Subcutaneous (SC) administration of anti-C5 antibodies for the treatment of complement-associated pathologies

Abstract

Methods for the clinical treatment of complement-associated conditions are provided, comprising administering to a patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is intended for administration) subcutaneously according to a specific clinical dosage regimen (i.e., at a specific dose size and according to a specific dosing schedule). In one embodiment, the patient has previously been treated with eculizumab (SOLIRIS®) or ravulizumab (ULTOMIRIS®); particularly intravenously administered SOLIRIS® or ULTOMIRIS®.

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the benefits of U.S. Provisional Patent Application No. 63 / 043613, filed on 24 June 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes a sequence listing filed electronically in ASCII format and incorporated herein by reference in its entirety. The ASCII copy was created on 28 April 2021, named 0633_WO_SL.txt, and is 58,818 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 complex aggregates of plasma proteins and membrane cofactors. Plasma proteins constitute approximately 10% of the globulins in vertebrate serum. Complement components achieve their immune defense functions through 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 summary of complement activation and associated biological activities can be found, for example, in The Merck Manual, 16. th It is included in the Edition.

[0004] A properly functioning complement system provides robust defense against infectious microorganisms, while improper regulation or activation of the complement pathway is involved in various disorders, such as the development of paroxysmal nocturnal hemoglobinuria (PNH). PNH is an extremely rare disorder caused by chronic, unregulated complement activation. The resulting inflammation and cellular damage lead to the devastating clinical manifestations of this disease.

[0005] PNH is a condition in which uncontrolled complement activity leads to systemic complications, primarily 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 triggered by various stressors, such as infection or physical exercise, leading to smooth muscle contraction (free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism is the most common cause of death in patients with PNH, and can result in pulmonary hypertension and damage to vital organs, such as the liver, kidneys, brain, and terminal intestines (see Hillmen, P., et al, Am.J. Hematol. 2010;85(8):553-559). As a result of these harmful pathogenic processes, patients with PNH have a reduced quality of life (QoL), which may include wasting fatigue, chronic pain, poor physical function, shortness of breath, abdominal pain, erectile dysfunction, need for anticoagulation therapy, need for blood transfusions, and in some cases, need for dialysis (Weitz, IC., et al., Thromb Res. 2012;130(3):361-368). Patients with PNH are at high risk of morbidity and mortality. Therefore, an object of the present invention is to provide an improved method for treating patients with PNH. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] The Merck Manual, 16th Edition [Non-Patent Document 2] Socie G, et al.,French Society of Haematology.Lancet.1996;348(9027):573-577 [Non-Patent Document 3] Brodsky,R.,Blood.2014;124(18):2804-2811

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0007] This application is in part based on data obtained from a Phase 3 randomized, open-label, parallel-group, multi-center joint study evaluating subcutaneous ravulizumab (ULTOMIRIS® SC) compared to intravenous ravulizumab (ULTOMIRIS® IV) in the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

[0008] As described herein, subcutaneous ravulizumab (ULTOMIRIS® SC) can be administered, for example, using a drug delivery device for the treatment of various complement-mediated disorders including, but not limited to, PNH, atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplantation-related thrombotic microangiopathy (HSCT-TMA), amyotrophic lateral sclerosis (ALS), complement-mediated thrombotic microangiopathy (CM-TMA), preeclampsia-hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), particularly including PNH and aHUS.

[0009] PNH is an extremely rare and severe blood disorder characterized by the destruction of red blood cells. Chronic hemolysis due to PNH leads to the formation of blood clots (which can occur in blood vessels throughout the body), damaging vital organs and potentially leading to premature death. Atypical HUS occurs when the complement system overreacts, causing the body to attack its own healthy cells. aHUS can cause progressive damage to vital organs, primarily the kidneys, through damage to blood vessel walls and blood clots. aHUS can lead to sudden organ failure or slow, gradual loss of function—which may require transplantation—and, in some cases, death. It occurs in both adults and children, and many patients are in critical condition, often requiring supportive care, including dialysis in the intensive care unit. Because the prognosis for aHUS can often be poor, timely and accurate diagnosis—in addition to treatment—is critically important for improving patient outcomes. aHUS can be distinguished from other hemolytic disorders by clinical testing.

[0010] This study, investigating ULTOMIRIS® SC in the treatment of PNH, included 136 clinically stable adult patients with a prior history of treatment with SOLIRIS® (eculizumab) for at least three months prior to study enrollment. The primary objective of this study was to determine the pharmacokinetic non-inferiority of ULTOMIRIS® SC compared to ULTOMIRIS® IV, as determined by ULTOMIRIS® serum trough concentration at day 71. Various secondary endpoints, including safety, immunogenicity, and various pharmacokinetic / pharmacodynamic (PK / PD), quality of life, device performance, and efficacy measures, were also continuously evaluated.

[0011] Patients were stratified by weight group (40kg to less than 60kg and 60kg to less than 100kg), and then randomized in a 2:1 ratio to receive either ULTOMIRIS® SC or ULTOMIRIS® IV. All patients received an initial IV loading dose on day 1. On day 15, patients in the ULTOMIRIS® SC group began receiving a fixed dose of ULTOMIRIS® SC self-administered once weekly, while patients in the ULTOMIRIS IV group received a single infusion of the approved weight-based IV dose.

[0012] In this study, its primary endpoint was achieved, and ULTOMIRIS®SC measured serum lablizumab trough concentration -C. トラフ Based on this, non-inferiority of the PK criteria compared to ULTOMIRIS® IV was demonstrated at day 71. For example, C トラフ Using geometric least squares mean (g-LSM) analysis of the levels, patients with ULTOMIRIS SC have a higher C than patients with ULTOMIRIS® IV. トラフ The levels were found to be high (the ratio of g-LSM in SC to g-LSM in IV was approximately 1.257). These data indicate that delivery of ULTOMIRIS® using the system and instrument of the present application results in a superior in vivo PK profile compared to conventional intravenous delivery methods.

[0013] In the comparative assessment of C5 marker levels, combined with the analysis of efficacy endpoints such as LDH levels, breakthrough hemolysis and transfusion avoidance, hemoglobin stability, and overall PNH symptoms, it was found that the patient profile of ULTOMIRIS® SC was comparable to, if not superior to, that of patients with ULTOMIRIS® IV. Therefore, regarding C5 inhibition, the results obtained in both the IV and SC groups throughout the randomized treatment period after the initial dose were below the defined threshold of 0.5 μg / mL; complete terminal complement inhibition. As a result of SC administration, ravulizumab exposure was ≥175 μg / mL, which was defined as the threshold for complete complement inhibition for all subjects without unexpected PK findings. Regarding the efficacy endpoints, (a) low breakthrough hemolysis levels were observed in both arms, with no events in the SC group; (b) transfusion avoidance was maintained in 94% and 87% of the SC and IV groups, respectively; (c) stable hemoglobin results were maintained in 94% and 82% of the SC and IV groups, respectively; and (d) symptoms of PNH were observed in 45% and 47% of the SC and IV groups, respectively.

[0014] Furthermore, preliminary safety data from this study throughout the 71-day randomized treatment period were consistent with the known safety profile for ULTOMIRIS®, and no unexpected safety findings occurred. Injection site reactions were reported in 26% of patients in the SC-treated arm.

[0015] All but one participant completed the randomized controlled treatment portion of this study and chose to continue in the ongoing open-label extension period. During the extension period, all patients will receive ULTOMIRIS® SC weekly for up to an additional 182 weeks. This extension period will provide 12 months of safety data for regulatory submissions.

[0016] This disclosure relates to the following non-limiting embodiments: In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition, comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs. 4, 5, and 6, respectively, during an administration cycle, wherein the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously (SC).

[0017] In some embodiments, the Disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is subcutaneously administered by a device containing an effective amount of anti-C5 antibody, such as ravulizumab or eculizumab or its biosimilar antibody, such as an on-body delivery system (OBDS).

[0018] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is subsequently administered at a dose of 490 mg per week.

[0019] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the human patient receives an intravenous loading dose before subcutaneous administration.

[0020] In some embodiments, the present disclosure relates to a method for treating human patients having the complement-related conditions described above or below, wherein the loading dose is a body weight-based dose, where (i) a dose of 2400 mg is administered to a patient weighing 40 kg or more but less than 60 kg, or (ii) a dose of 2700 mg is administered to a patient weighing 60 kg or more but less than 100 kg.

[0021] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the anti-C5 antibody or its antigen-binding fragment further 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, respectively, in EU numbering, at residues corresponding to methionine 428 and asparagine 434 in the natural human IgG Fc constant region.

[0022] In some embodiments, the disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is subcutaneously administered at a dose of 490 mg q1w on day 15 of the administration cycle and for at least 7 weeks thereafter.

[0023] In some embodiments, the present disclosure relates to a method for treating human patients having the complement-related conditions described above or below, wherein the treatment cycle comprises a total of 10 weeks of administration.

[0024] In some embodiments, the Disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is administered subcutaneously at a dose of 490 mg q1w for up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or chronically over the patient's lifetime.

[0025] In some embodiments, the disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the patient has a history of treatment with eculizumab.

[0026] In some embodiments, the disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the administration cycle is initiated at least two weeks after the patient's last dose of eculizumab.

[0027] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the anti-C5 antibody or its antigen-binding fragment comprises the heavy chain variable region of SEQ ID NO: 12 and the light chain variable region of SEQ ID NO: 8.

[0028] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the anti-C5 antibody or its antigen-binding fragment further comprises the heavy chain constant region of SEQ ID NO: 13.

[0029] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the 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.

[0030] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is present at pH 7.4 and 25°C with respect to human C5 at 0.1 nM ≤ K D affinity dissociation constant (K) in the range ≤ 1 nM D This concerns the method of joining using ).

[0031] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is converted to human C5 at pH 6.0 and 25°C. D This concerns a method for binding at a concentration of ≥10 nM.

[0032] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 100 μg / mL or higher during the administration cycle.

[0033] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the complement-related disorder is selected from the group consisting of atypical hemolytic uremic syndrome (aHUS), complement-mediated thrombotic microangiopathy (CM-TMA), paroxysmal nocturnal hemoglobinuria (PNH), neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), amyotrophic lateral sclerosis (ALS), pre-eclampsia / hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), generalized myasthenia gravis (gMG), dermatomyositis, and Guillain-Barré syndrome (GBS).

[0034] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment results in a reduction of terminal complement inhibition or hemolysis as determined by lactate dehydrogenase (LDH) levels.

[0035] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment produces at least one therapeutic effect selected from the group consisting of fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, and erectile dysfunction.

[0036] In some embodiments, the disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment causes a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones, and D-dimer.

[0037] In some embodiments, the disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment causes a shift toward normal levels of estimated glomerular filtration rate (eGFR) and chronic disease-related biomarkers selected from the group consisting of spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP).

[0038] In some embodiments, the Disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, the treatment resulting in a reduction in the need for blood transfusions and / or major adverse vascular events (MAVEs).

[0039] In some embodiments, the Disclosure relates to a method for treating human patients having complement-related conditions as described above or below, wherein the treatment results in a change from baseline in quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, 4th Edition, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Scale.

[0040] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is administered subcutaneously using an on-body delivery system (OBDS); preferably, the OBDS comprises a SMARTDOSE Gen I delivery platform; more preferably, the OBDS comprises a pharmaceutical formulation comprising 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and ravulizumab (70 mg / mL) in water for injection.

[0041] In some embodiments, the Disclosure relates to a method for treating human patients having the complement-related conditions described above or below, wherein the method is administered subcutaneously to deliver a serum ravulizumab trough concentration (C trough) of approximately 200 μg / ml to approximately 1000 μg / ml; preferably approximately 400 μg / ml to approximately 800 μg / ml; particularly approximately 550 μg / ml to approximately 650 μg / ml.

[0042] In some embodiments, the present disclosure relates to a method for treating human patients having the complement-related conditions described above or below, wherein an effective dose administered subcutaneously results in an increase in serum ravulizumab trough concentration (C trough) compared to an intravenous formulation containing ravulizumab; preferably the increase in C trough is about 5% to about 50%, preferably about 15% to about 35%.

[0043] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the treatment is administered subcutaneously to reduce the patient's free C5 level; preferably, the free C5 level is reduced to, for example, 0.5 μg / ml or less, until it falls below a defined threshold for complete terminal complement inhibition in the treated patient.

[0044] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein subcutaneous administration brings to the patient an in vivo rabulizumab level of complete complement inhibition threshold, for example, 175 μg / ml or higher.

[0045] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an effective dose of SC administration results in (a) attenuation of the patient's breakthrough hemolysis; (b) avoidance of blood transfusions in the patient; (c) stabilization of the patient's hemoglobin levels; and (d) reduction of at least one PNH symptom in the patient.

