety data from aHUS and PNH clinical studies.

[0220] aHUS is a rare, progressive, and life-threatening disorder characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury, with frequent extrarenal complications. Approval of ravulizumab IV for the treatment of pediatric patients with aHUS was based on data from controlled clinical studies in adults, along with additional PK, efficacy, and safety data obtained from a specialized study (ALXN1210-aHUS-312) in pediatric patients 10 months to less than 18 years of age.

[0221] Alexion developed a subcutaneous (SC) formulation of ravulizumab as an alternative to the intravenous administration route. The PK, PD, efficacy, and safety of ravulizumab SC were demonstrated in a Phase 3 study (ALXN1210-PNH-303) in adult patients with PNH who received ravulizumab via an on-body delivery system (OBDS) consisting of a filled cartridge containing ravulizumab packaged with an on-body injector (OBI).

[0222] In various embodiments, the formulations or devices of the present disclosure maintain the ravulizumab drug concentration above the PK target (175 μg / mL) and result in complete terminal complement inhibition (serum-free C5 < 0.5 μg / mL) and disease control in pediatric patients with PNH or aHUS, regardless of prior treatment with a complement inhibitor.

[0223] Using the formulations and devices of the present disclosure, the characteristic PK and PD of ravulizumab SC administered via OBI (patients ≥ 20 kg) or syringe (patients < 20 kg) were evaluated in patients aged 2 to < 18 years with either PNH or aHUS during a 10-week primary evaluation period for achievement of the following provided estimands and / or endpoints.

[0224] [Table 1-1]

[0225] [Table 1-2] Abbreviations: ADA = Anti-drug antibody, ADE = Device adverse effect, AE = Adverse event, aHUS = Atypical hemolytic uremic syndrome, BTH = Breakthrough hemolysis, C5 = Complement component 5, eGFR = Estimated glomerular filtration rate, FACIT = Functional assessment of chronic disease therapy - fatigue, IE = Intermediate event, LDH = Lactate dehydrogenase, OBDS = On-body delivery system, OBI = On-body syringe, PD = Pharmacodynamic, PedsQL = Quality of life questionnaire for children, PK = Pharmacokinetics, PNH = Paroxysmal nocturnal hemoglobinuria, QoL = Quality of life, SC = Subcutaneous, SAE = Serious adverse event

[0226] Overall design This is a phase 3, open-label, multicenter study to evaluate the pharmacokinetics (PK) and progression-progressive disease (PD) of ravulizumab SC in pediatric participants (2–18 years of age) with confirmed PNH or aHUS who are either newly treated with complement inhibitors or have previously received complement inhibitor treatment. Participants with a history of complement inhibitor treatment must be clinically stable and have been previously treated with eculizumab or ravulizumab for at least 90 days prior to screening.

[0227] The study consists of a screening period (up to 4 weeks for participants who are new to complement inhibitor treatment or have prior experience with eculizumab, and up to 8 weeks for participants who have prior experience with ravulizumab [4 weeks for participants weighing less than 20 kg]), a 10-week primary evaluation period, and an extension period (up to 42 weeks). All participants are followed up for safety for 8 weeks after the last dose of the study intervention. Therefore, the total treatment period is up to 1 year (52 weeks), and the total study period is up to 59 weeks (Note: The last dose of the study intervention is at week 51).

[0228] Approximately 22 participants will be enrolled and treated to obtain at least 20 pediatric participants (2–18 years) who are evaluable for the primary PK / PD analysis. The minimum number of participants in each age category is as follows: at least 3 participants in the 2–6 year group, at least 7 participants in the 6–12 year group, and at least 10 participants in the 12–18 year group.

[0229] All participants will be screened for eligibility during the screening period. Participants who are new to complement inhibitor treatment or have prior experience with eculizumab will be screened for eligibility for a maximum of 4 weeks (28 days). Participants who have prior experience with ravulizumab will be screened for eligibility for a maximum of 8 weeks (56 days) if they weigh 20 kg or more, and for a maximum of 4 weeks (28 days) if they weigh less than 20 kg.

[0230] Eligible participants who are either complement-neutral or have prior eculizumab experience will receive a weight-based ravulizumab IV loading dose on day 1. For participants with prior eculizumab experience, day 1 of the study intervention will occur 2 weeks (14 ± 2 days) after the participant's last eculizumab infusion. During the primary endpoint period, participants will receive weight-based ravulizumab SC maintenance doses on day 15 and weekly thereafter (qw).

[0231] For participants with prior ravulizumab experience, day 1 of the study intervention occurs 8 weeks (56 ± 5 days) after the participant's last ravulizumab infusion for participants weighing 20 kg or more, or 4 weeks (28 ± 2 days) after the participant's last ravulizumab infusion for participants weighing less than 20 kg. During the primary endpoint period, participants with prior ravulizumab experience receive a weight-based ravulizumab SC maintenance dose on day 1, followed by a weight-based maintenance dose of ravulizumab SC qw.

[0232] During the extension period, all participants will continue to receive a weight-based maintenance dose of ravulizumab SC qw until the end of the extension period.

[0233] If a participant discontinues the research intervention, they will be asked to leave the study and complete an Early Discontinuation (ED) visit as soon as possible.

[0234] Safety follow-up visits are conducted remotely 8 weeks (56 ± 7 days) after the last dose (SC or IV) of lebrikizumab to collect information on concomitant medications, non-pharmacological therapies and procedures, adverse events (AE), and device adverse effects (ADE).

[0235] The end of the study is defined as the date on which the last participant completed the last visit (including follow-up) indicated in the activity schedule.

[0236] This is a single-arm treatment study without blinding.

[0237] Number of participants: Approximately 22 participants will be enrolled in the PK / PD primary analysis.

[0238] Intervention group and duration: Eligible participants who are naïve to complement inhibitor treatment or have experience with eculizumab will receive an IV loading dose of lebrikizumab based on body weight on Day 1, and then a SC maintenance dose of lebrikizumab based on body weight qw for a total of 52 weeks during the study treatment starting from Day 15.

[0239] Participants with experience of lebrikizumab will receive a SC maintenance dose of lebrikizumab based on body weight on Day 1, followed by SC qw of the maintenance dose of lebrikizumab based on body weight.

[0240] The doses are based on the participant's body weight as shown in the following table.

[0241] [Table 2] Abbreviations: IV = intravenous, OBDS = on-body delivery system, qw = weekly, SC = subcutaneous

[0242] [Table 3] Abbreviations: OBDS = on-body delivery system, qw = weekly, SC = subcutaneous

[0243] Ethical considerations and benefits - risk assessment This study will be conducted in accordance with established ethical guidelines, as specified in this protocol.

[0244] Schema: Please refer to Figures 1 and 2. Note: All participants will be followed up for safety for 8 weeks after the last dose of the study intervention. The dosing regimen based on body weight is as follows:

[0245] [Table 4] a For participants with prior eculizumab experience, the ravulizumab IV loading dose will be administered 2 weeks (14 ± 2 days) after the participant's last eculizumab infusion. Abbreviations: IV = intravenous, OBDS = on-body delivery system, qw = weekly, SC = subcutaneous

[0246] Note: All participants will be followed up for safety for 8 weeks after the last dose of the study intervention. The dosing regimen based on body weight is as follows:

[0247] [Table 5] a For participants weighing less than 20 kg, the screening period is up to four weeks prior to day 1. b For participants with prior ravulizumab experience, the 1-day ravulizumab SC maintenance dose is administered approximately 8 weeks (56 ± 5 days) after the participant's last ravulizumab IV infusion for participants weighing 20 kg or more, or 4 weeks (28 ± 2 days) after the participant's last ravulizumab infusion for participants weighing less than 20 kg.

[0248] Abbreviations: IV = intravenous, OBDS = on-body delivery system, qw = weekly, SC = subcutaneous 1.1. Activity Schedule The activity schedule is provided as follows: ●Screening results up to the end of the primary evaluation period (week 10 visit) are provided in Table 1. ● Extension period: Visits from week 14 to week 52 are provided in Table 2.

[0249] [Table 6-1]

[0250] [Table 6-2]

[0251] [Table 6-3]

[0252] [Table 6-4] Note: Unless otherwise specified, all evaluations must be performed on the day of administration, prior to the administration of the research intervention. a Participants who are either new to complement inhibitor therapy or have prior experience with eculizumab will be screened for eligibility during a screening period of up to 4 weeks (28 days). Participants who have prior experience with ravulizumab will be screened for eligibility during a screening period of up to 8 weeks (56 days) for participants weighing 20 kg or more, and up to 4 weeks (28 days) for participants weighing less than 20 kg. b For participants with prior eculizumab experience, day 1 occurs 2 weeks (14 ± 2 days) after the participant's last eculizumab infusion. For participants with prior ravulizumab experience, day 1 occurs 8 weeks (56 ± 5 days) after the participant's last ravulizumab infusion (or 4 weeks [28 ± 2 days] for participants weighing less than 20 kg). cThe evaluation on day 71 of the primary endpoint must be performed before the administration on day 71. The administration on day 71 marks the start of the extension period, after which participants continue to receive the maintenance dose of ravulizumab SC throughout the extension period (Table 2). d For participants discontinuing the research intervention, ED visits should be completed as soon as possible. e Safety follow-up visits will be conducted 8 weeks (56 ± 7 days) after the last dose (ravulizumab IV or SC) of the study intervention participant to collect information on concomitant medications, non-pharmacological therapies and procedures, adverse events (AEs), and adverse drug reactions (ADEs). f Facility staff will contact participants / caregivers via telephone / video call at the scheduled administration time to ensure that participants / caregivers are asked questions regarding the study intervention dose and device status. g For participants with aHUS who have previously received eculizumab or ravulizumab, past trial results may be available via chart review. h Body weight is measured before administration. The dosage is based on the participant's body weight collected during the weight measurement required by the protocol. If the weight measurement required by the protocol is unavailable, the body weight recorded during the weight measurement required by the previous protocol will be used. i Vital signs are measured, including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. On the day of administration, vital signs are measured before administration and after the participant has rested for at least 5 minutes. j A simplified physical examination consists of physical system-related tests based on the judgment of the principal investigator (or a qualified designated person) and the participant's symptoms. At least one physical system must be checked for the simplified examination. k Leukocytes (granulocytes and monocytes) and RBC clone size measured by high-sensitivity flow cytometry. lParticipants must lie on their backs for approximately 5-10 minutes before ECG collection, and must remain awake while lying on their backs during ECG collection. m New or worsening abnormalities are reported as adverse events (AEs). n For participants enrolled in studies on eculizumab or ravulizumab therapy, screening LDH will be obtained within 24 hours prior to the scheduled eculizumab / ravulizumab administration. o If a suspected breakthrough hemolysis event occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory for analysis. If a suspected breakthrough hemolysis event does not occur during a scheduled visit, an unscheduled visit will be made for participant evaluation and collection of necessary blood samples. p All pre-administration samples are collected within 30 minutes prior to the administration of the research intervention. q Post-administration samples are collected within 60 minutes of completion of the study intervention. r For doses that coincide with the study visit day, ravulizumab SC may be self-administered (participants aged 12 years and older), administered by a caregiver (participants aged 2 to under 18 years), or administered by a trained research facility staff member. All other doses may be self-administered at home. s Qualified members of the site-based research team will provide caregivers and participants aged 12 years and older with initial (and, if necessary, ongoing) training on how to properly self-administer ravulizumab SC. If participants transition from syringe-based SC administration to ravulizumab OBDS-based SC administration during the study, the site-based research team will provide training for ravulizumab OBDS administration. Abbreviations: ADA = anti-drug antibody, ADAMTS13 = disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, ADE = device adverse effect, AE = adverse event, aHUS = atypical hemolytic uremic syndrome, BP = blood pressure, ECG = electrocardiogram, ED = early discontinuation, e-diary = e-diary, eGFR = estimated glomerular filtration rate, FACIT = functional assessment of chronic disease therapy - fatigue, Hib = Haemophilus influenzae type b, IV = intravenous, LDH = lactate dehydrogenase, PD = pharmacokinetic, PedsQL = quality of life questionnaire for children, PK = pharmacokinetics, PNH = paroxysmal nocturnal hemoglobinuria, qw = weekly, RBC = red blood cell, SC = subcutaneous, ST-HUS = Shiga toxin-associated hemolytic uremic syndrome, WOCBP = women of possible pregnancy

[0253] [Table 7-1]

[0254] [Table 7-2] Note: Unless otherwise specified, all evaluations must be performed on the day of administration, prior to the administration of the research intervention. a For participants discontinuing the research intervention, ED visits should be completed as soon as possible. b Safety follow-up visits will be conducted 8 weeks (±7 days) after the last dose (ravulizumab IV or SC) of the study intervention participant to collect information on concomitant medications, non-pharmacological therapies and procedures, adverse events (AEs), and adverse drug reactions (ADEs). c Body weight is measured before administration. The dosage is based on the participant's body weight collected during the weight measurement required by the protocol. If the weight measurement required by the protocol is unavailable, the body weight recorded during the weight measurement required by the previous protocol will be used. dVital signs are measured, including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. On the day of administration, vital signs are measured before administration and after the participant has rested for at least 5 minutes. e A simplified physical examination consists of physical system-related tests based on the judgment of the principal investigator (or a qualified designated person) and the participant's symptoms. At least one physical system must be checked for the simplified examination. f Participants must lie on their backs for approximately 5-10 minutes before ECG collection, and must remain awake while lying on their backs during ECG collection. g New or worsening abnormalities are reported as adverse events (AEs). h If a suspected breakthrough hemolysis event occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory for analysis. If a suspected breakthrough hemolysis event does not occur during a scheduled visit, an unscheduled visit will be made for participant evaluation and collection of necessary blood samples. i Pre-administration samples are collected within 30 minutes prior to the administration of the research intervention. j Post-administration samples are collected within 60 minutes of completion of the study intervention. k For doses that coincide with the study visit day, ravulizumab SC may be self-administered (participants aged 12 years and older), administered by a caregiver (participants aged 2 to under 18 years), or administered by a trained research facility staff member. All other doses may be self-administered at home. l Qualified members of the site-based research team will provide caregivers and participants aged 12 years and older with initial (and, if necessary, ongoing) training on how to properly self-administer ravulizumab SC. If participants transition from syringe-based SC administration to ravulizumab OBDS-based SC administration during the study, the site-based research team will provide training for ravulizumab OBDS administration. Abbreviations: ADA = Anti-drug antibody, ADE = Device adverse effect, AE = Adverse event, aHUS = Atypical hemolytic uremic syndrome, BP = Blood pressure, ED = Early discontinuation, ECG = Electrocardiogram, eGFR = Estimated glomerular filtration rate, FACIT = Functional assessment of chronic disease therapy - fatigue, IV = Intravenous, LDH = Lactate dehydrogenase, PD = Pharmacodynamic, PedsQL = Quality of Life Questionnaire for Children, PK = Pharmacokinetics, PNH = Paroxysmal nocturnal hemoglobinuria, qw = Weekly, SC = Subcutaneous, WOCBP = Women of possible pregnancy

[0255] 2. Introduction 2.1. Overview of the Research A labulizumab scalped (SC) formulation, developed as an alternative to the IV route of administration, was demonstrated to be effective and safe in a Phase 3 study in adult patients with PNH (Study ALXN1210-PNH-303). The labulizumab OBDS, a drug-device combination product consisting of a pre-filled cartridge containing labulizumab packaged with an on-body syringe (OBI), was used for SC delivery of labulizumab in adult patients.