[0046] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is administered by injection over 5 to 9 minutes.

[0047] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is administered by a single or tandem subcutaneous (SC) device; preferably by a tandem device.

[0048] In some embodiments, the present disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein an anti-C5 antibody or its antigen-binding fragment is administered at a constant flow rate, for example, by a plurality of electromechanical pins.

[0049] In some embodiments, this disclosure relates to a method for treating a human patient having a complement-related condition as described above or below, wherein the patient is an adult patient weighing between 40 kg and 100 kg.

[0050] In some embodiments, the present disclosure relates to a device for subcutaneous administration of an anti-C5 antibody or its antigen-binding fragment for treating complement-mediated conditions, comprising (a) an on-body delivery system (OBDS); and (b) a subcutaneous (SC) formulation of the anti-C5 antibody or its antigen-binding fragment.

[0051] In some embodiments, the Disclosure relates to a device for treating complement-mediated pathologies as described above or below, wherein OBDS includes a SMARTDOSE Gen I delivery platform.

[0052] In some embodiments, the present disclosure relates to a device for treating complement-mediated conditions as described above or below, wherein the subcutaneous formulation of an anti-C5 antibody or its antigen-binding fragment comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and ravulizumab (70 mg / mL) in water for injection.

[0053] In some embodiments, the disclosure relates to a device for treating the complement-mediated pathological conditions described above or below, which delivers a dose of 490 mg to a human patient over a week.

[0054] In some embodiments, the disclosure relates to an on-body delivery system (OBDS) comprising an effective amount of a subcutaneous (SC) formulation for treating complement-mediated conditions, wherein the SC formulation comprises an anti-C5 antibody, such as ravulizumab or eculizumab or a biosimilar antibody thereof, or an antigen-binding fragment of an anti-C5 antibody; in particular, to an on-body delivery system (OBDS) wherein the SC formulation comprises ravulizumab.

[0055] In some embodiments, the disclosure relates to an on-body delivery system (OBDS) for treating complement-mediated conditions as described above or below, comprising (a) an injection device (platform) for delivering an anti-C5 antibody; (b) a pre-filled cartridge (PFC) containing the anti-C5 antibody attached to the platform; and (c) a telescopic screw assembly (TSA). In some embodiments, the PFC contains approximately 3.5 ml of ravulizumab at a concentration of approximately 70 mg / ml.

[0056] In some embodiments, the Disclosure relates to a kit for treating complement-related disorders or conditions, comprising (a) a device relating to any one of the aforementioned devices, e.g., an on-body delivery system (OBDS); and (b) instructions for use of a device for subcutaneous administration of an anti-C5 antibody or its antigen-binding fragment to a patient, e.g., a human patient.

[0057] This specification provides compositions and methods for treating complement-related conditions (e.g., PNH) in human patients, comprising administering an anti-C5 antibody or its antigen-binding fragment to the patient, wherein the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously (or is intended for such administration) according to a specific clinical dosing regimen (i.e., in a specific dose size and according to a specific dosing schedule). In one embodiment, the patient has a history of treatment with eculizumab (SOLIRIS®) or ravulizumab (ULTOMIRIS®); in particular, intravenous administration of SOLIRIS® or ULTOMIRIS®. In some embodiments, the patient is treatment-naive, in particular, treatment with an anti-C5 antibody, e.g., (SOLIRIS®) or ravulizumab (ULTOMIRIS®) or its biosimilar antibody.

[0058] Exemplary anti-C5 antibodies include ravulizumab (also known as ULTOMIRIS®, ALXN1210, and antibody BNJ441), which comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs. 14 and 11, respectively, or its antigen-binding fragments and variants. In other embodiments, the antibody comprises the heavy chain and light chain complementarity-determining regions (CDRs) or variable regions (VRs) 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 CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively.

[0059] In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13. In another embodiment, the antibody comprises a heavy chain polypeptide as set forth in SEQ ID NO: 14 and a light chain polypeptide as set forth in SEQ ID NO: 11. In another embodiment, the antibody 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 native human IgG Fc constant region, respectively, in EU numbering.

[0060] In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences set forth in SEQ ID NO: 4, 5, and 6, respectively, and 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 native human IgG Fc constant region in EU numbering, respectively.

[0061] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as the above antibody. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the above antibody (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 and SEQ ID NO: 8).

[0062] In another embodiment, the antibody has an affinity dissociation constant (K D in the range of 0.1 nM ≦ K D ) that binds to human C5 at pH 7.4 and 25°C. In another embodiment, the antibody has a K DIt binds to human C5 at a concentration of ≥10 nM. In yet another embodiment, the antibody [(K of the antibody or its antigen-binding fragment against human C5 at pH 6.0 and 25°C) D ) / (K of antibody against human C5 or its antigen-binding fragment at pH 7.4 and 25°C) D )] is greater than 25.

[0063] Exemplary complement-related conditions that can be treated according to the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), and muscular atrophy. Lateral sclerosis (ALS), complement-mediated thrombotic microangiopathy (CM-TMA), pre-eclampsia / hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal disappearance, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent fetal disappearance, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric vascular disease / Intestinal vascular disorders, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, Takayasu's arteriovenous arthritis, dilated cardiomyopathy, diabetic vascular disorders, Kawasaki disease, venous gas embolism, restenosis after stent placement, rotational atherosclerosis, percutaneous transluminal coronary angioplasty, generalized myasthenia gravis (gMG), cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, Atherow Examples include thyroid arteriosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type 1 diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture syndrome, Degos disease, fulminant antiphospholipid syndrome, and severe acute respiratory syndrome. Coronavirus 2 (also known as "SARS-CoV-2", "COVID-19", and "coronavirus") is also mentioned. In a detailed embodiment, the complement-related condition is atypical hemolytic uremic syndrome (aHUS). In another detailed embodiment, the complement-related condition is paroxysmal nocturnal hemoglobinuria (PNH).

[0064] In one embodiment, a method is provided for subcutaneously administering an anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab) to a patient (e.g., a patient with PNH) at a dose of 400 mg to 600 mg. In one embodiment, the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously to the patient at a dose of 450 to 550 mg. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to the patient in doses of approximately 400 mg, 405 mg, 410 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to the patient in a dose of approximately 490 mg.

[0065] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to a patient (e.g., a patient with PNH) at a dose of approximately 490 mg once a week (e.g., over 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or chronically, e.g., over the patient's lifetime).

[0066] In another embodiment, a method is provided for treating a patient with a complement-related condition (e.g., PNH) in which the patient is intravenously administered an initial dose (e.g., a loading dose) of anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab), followed by subcutaneous administration of anti-C5 antibody or its antigen-binding fragment (e.g., two weeks later). In one embodiment, the intravenous dose of anti-C5 antibody or its antigen-binding fragment is calculated based on the patient's body weight. For example, in one embodiment, a patient weighing 40 kg or more but less than 60 kg is intravenously administered 2400 mg of anti-C5 antibody or its antigen-binding fragment before subcutaneous treatment with anti-C5 antibody or its antigen-binding fragment. In another embodiment, a patient weighing 60 kg or more but less than 100 kg is intravenously administered 2700 mg of anti-C5 antibody or its antigen-binding fragment before subcutaneous treatment with anti-C5 antibody or its antigen-binding fragment.

[0067] In another embodiment, the patient receives subcutaneous administration of an anti-C5 antibody or its antigen-binding fragment (for example, at a dose of 490 mg) once a week (for example, over a period of 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or chronically, for example, over the patient's lifetime).

[0068] In another embodiment, the patient receives an intravenous dose (e.g., 2400 mg or 2700 mg) of anti-C5 antibody or its antigen-binding fragment on day 1 of the administration cycle, followed by subcutaneous administration of anti-C5 antibody or its antigen-binding fragment (e.g., in a dose of 490 mg) on ​​day 15 of the administration cycle and thereafter weekly (e.g., over 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or chronically, for example, over the patient's lifetime).

[0069] In another embodiment, a method is provided for treating a human patient having a complement-related condition (e.g., PNH), the method comprising administering to the patient an effective amount of anti-C5 antibody or its antigen-binding fragment 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. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0070] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 40 kg and 60 kg by (a) intravenously at a dose of 2400 mg once on day 1 of the administration cycle, and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter.

[0071] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 60 kg and less than 100 kg by (a) intravenously at a dose of 2700 mg once on day 1 of the administration cycle, and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter.

[0072] In another embodiment, a method is provided for treating a human patient having a complement-related condition (e.g., PNH), the method comprising administering to the patient an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof, during a dosing cycle, comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody, or the antigen-binding fragment thereof, (a) Once on day 1 of the administration cycle, i. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0073] In another embodiment, a method is provided for treating a human patient having a complement-related condition (e.g., PNH), the method comprising administering to the patient an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof, during a dosing cycle, comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises, in EU numbering, Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 in the natural human IgG Fc constant region, and the anti-C5 antibody, or an antigen-binding fragment thereof, (a) On day 1 of the administration cycle, i. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0074] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is formulated for intravenous administration (e.g., as an initial loading dose). For example, in one embodiment, the formulation for intravenous administration comprises 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and 300 mg of ravulizumab (10 mg / mL) in water for injection. In another embodiment, the formulation for intravenous administration consists of 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and 300 mg of ravulizumab (10 mg / mL) in water for injection. In yet another embodiment, ravulizumab for intravenous administration is formulated as a sterile, preservative-free concentrated aqueous solution (10 mg / mL) in a single-use 30 mL vial.

[0075] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is formulated for subcutaneous administration. For example, in one embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the subcutaneous formulation consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In yet another embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the subcutaneous formulation consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the ravulizumab for subcutaneous administration is formulated at a pH of 7.4.

[0076] 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 suitable means. In addition, the anti-C5 antibody, or its antigen-binding fragment, can be administered subcutaneously by a healthcare professional or by self-administration. In one embodiment, the anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously using an on-body delivery system (OBDS). In one embodiment, ravulizumab for subcutaneous administration is supplied in a 3.5 mL single-use cartridge. In another embodiment, each cartridge of ravulizumab for subcutaneous administration contains 262.5 mg of ravulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. In another embodiment, each cartridge of ravulizumab for subcutaneous administration contains 245 mg of ravulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. In another embodiment, ravulizumab for subcutaneous administration is formulated as a sterile, preservative-free concentrated aqueous solution (70 mg / mL) in a single-use 3.5 mL pre-filled cartridge designed for use in a single-use on-body delivery system. In one embodiment, OBDS is a SmartDose® drug delivery platform. In another embodiment, ravulizumab is administered by subcutaneous injection using a single-use OBDS with West SmartDose® Gen.I 3.5 mL.

[0077] In one embodiment, the administration cycle is a treatment totaling 10 weeks. In another embodiment, the anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously once a week at a dose of 490 mg for up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or chronically, for example, over the patient's lifetime. In some embodiments, the patient treated according to the method described herein has a prior history of treatment with complement inhibitors. In one embodiment, the patient has a prior history of treatment with eculizumab. In another embodiment, the patient has a prior history of treatment with eculizumab for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months. In a detailed embodiment, the patient has a prior history of treatment with eculizumab for at least 6 months. In another embodiment, the patient has a history of treatment with eculizumab at doses of 900 mg every two weeks. In another embodiment, the treatment is initiated at least two weeks after the patient's last dose of eculizumab.

[0078] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal disease within three years prior to or at the time of commencement of treatment. In one embodiment, patients treated less than two weeks after receiving the meningococcal vaccine are also treated with appropriate prophylactic antibiotics for up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135, and / or B.

[0079] In another embodiment, the treatment regimens described herein are sufficient to maintain specific serum trough concentrations of anti-C5 antibody or its antigen-binding fragment. For example, in one embodiment, 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 The treatment maintains a serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 245, 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 another 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 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 the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 250 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 300 μg / ml or higher. In another embodiment, the treatment maintains the 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 the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at approximately 175 μg / ml.

[0080] In some embodiments, to obtain an effective response, the anti-C5 antibody is administered in doses of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 1 μg per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50 μg to 250 μg of antibody per milliliter of the patient's blood. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 100 μg to 200 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0081] The effectiveness of the treatment methods provided herein can be determined by any preferred means. In one embodiment, for patients with PNH, the treatment produces at least one therapeutic effect selected from the group consisting of fatigue, abdominal pain, dyspnea, anemia [hemoglobin <10 g / dL], dysphagia, chest pain, and reduction or cessation of erectile dysfunction.

[0082] In another embodiment, the treatment causes terminal complement inhibition.

[0083] In another embodiment, the procedure results in a reduction in the need for blood transfusions.

[0084] In another embodiment, the treatment results in an increase in hemoglobin stabilization from the patient's pre-treatment baseline.

[0085] In another embodiment, the treatment results in a shift toward 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.

[0086] In another embodiment, the treatment results in a reduction of breakthrough hemolysis compared to treatment with eculizumab. In another embodiment, the treatment results in the elimination of breakthrough hemolysis during the treatment period. In another embodiment, the treatment results in a reduction of breakthrough hemolysis compared to the baseline amount of breakthrough hemolysis before treatment.

[0087] In another embodiment, the treatment results in a reduction of major adverse vascular events (MAVE). In yet another embodiment, the treatment results in a shift toward normal levels of estimated glomerular filtration rate (eGFR) and chronic disease-related biomarkers selected from the group consisting of spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP).

[0088] In another embodiment, the treatment results in a change from baseline in quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, 4th Edition, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Scale.

[0089] In detailed embodiments, responsiveness to treatment is assessed using lactate dehydrogenase (LDH) levels (for example, a reduction in hemolysis as determined by lactate dehydrogenase (LDH) levels is an indicator of improvement in at least one sign of PNH). For example, in one embodiment, the treatment described herein results in normalization of LDH levels.

[0090] In one embodiment, patients treated according to the method of this disclosure show a decrease in LDH levels to near-normal levels, or to within 10% or 20% above what is considered normal levels (e.g., within the range of 105 to 333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH levels normalize throughout the entire maintenance period of the treatment. In another embodiment, the treated patient's LDH levels normalize for at least 95% of the time during the maintenance period of the treatment. In another embodiment, the treated patient's LDH levels normalize for at least 90%, 85%, or 80% of the time during the maintenance period of the treatment.

[0091] In one embodiment, patients treated according to the method of the present disclosure show a decrease in LDH levels that falls within the normal range, or within 10%, 20%, 30%, 40%, or 50% below what is considered the upper limit of the normal range (for example, within the range of 105 to 333 IU / L (international units per liter)).

[0092] In another embodiment, (a) On day 1 of the administration cycle, i. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. An anti-C5 antibody, or an antigen-binding fragment thereof, is provided, comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 8, for administration.

[0093] Also provided are kits comprising a pharmaceutical composition containing a therapeutically effective amount suitable for use in the methods described herein, an anti-C5 antibody, such as ravulizumab, or its antigen-binding fragment, and a pharmaceutically acceptable carrier. For example, in one embodiment, a kit is provided for treating a human patient having a complement-related condition (e.g., PNH), which comprises (a) a certain dose of an anti-C5 antibody, or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for the use of the anti-C5 antibody, or its antigen-binding fragment, in the methods described herein. In one embodiment, the anti-C5 antibody, or its antigen-binding fragment, is administered to a patient weighing 40 kg or more but less than 60 kg by (a) intravenously at a dose of 2400 mg once on day 1 of the administration cycle; and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 60 kg and 100 kg intravenously at a dose of 2700 mg once on day 1 of the administration cycle; and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. In a detailed embodiment, the anti-C5 antibody is ravulizumab.

[0094] Furthermore, a device is provided that includes a pre-filled cartridge of ravulizumab for subcutaneous administration, packaged integrally with an on-body injection device. In one embodiment, the device is sterile, for single use, disposable, and / or electromechanical. In another embodiment, the on-body injection device includes a 29-gauge needle. In another embodiment, the pre-filled cartridge is a 3.5 mL cartridge. In another embodiment, the ravulizumab for subcutaneous administration comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg of ravulizumab (70 mg / mL) in water for injection. In another embodiment, the ravulizumab for subcutaneous administration consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg of ravulizumab (70 mg / mL) in water for injection. In another embodiment, ravulizumab for subcutaneous administration comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, ravulizumab for subcutaneous administration consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, ravulizumab for subcutaneous administration is formulated at a pH of approximately 7.4. [Brief explanation of the drawing]

[0095] [Figure 1] The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Subscale, 4th Edition Questionnaire, is shown. [Figure 2A] [Figure 2A-2B] Shows the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30). [Figure 2B][Figure 2A-2B] Shows the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30). [Figure 3] A sample of the Treatment Administration Satisfaction Questionnaire for Intravenous Administration (TASQ-IV) is shown. [Figure 4] A sample of the Treatment Administration Satisfaction Questionnaire for Subcutaneous Administration (TASQ-SC) is shown. [Figure 5] This is a schematic diagram illustrating the design of a Phase 3 non-inferiority study of subcutaneous (SC) administration of ravulizumab (ULTOMIRIS®) instead of intravenous administration (IV) in adult PNH patients currently treated with eculizumab (SOLIRIS®). The ravulizumab (ULTOMIRIS®) SC dosage is as follows: Day 1 loading dose (IV) = 2400 mg for patients weighing 40 kg to less than 60 kg and 2700 mg for patients weighing 60 kg to less than 100 kg; Day 15 and all subsequent SC doses = 490 mg weekly for all patients. The dosage of ravulizumab (ULTOMIRIS®) IV is as follows: Day 1 loading dose (IV) = 2400 mg for patients weighing 40 mg or more but less than 60 kg, and 2700 mg for patients weighing 60 kg or more but less than 100 kg; Day 15 maintenance dose (IV) = 3000 mg for patients weighing 40 kg or more but less than 60 kg, and 3300 mg for patients weighing 60 kg or more but less than 100 kg. The extended period maintenance dose (SC) is 490 mg weekly for all patients. [Figure 6] Summary of patient allocation and analysis population. [Figure 7A] [Figures 7A-7B] Show the patient's demographic information and baseline characteristics. [Figure 7B][Figures 7A-7B] Show the patient's demographic information and baseline characteristics. [Figure 8] A first-order PK non-inferiority analysis is presented. The following abbreviations are used: SE = standard error; LSM = least squares mean; CI = confidence interval. [Figure 9] This is a forest plot demonstrating PK non-inferiority. [Figure 10] The mean serum ravulizumab concentration is shown in the figure. [Figure 11] The free C5 concentration is shown in the figure. [Figure 12] The average values ​​of lactate dehydrogenase (LDH) are shown in the figure. [Figure 13] This demonstrates a breakthrough in hemolysis and avoidance of blood transfusions. [Figure 14] Hemoglobin stability and overall PNH symptoms are observed. [Figure 15] This document provides an overview of adverse events (AEs) that occurred during treatment. [Figure 16] This is a summary of serious adverse events (SAEs). [Modes for carrying out the invention]

[0096] I. Definition As used herein, the terms “subject” or “patient” refer to a human patient (for example, a patient with paroxysmal nocturnal hemoglobinuria (PNH)).

[0097] Paroxysmal nocturnal hemoglobinuria (PNH) is the most common acquired hemolytic disorder in adults (Brodsky, RA., Blood. 2015;126:2459-65). This disorder begins with clonal proliferation of hematopoietic stem cells that have acquired somatic mutations in the PIGA gene (Brodsky, RA., Blood. 2014;124:2804-11). As a result, PNH hemocytes lack glycophosphatidylinositol (GPI) anchored proteins and are deficient in membrane-bound complement inhibitory proteins CD55 and CD59. In the absence of CD55, deposition of complement protein C3 cleavage products on the hemocyte membrane surface increases, subsequently leading to cleavage of C5 to C5a and C5b. The lesions and clinical findings in patients with PNH are caused by uncontrolled terminal complement activation.

[0098] C5a is a potent anaphylatoxin, chemochemitic factor, and cell-activating molecule that mediates 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. p. 967-95). C5b recruits terminal complement components C6, C7, C8, and C9 to form the pro-inflammatory and pro-thrombotic cell-lytic 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 proceed unchecked, leading to hemolysis, release of free hemoglobin, and 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 lead to the release of free intracellular hemoglobin and lactate dehydrogenase (LDH) into the circulation as a direct result of hemolysis, irreversible binding of hemoglobin to nitric oxide (NO) and its inactivation, inhibition of NO synthesis, vasoconstriction and tissue ischemia due to the absence of vasodilatory NO, and microthrombi, platelet activation, and pro-inflammatory and pro-thrombotic states that may manifest as abdominal pain, dysphagia, and erectile dysfunction (Hill, et al., Blood 2013;121:4985-96; Brodsky RA., Blood. 2014;124:2804-1).

[0099] A significant proportion of PNH patients experience renal failure 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 RA., Blood. 2014;124:2804-1).

[0100] As used herein, “effective treatment” means a treatment that produces a beneficial effect, for example, relief of at least one symptom of a disease or disorder. An effective treatment may mean the relief of at least one symptom of PNH (e.g., fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, or erectile dysfunction). The beneficial effect may take the form of improvement compared to baseline, i.e., improvement compared to measurements or observations made before the commencement of treatment according to this method.

[0101] The term “effective dose” refers to the amount of a drug that provides a desired biological, therapeutic, and / or prophylactic outcome. This outcome may be a reduction, improvement, alleviation, decrease, delay, and / or mitigation of one or more signs, symptoms, or causes of a disease, or any other desired modification of the biological system. For example, an “effective dose” is the amount of anti-C5 antibody, or its antigen-binding fragment, that has been clinically proven to alleviate at least one symptom of PNH (e.g., fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, or erectile dysfunction). An effective dose may be administered in one or more doses.

[0102] As used herein, the terms “induction” and “induction phase” are used synonymously and refer to the first stage of treatment.

[0103] As used herein, the terms “maintenance” and “maintenance phase” are used synonymously and refer to the second stage of treatment. In certain embodiments, treatment is continued as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs.

[0104] As used herein, the term “loading dose” refers to the initial dose administered to a patient. For example, the loading dose may be 2400 mg or 2700 mg. The potency of the loading dose may be determined on a weight basis. In one embodiment, the loading dose is administered intravenously to the patient. In another embodiment, the loading dose is administered subcutaneously to the patient.

[0105] As used herein, the term “maintenance dose” refers to the dose administered to a patient after a loading dose. For example, a maintenance dose may be approximately 400 mg, 405 mg, 410 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg. In one embodiment, the maintenance dose of the anti-C5 antibody, or its antigen-binding fragment, is 490 mg. In one embodiment, the loading dose is administered subcutaneously to the patient.

[0106] 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) or pharmaceutical product 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 value of the drug level in the serum over time.

[0107] In one embodiment, the treatment regimen described is sufficient to maintain a specific serum trough concentration of anti-C5 antibody or its antigen-binding fragment. For example, in one embodiment, the treatment results in serum trough concentrations of anti-C5 antibody or its antigen-binding fragment being 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, 195, 200, 205, 21 The concentration is maintained at 0, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 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 the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 100 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 150 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 200 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 250 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 300 μg / ml or higher. In another embodiment, the treatment maintains the 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 the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at approximately 175 μg / ml.

[0108] In some embodiments, to obtain an effective response, the anti-C5 antibody is administered in doses of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 1 μg per milliliter of patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 50 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 50 μg to 250 μg of antibody per milliliter of the patient's blood. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 100 μg to 200 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient at a dose and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0109] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimum free C5 concentration. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL, or less. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.309 to 0.5 μg / mL. 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.

[0110] The term "antibody" refers to 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. For example, an antibody may be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. An antibody may also be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or domain antibody. An antibody may be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE. An antibody may be a naturally occurring antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, or conjugation to a non-antibody portion). For example, an antibody may contain one or more variant amino acids (compared to a naturally occurring antibody) that alter the antibody's properties (e.g., functional properties). For example, numerous such modifications are known in the art and affect, for instance, the half-life of antibodies in patients, effector function, and / or the immune response to them. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0111] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit its cleavage into fragments C5a and C5b. Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the present invention can be produced using methods well known in the art. Alternatively, anti-C5 antibodies recognized in the art can be used. Antibodies that compete with any of these antibodies recognized in the art for binding to C5 can also be used.

[0112] Eculizumab (also known as SOLIRIS®) is an anti-C5 antibody comprising heavy and light chains having sequences shown in SEQ ID NOs. 10 and 11, respectively, or its antigen-binding fragments and variants. Eculizumab is described in PCT / US1995 / 005688 and U.S. Patent No. 6,355,245, 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 shown in SEQ ID NOs. 7, and the CDR1, CDR2, and CDR3 domains of the VL region of eculizumab having the sequence shown in SEQ ID NOs. 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having sequences shown in SEQ ID NOs. 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having sequences shown in SEQ ID NOs. 4, 5, and 6, respectively. In another embodiment, the antibody includes VH and VL regions having the amino acid sequences shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

[0113] Exemplary anti-C5 antibodies include ravulizumab, or its antigen-binding fragments and variants, comprising heavy and light chains having the sequences shown in SEQ ID NOs. 14 and 11, respectively. Rabulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference. The terms ULTOMIRIS®, BNJ441, and ALXN1210 may be used interchangeably throughout this document but all refer to the same antibody. 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 invasion complex (MAC) C5b-9, while preserving proximal or early components (e.g., C3 and 3b) of complement activation essential for microbial opsonization and immune complex clearance.