[0256] In this study, pediatric patients will receive ravulizumab SC via ravulizumab OBDS or via needle syringe, depending on their body weight. The primary objective of this study is to characterize ravulizumab pharmacokinetics (PK) and progression-deficiency disease (PD) after ravulizumab SC administration in pediatric patients (2 to under 18 years of age) with PNH or aHUS during a 10-week primary evaluation period. Both complement inhibitor-naive and complement inhibitor-treated patients are eligible to participate. Patients may be receiving anti-C5 antibody therapy (eculizumab or ravulizumab) and are eligible for enrollment as long as they are clinically stable at screening. For the purposes of this study, "self-administration" refers to administration by a caregiver (for participants 2 to under 18 years of age) or by the participant (for participants 12 years of age and older only) for patients with PNH or aHUS.

[0257] The study also aims to demonstrate the efficacy, safety, and immunogenicity of ravulizumab SC in pediatric participants with PNH and aHUS.

[0258] 2.2.Background Paroxysmal nocturnal hemoglobinuria is an extremely rare, progressive, debilitating, and life-threatening disease characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Approval of ravulizumab IV for the treatment of pediatric patients with PNH was based on data from controlled clinical studies in adult patients, along with additional PK, efficacy, and safety data obtained from a specialized study (study ALXN1210-PNH-304) in pediatric patients 9 to under 18 years of age. Use in pediatric patients with PNH under 9 years of age and weighing less than 30 kg was based on extrapolation of PK / PD, efficacy, and safety data from aHUS and PNH clinical studies.

[0259] Atypical hemolytic uremic syndrome is a rare, progressive, and life-threatening disorder characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury, with frequent extrarenal complications. Approval of ravulizumab IV for the treatment of pediatric patients with aHUS was based on data from controlled clinical studies in adults, along with additional PK, efficacy, and safety data obtained from a specialized study (study ALXN1210-aHUS-312) in pediatric patients aged 10 months to under 18 years.

[0260] A literature review on current state-of-the-art technologies for PNH and aHUS, their epidemiology and management, and available treatment options was conducted to provide the scientific background for this clinical investigation. There is an unmet medical need for drug delivery systems that improve the patient's treatment experience by providing options and flexibility, thereby reducing the impact of treatment administration on patient autonomy and quality of life. In addition, the coronavirus disease 2019 (COVID-19) pandemic highlighted the need for continuous patient care for chronic diseases outside of hospital and clinic settings, particularly for highly susceptible and immunocompromised patient populations. To minimize the risk of therapy discontinuation, treatment guidelines for certain chronic diseases have been updated during the pandemic, with an emphasis on self-administration and switching to SC therapy.

[0261] PNH and aHUS are rare diseases requiring long-term therapy. The majority of biologics approved for the treatment of these conditions are administered via IV infusion. The SC (sponge cell) administration route has been shown to be at the forefront of parenteral delivery of biologics for chronic conditions requiring lifelong treatment.

[0262] 2.3. Lablisma Rabulizumab (trademark ULTOMIRIS®) is a recombinant, humanized monoclonal antibody with high specificity for human complement component 5 (C5). Rabulizumab administered intravenously (IV) has been shown to achieve immediate, complete, and sustained inhibition of terminal complement, and is approved for the treatment of adult patients with AChR-Ab(+)gMG, as well as adult and pediatric patients with PNH and aHUS.

[0263] 2.4. Labrisma-on-body delivery system Rabulizumab OBDS is a drug-device combination product consisting of a pre-filled cartridge containing ravulizumab SC packaged with an OBI. The OBI is a small, sterile, single-use, disposable electromechanical (battery-powered, microprocessor-controlled) clinical trial medical device with a 29-gauge integrated needle (contract-manufactured by West Pharmaceuticals, Inc.) designed for use with a pre-filled, stoppered cartridge that has a piston and telescopic screw assembly (TSA).

[0264] The OBI used in ravulizumab OBDS is based on the same underlying technology, the West SMARTDOSE® platform, which is used with evolocumab (Repatha®), approved as a combination product in the United States, and is CE marked in the European Union as a Class IIA Medical Device.

[0265] Lablizumab OBDS is being used in the Phase 3 study ALXN1210-PNH-303 to treat adult participants with PNH.

[0266] 2.5. Benefits / Risks Assessment 2.5.1. Risk Assessment The safety profile of ravulizumab is well-established, including in pediatric patients treated in clinical studies for PNH and aHUS. Based on all currently available data from the clinical development program and post-marketing experience, ravulizumab is well-tolerated and no unexpected safety concerns have been identified. Rabulizumab works by blocking terminal complement, and therefore, participants have increased susceptibility to serious infections, particularly Neisseria meningitidis. Specific risk mitigation measures available to support the safe use of ravulizumab in participants of this study are listed in Table 3.

[0267] As with any therapeutic protein, administration of ravulizumab may result in the development of anti-drug antibodies (ADAs). Immunogenicity monitoring is planned during this study, as described in Section 4.30. Intravenous administration of any investigational drug may result in infusion reactions. Management of potential infusion reactions is described in Section 5.9.

[0268] [Table 8] Abbreviations: AE = Adverse event, ADA = Antidote, aHUS = Atypical hemolytic uremic syndrome, C5 = Complement component 5, IST = Immunosuppressive therapy, PNH = Paroxysmal nocturnal hemoglobinuria, SAE = Serious adverse event

[0269] The ravulizumab OBDS is considered an investigational drug-device combination product and inherently carries several potential risks arising from device defects or misuse. Risk management activities (risk control and mitigation measures) are carried out in accordance with ISO 14971. Table 4 lists specific risk mitigation measures available to guide the safe use of ravulizumab in participants of this study.

[0270] [Table 9] Abbreviations: OBDS = On-Body Delivery System, OBI = On-Body Syringe, SC = Subcutaneous

[0271] Details regarding expected adverse drug reactions (ADEs), contraindications, and warnings for ravulizumab OBDS are provided in the ravulizumab OBDS device investigational brochure.

[0272] 2.5.1.1. Coronavirus Disease 2019 The COVID-19 pandemic is active in many countries at the time of this protocol revision. Given this unique situation, specific considerations have been made to the risks and benefits of the study, as they relate to COVID-19 and vaccination against the disease.

[0273] 2.5.2. Profit Evaluation The primary goal of effective targeted therapy for pediatric PNH and aHUS is to provide immediate, complete, and sustained inhibition of terminal complement activity to block hemolysis in PNH, prevent thrombosis, and prevent thrombotic microangiopathy (TMA) in patients with aHUS. Given that PNH and aHUS are chronic diseases across all age categories, ravulizumab SC is expected to offer significant therapeutic benefits in pediatric patients who are not currently receiving complement inhibitor therapy or are receiving eculizumab.

[0274] Self-administered SC treatment for patients with PNH or aHUS [(i.e., for the purposes of the study, “self-administered” refers to study intervention administration by a caregiver (for participants aged 2 to under 18 years) or by the participant (for participants aged 12 years and older only)] may offer a greater degree of autonomy than treatment via IV infusion and may reduce the burden and risks associated with long-term IV treatment regimens while increasing patient compliance.

[0275] 2.5.3. Overall Benefits: Conclusions on Risks Considering the measures taken to minimize risk to participants in this study, the potential risks identified in relation to ravulizumab SC are justified by the expected benefits that may be provided to pediatric participants with PNH or aHUS.

[0276] [Table 10-1]

[0277] [Table 10-2] Abbreviations: ADA = Anti-drug antibody, ADE = Device adverse effect, AE = Adverse event, aHUS = Atypical hemolytic uremic syndrome, BTH = Breakthrough hemolysis, C5 = Complement component 5, eGFR = Estimated glomerular filtration rate, FACIT = Functional assessment of chronic disease therapy - fatigue, IE = Intermediate event, LDH = Lactate dehydrogenase, OBDS = On-body delivery system, OBI = On-body syringe, PD = Pharmacodynamic, PedsQL = Quality of life questionnaire for children, PK = Pharmacokinetics, PNH = Paroxysmal nocturnal hemoglobinuria, QoL = Quality of life, RBC = Red blood cell, SC = Subcutaneous, SAE = Serious adverse event

[0278] 2.6. Defining Endpoints 2.6.1. Breakthrough hemolysis (PNH cohort only) Breakthrough hemolysis is defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated lactate dehydrogenase (LDH), including fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g / dL], major vascular adverse events [including MAVE, thrombosis], dysphagia, or erectile dysfunction. ● For participants who have not previously received complement inhibitor treatment: After reducing LDH to less than 1.5 times the upper limit of normal (ULN) during therapy, LDH levels rose to more than 2 times the ULN. ● For participants with prior experience of eculizumab or ravulizumab: LDH increase of more than twice the ULN.

[0279] 2.6.2. Avoiding blood transfusions (PNH cohort only) Transfusion avoidance is defined as not using blood transfusions from baseline to the end of the target period, and not requiring any transfusions.

[0280] 2.6.3. Stabilized hemoglobin (PNH cohort only) Stabilized hemoglobin is defined as avoiding a decrease of 2 g / dL or more in hemoglobin levels from baseline to the end of the target period in the absence of blood transfusion.

[0281] 2.7. Common Main Estimates The primary objective of this study is to characterize the pharmacokinetic (PK) and progressive disease (PD) effects of ravulizumab SC in pediatric participants (2 to under 18 years of age) with PNH or aHUS.

[0282] The co-primary estimates corresponding to the primary PK / PD objectives are defined as follows: ●The primary PK estimate is defined as the summary statistics of ravulizumab concentrations after day 1, before day 15, after day 15, and before day 71 for pediatric participants with PNH or aHUS who are treated with ravulizumab SC included in the PK analysis set. ● Any data collected after the interruption of the research intervention before the end of the primary endpoint period, or after the initiation of specific prohibited medications or therapies during the primary endpoint period (Section 4.12.2), will not be used in the primary PK analysis. This represents a “treated” strategy. ●The primary PD estimate is defined as a summary statistic of serum free C5 concentration after day 1 administration, before day 15 administration, after day 15 administration, and before day 71 administration in pediatric participants with PNH or aHUS who are treated with ravulizumab SC included in the PD analysis set. ● Any data collected after the interruption of the study prior to the end of the primary endpoint period, or after the initiation of any prohibited medication or therapy during the primary endpoint period (Section 4.12.2), will not be used in the primary PD analysis. This represents a “treated” strategy.

[0283] The co-primary endpoint is supported by outcomes from the rabulizumab IV program in patients with PNH and aHUS. Evaluation of rabulizumab PK is considered the most appropriate measure for assessing the suitability of the rabulizumab SC dosing regimen in pediatric patients. Evaluation of serum rabulizumab concentration ensures that serum rabulizumab concentration after SC dosing exceeds the 175 μg / mL PK target concentration expected to be used to establish the rabulizumab IV dosing regimen and result in complete terminal complement inhibition.

[0284] In addition, the assessment of serum free C5 concentration further ensures that the ravulizumab SC administration regimen achieves the established ravulizumab administration goal of immediate and complete terminal complement inhibition, defined as serum free C5 < 0.5 ug / mL and sustained throughout the entire treatment, which is expected to lead to clinical efficacy in patients with PNH or aHUS.

[0285] 2.8. Secondary Estimate 2.9. Tertiary / Exploratory Estimates 3. Research design 3.1. Overall design This is a phase 3, open-label, multicenter study to evaluate the pharmacokinetics (PK) and progression-progressive disease (PD) of ravulizumab SC in pediatric participants (2–18 years of age) with confirmed PNH or aHUS who are either newly treated with complement inhibitors or have previously received complement inhibitor treatment. Participants with a history of complement inhibitor treatment must be clinically stable and have been previously treated with eculizumab or ravulizumab for at least 90 days prior to screening.

[0286] The study consists of a screening period (up to 4 weeks for participants weighing less than 20 kg, those previously untreated with complement inhibitors, those with prior experience with eculizumab, or those with prior experience with ravulizumab, and up to 8 weeks for participants with prior experience with ravulizumab [4 weeks for participants weighing less than 20 kg]), a 10-week primary evaluation period, and an extension period (up to 42 weeks). All participants are followed up for safety for 8 weeks after the last dose of the study intervention. Therefore, the total treatment period is up to 1 year (52 weeks), and the total study period is up to 59 weeks (Note: The last dose of the study intervention is at week 51).

[0287] Approximately 22 participants will be enrolled and treated to obtain at least 20 pediatric participants (2–18 years old) who are evaluable for the primary PK / PD analysis. The minimum number of participants in each age category is as follows: ● Ages 2-6: At least 3 participants ● Ages 6-12: At least 7 participants ● 12-18 years old: At least 10 participants All participants will be screened for eligibility during the screening period.

[0288] Participants who have not previously received complement inhibitor treatment or participants who have previously received eculizumab treatment. Participants who are either complement inhibitor-naïve or have prior eculizumab experience will be screened for eligibility during a screening period of up to 4 weeks (28 days). Participants will receive a weight-based ravulizumab IV loading dose on day 1 (Figure 1). For participants with prior eculizumab experience, day 1 of the study intervention will occur 2 weeks (14 ± 2 days) after the participant's last eculizumab infusion.

[0289] During the primary evaluation period, participants will receive ravulizumab SC maintenance doses on day 15 and thereafter based on qw and body weight.