[0114] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. For example, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0115] Another exemplary anti-C5 antibody is antibody BNJ421, which comprises heavy and light chains having the sequences shown in SEQ ID NOs. 20 and 11, respectively, or its antigen-binding fragments and variants. BNJ421 (also known as ALXN1211) is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference.

[0116] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NOs: 12 and 8, respectively.

[0117] The precise boundaries of CDRs have been defined in various ways according to different methods. In some embodiments, the location of a CDR or framework region within a light chain or heavy chain variable domain may be 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 a CDR in a light chain or heavy chain variable region may be as defined by Chothia et al. (1989) Nature 342:877-883. Thus, these regions may be referred to as “Chothia CDR” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the location of CDRs in light chain and heavy chain variable regions may be as defined by the Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as "combined Kabat-Chothia CDRs." Thomas et al. [(1996) Mol Immunol 33(17 / 18):1389-1401] illustrate the identification of CDR boundaries according to the definitions of Kabat and Chothia.

[0118] In some embodiments, the anti-C5 antibody described herein has the following amino acid sequence: [ka] It contains or comprises a heavy chain CDR1 comprising the following amino acid sequence: [ka] It contains or comprises a heavy chain CDR2 comprising the following amino acid sequence: [ka] It includes a heavy chain variable region.

[0119] In some embodiments, the anti-C5 antibody described herein has the following amino acid sequence: It includes a light chain variable region containing DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (Sequence ID 8).

[0120] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 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. Patent Nos. 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 shown in SEQ ID NOs. 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs. 24, 25, and 26, respectively. In another embodiment, the antibody, or its antigen-binding fragment, comprises the VH region of the 7086 antibody having the sequence shown in SEQ ID NO. 27, and the VL region of the 7086 antibody having the sequence shown in SEQ ID NO. 28.

[0121] Another exemplary anti-C5 antibody is the 8110 antibody described in U.S. Patent No. 8,241,628 and No. 8,883,158, respectively. 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 sequences shown in SEQ ID NOs. 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having sequences shown 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 shown in SEQ ID NO. 35, and the VL region of the 8110 antibody having the sequence shown in SEQ ID NO. 36.

[0122] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent Application Publication No. 2016 / 0176954A1. 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 sequences shown in SEQ ID NOs. 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having sequences shown 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 shown in SEQ ID NO. 43, and the VL region of the 305LO5 antibody having the sequence shown in SEQ ID NO. 44.

[0123] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa T., et al., Rep. 2017 Apr 24;7(1):1080). 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.

[0124] Another exemplary anti-C5 antibody is the REGN3918 antibody (also known as H4H12166PP) described in U.S. Patent Application Publication No. 20170355757. In one embodiment, the antibody comprises a heavy chain variable region including SEQ ID NO: 47 and a light chain variable region including SEQ ID NO: 48. In another embodiment, the antibody comprises a heavy chain including SEQ ID NO: 49 and a light chain including SEQ ID NO: 50.

[0125] In another embodiment, the antibody competes for binding with the aforementioned antibodies (e.g., eculizumab, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody) and / or binds to the same epitope on C5. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the aforementioned antibodies (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity).

[0126] The anti-C5 antibodies described herein, 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 is derived. For example, the Fc constant region may contain one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the variant human Fc constant region is derived. At pH 6.0, the substitutions may increase the binding affinity of the IgG antibody containing the variant Fc constant region to FcRn while maintaining the pH dependence of the interaction.

[0127] Substitutions that improve the binding affinity of the Fc constant region of antibodies to FcRn are known in the art and include, for example, (1) the M252Y / S254T / T256E triple substitution described by Dall'Acqua et al. (2006) J Biol Chem 281:23514-23524; (2) the M428L or T250Q / M428L substitution described by Hinton et al. (2004) J Biol Chem 279:6213-6216 and Hinton et al. (2006) J Immunol 176:346-356; and (3) the N434A or T307 / E380A / N434A substitution described by Petkova et al. (2006) Int Immunol 18(12):1759-69. Additional substitution pairs, P257I / Q311I, P257I / N434H, and D376V / N434H, are described, for example, in Datta-Mannan et al. (2007) J Biol Chem 282(3):1709-1717, the disclosure of which is incorporated herein by reference in whole. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region to FcRn at pH 6.0 (while maintaining the pH dependence of this interaction) are known in the art and illustrated in the examples. See, for example, PCT / US2015 / 019225 and U.S. Patent No. 9,079,949 (the disclosures of each of these are incorporated herein by reference in whole).

[0128] 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.

[0129] 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) relative 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 of the Fc constant region of native human IgG, respectively, in EU numbering. In some embodiments, the variant Fc steady-state region includes, for example, the 428L / 434S double substitution as described in U.S. Patent No. 8,088,376.

[0130] In some embodiments, the variant constant region includes substitutions of the amino acid at 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) relative to the natural human Fc constant region. In some embodiments, 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; alanine, glycine, isoleucine, leucine, methionine, Asparagine, serine, threonine, or valine; histidine in place of glutamic acid at position 258; alanine in place of aspartic acid at position 265; phenylalanine in place of aspartic acid at position 270; alanine or glutamic acid in place of asparagine at position 286; histidine in place of threonine at position 289; alanine in place of asparagine at position 297; glycine in place of serine at position 298; alanine in place of valine at position 303; alanine in place of valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine;Alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine replaces valine at position 308; alanine, aspartic acid, glutamic acid, proline, or arginine replaces leucine or valine at position 309; alanine, histidine, or isoleucine replaces glutamine at position 311; alanine or histidine replaces aspartic acid at position 312; leucine at position 314 is replaced by For lysine or arginine; alanine or histidine in place of asparagine at position 315; alanine in place of lysine at position 317; glycine in place of asparagine at position 325; valine in place of isoleucine at position 332; leucine in place of lysine at position 334; histidine in place of lysine at position 360; alanine in place of aspartic acid at position 376; alanine in place of glutamic acid at position 380; at position 382 Alanine replaces glutamic acid; alanine replaces asparagine or serine at position 384; aspartic acid or histidine replaces glycine at position 385; proline replaces glutamine at position 386; glutamic acid replaces proline at position 387; alanine or serine replaces asparagine at position 389; alanine replaces serine at position 424; alanine, aspartic acid, or phenylalanine replaces methionine at position 428. Selected from the group consisting of alanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine; lysine instead of histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine instead of asparagine at position 434; and histidine instead of tyrosine or phenylalanine at position 436.

[0131] In some embodiments, the exact locations of these mutations may be shifted from the natural human Fc constant region due to antibody manipulation. For example, the 428L / 434S double substitution when used in IgG2 / 4 chimeric Fc may correspond to 429L and 435S when found in the M429L and N435S variants of BNJ441 (ravulizumab), as described in U.S. Patent No. 9,079,949 (this disclosure is incorporated herein by reference in its entirety).

[0132] Suitable anti-C5 antibodies for use in the methods described herein include, in some embodiments, a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11. Alternatively, suitable anti-C5 antibodies for use in the methods described herein include, in some embodiments, a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11.

[0133] In one embodiment, the antibody has an affinity dissociation constant (K) 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 at 25°C (or under physiological conditions). D ) binds to C5. In some embodiments, an anti-C5 antibody or its antigen-binding fragment K D The saturation is 1 nM or less (for example, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 nM or less).

[0134] In another embodiment, the dissociation index [(K of the antibody against C5 at pH 6.0, 25°C] D ) / (K of antibody against C5 at pH 7.4, 25℃) 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, 240, These are 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 over 8000.

[0135] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. For example, antibody binding to a protein antigen can be detected and / or quantified using various techniques, for example, but not limited to, Western blotting, dot blotting, surface plasmon resonance (SPR) (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA). For example, see Benny KCLo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne et al. (1993) J Immunol Meth 160:191-198; Jonsson et al. (1993) Ann Biol Clin 51:19-26; and Jonsson et al. (1991) Biotechniques 11:620-627. Furthermore, methods for measuring affinity (e.g., dissociation and association constants) are shown in the examples.

[0136] As used herein, the term "k a " refers to the rate constant for the association of antibodies with an antigen. d" refers to the rate constant for the dissociation of antibodies from antibody / antigen complexes. And the term "K" D " refers to the equilibrium dissociation constant of antibody-antigen interaction. The equilibrium dissociation constant is the ratio K of the kinetic rate constants. D =k a / k d This is estimated from the above. Such determinations are preferably measured at 25°C or 37°C (see Examples). For example, the kinetics of antibody binding to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5, and 6.0 via surface plasmon resonance (SPR) on a BIAcore3000 instrument using an anti-Fc capture method for immobilizing the antibody.

[0137] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment, blocks the generation or activity of 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 invasion complex (MAC) on the cell surface.

[0138] Methods for determining whether the specific antibodies described herein inhibit C5 cleavage are known in the art. Inhibition of human complement component C5 may reduce the cytolytic capacity of complement in the body fluid of the subject. Such reduction of the cytolytic capacity of complement present in body fluid can be achieved by methods well known in the art, for example, conventional hemolysis assays, e.g., Kabat and Mayer (eds.), “Experimental Immunochemistry, 2 ndThe hemolysis assay described in "Edition," 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or a modified version of the assay, for example, the chicken erythrocyte hemolysis method described in Hillmen et al. (2004) N Engl J Med 350(6):552, can be used for measurement. A method for determining whether a candidate compound inhibits the cleavage of human C5 to morphologies C5a and C5b is known in the art, as described in Evans et al. (1995) Mol Immunol This is described in 32(16):1183-95. For example, the concentrations and / or physiological activities of C5a and C5b in body fluids can be measured by methods well known in the art. For C5b, the hemolytic assays or assays for soluble C5b-9 discussed herein can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen for candidate agents that can inhibit human complement component C5.

[0139] Immunological techniques, such as ELISA (but not limited to ELISA), can be used to measure the protein concentrations of C5 and / or its fractional products 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, the production of C5a is measured. In some embodiments, terminal complement formation is detected using a C5b-9 neoepitope-specific antibody.

[0140] A hemolysis assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment against complement activation. For example, using hemolysin-coated sheep erythrocytes or chicken erythrocytes sensitized with an anti-chicken erythrocyte antibody as target cells, the effect of an anti-C5 antibody or its antigen-binding fragment on classical complement pathway-mediated hemolysis in serum reagents can be determined in vitro. The lysis rate is normalized by considering 100% lysis, which is equivalent 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, for example, as 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 fluorescent substrate, and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of an anti-C5 antibody or its antigen-binding fragment. In some embodiments, the test serum is C5-deficient serum reconstituted with a C5 polypeptide.

[0141] The effect of anti-C5 antibodies, or their antigen-binding fragments, on alternative pathway-mediated hemolysis can be determined by using unsensitized rabbit or guinea pig erythrocytes as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The lysis rate 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 lipopolysaccharide molecules, for example, as used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with 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 fluorescent substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum is incubated in the absence of anti-C5 antibody, or its antigen-binding fragment.

[0142] 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 is a lysis assay that determines the amount (CH50) required to obtain 50% lysis using antibody-sensitized erythrocytes and various dilutions of the test serum as activators of the classical complement pathway. The hemolysis rate can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, as the TCC itself is directly responsible for the measured hemolysis.

[0143] This assay is well known and commonly performed by those skilled in the art. 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 is then diluted in microassay wells coated with a capture reagent (e.g., an antibody that binds to one or more components of TCCs). The TCCs present in the activated sample bind to the monoclonal antibody coating the surface of the microassay well. The wells are washed, and a detection reagent, which is detectably labeled and recognizes the bound TCCs, is added to each well. The detectable label may be, for example, fluorescent or enzymatic. The assay results are expressed in units of CH50 equivalents per milliliter (CH50U Eq / mL).

[0144] Inhibition, for example, in relation to terminal complement activity, may include 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) at equimolar concentrations under similar conditions. Significant 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 or more) 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 to the CDR of eculizumab (i.e., SEQ ID NOs: 1-6) and still 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.

[0145] The anti-C5 antibodies described herein have a serum half-life of at least 20 days in humans (for example, 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 of at least 40 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of about 43 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of 39 to 48 days in humans. Methods for measuring the serum half-life of antibodies are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments described herein have a serum half-life 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 when 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).

[0146] 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 the antigen:antibody complex crystals and hydrogen / deuterium exchange mass spectrometry (HDX-MS), which provide atomic resolution of the epitope. Other methods involve monitoring the binding of the antibody to peptide antigen fragments or mutant variations of the antigen, in which case the loss of binding due to alteration of amino acid residues in the antigen sequence is often considered an indicator of the epitope component. Furthermore, combinatorial calculation methods can also be used for epitope mapping. These methods depend on the ability of the target antibody to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL sequences, or the same CDR1, 2, and 3 sequences, are expected to bind to the same epitope.

[0147] An antibody that "competes with another antibody for binding to a target" refers to an antibody that (partially or completely) inhibits the binding of another antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether one antibody inhibits the binding of the other antibody to the target and to what extent, can be determined using known competition experiments. In some embodiments, an antibody competes with another antibody and inhibits the binding of the other antibody to the target 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 the "blocking antibody" (i.e., the cold antibody initially incubated with the target). Competing antibodies bind to the same epitope, overlapping epitope, or adjacent epitope (e.g., demonstrated by steric hindrance).

[0148] The anti-C5 antibodies described herein, or their antigen-binding fragments, used in the methods described herein, can be produced using various techniques recognized in the art. Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, splenocytes from animals immunized with the desired antigen are immortalized, generally by fusion with myeloma cells (see Kohler & Milstein, Eur.J.Immunol.6:511-519 (1976)). Alternative methods of immortalization include transformation using Epstein-Barr virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies resulting from single immortalized cells can be 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 improved by various techniques, e.g., intraperitoneal injection of vertebrate hosts. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening a DNA library from human B cells according to a general protocol outlined by Huse, et al., Science 246:1275-1281 (1989).

[0149] III. Composition Furthermore, this specification also provides compositions (e.g., formulations) comprising an anti-C5 antibody or an antigen-binding fragment thereof for use in the treatment methods described herein. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2, and CDR3 domains in a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains in a light chain variable region having the sequence shown 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.

[0150] The composition may be formulated, for example, as a pharmaceutical solution for administration to subjects for the treatment or prevention of complement-related conditions such as PNH. 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 contain pharmaceutically acceptable salts, such as acid addition salts or base addition salts, sugars, carbohydrates, polyols and / or tension modifiers.

[0151] The composition can be formulated according to standard methods. Pharmaceutical formulation is an established technology, for example, 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 rdFurther details are provided in Edition (ISBN: 091733096X). In some embodiments, the compositions can be formulated, for example, as buffer solutions suitable for storage at 2-8°C (e.g., 4°C) at a preferred concentration. In some embodiments, the compositions can be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions 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.

[0152] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquids (e.g., injections and infusions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended method of administration and therapeutic use. For example, a composition containing a composition intended for systemic or local delivery may be in the form of an injection or infusion. Thus, a composition may be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). When used herein, “parenteral administration,” “administer parenterally,” and other grammatically equivalent terms refer to methods of administration other than intestinal and topical administration, usually by injection, including, but not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intrathecal, epidural, intracerebral, intracranial, carotid, and intrasternal injections and infusions.

[0153] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is formulated for intravenous administration. For example, in one embodiment, the formulation for intravenous administration comprises 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and 300 mg of ravulizumab (10 mg / mL) in water for injection. In another embodiment, the formulation for intravenous administration consists of 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and 300 mg of ravulizumab (10 mg / mL) in water for injection. In yet another embodiment, ravulizumab for intravenous administration is formulated as a sterile, preservative-free concentrated aqueous solution (10 mg / mL) in a single-use 30 mL vial.

[0154] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is formulated for subcutaneous administration. For example, in one embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In yet another embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the subcutaneous formulation comprises 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the ravulizumab for subcutaneous administration is formulated at a pH of 7.4. In another embodiment, the ravulizumab for subcutaneous administration is supplied in a 3.5 mL single-use cartridge. In another embodiment, each cartridge of ravulizumab for subcutaneous administration contains 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, each cartridge of ravulizumab for subcutaneous administration contains 245 mg of ravulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. In another embodiment, ravulizumab for subcutaneous administration is formulated as a sterile, preservative-free concentrated aqueous solution (70 mg / mL) in a single-use 3.5 mL pre-filled cartridge designed for use in a single-use on-body delivery system.

[0155] IV. Method This specification provides compositions and methods for treating complement-related conditions (e.g., PNH) in human patients, comprising administering an anti-C5 antibody or its antigen-binding fragment to the patient, wherein the anti-C5 antibody or its antigen-binding fragment is administered subcutaneously (or is intended for such administration) according to a specific clinical dosing regimen (i.e., in a specific dose size and according to a specific dosing schedule). In one embodiment, the patient has a prior history of treatment with eculizumab (SOLIRIS®).

[0156] Exemplary complement-related conditions that can be treated according to the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), and muscular atrophy. Lateral sclerosis (ALS), complement-mediated thrombotic microangiopathy (CM-TMA), pre-eclampsia / hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal disappearance, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent fetal disappearance, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric vascular disease / Intestinal vascular disorders, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, Takayasu's arteriovenous arthritis, dilated cardiomyopathy, diabetic vascular disorders, Kawasaki disease, venous gas embolism, restenosis after stent placement, rotational atherosclerosis, percutaneous transluminal coronary angioplasty, generalized myasthenia gravis (gMG), cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, Atherow Examples include thyroid arteriosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type 1 diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture syndrome, Degos disease, fulminant antiphospholipid syndrome, and severe acute respiratory syndrome. Coronavirus 2 (also known as "SARS-CoV-2", "COVID-19", and "coronavirus") is also mentioned. In a detailed embodiment, the complement-related condition is atypical hemolytic uremic syndrome (aHUS). In another detailed embodiment, the complement-related condition is paroxysmal nocturnal hemoglobinuria (PNH).

[0157] In one embodiment, a method is provided for subcutaneously administering an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), to a patient (e.g., a patient with PNH) at a dose of 400 mg to 600 mg. In one embodiment, the anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to a patient (e.g., a patient with PNH) at a dose of 450 to 550 mg. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to the patient in doses of approximately 400 mg, 405 mg, 410 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to the patient in a dose of approximately 490 mg.

[0158] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously to a patient with a complement-related condition (e.g., PNH) at a dose of approximately 490 mg once weekly (e.g., over 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or chronically, e.g., over the patient's lifetime).

[0159] In another embodiment, a method is provided for treating a patient with a complement-related condition (e.g., PNH) in which the patient is intravenously administered an initial dose (e.g., a loading dose) of anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab), followed by subcutaneous administration of anti-C5 antibody or its antigen-binding fragment (e.g., two weeks later). In one embodiment, the intravenous dose of anti-C5 antibody or its antigen-binding fragment is calculated based on the patient's body weight. For example, in one embodiment, a patient weighing 40 kg or more but less than 60 kg is intravenously administered 2400 mg of anti-C5 antibody or its antigen-binding fragment before subcutaneous treatment with anti-C5 antibody or its antigen-binding fragment. In another embodiment, a patient weighing 60 kg or more but less than 100 kg is intravenously administered 2700 mg of anti-C5 antibody or its antigen-binding fragment before subcutaneous treatment with anti-C5 antibody or its antigen-binding fragment.

[0160] In another embodiment, the patient receives an intravenous dose (e.g., 2400 mg or 2700 mg) of anti-C5 antibody or its antigen-binding fragment on day 1 of the administration cycle, followed by subcutaneous administration of anti-C5 antibody or its antigen-binding fragment (e.g., in a dose of 490 mg) on ​​day 15 of the administration cycle and thereafter weekly (e.g., over 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or chronically, for example, over the patient's lifetime).

[0161] In another embodiment, a method is provided for treating a human patient having a complement-related condition (e.g., PNH), the method comprising administering to the patient an effective amount of anti-C5 antibody or its antigen-binding fragment 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. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0162] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 40 kg and 60 kg (e.g., PNH patients) (a) intravenously at a dose of 2400 mg once on day 1 of the administration cycle, and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter.

[0163] In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 60 kg and 100 kg (e.g., PNH patients) (a) intravenously at a dose of 2700 mg once on day 1 of the administration cycle, and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter.

[0164] In another embodiment, a method is provided for treating a human patient having a complement-related condition, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof, during a dosing cycle, comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody, or the antigen-binding fragment thereof, (a) Once on day 1 of the administration cycle, i. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0165] In another embodiment, a method is provided for treating a human patient having a complement-related condition (e.g., PNH), the method comprising administering to the patient an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof, during a dosing cycle, comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises, in EU numbering, Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 in the natural human IgG Fc constant region, and the anti-C5 antibody, or an antigen-binding fragment thereof, (a) On day 1 of the administration cycle, i. 2400 mg for patients weighing 40 kg or more but less than 60 kg, ii. 2700 mg for patients weighing between 60 kg and 100 kg. Intravenously in the dose of; and (b) Subcutaneously administer a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. It will be administered.

[0166] In one embodiment, the administration cycle is a treatment totaling 10 weeks. In another embodiment, the anti-C5 antibody, or its antigen-binding fragment, is administered subcutaneously once a week at a dose of 490 mg for up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or chronically, for example, over the patient's lifetime.

[0167] In some embodiments, the patient treated according to the method described herein has a prior history of treatment with complement inhibitors. In one embodiment, the patient has a prior history of treatment with eculizumab. In another embodiment, the patient has a prior history of treatment with eculizumab for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months. In a detailed embodiment, the patient has a prior history of treatment with eculizumab for at least 6 months. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is administered to a patient who has a history of treatment with eculizumab for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months prior to day 1 of the administration cycle. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to a patient who has a history of treatment with eculizumab for at least about 1 year prior to day 1 of the administration cycle. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to a patient who has a history of treatment with eculizumab for at least about 6 months prior to day 1 of the administration cycle.

[0168] In some embodiments, an anti-C5 antibody, or its antigen-binding fragment, is administered to a patient who has a prior history of treatment with eculizumab at doses of approximately 600 mg, 700 mg, 800 mg, or 900 mg every two weeks. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to a patient who has a prior history of treatment with eculizumab at doses of approximately 900 mg every two weeks ([q2w]).

[0169] In some embodiments, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is administered to the patient, where the administration cycle is initiated at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 7 weeks, or at least about 8 weeks after the patient's last dose of eculizumab. In other embodiments, an anti-C5 antibody, or its antigen-binding fragment (e.g., ravulizumab), is administered to the patient, where the administration cycle is initiated at least 2 weeks after the patient's last dose of eculizumab.

[0170] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal disease within three years prior to or at the time of commencement of treatment. In one embodiment, patients treated less than two weeks after receiving the meningococcal vaccine are also treated with appropriate prophylactic antibiotics for up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135, and / or B.

[0171] In another embodiment, the treatment regimen described is sufficient to maintain a specific serum trough concentration of anti-C5 antibody or its antigen-binding fragment. For example, in one embodiment, 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, 195, 200, 205, 210, 215, 220, 225, 230, 235, 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, 275, 280, 285, 290, 295, 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 another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 200 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 250 μg / ml or higher. In another embodiment, the treatment maintains the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at 300 μg / ml or higher. In another embodiment, the treatment maintains the 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 the serum trough concentration of anti-C5 antibody or its antigen-binding fragment at approximately 175 μg / ml.

[0172] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered in doses of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 15 μg per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 0 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50 μg to 250 μg of antibody per milliliter of the patient's blood. In yet another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 100 μg to 200 μg of antibody per milliliter of the patient's blood. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0173] V. Outcome This specification provides a method for treating PNH in patients. Symptoms of PNH include, but are not limited to, fatigue (e.g., fatigue, difficulty performing daily activities, difficulty concentrating, dizziness, weakness), pain (e.g., stomach pain, pain or swelling of the lower extremities, chest pain, back pain), dark urine, shortness of breath, anemia, dysphagia, yellowing of the skin and / or eyes, anemia, cytopenia, erectile dysfunction, blood clots, kidney disease, organ injury, stroke, or heart attack. Patients treated according to the methods disclosed herein will preferably experience improvement in at least one sign of PNH. For example, treatment may produce at least one therapeutic effect selected from the group consisting of reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

[0174] 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 outcomes are 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 subsequently continuous 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 with LDH levels greater than ≥1.5 times the upper limit of normal (LDH ≥ 1.5 × ULN), and there is a significant correlation between LDH and cell-free plasma hemoglobin (Hillmen, P. et al., N. Engl. J. Med., 355:1233-43, 2006). The normal LDH range is 105–333 IU / L (International Units per Liter).