[0290] Participants with prior ravulizumab experience Participants with prior ravulizumab experience will be screened for eligibility during a screening period of up to 8 weeks (56 days) for participants weighing 20 kg or more, and up to 4 weeks (28 days) for participants weighing less than 20 kg. For participants with prior ravulizumab experience, day 1 of the study intervention will occur 8 weeks (56 ± 5 days) from the participant's last ravulizumab infusion for participants weighing 20 kg or more, or 4 weeks (28 ± 2 days) from the participant's last ravulizumab infusion for participants weighing less than 20 kg.

[0291] During the primary evaluation period, participants with prior ravulizumab experience received a body weight-based ravulizumab SC maintenance dose on day 1 (Figure 2), followed by a body weight-based maintenance dose of ravulizumab SC qw.

[0292] Extension period (all participants) For all participants, day 71 marks the end of the primary evaluation period and the beginning of the extension period. All evaluations completed on day 71 prior to administration are considered part of the primary evaluation period. Administration on day 71 marks the beginning of the extension period.

[0293] During the extension period, all participants will continue to receive a weight-based maintenance dose of ravulizumab SC on day 71 and thereafter every quarter week until the end of the extension period.

[0294] If a participant discontinues the research intervention, they will be asked to withdraw from the study and complete their ED visits as soon as possible.

[0295] Safety follow-up visits are conducted via telephone / video call approximately 8 weeks (56 ± 7 days) after the last dose (SC or IV) of ravulizumab to collect information on concomitant medications, non-pharmacological therapies and procedures, adverse events (AEs), and adverse drug reactions (ADEs).

[0296] 3.2. Scientific basis for research design Participants receiving ravulizumab SC will receive ravulizumab C at concentrations exceeding the PK target concentration required to achieve immediate and complete terminal complement inhibition. トラフ The concentration is expected to be maintained. PK evaluation is planned for day 71 (before administration). トラフ (At that time). The extension of treatment with ravulizumab for up to 42 weeks allows for long-term monitoring of the safety and efficacy of ravulizumab treatment in pediatric patients with PNH and aHUS.

[0297] A single-group design is considered appropriate for investigating the pharmacokinetics (PK), disease progression (PD), efficacy, and safety of ravulizumab SC in a pediatric population. The rarity of PNH or aHUS in the pediatric population negates the feasibility of studies with larger sample sizes. Twenty patients are considered sufficient to adequately describe PK / PD in this population.

[0298] The efficacy parameters in study ALXN1210-PED-316 were in complete agreement with those established in a Phase 3 study in adult patients with PNH or aHUS, which is justified by similar disease pathophysiology and the expected clinical response to ravulizumab treatment in children and adolescents.

[0299] The availability of treatment with ravulizumab SC qw provides patients with further treatment options, which can alleviate the burden associated with long-term treatment with eculizumab IV administered every two weeks, ravulizumab IV administered every four weeks for patients weighing less than 20 kg, or ravulizumab IV administered every eight weeks for patients weighing 20 kg or more, by providing patients with a simpler method of dose administration (self-administration of ravulizumab SC via OBI or syringe in a home setting).

[0300] Labulizumab SC, administered via OBI, offers patients and physicians weighing 20 kg or more a less frequent clinic visit option for dose administration, which may improve quality of life (QoL) through reduced days missed from work or school and improved accessibility.

[0301] 3.3 Justification for Dosage The rabulizumab SC administration target in pediatric patients with PNH or aHUS remains unchanged from all other rabulizumab IV and SC programs, namely, achieving immediate and complete terminal complement inhibition (defined as a serum free C5 concentration of less than 0.5 ug / mL) sustained throughout the entire treatment in all patients. This target is achieved by maintaining a serum rabulizumab concentration greater than 175 μg / mL, as supported by previous rabulizumab development programs.

[0302] Using a previous ravulizumab population-PK model developed with PK data from the ravulizumab IV study (adult and pediatric patients with PNH or aHUS) or the SC study (adult patients with PNH), dose simulations were performed to propose a body weight-based ravulizumab SC regimen predicted to achieve immediate, complete, and sustained inhibition of terminal complement activity in pediatric patients with PNH or aHUS. The use of dose simulations to characterize exposure-response relationships as support for phase 3 dose selection is well-established (FDA Guidance for Industry: Exposure-Response Relationships - Study Design, Data Analysis, and Regulatory Applications) and is a similar approach to that used to inform all approved ravulizumab dose regimens.

[0303] The weight-based dosing regimen (detailed in Section 4.6) is expected to maintain serum drug concentrations above the target concentration required for complete terminal complement inhibition in all pediatric participants weighing 10 kg or more from the start of treatment. Rabulizumab IV has been shown to be well-tolerated in healthy subjects when administered via syringe at a dose of 400 mg in studies ALXN1210-HV-105 and ALXN1210-SC-101. Interim analyses will be performed to confirm or adjust the SC dosing regimen in pediatric participants, as outlined in Section 5.5.

[0304] 3.4. Justification of the selected device Labulizumab SC is intended to be administered via SC injection for maintenance administration in a clinical or home setting. The Labulizumab OBDS kit consists of labulizumab SC in a sterile, single-use, pre-filled cartridge, packaged with a single-use OBI. Each OBDS delivers a fixed dose of 245 mg of labulizumab. Participants weighing less than 20 kg require a weekly dose of 150 mg of labulizumab, which is less than the total dose of labulizumab OBDS (245 mg). Therefore, this patient population receives labulizumab SC via syringe without using an OBDS.

[0305] The selection criteria for the SC device included dose volume capacity, proven reliability, and patient-centered usability requirements, including minimal steps, minimal discomfort, concealed needles, and the ability to move around and perform moderate physical activities such as walking, reaching, and bending during administration. The West SMARTDOSE® Gen I 3.5mL device platform meets these criteria.

[0306] Rabulizumab OBDS is a disposable, single-use drug-device combination product configured to deliver a fixed dose of ravulizumab via SC injection in approximately 10 minutes. The device is designed for ease of use, featuring a single button to initiate administration, visual and auditory cues for device readiness and dose completion, and a safety latch to prevent needlestick injuries. The small-gauge needle and administration route within the device may carry a reduced risk of systemic infection and other complications compared to IV infusion.

[0307] 3.5. Remote Visit Options In emergency situations (e.g., the COVID-19 pandemic), to ensure participant safety and continuity of treatment, if a participant is unable to travel to the research facility, the following will apply until the participant is able to resume research visits to the facility:

[0308] Remote visit options may be implemented at the discretion and supervision of the Principal Investigator, in accordance with local regulations, and may be conducted by a qualified healthcare professional. Remote visit options may include visits substantially conducted at the participant's home, at an alternative qualified healthcare facility, or via telephone / video call. All assessments on the study visit day will be conducted in accordance with the activity schedule (Section 1.1). Information on concomitant medications, non-pharmacological therapies, and procedures (including background therapy), disease-related signs or symptoms, AEs, and ADEs must be sent to the Principal Investigator's facility for assessment on the day of the remote visit. If there are any signs or symptoms indicating a serious adverse event (SAE), the participant must be evaluated at the study site.

[0309] 3.6. End of Research Definition Participants are considered to have completed the study if they have completed all periods of the study, including the final scheduled procedure as outlined in the activity schedule (Section 1.1).

[0310] The end of the study is defined as the date on which the last participant completes their final visit (including follow-up).

[0311] 4. Research Group Prior approval (also known as protocol abandonment or exemption) of protocol deviations from recruitment and inclusion criteria is not permitted.

[0312] 4.1. Inclusion Criteria Participants are eligible to be included in the study only if all of the following criteria apply.

[0313] 4.1.1. Common inclusion criteria for both cohorts age 1. The person must be between 2 and 18 years old at the time of informed consent.

[0314] sex 2. Male or female 3. Female and male participants who may become pregnant must be willing to follow the contraception guidance specified in the protocol.

[0315] body weight 4. Weight of 10 kg or more at the time of screening.

[0316] Vaccination and antibiotics 5. To reduce the risk of meningococcal disease (N meningitidis), all participants must be vaccinated against meningococcal disease from serogroups A, C, Y, W135, and B within three years prior to day 1, or at least two weeks prior to day 1, in accordance with national / regional guidelines. Participants who do not meet this requirement must be vaccinated against meningococcal disease in accordance with national / regional guidelines, and if day 1 occurs less than two weeks after the initial vaccination, they must receive prophylactic antibiotics for at least two weeks after meningococcal vaccination. 6. You must be vaccinated against Streptococcus pneumoniae in accordance with national and local vaccination schedule guidelines. 7. You must be vaccinated against Haemophilus influenzae type b in accordance with national and local vaccination schedule guidelines.

[0317] Preceding / Combination Therapy 8. Participants with prior complement inhibitor experience must have received eculizumab or ravulizumab according to labeled administration recommendations for at least 90 days prior to screening, with no more than two doses administered outside of scheduled visits within two months prior to study entry.

[0318] Informed consent 9. The participant's legal guardian / legal representative must be able to provide written informed consent, and the participant must be able to provide written informed assent (where applicable, as determined by the central or regional institutional review board (IRB) / independent ethics committee (IEC)), including compliance with the informed consent form (ICF) and the requirements and limitations listed in this protocol.

[0319] 4.1.2. Inclusion Criteria Specific to PNH Cohorts Disease characteristics Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation of red blood cells (RBCs) and white blood cells (WBCs) with granulocyte or monocyte clone size of 10.5% or more (Borowitz et al., Cytometry Part B Clinical Cytometry. 78(4):211-230. 2010) 11. Participants who have not previously received complement inhibitor treatment must have had one or more of the following PNH-related signs or symptoms within three months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, a history of MAVE (including thrombosis), dysphagia, or erectile dysfunction, or a history of packed red blood cell transfusion due to PNH. 12. LDH values ​​at the time of screening: a. Participants who have not previously received complement inhibitor treatment must have an LDH level of 1.5 times or more their ULN as analyzed by the central laboratory. b. Participants with prior experience of eculizumab or ravulizumab must have an LDH level of 1.5 times or less of their ULN (samples must be taken within one day prior to the scheduled eculizumab / ravulizumab administration day [i.e., at the trough level of eculizumab / ravulizumab] and analyzed by a central laboratory).

[0320] 4.1.3.a Inclusion criteria specific to the HUS cohort Disease characteristics 13. Participants who have not previously received complement inhibitor treatment must have evidence of thrombocytopenia, hemolysis, and TMA, including renal injury, based on the following laboratory findings: a. A platelet count of less than 150,000 / μL during the screening period or within 28 days prior to the start of the screening period, b. An LDH of 1.5 times or more the ULN for age and sex during the screening period or within 28 days prior to the start of the screening period, and c. Hemoglobin levels below the lower limit of normal (LLN) for age and sex during the screening period or within 28 days prior to the start of the screening period, and d. Serum creatinine level above the 97.5th percentile of age at screening (participants requiring dialysis due to acute kidney injury are eligible regardless of serum creatinine level). 14. Participants with prior experience of eculizumab or ravulizumab must have confirmed a diagnosis of aHUS, including all of the following laboratory findings documented by the local laboratory at the time of the TMA event. a. Increase in LDH exceeding ULN, and b. Increased serum creatinine exceeding ULN, and c. Thrombocytopenia below LLN 15. Participants with prior experience of eculizumab or ravulizumab must have clinical evidence of a response to eculizumab or ravulizumab at the time of screening, indicated by stable TMA parameters (via central laboratory results), including: a. LDH less than 1.5 times ULN, and b. A platelet count of 150,000 / μL or more, and c. Using Schwarz's formula, 30 mL / min / 1.73 m 2 Estimated glomerular filtration rate (eGFR) 16. Among participants who received kidney transplants: a. A known history of aHUS prior to the current kidney transplant, or b. Unknown history of HUS, sustained evidence of TMA at least 4 days after modification (e.g., temporary discontinuation or dose reduction) of an immunosuppressive regimen with a calcineurin inhibitor (CNI), e.g., cyclosporine, tacrolimus, or mammalian target of rapamycin inhibitor (mTORi), e.g., sirolimus, everolimus) 17. In participants who developed TMA postpartum, sustained evidence of TMA lasting more than 3 days from the date of delivery.

[0321] 4.2. Exclusion criteria Participants will be excluded from the study if any of the following criteria apply.

[0322] 4.2.1. Common Exclusion Criteria for Both Cohorts Participants from both cohorts will be excluded from the study if any of the following criteria apply.

[0323] Medical condition 1. History of bone marrow transplantation 2. Medical history of N meningitidis infection 3. History of infections of unknown cause 4. Active systemic bacterial, viral, or fungal infection within 14 days prior to the administration of the study intervention on day 1. 5.1 Presence of a fever of 38°C (100.4°F) or higher within 7 days prior to the administration of the study intervention on day 1. 6. Known medical history of hepatitis B or C virus infection or positive serological test 7. Known human immunodeficiency virus (HIV) infection (known medical history or evidenced by HIV type 1 or HIV type 2 (HIV-1, HIV-2) antibodies) 8. A history of malignancy within 5 years of screening, excluding non-melanoma skin cancer or cervical intraepithelial neoplasia that has been treated without evidence of recurrence. 9. A history or ongoing major heart, lung, kidney, endocrine, or liver disease (e.g., active hepatitis) that, in the opinion of the principal investigator or Alexion, would prevent the participant from participating in the clinical trial. 10. Unstable medical conditions that would make it less likely for a participant to accept the protocol requirements (e.g., myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within the last six months on day 1, chronic anemia unrelated to PNH). 11. Known medical or psychological conditions or risk factors that, in the opinion of the principal investigator, could prevent the participant from fully participating in the study, impose any additional risks on the participant, or confound the participant's evaluation or the outcome of the study. 12. Known or suspected history of drug or alcohol abuse or dependence within one year prior to the start of the screening period. 13. A history of hypersensitivity reactions to commonly used antimicrobial agents, including beta-lactams, penicillins, aminopenicillins, fluoroquinolones (especially ciprofloxacin), cephalosporins, and carbapenems, which, in the opinion of the principal investigator, would make it difficult to adequately provide empirical antibiotic therapy or treat an active infection.

[0324] Preceding / Combination Therapy 14. Concomitant use of anticoagulants is prohibited if the patient has not been on a stable regimen for at least two weeks prior to study entry.

[0325] Prior / concurrent clinical research experience 15. Participation in another experimental therapy or investigational device study (excluding participation in observational studies [e.g., PNH registration]) within four weeks prior to the start of the Day 1 study intervention, or within five half-lives of the investigational drug, whichever is longer. 16. At any point in time, any other experimental C5 antagonist was used.

[0326] Other exclusions 17. You are pregnant, breastfeeding, or intend to become pregnant during the course of the research. 18. Participant / caregiver is unable to complete the requirements for self-administration of SC. 19. Inability to travel to the clinic for a designated visit during the primary evaluation period, or inability to meet the logistical requirements for the study intervention dose.

[0327] 4.2.2. Exclusion Criteria Specific to the PNH Cohort Medical condition 20. Two or more LDH levels more than twice the ULN within the three months prior to study entry (only for participants with prior eculizumab or ravulizumab experience). 21. MAVE during the 6 months prior to study entry (only for participants with prior eculizumab or ravulizumab experience) 22. 30,000 / mm² at screening 3 (30×10 9 Platelet count less than / L 23. At the time of screening, 500 / μL (0.5 × 10 9 Absolute number of neutrophils less than / L

[0328] 4.2.3.a Exclusion Criteria Specific to the HUS Cohort Disease characteristics 24. Hemolytic uremic syndrome associated with known genetic defects in cobalamin C metabolism 25. Identified drug exposure-related HUS 26. Any known abnormal TMA parameters within 90 days prior to screening (i.e., LDH ≥ 1.5 times ULN, or platelet count < 150,000 / μL, or 30 mL / min / 1.73 m using Schwarz's formula) 2 The following eGFRs (only for participants with prior eculizumab or ravulizumab experience):

[0329] Medical condition 27. Known familial or acquired ADAMTS13 ("disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13") deficiency (activity less than 5%) 28. Known Shiga toxin-associated hemolytic uremic syndrome (ST-HUS) demonstrated by positive testing for Shiga toxin or cultures of Shiga toxin-producing bacteria. 29. A positive direct Coombs test showing clinically significant immune-mediated hemolysis not attributable to TMA, as determined by the principal investigator. 30. Participants who have a confirmed diagnosis of ongoing sepsis as defined by a positive blood culture within 7 days prior to the start of screening and who have not been treated with antibiotics. 31. The presence or suspicion of an active and untreated systemic bacterial infection that, in the opinion of the principal investigator, confounded the accurate diagnosis of aHUS or interfered with the ability to manage the aHUS disease. 32. Heart, lung, small intestine, pancreas, or liver transplant 33. Participants who underwent kidney transplantation experienced acute renal dysfunction within 4 weeks of transplantation, consistent with a diagnosis of acute cell-mediated or antibody-mediated rejection according to the Banff 2013 criteria. 34. Among participants who have not received a kidney transplant, those with a history of kidney disease other than aHUS, for example, a. Known renal biopsy findings suggestive of an underlying disease other than aHUS b. Known renal ultrasound findings consistent with an alternative diagnosis of HUS (e.g., kidneys smaller than average for age) c. Known family history and / or genetic diagnosis of non-complement-mediated hereditary kidney disease (e.g., focal segmental glomerulosclerosis). 35. Known systemic sclerosis (scleroderma), systemic lupus erythematosus, or positive for antiphospholipid antibodies or syndromes.

[0330] Preceding / Combination Therapy 36. Long-term dialysis (defined as regular dialysis as renal replacement therapy for end-stage renal disease) 37. Unless there is an unrelated medical condition (e.g., hypogammaglobulinemia), the individual received long-term IV immunoglobulin therapy within 8 weeks prior to the start of screening, or long-term rituximab therapy within 12 weeks prior to the start of screening. 38. Except as listed below, the patient received other immunosuppressive therapies such as steroids, mTORi (e.g., sirolimus, everolimus), or CNI (e.g., cyclosporine or tacrolimus). a. In the case of part of an established post-transplant anti-rejection regimen, or b. If the participant has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, c. If steroids were used for a condition other than aHUS (e.g., asthma) 39. Use of tranexamic acid within 7 days prior to screening. 40. Participants who were previously untreated with complement inhibitors received plasma exchange / plasma infusion for at least 28 days prior to the start of the current TMA screening period.

[0331] For participants with aHUS who are previously untreated with complement inhibitors, samples taken at screening may be tested in either a local or central laboratory. If eligibility is defined using a local laboratory, additional samples for platelet count, LDH, hemoglobin, and serum creatinine will be taken during the screening period and tested in the central laboratory. All analyses in this study will be based on results from the central laboratory (unless results are missing). If a participant who is previously untreated with complement inhibitors is found not to meet the eligibility criteria for serum creatinine (inclusion criterion 13d) based on central laboratory results, they should not be enrolled in the study, and if the participant receives the first dose of ravulizumab (IV or SC), the participant should be withdrawn from the study and may be replaced.

[0332] For participants with aHUS and prior experience with eculizumab or ravulizumab, the samples taken at screening must be tested in the central laboratory; however, the history of test results will be used for inclusion criteria 14 and exclusion criteria 27, 28, and 29.

[0333] 4.3. Considerations regarding lifestyle habits 4.4. Screening failures Screening failure is defined as a participant who consents to participate in a clinical study but is not subsequently enrolled (i.e., not treated by the study intervention). A minimum set of screening failure information is required to meet the disclosure requirements of the Consolidated Standards of Reporting Trial and to ensure transparent reporting of screening failure participants in order to respond to inquiries from regulatory authorities. This minimum information includes demographics, details of the screening failure (e.g., the eligibility criterion that caused the failure), and any AEs, including any SAEs and any related concomitant medications that occur during the screening period.

[0334] Individuals who fail to meet the criteria for participation in this study (screening failure) due to reasons that are expected to be resolved or have been resolved may be rescreened once based on consideration and consent between the principal investigator and the medical monitor. Participants rescreened outside the screening framework (Section 1.1) will be required to sign a new ICF.

[0335] research intervention A research intervention is defined as any clinical trial intervention, marketed product, placebo, or medical device intended to be administered to research participants in accordance with a research protocol.

[0336] The following terms will be used in this study. ● The term “research intervention” includes “labulizumab IV,” “labulizumab SC via injection,” and “labulizumab SC via OBI.” ● The term "investigational drug" refers to "ravulizumab" regardless of the route of administration. ● The term "research device" refers to "OBI".

[0337] 4.5. Research interventions administered Details of the research intervention are shown in Table 6.

[0338] [Table 11] Abbreviations: AxMP = Auxiliary drug, IMP = Investigational drug, IV = Intravenous, NIMP = Non-investigational drug, OBDS = On-body delivery system, OBI = On-body syringe, SC = Subcutaneous, TSA = Telescopic screw assembly a Dilution is not required for SC administration. Source: Labulizumab IV Investigational Drug Briefing, Labulizumab OBDS Investigational Drug Briefing All ravulizumab SC and ravulizumab IV formulations are suitable for human use and are manufactured under current Good Manufacturing Practices.

[0339] 4.5.1. Lablisma Labulizumab IV is formulated at pH 7.4 and supplied in 3 mL vials. Each vial of Labulizumab IV contains 300 mg of labulizumab (100 mg / mL) in 50 mM sodium phosphate, 5% sucrose, 25 mM l-arginine, 0.05% polysorbate 80, and sterile water for injection.

[0340] For participants weighing less than 20 kg, the same formulation as ravulizumab IV will be used for SC injection and will be supplied in a 3 mL vial.

[0341] For participants weighing 20 kg or more, ravulizumab SC is supplied in a kit consisting of a pre-filled cartridge assembly packaged with a single-use OBI, configured to deliver a fixed dose of ravulizumab via SC injection in approximately 10 minutes (see ravulizumab OBDS, Section 4.5.2). Rabulizumab SC is formulated at pH 7.4 and supplied in a 3.5 mL single-use pre-filled cartridge. Each cartridge of ravulizumab SC contains 245 mg of ravulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM L-arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.

[0342] 4.5.2. Labrisma-on-body delivery system The drug-device combination product ravulizumab OBDS consists of a pre-filled cartridge containing ravulizumab and an OBI. The OBI is a small, sterile, single-use, electromechanical, wearable injection device that delivers a fixed dose of ravulizumab from the pre-filled cartridge assembly to SC tissue at a fixed rate via a 29-gauge stainless steel needle. The device is a sterile, disposable, surgically invasive active medical device for temporary use, as defined from the European Union Medical Device Regulation (EU MDR) 2017 / 745. The device houses a non-removable battery and includes an adhesive patch. The device with adhesive is removed from the skin after completion of administration.

[0343] The primary container closure (cartridge) consists of a cartridge with a chlorobutyl elastomer septum, a chlorobutyl elastomer piston, and a TSA screwed onto the piston. The pre-filled CZ cartridge is packaged with the OBI in a two-compartment blister tray. The pre-filled cartridge assembly is loaded into the device immediately before use by the participant. This device is designed for use only with the provided 3.5 mL pre-filled cartridge.

[0344] After loading the cartridge into the device, attaching the device to the skin, and activating the device, a 3.5 mL dose (245 mg of ravulizumab) is delivered in approximately 10 minutes.

[0345] Further details regarding the device, including its intended use, are provided in the ravulizumab OBDS IB and the Instructions for Use (IFU).

[0346] 4.6. Research intervention dosing regimens For participants who are either previously untreated with complement inhibitors or have received eculizumab, the body weight-based ravulizumab SC regimen consists of a ravulizumab IV loading dose (Table 7) and a maintenance dose initiated two weeks after the loading dose.

[0347] Participants with prior ravulizumab experience did not require a ravulizumab IV loading dose and received only body weight-based ravulizumab SC during the study (Table 8).

[0348] For participants weighing between 10 kg and 20 kg, a single complete maintenance dose of ravulizumab (150 mg) requires a 1.5 mL SC injection as a single dose using a syringe.

[0349] For participants weighing between 20 kg and 40 kg, a single complete maintenance dose of ravulizumab (245 mg) requires one ravulizumab OBDS (delivering 245 mg). For participants weighing 40 kg or more, a single complete maintenance dose of ravulizumab (490 mg) requires two ravulizumab OBDS (delivering 245 mg each), administered either concurrently or consecutively.

[0350] The dosage will be based on the participant's weight collected during the weight measurement required by the protocol. If the weight measurement required by the protocol is unavailable, the weight recorded during the weight measurement required by the previous protocol will be used.

[0351] If a participant weighs less than 20 kg at study entry (Day 1) and subsequently gains more than 20 kg during a follow-up visit requiring a weight measurement protocol, the participant will be switched from ravulizumab SC administration via syringe to ravulizumab SC administration via OBI for the remainder of the study.

[0352] [Table 12] Abbreviations: IV = intravenous, OBDS = on-body delivery system, qw = weekly, SC = subcutaneous

[0353] [Table 13] Abbreviations: OBDS = On-Body Delivery System, qw = Weekly, SC = Subcutaneous

[0354] 4.7. Instructions for Dosage and Administration 4.7.1. Rabulizumab IV - In-clinic administration For participants who are either previously untreated with complement inhibitors or have previously received eculizumab, the 1st dose of ravulizumab IV will be administered in the clinic by a qualified research facility staff member. The ravulizumab loading dose for each participant will be based on their body weight at screening.

[0355] 4.7.2. Rabulizumab SC - Administration in a clinic or at home On the first day of ravulizumab SC administration, a qualified member of the site study team will provide participants / caregivers with initial (and, if necessary, ongoing) training on how to properly self-administer ravulizumab SC (i.e., administration by caregivers of participants aged 2–18 years or older, or by participants aged 12 years or older).

[0356] The training includes procedures for the use of ravulizumab OBDS (drug-device combination) for participants weighing 20 kg or more, or for syringe injection for participants weighing less than 20 kg. Upon completion of the required training, caregivers / participants may self-administer subsequent ravulizumab SC injections at home on administration days that do not overlap with facility visits as specified in the activity schedule (Section 1.1). Caregivers / participants are expected to follow training instructions on each administration day to ensure appropriate administration of the ravulizumab dose. Participants weighing less than 20 kg will be provided with an injection guide for parent / caregivers for syringe injection. Participants weighing 20 kg or more will be provided with an IFU for ravulizumab OBDS.

[0357] Upon completion of training, ravulizumab SC may be self-administered at home by the participant / caregiver. Participants / caregivers may administer ravulizumab SC at the clinic on administration days other than scheduled clinic visits. Doses overlapping with in-situ study visits may be self-administered at the clinic under the supervision of a qualified research facility staff member, or administered by a research facility staff member.

[0358] In the event of any device malfunction resulting in no dose being delivered or only a partial dose being delivered, the facility or participant / caregiver must contact the call center to ensure that the participant receives at least 245 mg of ravulizumab SC (for participants weighing 20 kg or more but less than 40 kg) or at least 490 mg of ravulizumab SC (for participants weighing 40 kg or more) (see Section 4.24 for reporting device complaints).

[0359] For study visits requiring PK sample collection, caregivers / participants are instructed to refrain from administering their ravulizumab dose on the day of the study visit, allowing the participant to receive the dose at the clinic in accordance with the assessments required by the protocol. Upon clinic visit, the ravulizumab dose allocated for that day is administered last, after the participant has had blood drawn for other assessments outlined in the clinical laboratory and activity schedule (Section 1.1).

[0360] 4.8. Packaging and Labeling In embodiments, the devices and systems of the present invention for subcutaneous administration of research interventions (e.g., ravulizumab) may be labeled in accordance with national regulatory requirements.

[0361] 4.8.1. Lablizumab vial packaging The primary packaging for ravulizumab IV consists of a 3 mL vial (Type I borosilicate glass) with a stopper and seal. The secondary packaging consists of a single vial carton. Both the primary (vial) and secondary (carton) packaging include a booklet label with relevant information.

[0362] The 3 mL vial is used for the IV loading dose for participants who have not previously received complement inhibitor treatment or who have previously received eculizumab. The 3 mL vial is also used for SC maintenance in participants weighing between 10 kg and 20 kg.

[0363] 4.8.2. Device Packaging The drug-device combination product ravulizumab OBDS consists of two parts: a pre-filled cartridge containing ravulizumab and the OBI (On-Body Inspection Device). The pre-filled cartridge and device components are packaged together in a thermoformed blister pack with a Tyvek lid covering the compartment housing the device, providing a sterile barrier. The secondary packaging consists of a blank carton containing the blister pack and a booklet label with associated instructions.

[0364] An identification trace label is attached to the blister pack covered with Tyvek, a serial number label is attached to the side of the device, and a single panel label is affixed to each cartridge.