[0175] Previously published data support that LDH is a reliable, objective, and direct measure of intravascular hemolysis in PNH patients, and experts consider it to be the best measure of complement-mediated hemolysis, a prominent feature of PNH disease activity (Dale J. et al., Acta Med Scand., 191(1-2):133-136, 1972; Parker C. et al., Blood. 106(12):3699-3709, 2005; Canalejo K et al., Int J Lab Hemat., 36(2):1213-1221, 2013). Results from the eculizumab clinical program revealed that in untreated (placebo) patients, LDH levels remained significantly elevated and unchanged, while in patients treated with eculizumab, serum LDH levels decreased immediately (within one week of treatment initiation) to normal or near-normal levels (Brodsky RA et al., Blood, 111(4):1840-1847, 2008; Hillmen P et al., Am J Hematol., 85(8):553-559, 2010. Erratum in Am J Hematol. 2010; 85(11):911). This decrease was reflected in a rapid reduction in symptoms and improvement in fatigue (Hillmen P et al., Am J Hematol., 85(8):553-559, 2010; Brodsky RA et al., Blood, 111(4):1840-1847, 2008).

[0176] LDH levels can be measured using any suitable test or assay, for example, 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 various samples obtained from patients, particularly serum samples. As used herein, the term “sample” refers to biological material from a subject. While serum LDH concentrations are the focus, the sample may originate from other resources, such as single cells, multiple cells, tissues, tumors, body fluids, biological molecules, or supernatants or extracts of any of the above. Examples include tissues taken for biopsy, tissues taken during excision, blood, urine, lymphoid tissue, lymph fluid, cerebrospinal fluid, mucous membranes, and fecal samples. The samples used will vary depending on the assay format, detection method, and the nature of the tumor, tissue, cell, or extract to be assayed. Methods for preparing samples are known in the art and can be easily adapted to obtain samples that are compatible with the method being used.

[0177] In one embodiment, LDH levels are used to assess responsiveness to treatment (for example, a reduction in hemolysis as determined by LDH levels is an indicator of improvement in at least one sign of PNH). For example, in one embodiment, the treatment described herein results in normalization of LDH levels. In another embodiment, patients treated according to the method of this disclosure show a decrease in LDH levels to near-normal levels, or to within 10% or 20% above what is considered normal levels (e.g., within the range of 105–333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH level is 1.5 times or more above the upper limit of normal (LDH ≥ 1.5 × ULN) before the start of treatment. In another embodiment, the patient's LDH level normalizes throughout the entire maintenance period of treatment. In another embodiment, the treated patient's LDH level normalizes for at least 95% of the time during the maintenance period of treatment. In another embodiment, the treated patient's LDH level normalizes for at least 90%, 85%, or 80% of the time during the maintenance period of treatment. 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 the start of treatment.

[0178] In another embodiment, the treatment results in a reduction of breakthrough hemolysis compared to treatment with eculizumab. In another embodiment, the treatment results in the elimination of breakthrough hemolysis during the treatment period. In another embodiment, the treatment results in a reduction of breakthrough hemolysis compared to the baseline amount of breakthrough hemolysis before treatment.

[0179] In another embodiment, the treatment results in a reduction in the need for blood transfusions. In another embodiment, the treatment results in an increase in blood transfusion avoidance. In another embodiment, the treatment results in an increase of at least 50% in blood transfusion avoidance. In another embodiment, the treatment results in an increase of at least 60% in blood transfusion avoidance. In another embodiment, the treatment results in an increase of more than 70% in blood transfusion avoidance. In all cases, blood transfusion avoidance is measured relative to the frequency with which a blood transfusion would have been necessary before the treatment.

[0180] In another embodiment, the treatment results in a reduction of major adverse vascular events (MAVEs) (e.g., thrombophlebitis / deep vein thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis / renal artery thrombosis / glomerulostomy, renal infarction, acute peripheral vascular occlusion, mesenteric / visceral vein / arterial thrombosis or infarction, hepatic vein / portal vein thrombosis, cerebral artery occlusion / cerebrovascular attack, cerebral vein occlusion, renal artery thrombosis, or multiple stroke dementia) as described in further detail in the examples.

[0181] In another embodiment, the treatment results in a shift toward 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 yet another embodiment, the treatment results in increased hemoglobin stabilization from the patient's pre-treatment baseline.

[0182] In another embodiment, the treatment results in a shift toward normal levels of estimated glomerular filtration rate (eGFR) and chronic disease-related biomarkers selected from the group consisting of spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP).

[0183] In another embodiment, the treatment results in a change from baseline in quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, 4th Edition and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Scale, and as described in more detail in the examples. In another embodiment, the treatment results in a change from baseline in quality of life of at least 7 points from the patient's untreated baseline score as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, 4th Edition and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Scale.

[0184] VI. Kit Furthermore, this specification also provides a kit comprising a pharmaceutical composition containing a therapeutically effective amount suitable for use in the methods described above, comprising an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, and a pharmaceutically acceptable carrier. The kit may also optionally include instructions, such as an administration schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the composition to a patient having a complement-related condition (e.g., PNH). The kit may also include a syringe or an on-body delivery system (OBDS). In one embodiment, the OBDS is a SmartDose® drug delivery platform. In another embodiment, ravulizumab is administered by subcutaneous injection using a single-use OBDS with West SmartDose® Gen.I 3.5 mL.

[0185] In one embodiment, a kit is provided for treating a complement-related condition (e.g., PNH) in a human patient, the kit comprising (a) a certain dose of an anti-C5 antibody or its antigen-binding fragment comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12 and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for the use of the anti-C5 antibody or its antigen-binding fragment in the method described herein. In one embodiment, the anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 40 kg or more but less than 60 kg by (a) intravenously at a dose of 2400 mg once on day 1 of the administration cycle; and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. In another embodiment, an anti-C5 antibody, or its antigen-binding fragment, is administered to patients weighing between 60 kg and 100 kg intravenously at a dose of 2700 mg once on day 1 of the administration cycle; and (b) subcutaneously at a dose of 490 mg on day 15 of the administration cycle and weekly thereafter. In a detailed embodiment, the anti-C5 antibody is ravulizumab.

[0186] VII.Equipment Furthermore, an instrument is provided (e.g., an on-body delivery system (OBDS)) that includes a pre-filled cartridge of ravulizumab for subcutaneous administration packaged integrally with the on-body injection device. In one embodiment, the instrument is sterile, for single use, disposable, and / or electromechanical. In another embodiment, the on-body injection device includes a 29-gauge needle. In another embodiment, the pre-filled cartridge is a 3.5 mL cartridge. In another embodiment, the ravulizumab for subcutaneous administration includes 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg ravulizumab (70 mg / mL) in water for injection. In another embodiment, the ravulizumab for subcutaneous administration In another embodiment, rabulizumab consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 262.5 mg rabulizumab (70 mg / mL) in water for injection. In yet another embodiment, rabulizumab for subcutaneous administration contains 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg rabulizumab (70 mg / mL) in water for injection. In yet another embodiment, rabulizumab for subcutaneous administration consists of 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and 245 mg rabulizumab (70 mg / mL) in water for injection. In yet another embodiment, rabulizumab for subcutaneous administration is formulated at a pH of approximately 7.4.

[0187] An exemplary device for use in combination with ravulizumab for subcutaneous administration as described herein is the On-Body Delivery System (OBDS) manufactured by West Pharmaceuticals, Inc., which is currently approved in the United States for use in combination with evolocumab (Repatha®) and is CE marked as a Class IIA medical device in the European Union. In one embodiment, the OBDS is the SmartDose® drug delivery platform (see westpharma(dot)com / products / self-injection-platforms / smartdose / smartdose-gen-I on the World Wide Web; West Catalog # 11262 0919 (2019)). In another embodiment, the device is a compact, sterile, single-use, disposable, electromechanical (battery-powered, microprocessor-controlled) investigational medical device with a 29-gauge integrated needle designed for use with a pre-filled, capped Crystal Zenith® cartridge with a piston and telescopic screw assembly (TSA) (manufactured by West Pharmaceuticals, Inc.). In another embodiment, ravulizumab is administered by subcutaneous injection using a single-use OBDS with West SmartDose® Gen.I 3.5 mL. In another embodiment, the OBDS is a complete, integrated packaging combination product consisting of the device components for the drug delivery platform and a pre-filled cartridge (PFC) containing 3.5 mL of ravulizumab 70 mg / mL with an assembled TSA. In another embodiment, the “on-body injection device” is the device components only (OBDS without PFC and TSA). In another embodiment, user interaction is required to activate the OBDS, such as by applying a starting force. In another embodiment, design requirements essential for use and achieving the intended use (e.g., accuracy of deliverable volume / dose) are fundamental critical performance requirements, regardless of the associated risk / severity level (low or high).In another embodiment, a fundamental important performance requirement is notification of the delivery status at the end of injection (i.e., notification to the user informing them of the success or failure of delivery).

[0188] The following examples are for illustrative purposes only, and as a number of modifications and equivalents will become apparent to those skilled in the art upon reading this disclosure, they should not be construed in any way as limiting the scope of this disclosure.

[0189] All references cited throughout this application, including GENBANK / UNIPROT / PUBMED entries, patents, and published patent applications, are expressly incorporated herein by reference. [Examples]

[0190] Example 1: Phase 3 Clinical Trial A phase 3, randomized, parallel-group, multicenter, open-label, pharmacokinetic, and non-inferiority study comparing subcutaneous administration of ravulizumab to intravenous administration in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) currently treated with eculizumab will be conducted according to the following protocol.

[0191] The objective of this study is to compare the pharmacokinetics (PK) of subcutaneous ravulizumab (SC) administered via on-body delivery system (OBDS) with intravenous ravulizumab (IV) in clinically stable patients with paroxysmal nocturnal hemoglobinuria (PNH) who have a prior history of eculizumab treatment within at least three months prior to study enrollment. Based on the established relationship between PK exposure and clinical efficacy of ravulizumab IV, the non-inferiority of ravulizumab SC PK to ravulizumab IV should enable the bridging of efficacy and safety data from ravulizumab IV to ravulizumab SC. The study hypothesis is that serum C2 levels of ravulizumab SC on day 71 will be... トラフ Day 71: Rabulizumab IV serum C トラフ This study demonstrates non-inferiority compared to [another study]. This study also aims to demonstrate the safety and tolerability of ravulizumab SC and its drug-device combination product, ravulizumab OBDS.

[0192] 1. Objectives and Evaluation Items The primary objective of this study is to study adult PNH patients (e.g., serum ravulizumab C on day 71). トラフ The objective is to evaluate the non-inferiority of pharmacokinetics (PK) of ravulizumab SC compared to ravulizumab IV, as determined by (pre-administration concentration).

[0193] Secondary objectives include (1) (for example, C over time) トラフ(2) Characterizing the PK of ravulizumab SC as determined by (a) the PD of ravulizumab SC (e.g., as determined by free serum C5 concentration over time), (3) Characterizing the immunogenicity of ravulizumab SC (e.g., as determined by the incidence of anti-drug antibodies (ADAs) developed under treatment over time), (4) Health-related quality of life (HRQoL) and treatment satisfaction with ravulizumab subcutaneous (SC) (e.g., (a) Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale, 4th edition, change from baseline to day 183, (b) European Organisation for Research and Treatment of Cancer (c) Changes from baseline to day 183 in the Quality of Life Questionnaire-Core 30 Scale (QLQ-C30) version 3.0, and (c) Treatment Administration Satisfaction Questionnaire at baseline and day 183. This includes (5) evaluating the reported treatment satisfaction and patient choice as measured by the Questionnaire:TASQ score, (6) evaluating the safety of ravulizumab SC and ravulizumab OBDS (e.g., as determined by (a) changes in physical examination, vital signs, electrocardiogram, and laboratory findings over time, (b) incidence of adverse and serious adverse events, and (c) incidence of adverse and serious adverse events caused by the device), (7) evaluating the efficacy of ravulizumab SC (e.g., as determined by (a) changes in lactate dehydrogenase (LDH) over time, (b) incidence of breakthrough hemolysis, (c) achievement of transfusion avoidance, and (d) achievement of hemoglobin stabilization), and (8) evaluating the performance of ravulizumab OBDS (e.g., as determined by reported outcomes of intended dose administration, including device malfunctions / failures).

[0194] 2. Overall Design This is a phase 3, randomized, open-label, parallel-group, multicenter study to evaluate the PK non-inferiority of ravulizumab SC administered via OBDS compared to intravenously administered ravulizumab IV in adult PNH patients who are clinically stable and have a prior history of eculizumab treatment within at least 3 months prior to study enrollment.

[0195] This study consists of a screening period of up to 30 days, a randomization treatment period of 10 weeks, and an extension period of up to 3.5 years (182 weeks), or until the product is registered or approved (according to national regulations), whichever comes first. Patients will be stratified by weight group (40 kg to less than 60 kg and 60 kg to less than 100 kg) and then randomized in a 2:1 ratio to receive either ravulizumab SC or ravulizumab IV.