[0365] 4.9. Preparation / Handling / Storage / Accountability The research intervention kit will be made available to each institution after all necessary documentation has been received, in accordance with applicable regulations.

[0366] 4.10. Measures to minimize bias: Randomization and blinding This is an open-label study. Specific interventions administered to participants are assigned by an Interactive Response Technology (IRT) system based on their prior C5 treatment experience and body weight.

[0367] 4.11. Adherence to Research Interventions Rabulizumab IV will be administered in a controlled setting under the supervision of the principal investigator or designated investigator, thereby ensuring adherence to the study intervention dosage.

[0368] During scheduled clinic visits, the ravulizumab SC dose may be administered by the participant themselves (12 years of age or older), by a caregiver (2 to under 18 years of age), or by a trained research facility staff member, thereby ensuring adherence to the study intervention dose.

[0369] The role of the person administering the SC dose, the location of the SC dose administration (i.e., at home or in a research facility), and the site of SC administration on the participant's body are recorded in the case report form (CRF).

[0370] Research facility staff will monitor the self-administration of ravulizumab SC via telephone / video call with participants / caregivers on scheduled home administration days during the primary evaluation period, ensuring that participants / caregivers are questioned about the study intervention dose administered and the status of their devices.

[0371] The facility will monitor participants' self-administration of ravulizumab SC through their electronic diaries (e-diaries) throughout the study. Participants / caregivers will be instructed to contact a call center if they experience any problems with dosage administration.

[0372] The number of kits distributed to and administered to each participant must be maintained at the research facility and must match the number of kits and compliance records. The date and time of each dose administered must be recorded in the source document and CRF.

[0373] 4.12. Combination Therapy Concomitant medications (including any drugs, vitamins, herbal remedies, or supplements) and non-pharmacological therapies / procedures (including any therapeutic interventions such as surgery / biopsy or physiotherapy) received on or after the day of the initial dose of the study intervention (Day 1), including those initiated before Day 1 and continued after Day 1.

[0374] Any concomitant medications deemed necessary for the care of the participant in the study or for the treatment of any adverse events, in addition to any other medications listed as prohibited in Section 4.12.2, may be prescribed at the discretion of the Principal Investigator. However, it is the Principal Investigator's responsibility to ensure that all details regarding the medications are fully documented in the participant's source documentation / medical record and CRF (Section 4.25.1).

[0375] If you have any questions regarding concurrent or prior treatments, you should contact the medical monitor.

[0376] 4.12.1. Approved medicines and therapies Any concomitant medications or non-pharmacological therapies / procedures deemed necessary for the standard treatment of participants in the study, or for the treatment of any adverse events, may be given at the discretion of the principal investigator, along with the permitted medications listed below.

[0377] 4.12.2. Unapproved drugs and therapies Participants in both cohorts are prohibited from receiving any of the following medications and therapies throughout the entire duration of their study participation. ● Eculizumab or other complement inhibitors ● Other investigational drugs or devices as part of the clinical study ● Anticoagulants not in a stable administration regimen for at least two weeks prior to study entry

[0378] Participants in the aHUS cohort are also prohibited from receiving any of the following medications and therapies during the screening period and throughout the study: ● Intravenous immunoglobulin (unless there is an unrelated medical need such as hypogammaglobulinemia) ● Rituximab ●Plasma exchange / plasma infusion New dialysis within the first 48 hours following the initial dose of ravulizumab, except in cases of urgent medical need assessed by (1) diuretic-unresponsive circulating blood volume, (2) refractory electrolyte imbalance, or (3) newly diagnosed uremic encephalopathy. Exceptions must be individually approved by a medical monitor before administering dialysis.

[0379] For participants in the aHUS cohort, the following concomitant medications and procedures are permitted under certain circumstances and with the following limitations. ● The use of other immunosuppressive therapies during the study (such as steroids, mTORi (e.g., sirolimus, everolimus), CNI (e.g., cyclosporine or tacrolimus)) is not permitted unless a) it is part of an established post-transplant anti-rejection regimen, or b) the participant has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, or c) steroids are being used for a condition other than aHUS (e.g., asthma), or d) steroids have been empirically initiated prior to enrollment and tapered off as standard treatment.

[0380] If a participant receives a prohibited medication and / or therapy, the participant may be required to discontinue the research intervention and withdraw from the study (Section 4.15).

[0381] 4.13. Dosage Change Dosage adjustments to the research intervention for individual participants are not permitted in this study.

[0382] 4.14. Post-Study Interventions After a participant completes the study or discontinues the study intervention, ravulizumab will not be provided to the participant as part of this protocol (Section 1.1).

[0383] Upon completion of their final study visit before leaving the study, participants return to the care of their treating physician.

[0384] Interruption of research intervention and participant interruption / withdrawal 4.15. Discontinuation of research intervention Participants or their legal guardians / legal representatives have the right to discontinue the research intervention at any time (the objections of pediatric participants must be respected).

[0385] Participants must discontinue the research intervention if any of the following occurs during the study: ● Severe, uncontrolled infection ● Severe injection or hypersensitivity reaction ● Pregnancy or planned pregnancy

[0386] In addition, research interventions may be interrupted for any of the following reasons: ● AEs that, in the opinion of the principal investigator, would make continued participation in the study unacceptable. ● Use of prohibited drugs as defined in Section 4.12.2 ● Deviation from the protocol ● Serious non-compliance ● Alexion or the principal investigator deems it necessary for the participant ● End of research

[0387] If the research intervention is discontinued, participants will withdraw from the study.

[0388] If a participant discontinues a research intervention due to an adverse event (AE), including a SAE, the event must be followed up on.

[0389] Data collected at the time of study intervention discontinuation and at the time of necessary safety follow-up assessments will be provided in the activity schedule (Section 1.1). The reasons for study intervention discontinuation will be recorded in the source documents and CRFs.

[0390] 4.16. Participant interruption / withdrawal from the study ● Before implementing screening procedures, all efforts should be made to ensure that participants are willing to participate in the study. ● Research staff must notify Alexion and their facility monitor of all study withdrawals as soon as possible. The reason for a participant's withdrawal must be recorded in the source document and CRF. ● Participants may withdraw from the study at any time at their own request or at the request of their legal guardian / legal representative, or at any time at the discretion of the principal investigator for safety, conduct, compliance, or administrative reasons. ●The following activities should be completed upon withdrawal from the research: - Where possible, ED visits should be conducted as outlined in the activity schedule (Section 1.1). - Safety follow-up visits (via telephone / video call) will be conducted 8 weeks (56 days) ± 7 days after the participant's last dose of the study intervention to collect AEs / ADEs, concomitant medications, non-pharmacological therapies, and procedures. ●If a participant or their legal guardian / legal representative withdraws their consent to future disclosure of information, Alexion may retain and continue to use any data collected prior to such withdrawal of consent. ● If a participant withdraws from the study, the participant or their legal guardian / legal representative may request the destruction of any samples collected but not tested, and the principal investigator must document this in the site study record.

[0391] 4.17. Unable to follow up. If a participant repeatedly fails to return for scheduled visits and the research facility is unable to contact them, the participant is considered unfollowable.

[0392] If a participant is unable to return to the clinic for a necessary research visit, the following actions must be taken: ● The facility must contact the participant's legal guardian / representative as soon as possible to reschedule any missed visits, advise the participant's legal guardian / representative and the participant on the importance of maintaining the assigned visit schedule, and attempt to ascertain whether the participant wishes to continue the study and / or should continue it. ● Before a participant is deemed unresponsive to follow-up, the principal investigator or designated investigator must make every effort to re-establish contact with the participant's legal guardian / legal representative (including, if possible, three phone calls and, if necessary, certified mail to the last known mailing address, or equivalent local method). These attempts at contact must be documented in the participant's medical records. ● If a participant's legal guardian / legal representative remains unreachable, the participant will be deemed unfollowable.

[0393] Research evaluation and procedures ● The research procedures and their timing are summarized in the activity schedule (Section 1.1). No waiver or exemption from the protocol is permitted. ● Imminent safety concerns will be discussed with Alexion immediately after their occurrence or awareness to determine whether the participant should continue or discontinue the research intervention. Adherence to the research design requirements, including those specified in the activity schedule (Section 1.1), is essential and necessary for conducting the research. ● All screening evaluations must be completed and reviewed to ensure that potential participants meet all eligibility criteria. The principal investigator must maintain a screening log to record details of all screened participants and to verify eligibility, or, where applicable, to record reasons for screening failures. ●For a list of clinical laboratory tests, please refer to Section 5.8. ● Procedures performed as part of the participant's routine clinical management (e.g., blood cell count) and obtained before signing the ICF may be used for screening or baseline purposes, provided that the procedure meets the protocol-specified criteria and is performed within the time frame defined in the activity schedule (Section 1.1). ● If a participant is unable to return to the clinic, or otherwise unable to make a scheduled visit within an acceptable time slot, the site research staff must make reasonable attempts to contact the participant / participant's caregiver to determine the reason for the missed appointment. The participant / participant's caregiver will be advised to return to the clinical trial site for evaluation if an adverse event (AE) is suspected. In this case, the clinical trial site will make reasonable attempts to obtain all relevant medical records and, where necessary, enter the relevant data into the CRF. ● Unscheduled visits other than those specified in the protocol are permitted at the discretion of the principal investigator. The results of procedures, tests, and evaluations performed during unscheduled visits will be documented in the CRF.

[0394] 4.18. General Evaluation and Procedures 4.18.1. Informed Consent The principal investigator or a qualified nominee must obtain a signed and dated informed consent form from each participant before conducting the study procedure. All efforts will be made to ensure that participants are willing to participate in the study before conducting the screening procedure.

[0395] 4.18.2. Inclusion / Exclusion Criteria To determine whether a participant is eligible for the study, all inclusion criteria (Section 4.1) and exclusion criteria (Section 4.2) must be reviewed by the principal investigator or a qualified nominee.

[0396] 4.18.3. Demographics Demographic parameters are documented in the CRF if permitted in accordance with country-specific regulations.

[0397] 4.18.4. Medical history and PNH / aHUS history The principal investigator will review the participant's medical history and diagnosis during the screening visit and record the following: ● Medical history including all relevant medical / surgical history ● Diagnosis of PNH confirmed by high-sensitivity flow cytometry (only for participants in the PNH cohort) ● aHUS medical history, including the date of onset and diagnosis of the first aHUS symptom (only for participants in the aHUS cohort) ● ADAMTS13 and Shiga toxin status can be documented using medical history (only for participants in the aHUS cohort).

[0398] Document any changes in medical history that occurred during the screening period and before the first dose of the study intervention on day 1.

[0399] 4.18.5. Vaccination and Antibiotic Prevention Due to its mechanism of action, the use of ravulizumab increases participants' susceptibility to meningococcal infection (N meningitidis). To reduce the risk of N meningitidis, all participants must be vaccinated against N meningitidis within three years prior to the first dose of the study intervention and at least two weeks prior. Participants who, for any reason, have not been vaccinated before starting the study intervention must receive appropriate prophylactic antibiotics before day 1 of administration and at least two weeks after vaccination. Vaccines against serotypes A, C, Y, W135, and B are recommended if available. Participants must receive a complete primary vaccination series and be revaccinated if indicated in accordance with current national vaccination guidelines. Vaccination may not be sufficient to prevent N meningitidis.

[0400] If the research intervention begins less than two weeks after the first vaccination, participants will receive prophylactic antibiotics for meningococcal infection until at least two weeks after vaccination. The appropriate use of prophylactic antibiotics should be considered in accordance with official guidance and local practice. All participants will be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary.

[0401] To enhance risk awareness and facilitate the prompt disclosure of any potential signs or symptoms of infection experienced by participants during the course of the study, participants will be provided with participant safety cards and will carry them at all times (Section 4.21.1).

[0402] Meningococcal vaccination within three years prior to the initial dose of the study intervention, as well as vaccination history against Haemophilus influenzae type b and Streptococcus pneumoniae since birth, are recorded in the CRF.

[0403] 4.19. Effectiveness Evaluation 4.19.1. Laboratory evaluation for efficacy endpoints The following disease-related laboratory parameters will be measured during the study and performed as part of the efficacy endpoints, according to the activity schedule (Section 1.1).

[0404] PNH cohort: ● LDH (If an event suspected of breakthrough hemolysis occurs, an unscheduled hospital visit is required for sample collection for LDH analysis by the central laboratory.) ● Hemoglobin ●PNH clone size

[0405] For participants in the PNH cohort, hemoglobin and LDH are assessed based on predetermined criteria for determining breakthrough hemolysis and stabilized hemoglobin, as defined in Section 2.6.

[0406] aHUS cohort: ● Estimated glomerular filtration rate (calculated using Schwarz's formula) ●Serum creatinine ● Platelets ●LDH ● Hemoglobin

[0407] The laboratory evaluation and procedures for blood collection are outlined in sections 5.8 and 5.10, respectively.

[0408] 4.19.2. Transfusion history and transfusion needs during the study (PNH cohort only) The number and volume of transfusions within one year prior to the initial dose of the study intervention and during the study will be documented in the CRF. The information collected will include the date of the transfusion, the number of units, the volume of each blood component given, the hemoglobin result, and the symptoms that induced the transfusion.

[0409] 4.19.3. Dialysis status (aHUS cohort only) The dialysis status of participants within 56 days prior to the first dose of the study intervention and during the study will be documented in the CRF.

[0410] 4.20. Health-related quality of life Quality of Life (QoL) assessments should be performed whenever possible, before other research procedures are carried out, and must be performed before the administration of the research intervention.

[0411] 4.20.1. Pediatric FACIT - Fatigue The Functional Assessment of Chronic Disease Therapy in Children - Fatigue (FACIT-Fatigue) Scale is a 13-item questionnaire that assesses fatigue over the past 7 days and its impact on daily activities and function. Each item is scored on a 5-point scale, with a total score ranging from 0 to 52, where a higher score indicates less fatigue. The questionnaire is self-reported by participants who were 8 years of age or older at the time of informed consent. Patients under 8 years of age at the time of informed consent are not assessed. The Pediatric FACIT-Fatigue Scale is shown in Figure 5.

[0412] 4.20.2. Quality of Life Questionnaire for Children The Pediatric Quality of Life (PedsQL) 4.0 General Core Scale (Figures 6A and 6B) is a multidimensional pediatric self-report and parent-surrogate reported standardization tool for measuring health-related quality of life in children and adolescents aged 2 to under 18 years.