[0196] During the randomization treatment period, ravulizumab IV will be administered at the clinic by experienced members of the site research team. Day 1 of the study treatment will occur 12–16 days after the patient's final dose of eculizumab. The timing of investigational drug administration and pre-administration PK sample collection is critically important to ensure an appropriate number of patients with evaluable PK data (Table 1). The initiation time of the dose administered on Day 1 is the nominal time for all subsequent doses and PK / PD sample collection. Specifically, all subsequent doses during the randomization treatment period will be administered at the same time as the dose administered on Day 1. PK samples will be collected as close as possible to the dose administration (or, on days without administration, from the nominal time of the Day 1 dose initiation).

[0197] Rabulizumab OBDS is supplied in a kit containing 245 mg of ravulizumab SC in a sterile, single-use pre-filled cartridge assembly packaged with a single-use injector. Two kits are used to deliver the prescribed 490 mg dose of ravulizumab SC.

[0198] The ravulizumab IV loading dose and maintenance dose were calculated based on the patient's pre-administration weight at each hospital visit, as shown in Table 1.

[0199] During the randomization treatment period, patients assigned to the ravulizumab SC group will receive a loading dose of ravulizumab IV on day 1, followed by a maintenance dose of ravulizumab SC on day 15 and weekly thereafter (qw) until completion of the randomization treatment period. Patients assigned to the ravulizumab IV group will receive a loading dose of ravulizumab IV on day 1, followed by a maintenance dose of ravulizumab IV on day 15, as shown in Table 1.

[0200] [Table 1]

[0201] Day 71 marks the end of the randomization treatment period and the beginning of the extension period. All Day 71 assessments completed before medication are considered part of the randomization treatment period. Medication on Day 71 marks the beginning of the extension period. During the extension period, patients randomized to the ravulizumab SC group will continue to receive 490 mg of ravulizumab SC using two OBDS kits on Day 71 and weekly thereafter until the end of the extension period (maximum Day 1275). Patients randomized to the ravulizumab IV group will switch to 490 mg of ravulizumab SC using two OBDS kits on Day 71 and weekly thereafter until the end of the extension period (maximum Day 1275).

[0202] During the extension period, ravulizumab SC can be self-administered at home by the patient, except when ravulizumab SC is administered at the clinic. For patients randomized to ravulizumab IV group, the 71-day dose of ravulizumab SC 490 mg will be self-administered by the patient at the clinic under the supervision of a skilled research facility staff member as part of the necessary training program for home self-administration. For all patients, doses that overlap with research visits designated in the activity schedule will be self-administered by the patient at the clinic under the supervision of a skilled research facility staff member. With permission, patients may self-administer ravulizumab SC at the clinic (under the supervision of a skilled research facility staff member) on medication days that are not scheduled in-person visits.

[0203] The study for each patient ends when safety follow-up is completed. Safety follow-up consists of a telephone call 30 days after the final dose. Data collection during safety follow-up is limited to reports of adverse events and concomitant drug therapy. If a patient discontinues treatment but the study is not discontinued, the study for such a patient ends at their final visit, provided that more than 30 days have passed since their final dose. The study ends when the patient visit or the final day of safety follow-up occurs, whichever comes later.

[0204] This study will enroll approximately 105 patients (70 in the ravulizumab SC group and 35 in the ravulizumab IV group). An interim analysis will be conducted to re-estimate the sample size, which could increase the sample size to a maximum of 144 patients.

[0205] 3. Inclusion and Exclusion Criteria Patients must meet all inclusion criteria and not meet any exclusion criteria. Patients who are ineligible for the study may be rescreened once, subject to discussion and agreement. Patients are eligible for inclusion in this study only if they meet all of the following criteria: A. The patient must be at least 18 years old at the time of signing the informed consent form. B. The patient was treated with eculizumab according to the recommended dose indication for PNH (900 mg every 14 ± 2 days) for at least 3 months prior to study enrollment, did not skip any doses within 2 months prior to study enrollment, and did not exceed 2 doses outside the visit window. C. At the time of screening, according to the central laboratory, lactate dehydrogenase levels ≤ 1.5 × ULN (upper limit of normal). Samples must be obtained within 24 hours prior to or immediately before the scheduled administration of the eculizumab dose (i.e., at the trough eculizumab level). D. There is a documented record of a diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation (see, for example, Borowitz et al., "Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry", Cytometry B. Clin. Cytom. 2010;78(4):211-230). E. The patient has been vaccinated against meningococcal disease within three years prior to or at the time of initiation of the investigational drug, and their risk of meningococcal disease (Neisseria meningitidis) is reduced. F. Participants weigh between 40 kg and 100 kg, and are expected to remain within this weight range throughout the study period. G. Female patients of childbearing potential and male patients with female partners of childbearing potential must follow the protocol-specified contraception guidelines throughout the course of treatment and for at least eight months after the final dose of the investigational drug. H. The patient must be willing and capable of submitting written informed consent and complying with all study visits and procedures, including self-administration of ravulizumab SC doses and the use of any one or more data acquisition devices to directly record patient data.

[0206] Patients will be excluded from the study if they meet any of the following criteria: A. LDH levels > 2×ULN more than once within 3 months prior to study registration. B. Major adverse vascular events (MAVEs) in the 6 months prior to study enrollment. C. Platelet count <30,000 / mm³ at screening 3 (30×10 9 / L). D. Neutrophil absolute count <500 / μL (0.5 × 10⁻¹⁰) at screening 9 / L). E. History of bone marrow transplant. History of infection with Neisseria meningitidis. G. History of an infection of unknown cause. H. Active systemic bacterial, viral, or fungal infection within 14 days prior to administration of the investigational drug on day 1. I. The patient has a fever of ≥38°C (100.4°F) within 7 days prior to the administration of the investigational drug on Day 1. J. Human immunodeficiency virus (HIV) infection (with evidence based on HIV-1 or HIV-2 antibody titers). K. History of malignant tumor within 5 years of screening, with the exception of treated non-melanoma skin cancer or cervical carcinoma in situ with no evidence of recurrence. L. The patient has a history or ongoing condition of a serious heart, lung, kidney, endocrine, or liver disease (e.g., active hepatitis) that would prevent them from participating in the clinical trial. M. Any unstable medical condition that would likely cause the patient to become unable to tolerate the protocol requirements (e.g., myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, the need for major surgery expected within 6 months from day 1, or chronic anemia unrelated to PNH). N. History of hypersensitivity to any ingredient in the investigational drug, including hypersensitivity to mouse proteins. O. Female patients who are planning to become pregnant, or who are currently pregnant or breastfeeding. P. Female patients whose pregnancy test result is positive at the time of screening or on day 1. Q. Are there any known medical or psychological conditions or risk factors that could prevent patients from fully participating in this study, which would pose an additional risk to the patient or confuse the outcomes of this study? R. Known or suspected history of drug or alcohol abuse or addiction within one year prior to screening. Unable to complete the requirements for self-administration of S.SC. T. During the randomization treatment period, the patient is unable to travel to the clinic for the designated visit or is unable to meet the logistics requirements for the investigational drug. U. Concomitant use of anticoagulants is prohibited if a stable regimen has not been maintained for at least two weeks prior to study enrollment. V. Participation in another study or use of any experimental treatment (excluding participation in observational studies [e.g., PNH Registry]) within 30 days prior to the start of the investigational drug in this study or within 5 half-lives of the investigational product, whichever is longer. W. received any other experimental C5 antagonist at any given time.

[0207] 4. Activity Schedule The schedule of activities (SoA) for the screening and randomization treatment period is provided in Table 2 for the ravulizumab SC group and in Table 3 for the ravulizumab IV group. Day 71 marks the end of the randomization treatment period. All assessments on Day 71 are performed before medication administration. On Day 15, a qualified member of the site research team trains patients randomized to ravulizumab SC on self-administration of ravulizumab SC using the OBDS kit before patient self-administration. Patients self-administer the Day 15 dose of ravulizumab SC at the clinic under the supervision of a skilled research facility staff member. On Days 22, 36, and 50, ravulizumab SC may be self-administered by patients at home. On these days, with permission, patients may self-administer ravulizumab SC at the clinic (under the supervision of a skilled research facility staff member). On Days 29, 43, 57, and 64, ravulizumab SC is self-administered by patients at the clinic under the supervision of a skilled research facility staff member.

[0208] The evaluation schedule for the extension period is provided in Tables 4 and 5. The medication on day 71 marks the beginning of the extension period. For patients randomized to ravulizumab IV during the randomization treatment period, the first dose of ravulizumab SC is on day 71. On day 71, a qualified member of the site research team will train patients randomized to ravulizumab IV on self-administration of ravulizumab SC using the OBDS kit before patient self-administration. Patients will self-administer the day 71 dose of ravulizumab SC at the clinic under the supervision of a skilled research site staff member. For patients randomized to ravulizumab SC, the day 71 medication will be self-administered during an in-person consultation visit. For the remainder of the extension period, weekly doses of ravulizumab SC for all patients may be self-administered at home or at the clinic during visits as specified in Tables 4 and 5. With permission, patients may self-administer ravulizumab SC at the clinic (under the supervision of a skilled research facility staff member) on medication days other than scheduled in-person appointments.

[0209] Procedures performed as part of a patient's routine clinical management (e.g., hematological assessment) and completed before signing an informed consent form (ICF) may be used for screening purposes if those procedures meet the protocol-specified criteria and are performed within the time frame specified in the evaluation schedule.

[0210] Throughout this study, quality of life assessments will be conducted and documented. Data related to ravulizumab SC administration will be recorded in the patient's e-diary if it is administered in a home setting during the extension period.

[0211] During the randomization treatment period (for patients randomized to ravulizumab SC), the facility will monitor the patient's self-administration of ravulizumab SC by telephone on scheduled home administration days to ensure the patient is available to answer questions regarding the investigational drug dosage and device status. During the extension period, the facility will contact the patient by telephone on day 78 to inquire about the patient's investigational drug administration and completion of the patient e-diary. After day 78, the facility will monitor the patient's self-administration of ravulizumab SC via the patient e-diary.

[0212] Instructions for handling and processing laboratory specimens are provided in the research laboratory manual. Blood samples should not be taken from heparinized lines. Blood samples taken after IV dose (on day 1 for both cohorts, and also on day 15 for the ravulizumab IV cohort) must be taken from the opposite arm.

[0213] Unscheduled visits outside of protocol-specified visits are permitted at the discretion of the physician. Procedures, tests, and assessments performed during unscheduled visits are also to be carried out at the discretion of the physician.

[0214] If breakthrough hemolysis is suspected, LDH, PK, PD, and anti-drug antibody (ADA) samples must be collected for analysis in the central laboratory. If an event suspected of breakthrough hemolysis occurs outside of a scheduled hospital visit, the patient is expected to revisit the facility for evaluation and collection of the necessary LDH, PK, PD, and ADA samples. For the purpose of confirming breakthrough hemolysis, LDH values ​​must be based on central laboratory values.

[0215] [Table 2-1]

[0216] [Table 2-2]

[0217]

Table 2-3

[0218]

Table 3-1

[0219]

Table 3-2

[0220]

Table 4-1

[0228] Rablizumab IV is formulated at pH 7.0 and supplied in a single-use 30 mL vial. Each vial of Rablizumab IV contains 300 mg of rablizumab (10 mg / mL) in 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for injection.

[0229] Both the Rablizumab SC formulation and the Rablizumab IV formulation are suitable for human use and are manufactured in accordance with current Good Manufacturing Practices.

[0230] Details regarding the Rablizumab SC formulation and the Rablizumab IV formulation are presented in Table 7. The dosing reference tables for the Rablizumab SC group and the Rablizumab IV group are presented in Tables 8 and 9, respectively.

[0231]

Table 7

[0232]

Table 8

Table 9

[0234] Rabulizumab IV will be prepared and administered by experienced members of the site research team. Rabulizumab SC can be self-administered by patients who have completed the necessary training for self-administration of ravulizumab SC. The investigational drug should only be distributed to enrolled patients who have been confirmed as eligible to participate.

[0235] On day 15 of the randomization treatment period (for patients randomized to ravulizumab SC) and on day 71 of the extension period (for patients randomized to ravulizumab IV), qualified members of the site research team will provide initial (and, as appropriate, ongoing) training on how to properly self-administer ravulizumab SC using the two required OBDS kits. After completion of the required training, all patients will self-administer the SC infusion once a week at home or in the clinic (under the supervision of a skilled research site staff member) on the days specified in the activity schedule. With permission, patients may self-administer ravulizumab SC in the clinic on medication days other than scheduled in-person appointments.