[0413] The trial is designed for self-completion in participants aged 5 years and older, using the PedsQL trial, which is available in three age-appropriate versions for participants aged 5–7, 8–12, and 13–under 18 years, as well as parental surrogate reporting. For participants aged 2–under 5 years, the trial is designed for completion by parental surrogate reporting only. Whenever feasible, efforts should be made to have the same surrogate complete the assessment at each visit.

[0414] An age-appropriate assessment for a participant at the time of informed consent will be used for that participant throughout the study. Age changes during the study will not constitute a change in the type of survey the participant completes (for example, for participants aged 2 to under 5 years at the time of informed consent, PedsQL Parental Surrogacy will be used throughout the study).

[0415] 4.21. Safety Assessment 4.21.1. Participant Safety Card Prior to the first dose of the study intervention, participant safety cards will be provided to participants / caregivers and they will carry them at all times until eight months after the last dose of the study intervention. These cards are provided to increase participant / caregiver awareness of the risk of meningococcal infection, to facilitate the rapid recognition and disclosure of any potential signs or symptoms of infection experienced during the course of the study, and to inform participants of what actions should be taken if they experience signs or symptoms of infection.

[0416] Throughout the study, at each visit, the research staff will review to ensure that participants have a participant safety card.

[0417] 4.21.2. Physical Examination ● A complete physical examination includes, at a minimum, an assessment of the following organs / systems: skin, head, ears, eyes, nose, throat, chest, heart, abdomen, limbs, musculoskeletal system, and neurological condition. ● A simplified physical examination consists of physical system-related tests based on the judgment of the principal investigator (or a qualified designated person) and the participant's symptoms. At least one physical system must be checked for the simplified examination. ● The principal investigator should pay special attention to clinical signs associated with previous serious illnesses. ● For consistency, all efforts should be made to ensure that physical examinations are conducted by research staff with the same qualifications. ● The weight and height of all participants at the time of evaluation, as well as the head circumference of participants aged 3 years or younger, will be measured and recorded at the designated visits in the activity schedule (Section 1.1).

[0418] 4.21.3. Vital Signs ●Body temperature (°C or °F), respiratory rate, systolic and diastolic blood pressure (mm Hg), and heart rate (beats / min) are evaluated. ● Blood pressure and heart rate are assessed in seated or supine participants using fully automated devices. Manual techniques are used only when automated devices are unavailable. ● Before measuring blood pressure and heart rate, participants must rest for at least 5 minutes in a quiet environment free from distractions (e.g., television, mobile phone). Ideally, the same arm should be used for each participant's measurement. ●Vital signs are collected before administration at the time of ravulizumab administration visit.

[0419] 4.21.4. Electrocardiogram ● A single 12-lead electrocardiogram (ECG) is performed locally to obtain heart rate, PR, QRS complex, the interval between the start of the Q wave and the end of the T wave in the ECG (QT), and the corrected QT (QTc) interval. The QT interval is corrected for heart rate using Fridericia's formula (QTcF). ● Participants should lie on their backs for approximately 5-10 minutes before ECG collection, and should remain awake while lying on their backs during ECG collection. ● The principal investigator or designated investigator is responsible for reviewing the ECG to determine whether it is within the normal range and to determine the clinical significance of the results.

[0420] 4.21.5. Clinical Safety Laboratory Evaluation ● The principal investigator must review laboratory reports, document this review, and record any clinically significant changes that occurred during the study in the AE section of the CRF. Laboratory reports must be submitted along with the source documentation. Clinically significant abnormal laboratory findings are those unrelated to the underlying disease unless they are judged by the principal investigator to be more severe than expected for the participant's condition. ● All laboratory tests that show values ​​considered clinically significant abnormalities during participation in the study or within 8 weeks after the last dose of the study intervention will be repeated until the values ​​return to normal or baseline, or until the principal investigator or medical monitor deems them no longer clinically significant. - If such values ​​do not return to normal / baseline within a period deemed reasonable by the principal investigator, the etiology should be identified and Alexion should be notified. - All laboratory assessments required by the protocol, as defined in Section 5.8, must be collected in accordance with the laboratory manual, blood volume (Section 5.10), and activity schedule (Section 1.1). - Laboratory evaluations conducted at the site's regional laboratory that require changes in participant management or are deemed clinically important by the principal investigator must be documented in the AE or SAE CRF.

[0421] 4.21.6. Pregnancy ● Pregnancy tests must be performed on all women of childbearing potential (WOCBP) at the time specified in the protocol in the activity schedule (Section 1.1). Pregnancy tests (urine or serum) may also be performed at any time during the study at the discretion of the principal investigator. ●A negative pregnancy test for WOCBP is required before administering the study intervention. ● Pregnancy data from female participants and female spouses / partners of male participants will be collected from the first dose of the study intervention and at the points specified in the activity schedule (Section 1.1). Female participants who become pregnant during the study will discontinue the study intervention and withdraw from the study. If a pregnancy is reported, the principal investigator must immediately notify Alexion within 24 hours of recognizing the pregnancy. ● For pregnant female participants, this information will be shared with the participant's legal guardian / legal representative as required by local regulations.

[0422] 4.22. Adverse events, serious adverse events, device adverse effects, unexpected serious device adverse effects, and serious device adverse effects All adverse events (AEs) and adverse events (ADEs) must be reported to the Principal Investigator or a qualified designated investigator by the participant (or, where appropriate, their caregiver / legal guardian / legal representative), facility staff operating the device, or any other person who may suffer any unforeseen medical event related to the device or its use.

[0423] Research facility staff will instruct participants' caregivers / legal guardians / legal representatives on how to report signs and symptoms (e.g., crying and pain) in individual pediatric participants. They will be instructed to report both specific and nonspecific symptoms (including vomiting, diarrhea, drowsiness, and changes in the intensity and pattern of crying). Care should be taken to ensure that clinical symptoms of AEs are not misinterpreted as manifestations of pre-existing conditions. Furthermore, symptoms that depend on the participant's communication abilities in young children or children with developmental delays (e.g., nausea, pain, mood changes) may be at risk of being underreported or misreported.

[0424] The principal investigator and any qualified designated person are responsible for detecting, documenting, and recording events that meet the definitions of AE, SAE, ADE, or SADE, and remain responsible for following up on any serious AE / ADE that is thought to be related to the study intervention or procedure, or (as described herein) causes a participant to discontinue the study intervention.

[0425] 4.22.1. Period and frequency of collecting AE, SAE, ADE, and SADE information All adverse events (AEs) and safety emergencies (SAEs) are collected from the time of ICF signature until 8 weeks after the last dose of the study intervention (i.e., safety follow-up visit).

[0426] All ADEs and SADEs will be collected from immediately before the first dose of ravulizumab OBDS until 8 weeks after the last dose of the study intervention (i.e., at the safety follow-up visit).

[0427] All SAEs and SADEs are to be recorded immediately and reported to Alexion, and under no circumstances will they exceed 24 hours. The principal investigator will submit any updated SAE data to Alexion within 24 hours of the site becoming aware of the event.

[0428] The principal investigator is not obligated to proactively seek AE, SAE, ADE, or SADE data after the completion of study participation. However, if the principal investigator becomes aware of any SAE or SADE, including death, at any time after the participant has been released from the study, and believes that the event is reasonably related to the study intervention or participation in the study, the principal investigator must promptly notify Alexion.

[0429] 4.22.2. Method for detecting AE, SAE, ADE, and SADE Care should be taken to avoid introducing bias when detecting AEs, SAEs, ADEs, and / or SADEs. Open-ended, unguided verbal questioning of participants / caregivers is the preferred method for inquiring about the occurrence of AEs and ADEs. Each ADE should be associated with at least one unit (kit) of the research device. Once an ADE is collected, the serial number / lot number of the unique research device (kit), or any other device identification information, must be immediately obtained and recorded along with the corresponding ADE.

[0430] Note: The word “kit” refers to a unique number assigned by Alexion to a device / drug combination product and is not intended to refer to a combination kit (according to 21 CFR 3.2(e)), an in vitro diagnostic device kit (according to the European Union In Vitro Medical Devices Regulation, EU IVDR 2017 / 746), or a convenience kit (according to 21 CFR 801.3).

[0431] 4.22.3. Follow-up of AE, SAE, ADE, and SADE Following the initial AE / SAE report, the principal investigator must proactively follow up with each participant during subsequent visits / contacts. All SAEs will be followed up until they resolve, stabilize, the event is otherwise explained, or the participant is unable to follow up (as defined in Section 4.17).

[0432] 4.22.4. Regulatory reporting requirements for SAE and SADE ● Prompt notification of SAEs to Alexion by the principal investigator is essential to ensure that legal obligations and ethical responsibilities regarding participant safety and the safety of research interventions under clinical investigation are fulfilled. ● Alexion has a legal responsibility to notify both local and other regulatory authorities about the safety of research interventions under clinical investigation. Alexion will comply with country-specific regulatory requirements regarding safety reporting to regulatory authorities, IRBs / IECs, and principal investigators. ● Alexion is required to submit individual suspected unexpected serious adverse reaction (SUSAR) reports to the health agency and the principal investigator, as necessary, in the form of MedWatch 3500 or CIOMS I Form. The forms submitted to the principal investigator will be blinded regarding the assignment of treatment. In limited circumstances, blinding may be broken in the event of an urgent safety issue that could compromise participant safety. ● Upon receiving an investigator safety report from Alexion containing SAEs or other specific safety information (e.g., a summary or list of SAEs), the investigator shall review it and then submit it together with the investigational drug brochure, and, where appropriate, notify the IRB / IEC in accordance with local requirements. ● SADE reporting is carried out in accordance with local, national, and regional requirements. ●Under EU CTR 536 / 2014, events other than SAEs that could affect the benefit-risk balance (e.g., unexpected events) should be reported.

[0433] 4.22.5. Medication errors, drug abuse, and drug misuse 4.22.5.1. Timeline If an event of medication error, drug abuse, or drug misuse occurs during the study, the principal investigator or staff of another site shall notify the Alexion representative within one calendar day, i.e., immediately, but within 24 hours of becoming aware of the event.

[0434] The designated Alexion representative will work with the principal investigator to ensure that all relevant information is completed within 1 calendar day (for initial fatal / life-threatening or follow-up fatal / life-threatening) or 5 calendar days (for other serious initial and follow-up) if there is a SAE related to a medication error, drug abuse, or misuse event, and within 30 days for all other events.

[0435] 4.22.5.2. Medication Errors For the purposes of this clinical study, a medication error is an unintended failure or mistake in the treatment process of a research intervention that is harmful to or could potentially harm a participant.

[0436] 4.22.5.3. Drug Abuse Substance abuse is the maintenance or sporadic, intentional, non-therapeutic overuse of research interventions for perceived rewards or desired non-therapeutic effects.

[0437] 4.22.5.4. Misuse of drugs Drug misuse is the intentional and inappropriate use (by a research participant) of a research intervention for medicinal purposes outside the scope of the authorized product information or outside the scope of the intended use specified in the protocol, including intentional administration of the product via an incorrect route.

[0438] 4.22.6. Particularly interesting adverse events Meningococcal infection is considered a particularly interesting adverse event (AE).

[0439] 4.22.7. Injection reaction Local (injection site or injection site reaction), systemic (injection-related reaction), and immune-mediated reactions (hypersensitivity) will be evaluated during the study.

[0440] 4.23. Major vascular adverse events (PNH cohort only) Major vascular adverse events are assessed as part of a planned assessment of AEs, as described in Section 4.22. MAVE is defined as any of the following:

[0441] [Table 14]

[0442] A description of MAVE, including the diagnostic method (e.g., magnetic resonance imaging, ultrasound, angiography), the date of diagnosis, and the date of resolution (or ongoing), is collected in the CRF (before baseline) as part of the patient's medical history.

[0443] 4.24. Defects / Complaints about Medical Devices To fulfill regulatory reporting obligations worldwide, the principal investigator is responsible for detecting and documenting events that meet the definition of a medical device defect / complaint that occur during research involving a medical device.

[0444] All device problems must be reported, regardless of whether the entire volume of the drug was administered via ravulizumab OBI.

[0445] Note: Defects / complaints that meet the definition of ADE / SADE also follow the process outlined in section 4.22 of the protocol.

[0446] 4.24.1. Period for detecting defects / complaints regarding medical devices ● Any medical device defects / complaints, whether or not they result in ADEs, will be detected, documented, and reported throughout the entire duration of the study in which the medical device is used. ● If, at any point after a participant has withdrawn from the study, the principal investigator becomes aware of any defect / complaint regarding the medical device and believes that such defect / complaint is reasonably related to the medical device used in the clinical trial, the principal investigator shall promptly notify Alexion.

[0447] 4.24.2. Follow-up on defects in medical devices ● Follow-up will apply to all participants, including those who discontinued the study intervention. The principal investigator is responsible for ensuring that follow-up includes any supplementary investigations as indicated to clarify the nature of the defect / complaint and / or causal relationship. For each medical device defect / complaint, the research site must send the OBI to Alexion or the designated person for investigation. Instructions for the return of these devices are provided in the Investigational Drug Management Procedures.

[0448] 4.24.3. Prompt reporting of medical device defects / complaints to Alexion ● Medical device defects / complaints must be reported to Alexion within one business day after the principal investigator determines that the event meets the protocol definition for medical device defects / complaints. ● Medical device defects / complaints should be reported to Alexion either by calling the call center using the local telephone number listed in the IFU document, or by submitting a complaints form in accordance with the instructions in the Investigational Drug Management Procedures Manual. ● Alexion is the point of contact for receiving complaint reports.

[0449] 4.24.4. Regulatory reporting requirements for defects in medical devices ● The principal investigator shall promptly report any medical device defects / complaints that occur with any medical device provided for use in the study within one business day of recognition, in order for Alexion to fulfill its legal responsibility to notify appropriate regulatory authorities and other entities of certain safety information regarding medical devices used in the clinical study. ● The principal investigator or qualified nominee shall comply with applicable local regulatory requirements regarding the reporting of medical device defects / complaints to the IRB / IEC.

[0450] 4.25. Review of prior and contemporaneous medication and procedures It is important for the principal investigator or designated investigator to review each medication the participant is taking before the start of the study and at each study visit (Section 1.1), and to record any relevant changes in the CRF.

[0451] 4.25.1. Previous medication and procedures Prior medications and / or vaccines (including vitamins, plant preparations, and those considered in eligibility criteria (Section 4)) and procedures (such as mechanical ventilation, renal replacement therapy, surgery / biopsy, or physiotherapy) received or experienced by participants within 28 days prior to screening or during the screening period, as well as any meningococcal vaccines administered within the last three years, will be recorded in the participant's CRF. Transfusions of filled RBCs received during the year prior to the initial study intervention will also be recorded in the participant's CRF. Previous use of eculizumab and ravulizumab (start / stop dates, dosage) will also be recorded.

[0452] 4.25.2. Concomitant medications and procedures Concomitant medications (including any drugs, vitamins, herbal medicines, or supplements) and procedures (as defined in Section 4.12) received on or after the day of the initial dose of the study intervention (Day 1), including those initiated before Day 1 and continued after Day 1. At each study visit, participants will be questioned about any new medications, non-pharmacological therapies, or procedures since their last visit, and / or changes to medications, non-pharmacological therapies, or procedures. Concomitant medications, non-pharmacological therapies, and procedures will be documented in the source documents and the participant's CRF, and will include: ●Reason for use ● Date of administration, including start and end dates ● Dosage information including dosage and frequency

[0453] Any concomitant medications deemed necessary for the care of the participant during the study or for the treatment of any adverse events, in addition to any other medications listed as prohibited in Section 4.12.2, may be prescribed at the discretion of the Principal Investigator. However, it is the Principal Investigator's responsibility to ensure that all details regarding medications are fully documented in the participant's source documentation and CRF.

[0454] Vaccinations and antibiotics administered during the study to prevent meningococcal infection (if applicable) will also be recorded.

[0455] If you have any questions regarding concomitant medications or procedures, you should contact your medical monitor.

[0456] 4.26. Excessive Intake Any IV or SC dose of ravulizumab exceeding those specified / required in the protocol (as outlined in Tables 7 and 8) for this study will be considered an overdose medication error. An overdose is a medication error that is not considered an adverse event (AE) unless it results in an adverse medical outcome.

[0457] A broad, previously clinically studied safe dose...

Claims

1. An on-body delivery system (OBDS) configured to administer an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the complementarity-determining regions (CDRs) 1, 18, and 3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, 5, and 3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naive or has received eculizumab treatment, and the therapeutic anti-C5 antibody or its antigen-binding fragment is administered to: (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) On-body delivery system (OBDS) administered subcutaneously once weekly at a dose of 490 mg to patients weighing 40 kg or more.

2. An OBDS configured for use in pediatric human patients requiring treatment for aHUS or PNH, wherein the OBDS comprises an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, each comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naïve or has received eculizumab treatment, and the OBDS is, (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) OBDS comprising means for subcutaneous administration of 490 mg to patients weighing 40 kg or more.

3. An OBDS configured to administer an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, for use in pediatric human patients requiring treatment for aHUS or PNH, wherein the patient has a history of ravulizumab administration, and the therapeutic anti-C5 antibody or its antigen-binding fragment is (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) OBDS administered subcutaneously once weekly at a dose of 490 mg to patients weighing 40 kg or more.

4. An OBDS configured for use in pediatric human patients requiring treatment for aHUS or PNH, wherein the OBDS comprises an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, each comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a history of ravulizumab, and the OBDS is (i) 245 mg for patients weighing 20 kg or more but less than 40 kg, (ii) OBDS comprising means for subcutaneous administration of 490 mg to patients weighing 40 kg or more.

5. The OBDS according to any one of claims 1 to 4, wherein the pediatric human patient is under 21 years of age.

6. The OBDS according to claim 5, wherein the pediatric human patient is between 2 and 18 years of age.

7. The OBDS according to any one of claims 1 to 6, comprising a cartridge containing the therapeutic anti-C5 antibody or its antigen-binding fragment, and an on-body syringe (OBI).

8. The OBDS according to any one of claims 1 to 7, wherein the OBDS is configured to subcutaneously administer the therapeutic anti-C5 antibody or its antigen-binding fragment to a patient weighing 20 kg or more but less than 40 kg at a dose of 245 mg using one OBDS.

9. The OBDS according to claim 8, wherein the 245 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v polysorbate 80 (PS80), and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

10. The OBDS according to any one of claims 1 to 7, wherein the OBDS is configured to be used in combination with a second OBDS to subcutaneously administer the therapeutic anti-C5 antibody or its antigen-binding fragment to a patient weighing 40 kg or more in a dose of 490 mg.

11. The OBDS according to claim 10, wherein the 490 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

12. The OBDS according to any one of claims 1 to 11, wherein the OBDS is a single-use electromechanical medical device comprising a syringe including a 29-gauge needle and a cartridge including a piston and a retractable screw assembly.

13. The OBDS according to any one of claims 7 to 12, wherein the cartridge has a volume of 3.5 mL.

14. The OBDS according to any one of claims 7 to 13, wherein the OBDS is configured to deliver the therapeutic anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes.

15. The OBDS according to any one of claims 7 to 14, wherein the cartridge comprises the therapeutic anti-C5 antibody or an antigen-binding fragment thereof, and an opening sealed by a puncturable septum.

16. The aforementioned OBDS, (i) Syringe housing and (ii) An injection needle, wherein at least the tip of the injection needle is translatable between a retracted position in which it is housed within the syringe housing and an injection position in which at least the tip of the injection needle protrudes from the syringe housing, (iii) A start button assembly movably mounted to the syringe housing and operably connected to the injection needle, wherein the start button assembly is translatable from a non-operating position to an operating position in order to drive the injection needle from its retracted position to its injection position, (iv) A cartridge door that is movable between an open position and a closed position, wherein the cartridge door is open end, An internal channel having a cartridge, wherein the cartridge contains the therapeutic anti-C5 antibody or its antigen-binding fragment to be dispensed, and the cartridge has an opening at the front end and a flange at the rear end, which are sealed by a puncturable septum, and A cartridge door includes a cartridge puncture needle, which is mounted within the internal channel and connected to the injection needle in fluid communication, wherein the cartridge puncture needle is configured to completely penetrate the puncturable septum of the cartridge and to connect the material inside the cartridge to the injection needle in fluid communication. (v) A deflectable interfering member which, in a stationary position of the interfering member, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position in which the cartridge puncture needle does not completely penetrate the punctureable septum, The OBDS according to any one of claims 1 to 15, wherein the cartridge door is movable to the closed position in the sealed position of the cartridge, and the movement of the activation button assembly from the non-operated position to the operated position in the closed position of the cartridge door deflects an interfering element and disengages it from the rear end flange of the cartridge, thereby allowing the cartridge door to advance further into the internal channel to the unsealed position of the cartridge, so that the cartridge puncture needle can fully penetrate the puncturable septum.

17. The OBDS according to claim 15 or 16, wherein the cartridge has a volume of 10 mL.

18. The OBDS according to any one of claims 1 to 17, wherein the OBDS is configured to subcutaneously self-administer the therapeutic anti-C5 antibody or its antigen-binding fragment to the patient.

19. The OBDS according to any one of claims 1 to 18, wherein the OBDS is configured for subcutaneously administering the therapeutic anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh.

20. A needle syringe configured for administering an effective amount of therapeutic anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, for use in pediatric human patients requiring treatment for aHUS or PNH, wherein the patient weighs 10 kg or more but less than 20 kg, is either complement inhibitor-naïve, has a history of eculizumab, or has a history of ravulizumab, and the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once weekly at a dose of 150 mg.

21. A needle syringe configured for administering treatment to a pediatric human patient requiring treatment for aHUS or PNH, wherein the needle syringe is configured for subcutaneous administration and contains 150 mg of a therapeutic anti-C5 antibody or its antigen-binding fragment, each comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient weighs 10 kg or more but less than 20 kg and is either new to complement inhibitor treatment, has experience with eculizumab, or has experience with ravulizumab.

22. The needle syringe according to claim 20 or 21, wherein the 150 mg dose of the therapeutic anti-C5 antibody or its antigen-binding fragment is formulated in sodium phosphate, sucrose, L-arginine, PS80, and water for injection, at pH 7.4 and a concentration of 100 mg / mL.

23. The needle syringe according to any one of claims 20 to 22, wherein the needle syringe is configured to administer the therapeutic anti-C5 antibody or its antigen-binding fragment to a site selected from the patient's arm, abdomen, and thigh.

24. The OBDS according to any one of claims 1 to 19, or the needle syringe according to any one of claims 20 to 23, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region in EU numbering, respectively.

25. The OBDS according to any one of claims 1 to 19 and 24, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 12 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8, or the needle syringe according to any one of claims 20 to 23 and 24.

26. The OBDS according to any one of claims 1 to 19, 24, and 25, or the needle syringe according to any one of claims 20 to 25, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:

13.

27. The OBDS according to any one of claims 1 to 19 and 24 to 26, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide having the amino acid sequence of SEQ ID NO: 11, or the needle syringe according to any one of claims 20 to 26.

28. The OBDS according to any one of claims 1 to 19 and 24 to 27, wherein the heavy chain variable region includes an N-terminal pyroglutamic acid residue, or the needle syringe according to any one of claims 20 to 27.

29. A kit comprising an OBDS according to any one of claims 1 to 19 and 24 to 28 or a needle syringe according to any one of claims 20 to 28, and instructions for using the OBDS or the needle syringe for the treatment of PNH or aHUS.

30. A method for treating a pediatric human patient having PNH or aHUS, wherein the patient is either complement inhibitor-naïve or has received eculizumab treatment, the method comprising administering to the patient in an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment, during a treatment cycle, the therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) Once on the first day of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, administered intravenously at a dose of 2700 mg, (b) On the 15th day of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method of subcutaneous administration of 490 mg to patients weighing 40 kg or more.

31. A method for treating a pediatric human patient having PNH or aHUS, wherein the patient has a history of ravulizumab administration, the method comprising administering to the patient in an effective amount of a therapeutic anti-C5 antibody or its antigen-binding fragment during an administration cycle, the therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is On day 1 of the aforementioned administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A method of subcutaneous administration of 490 mg to patients weighing 40 kg or more.

32. The method according to claim 30 or 31, wherein the pediatric human patient is under 21 years of age.

33. The method according to claim 32, wherein the pediatric human patient is between 2 and 18 years of age.

34. The method according to any one of claims 30 to 33, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to a patient weighing 10 kg or more but less than 20 kg in a dose of 150 mg using a syringe of 1.5 mL volume.

35. The method according to any one of claims 30 to 34, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment in a dose of 150 mg is formulated in sodium phosphate, sucrose, L-arginine, PS80, and water for injection, at pH 7.4 and a concentration of 100 mg / mL.

36. The method according to any one of claims 30 to 33, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to a patient weighing 20 kg or more using an OBDS.

37. The method according to claim 36, wherein the OBDS comprises a cartridge containing the therapeutic anti-C5 antibody or its antigen-binding fragment, and an OBI.

38. The method according to claim 36 or 37, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to a patient weighing 20 kg or more but less than 40 kg at a dose of 245 mg using OBDS.

39. The method according to any one of claims 36 to 38, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment in a dose of 245 mg is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and the OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

40. The method according to claim 36 or 37, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to a patient weighing 40 kg or more in a dose of 490 mg using two OBDS.

41. The method according to any one of claims 36, 37, and 40, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment in a dose of 490 mg is formulated with 50 mM sodium phosphate, 25 mM L-arginine, 5% w / v sucrose, 0.05% w / v PS80, and water for injection, at pH 7.4 and a concentration of 70 mg / mL, and each OBDS comprises one OBI and one pre-filled cartridge containing 245 mg of the therapeutic anti-C5 antibody or its antigen-binding fragment.

42. The method according to any one of claims 36 to 41, wherein the OBDS is a single-use electromechanical medical device comprising a syringe including a 29-gauge needle and a cartridge including a piston and a retractable screw assembly.

43. The method according to any one of claims 37 to 42, wherein the cartridge has a volume of 3.5 mL.

44. The method according to any one of claims 37 to 43, wherein the OBDS is configured to deliver the therapeutic anti-C5 antibody or its antigen-binding fragment via subcutaneous injection in about 10 minutes.

45. The method according to any one of claims 37 to 41, wherein the cartridge comprises the therapeutic anti-C5 antibody or an antigen-binding fragment thereof, and an opening sealed by a puncturable septum.

46. The aforementioned OBDS, (i) Syringe housing and (ii) An injection needle, wherein at least the tip of the injection needle is translatable between a retracted position in which it is housed within the syringe housing and an injection position in which at least the tip of the injection needle protrudes from the syringe housing, (iii) A start button assembly movably mounted to the syringe housing and operably connected to the injection needle, wherein the start button assembly is translatable from a non-operating position to an operating position in order to drive the injection needle from its retracted position to its injection position, (iv) A cartridge door that is movable between an open position and a closed position, wherein the cartridge door is open end, An internal channel having a cartridge, wherein the cartridge contains the therapeutic anti-C5 antibody or its antigen-binding fragment to be dispensed, and the cartridge has an opening at the front end and a flange at the rear end, which are sealed by a puncturable septum, and A cartridge door includes a cartridge puncture needle, which is mounted within the internal channel and connected to the injection needle in fluid communication, wherein the cartridge puncture needle is configured to completely penetrate the puncturable septum of the cartridge and to connect the material inside the cartridge to the injection needle in fluid communication. (v) A deflectable interfering member which, in a stationary position of the interfering member, engages with the rear end flange of the cartridge, thereby limiting the insertion depth of the cartridge into the internal channel of the cartridge door to a sealed position in which the cartridge puncture needle does not completely penetrate the punctureable septum, The method according to any one of claims 36 to 41, wherein the cartridge door is movable to the closed position in the sealed position of the cartridge, and the movement of the activation button assembly from the non-operated position to the operated position in the closed position of the cartridge door deflects an interfering element and disengages it from the rear end flange of the cartridge, thereby allowing the cartridge door to advance further into the internal channel to the unsealed position of the cartridge, so that the cartridge puncture needle can fully penetrate the puncturable septum.

47. The method according to claim 45 or 46, wherein the cartridge has a volume of 10 mL.

48. The method according to any one of claims 30 to 47, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to the patient.

49. The method according to any one of claims 30 to 48, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered to a site selected from the patient's arm, abdomen, and thigh.

50. The method according to any one of claims 30 to 49, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered subcutaneously once a week for a long period of up to three months, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, two years, or the remainder of the patient's life, after the administration cycle.

51. The method according to any one of claims 30 and 34-50, wherein the patient has been previously treated with eculizumab or its biosimilar, or with an anti-C5 antibody selected from tecidomab, clobalimab, CAN106, or pozelimuab.

52. The method according to claim 51, wherein the patient has been previously treated with eculizumab or a biosimilar thereof.

53. The method according to claim 51 or 52, wherein the administration cycle is initiated about two weeks after the patient's last dose of eculizumab or its biosimilar, or an anti-C5 antibody selected from tecidomab, clovalimab, CAN106, or pozelimuab.

54. The method according to claim 53, wherein the administration cycle begins approximately two weeks after the patient's last dose of eculizumab or its biosimilar.

55. The method according to any one of claims 51 to 54, wherein the patient has been treated with eculizumab or a biosimilar thereof for at least 90 days prior to day 1 of the administration cycle.

56. (i) The patient weighs less than 20 kg and the administration cycle begins approximately 4 weeks after the patient's last dose of ravulizumab, or (ii) The method according to any one of claims 31 to 55, wherein the patient weighs 20 kg or more, and the administration cycle is started about 8 weeks after the patient's last dose of ravulizumab.

57. The method according to any one of claims 30 to 56, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region in EU numbering, respectively.

58. The method according to any one of claims 30 to 57, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 12 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

8.

59. The method according to any one of claims 30 to 58, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment further comprises a heavy chain constant region containing the amino acid sequence of SEQ ID NO:

13.

60. The method according to any one of claims 30 to 59, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide having the amino acid sequence of SEQ ID NO:

11.

61. The method according to any one of claims 30 to 60, wherein the heavy chain variable region includes an N-terminal pyroglutamic acid residue.

62. The therapeutic anti-C5 antibody or its antigen-binding fragment exhibits a range of 0.1 nM ≤ K at pH 7.4 and 25°C. Ｄ Affinity dissociation constant (K) in ≤ 1 nM Ｄ The method according to any one of claims 30 to 61, wherein the human C5 is bound to the human C5.

63. The therapeutic anti-C5 antibody or its antigen-binding fragment has a K content of 10 nM or higher at pH 6.0 and 25°C. Ｄ The method according to any one of claims 30 to 62, wherein the C5 is bound to human C5.

64. The method according to any one of claims 30 to 63, wherein the therapeutic anti-C5 antibody is ravulizumab.

65. The method according to any one of claims 30 to 64, wherein the patient has been vaccinated against meningococcal infection from serogroups A, C, Y, W135, and B within three years prior to day 1 of the administration cycle, or for at least two weeks prior thereto, and the patient has been vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b.

66. The method according to any one of claims 30 to 65, wherein the patient has PNH.

67. The method according to claim 66, wherein the patient has PNH confirmed by flow cytometry evaluation of red blood cells (RBCs) and white blood cells (WBCs) having a granulocyte or monocyte clone size of 5 or more.

68. The method according to claim 66 or 67, wherein the patient is unaccustomed to complement inhibitor treatment and has at least one of the following symptoms prior to treatment: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, a history of major cardiovascular adverse events (MAVE) (including thrombosis), dysphagia, or erectile dysfunction, or a history of concentrated red blood cell transfusion due to PNH.

69. (i) The patient is untreated with complement inhibitors and has lactate dehydrogenase (LDH) levels 1.5 times or higher than the upper limit of normal (ULN), or (ii) The method according to any one of claims 66 to 68, wherein the patient has a history of eculizumab or ravulizumab and has an LDH of 1.5 times or less the ULN.

70. The aforementioned treatment, (i) Change in LDH levels relative to baseline, (ii) Reduction of the incidence of breakthrough hemolysis, (iii) Achievement of avoiding blood transfusions, (iv) Achievement of stabilized hemoglobin, and / or (v) The method according to any one of claims 66 to 69, which results in a change from baseline in PNH RBC clone size.

71. The aforementioned treatment, (i) Percentage change in LDH levels relative to baseline at weeks 10 and 52, (ii) Reduction in the incidence of breakthrough hemolysis at weeks 10 and 52, (iii) Achievement of transfusion avoidance at weeks 10 and 52, (iv) Achievement of stable hemoglobin levels at weeks 10 and 52, and (v) The method according to claim 70, which brings about a change from baseline in PNH RBC clone size at 52 weeks.

72. The method according to any one of claims 30 to 65, wherein the patient has aHUS.

73. The aforementioned treatment, (i) Changes in the need for dialysis, (ii) Changes in the observed and baseline values ​​of the estimated glomerular filtration rate (eGFR), (iii) Changes in observed serum creatinine levels and changes from baseline, and / or The method according to claim 72, which results in (iv) changes in observed values ​​and changes from baseline of a hematological parameter selected from (1) platelets, (2) lactate dehydrogenase (LDH), and / or (3) hemoglobin.

74. The aforementioned treatment, (i) Changes in dialysis requirements relative to baseline over weeks 10 and 52, (ii) Changes in observed eGFR values ​​and changes from baseline over weeks 10 and 52, (iii) Changes in observed serum creatinine levels and changes from baseline over weeks 10 and 52, and / or (iv) The method according to claim 72 or 73, which results in changes in observed values ​​and changes from baseline of a hematological parameter selected from (1) platelets, (2) lactate dehydrogenase (LDH), and / or (3) hemoglobin over weeks 10 and 52.

75. The aforementioned patient, (a) In the case of an established post-transplant anti-rejection regimen, (b) If the patient has been found to have anti-complement factor antibodies requiring immunosuppressive therapy, (c) When steroids are used to treat conditions other than aHUS, (d) The method according to any one of claims 72 to 74, wherein no immunosuppressive therapy comprising the steroid, a mammalian targeted (mTOR) inhibitor of rapamycin, or a calcineurin inhibitor is administered, except when the steroid is empirically initiated before treatment and tapered off as standard treatment.

76. The aforementioned patient had no prior experience with complement inhibitor therapy, and prior to the aforementioned administration cycle, the following occurred: (a) Platelet count less than 150,000 / μL, (b) LDH levels 1.5 times or higher than the upper limit of normal (ULN), (c) Hemoglobin below the lower limit of normal (LLN) for age and sex, (d) The method according to any one of claims 72 to 75, wherein evidence of thrombotic microangiopathy (TMA) is provided based on a serum creatinine level of the 97.5th percentile or higher of age.

77. The patient in question has prior experience with eculizumab or ravulizumab, and at the time of the TMA event, the following applies: (a) Increase in LDH exceeding ULN, (b) Increase in serum creatinine above ULN, and (c) The method according to any one of claims 72 to 75, wherein the platelet count was below LLN.

78. The aforementioned patient has experience with eculizumab or ravulizumab, (a) LDH less than 1.5 times ULN, (b) A platelet count of 150,000 / μL or more, (c) Using Schwarz's formula, 30 mL / min / 1.73 m ２ The method according to any one of claims 72-75 and 77, wherein there was clinical evidence of a response to eculizumab or ravulizumab, as indicated by stable TMA parameters including an estimated glomerular filtration rate (eGFR) of more than 100%.

79. The aforementioned patient has had a kidney transplant, (a) Having a known history of aHUS prior to the current kidney transplant, or (b) The method according to any one of claims 72 to 78, wherein the patient has no known history of HUS and has sustained evidence of TMA at least 4 days after modification of a mammalian-targeted immunosuppressive regimen of a calcineurin inhibitor or rapamycin inhibitor.

80. The method according to any one of claims 72 to 79, wherein the patient develops TMA postpartum and has persistent symptoms of TMA for more than three days from the date of delivery.

81. The aforementioned treatment, (i) Improvement of the patient's condition requiring dialysis, (ii) Change in eGFR level relative to baseline, (iii) Change in serum creatinine level relative to baseline, (iv) The method according to any one of claims 72 to 80, which results in a change from baseline of hematological parameters, including platelet, LDH, and / or hemoglobin levels.

82. The method according to any one of claims 30 to 81, wherein the treatment maintains (a) a serum trough concentration of free C5 less than 0.5 μg / mL during the administration cycle, and / or (b) a serum concentration of the therapeutic anti-C5 antibody or its antigen-binding fragment of 175 μg / mL during the administration cycle.

83. The method described above is (a) serum anti-C5 antibody or its antigen-binding fragment, and / or (b) The method according to any one of claims 30 to 82, further comprising monitoring the concentration of serum free C5.

84. (a) serum anti-C5 antibody or its antigen-binding fragment, and / or (b) The concentration of serum free C5 is, The method according to claim 83, determined from blood samples taken before and after each administration of the therapeutic anti-C5 antibody or its antigen-binding fragment.

85. The method according to claim 84, wherein the blood sample is collected within 30 minutes before the administration of the therapeutic anti-C5 antibody or its antigen-binding fragment and within 60 minutes after each administration.

86. The method according to any one of claims 30 to 85, wherein the treatment results in terminal complement inhibition.

87. The method according to any one of claims 30 to 86, wherein the treatment results in a reduction of hemolysis as assessed by LDH levels.

88. The method described above is (a) (i) adverse events (AEs) and serious AEs, and (ii) incidence rates of adverse drug events (ADEs) and serious ADEs, (b) the results of attempts to administer the full dose via OBI, and / or reported device defects or complaints, and investigation of the relevant devices, and / or (c) The method according to any one of claims 30 to 87, comprising monitoring the incidence, response category, and titer of anti-drug antibodies (ADAs).

89. The method according to any one of claims 30 to 88, wherein the treatment results in a change from baseline in patient-reported fatigue, as measured by Pediatric FACIT-Fatigue, and optionally, the patient is 8 years of age or older.

90. The method according to any one of claims 30 to 89, wherein the treatment results in a change from baseline on the PedsQL 4.0 general core scale.

91. A kit for treating PNH or aHUS in pediatric human patients, wherein the patient is either untreated with complement inhibitors or has received eculizumab treatment, (a) A certain dose of a therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, (b) A kit comprising instructions for using the therapeutic anti-C5 antibody or its antigen-binding fragment, according to any one of claims 30 and 32 to 89.

92. The therapeutic anti-C5 antibody or its antigen-binding fragment, (a) Once on the first day of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, administered intravenously at a dose of 2700 mg, (b) On the 15th day of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) The kit according to claim 91, which is administered subcutaneously to a patient weighing 40 kg or more at a dose of 490 mg.

93. The kit according to claim 91 or 92, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is provided in a 3 mL vial containing type I borosilicate glass for (a) intravenous administration and (b) subcutaneous administration to patients weighing 10 kg or more and less than 20 kg.

94. A kit for treating PNH or aHUS in a pediatric human patient, wherein the patient has prior experience with ravulizumab, (a) A certain dose of a therapeutic anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, (b) A kit comprising instructions for using the therapeutic anti-C5 antibody or its antigen-binding fragment, according to the method of any one of claims 31 to 89.

95. The therapeutic anti-C5 antibody or its antigen-binding fragment, On day 1 of the aforementioned administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) The kit according to claim 94, which is administered subcutaneously to a patient weighing 40 kg or more at a dose of 490 mg.

96. The kit according to any one of claims 91 to 95, wherein the pediatric human patient is under 21 years of age.

97. The kit according to claim 96, wherein the pediatric human patient is between 2 and 18 years of age.

98. The kit according to any one of claims 91 to 97, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is administered to a site selected from the patient's arm, abdomen, and thigh.

99. A therapeutic anti-C5 antibody or its antigen-binding fragment for use in the treatment of a pediatric human patient having PNH or aHUS, wherein the patient is either complement inhibitor-naïve or has received eculizumab treatment, wherein the treatment comprises administering to the patient in an effective amount during a treatment cycle the therapeutic anti-C5 antibody or its antigen-binding fragment, which comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) Once on the first day of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) In patients weighing 60 kg or more, administered intravenously at a dose of 2700 mg, (b) On the 15th day of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A therapeutic anti-C5 antibody or its antigen-binding fragment, administered subcutaneously at a dose of 490 mg to patients weighing 40 kg or more.

100. The use of a therapeutic anti-C5 antibody or its antigen-binding fragment in the manufacture of a drug for treating aHUS or PNH in a pediatric human patient requiring such treatment, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient is either complement inhibitor-naïve or has received eculizumab treatment, and the therapeutic anti-C5 antibody or its antigen-binding fragment is (a) Once on the first day of the administration cycle, (i) 600 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 900 mg for patients weighing 20 kg or more but less than 30 kg, (iii) 1200 mg for patients weighing 30 kg or more but less than 40 kg, (iv) 2400 mg for patients weighing 40 kg or more but less than 60 kg, (v) Administer intravenously to patients weighing 60 kg or more at a dose of 2700 mg, and (b) On the 15th day of the administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) Formulated for subcutaneous administration at a dose of 490 mg to patients weighing 40 kg or more.

101. A therapeutic anti-C5 antibody or its antigen-binding fragment for use in the treatment of a pediatric human patient having PNH or aHUS, wherein the patient has a history of ravulizumab therapy, wherein the treatment comprises administering to the patient in an effective amount during a treatment cycle the therapeutic anti-C5 antibody or its antigen-binding fragment, which comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment is On day 1 of the aforementioned administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) A therapeutic anti-C5 antibody or its antigen-binding fragment, administered subcutaneously at a dose of 490 mg to patients weighing 40 kg or more.

102. The use of a therapeutic anti-C5 antibody or its antigen-binding fragment in the manufacture of a drug for treating aHUS or PNH in a pediatric human patient requiring such treatment, wherein the therapeutic anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, wherein the patient has a history of ravulizumab treatment, and the therapeutic anti-C5 antibody or its antigen-binding fragment is On day 1 of the aforementioned administration cycle and every week thereafter, (i) 150 mg for patients weighing 10 kg or more but less than 20 kg, (ii) 245 mg for patients weighing 20 kg or more but less than 40 kg, (iii) Formulated for use in patients weighing 40 kg or more, administered subcutaneously once a week at a dose of 490 mg.

103. The therapeutic anti-C5 antibody or antigen-binding fragment thereof according to claim 99 or 101, or the use according to claim 100 or 102, wherein the pediatric human patient is under 21 years of age.

104. The therapeutic anti-C5 antibody or antigen-binding fragment thereof according to any one of claims 99, 101, and 103, wherein the pediatric human patient is 2 to 18 years of age, or the use according to any one of claims 100, 102, and 103.

105. A therapeutic anti-C5 antibody or antigen-binding fragment thereof according to any one of claims 99, 101, and 103-104, configured for subcutaneous administration to a site selected from the arm, abdomen, and thigh of the patient, or the use according to any one of claims 100 and 102-104.

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