[0236] Patients are instructed to follow the instructions in the Instructors for Use (IFU). Detailed instructions regarding self-administration of the investigational drug will be provided in the IFU.

[0237] If the OBDS malfunctions and the dose or part of the dose is not delivered, the patient should use a new OBDS to ensure that the patient receives at least 490 mg of ravulizumab SC.

[0238] Rabulizumab IV is not administered as an IV push or bolus injection. Rabulizumab IV infusions are prepared using sterile methods. The patient's required dose of ravulizumab is further diluted as specified in Tables 7 and 8. Once the patient's medication solution is prepared, it may only be administered to that patient. The drug is administered via an infusion pump using an IV tubing set. A 0.2-micron filter is required during ravulizumab IV infusion. Each investigational drug vial is for single use only; any remaining drug product in the vial should not be used for another patient.

[0239] The effective period of the medication solution is 6 hours at ambient temperature. The expiration date of the medication solution is calculated from the date of expiration of the first vial. The dosage should be administered before the expiration date.

[0240] The primary packaging for ravulizumab IV consists of a 30 mL vial (Type I borosilicate glass) with a stopper and seal. The secondary packaging consists of a single cardboard box for the vial. Both the primary (vial) and secondary (cardboard box) packaging include a booklet label containing relevant information.

[0241] 6. On-Body Delivery System Labulizumab SC is intended to be self-administered via SC infusion in a clinic or home setting using labulizumab OBDS for maintenance dose delivery. Factors driving the selection of the SC device included dose volume capacity, proven reliability, and patient-centered usability requirements, namely, minimal procedure and ease of use, minimal discomfort, concealed needle, and the ability to move around and perform moderate physical activity, such as walking, reaching, and bending, during infusion. The West SmartDose Gen 1 device platform meets these criteria.

[0242] The ravulizumab OBDS drug-device combination product consists of a pre-filled cartridge containing ravulizumab SC and an on-body infusion device. The ravulizumab OBDS is a compact, sterile, single-use, electromechanical infusion device that delivers a fixed dose of ravulizumab from the pre-filled cartridge assembly into the SC tissue at a constant rate through a stainless steel 29-gauge needle. According to the definition in the Medical Device Directive 93 / 42 / EEC, this device is a sterile, single-use, surgically invasive active medical device for temporary use. The device contains a non-removable battery and is equipped with a biocompatible adhesive patch. The device, including the adhesive, is removed from the skin after dose delivery is complete.

[0243] The primary sealed container (cartridge) consists of a 5 mL CZ cartridge having a chlorobutyl elastomer septum, a chlorobutyl elastomer piston, and a TSA screwed into the piston. This pre-filled CZ cartridge is packaged together with the on-body injector in a blister tray divided into two compartments. The pre-filled cartridge assembly is loaded into the device by the patient immediately before use. This device is designed for use only with the 3.5 mL pre-filled cartridge provided.

[0244] After the cartridge is loaded into the device, the device is attached to the skin, and the device is activated, a 3.5 mL dose is delivered in less than 10 minutes.

[0245] Following completion of device usage training by qualified members of the site research team, all patients will self-administer the ravulizumab SC dose as specified in the State of Action (SoA). Further instructions will be provided to the Intensive Care Unit (IFU). Further details regarding this device can be found in the ravulizumab OBDS Investigational Brochure.

[0246] The ravulizumab OBDS drug-device combination consists of two components: a pre-filled cartridge containing ravulizumab and an on-body injection device. The pre-filled cartridge and device components are packaged together in a thermoformed blister pack with a Tyvek lid that covers the compartment containing the device to provide a sterile barrier. The secondary packaging consists of a plain cardboard box containing the blister pack and a booklet label with associated instructions.

[0247] The blister pack, covered with a Tyvek cover, is adorned with an identification trace label, which is a serial number label attached to the side of the device, and each cartridge is also affixed with a single panel label.

[0248] 7. Rabulizumab IV and Rabulizumab SC - In-person administration Once all necessary documents based on applicable regulations have been received, the investigational drug kits will be shipped to each facility.

[0249] Upon arrival of the investigational drug kit at the research facility, a pharmacist or designated person shall promptly remove the investigational drug kit from the delivery cooler, place it back into its original cardboard box, and store it in a light-shielded, refrigerated environment at 2°C to 8°C (35°F to 47°F).

[0250] The ravulizumab IV mixed drug product and the ravulizumab OBDS kit should be at ambient temperature before administration. The materials should not be heated (for example, by using microwaves or other heat sources).

[0251] Only authorized facility staff may supply or, at times, administer the investigational drug.

[0252] Patients will self-administer ravulizumab OBDS on day 15 (for patients randomized to ravulizumab SC) and on day 71 during the extension period (for patients randomized to ravulizumab IV) after receiving training from a qualified member of the site research team. After completion of training, patients may self-administer ravulizumab SC at home or at a clinic under the supervision of a skilled research site staff member at the time noted. All investigational drugs must be stored in a safe, environmentally controlled, and monitored (manual or automated) area, in accordance with the indicated storage conditions, with access limited to the principal investigator and authorized site staff.

[0253] The principal investigator, the institution, the pharmacist, or the representative of the medical institution (if applicable) is responsible for the receipt, verification, and record-keeping of the investigational drug (i.e., records of receipt, verification, and final distribution).

[0254] Unless it is necessary to immediately destroy used ravulizumab IV vials according to internal procedures, inventory management will be performed for both used and unused IV investigational drug vials.

[0255] The ravulizumab OBDS is a single-use device that is immediately disposed of in a biowaste container after drug administration. Inventory management is conducted for both used and unused cartridges and devices.

[0256] During the supply, distribution, and subsequent destruction of the investigational drug kit, or upon return to Alexion.

[0257] 8. Lablizumab SC - Home administration The ravulizumab OBDS kit for self-administration will be provided to patients according to local and site requirements.

[0258] Upon receiving the ravulizumab OBDS kit, patients are expected to promptly store it according to the IFU instructions.

[0259] Patients are expected to follow training instructions and IFUs to ensure the correct dosage of ravulizumab on each medication day. During the randomization treatment period, research staff will monitor patients' self-administration of ravulizumab SC by telephone on scheduled home medication days to ensure that patients are available to answer questions regarding the investigational drug dosage and device status. During the extension period, ravulizumab SC will be self-administered by patients at home or at the clinic under the supervision of experienced research staff on scheduled clinic visits. With permission, patients may self-administer ravulizumab SC at the clinic on medication days that are not scheduled in-person clinic visits. On day 71, patients randomized to ravulizumab IV will self-administer ravulizumab SC at the clinic under the supervision of experienced research staff as part of the necessary training program for home self-administration.

[0260] Each patient will be provided with a biowaste container for the home disposal of used ravulizumab OBDS.

[0261] 9. Measures to minimize bias: randomization and blinding This is an open-label study. Measures to reduce potential bias include stratification and randomization. After stratification by weight (40kg to less than 60kg or 60kg to less than 100kg), each patient will be randomly assigned to a treatment group in a 2:1 ratio using a centralized voice or web-based automated response system.

[0262] 10. Prior treatment and combination therapy Prior to the start of screening, and up to the first dose of the investigational drug, all prior drug therapies (including vitamins and herbal preparations) and procedures (such as surgery / biopsy or physiotherapy, or any other therapeutic interventions) taken or received by the patient, including those considered in the exclusion criteria, will be recorded in the patient's electronic case report form (eCRF). In addition, the patient's meningococcal vaccination history for the three years prior to the first dose of the investigational drug will be collected.

[0263] Record any packed red blood cell transfusions received within one year prior to the initial administration of the investigational drug in the patient's eCRF.

[0264] All drug therapy use and procedures performed during the study will be recorded in the patient's source document / chart and eCRF. This record will include all prescription drugs, herbal products, vitamins, minerals, commercially available drug therapies, and current drug therapies for PNH. Concomitant drug therapies will be recorded from the first infusion of the investigational drug until 30 days after the patient's final dose of the investigational drug, unless the patient transitions to another treatment for PNH. Any changes in concomitant drug therapies will be recorded in the patient's source document / chart and eCRF. During the study, any concomitant drug therapies deemed necessary for the patient's standard care or for the treatment of any adverse events may be given at the discretion of the patient, along with the permissible drug therapies listed below.

[0265] Concomitant use of anticoagulants is prohibited unless a stable dose regimen has been maintained for at least two weeks prior to study enrollment. Use of complement inhibitors other than those assigned to the patient for the study is prohibited.

[0266] 11. Modification of dosage or treatment group Patients who received ravulizumab IV during the randomization treatment period will switch to ravulizumab SC 490 mg once weekly at the start of the extension period and continue this treatment throughout the study period.

[0267] If any patient receiving ravulizumab IV reaches a weight of 100 kg or more by day 71 during the randomization treatment period, their data will be excluded from the primary endpoint analysis, and the patient will be discontinued from the study. If a patient's weight is less than 100 kg on day 71, their data will be included in the primary analysis. The patient will be discontinued from the study after completion of the pre-treatment assessment on day 71.

[0268] If any patient receiving ravulizumab SC reaches a weight of 100 kg or more during the randomized treatment period, treatment will be discontinued. Unless the patient's weight was first observed at the 71st day assessment, the patient's data will not be included in the primary endpoint analysis. The patient will be discontinued from the study.

[0269] If any patient receiving rabulizumab SC reaches a weight of 100 kg or more, treatment should be discontinued.

[0270] During the study, modifications to the dosage or treatment group are not permitted.

[0271] 12. Potential and confirmed risks Increased susceptibility to meningococcal infections (Neisseria meningitidis) is a known risk associated with terminal complement inhibition. Similar to eculizumab, the primary risk associated with ravulizumab is the risk of meningococcal infection.

[0272] To address this risk, special risk mitigation measures will be implemented.

[0273] Administration of any therapeutic protein, including rabulizumab, may induce an immunogenic response, potentially leading to adverse drug reactions (ADA). Potential clinical consequences may include severe hypersensitivity reactions and reduced efficacy (PK and / or PD neutralization) due to the development of neutralizing ADA.

[0274] In the ravulizumab IV clinical study, one patient out of 261 PNH patients treated with ravulizumab developed treatment-induced ADA. Treatment-induced ADA was observed in three healthy subjects treated with ravulizumab SC and one healthy subject treated with ravulizumab IV in study ALXN1210-SC-101, and in four healthy Japanese subjects in study ALXN1210-HV-104. The ADA positive titer was low in all cases, and cross-reactivity with eculizumab was negative. The immunogenic effect of ravulizumab on PK or PD was not clear.

[0275] In studies of patients with atypical hemolytic uremic syndrome (aHUS), only one case of ADA occurring under treatment has been reported with ravulizumab.

[0276] Protein therapy administered via either SC or IV carries a potential risk of causing local (injection-site) and systemic (injection-related) reactions. Injection-site reactions are localized to the SC or IV drug administration site and may include reactions such as erythema, itching, and subcutaneous bleeding. Injection-related reactions are systemic in nature and may be immune-mediated or non-immune-mediated, generally occurring within a few hours of drug administration. Immune-mediated reactions may include allergic reactions (e.g., anaphylaxis), while non-immune-mediated reactions are nonspecific (e.g., headache, dizziness, nausea). Monitoring of these reactions will be performed as part of the routine safety assessment in this study.

[0277] No studies on ravulizumab have been conducted on pregnant women.

[0278] Pregnant or breastfeeding women will be excluded from this clinical trial. Patients enrolled in this study, and their spouses / partners, will use highly effective or acceptable methods of contraception. If a patient becomes pregnant, they will discontinue the investigational drug.

[0279] There is no clinical experience with ravulizumab OBDS. It is considered an investigational medical device and therefore carries some potential risks arising from device malfunction or user negligence. Risk management activities (risk control and mitigation measures) are in place. For a more complete description of the device and potential benefits / risks, please refer to the ravulizumab OBDS Investigational Brochure.

[0280] Data supporting the development of ravulizumab OBDS includes data from a healthy volunteer study using the SmartDose device, which demonstrated that the device was well-tolerated and safe to use. A risk management study of ravulizumab OBDS was conducted by Alexion and West Pharmaceutical Services, Inc., with a risk analysis performed in accordance with EN ISO 14971:2012. The results of this risk assessment indicate that all residual risks fall into the low / acceptable or intermediate / investigation risk categories. Management strategies will be established to further mitigate the risks in the intermediate / investigation category. Therefore, these potential risks are considered to be balanced by the opportunity to develop ravulizumab OBDS as an alternative, more convenient method of drug administration in patients requiring chronic treatment.

[0281] 13. Definition of research completion The study for each patient ends when safety follow-up is completed. Safety follow-up consists of a telephone call 30 days after the final dose. Data collection during safety follow-up is limited to reports of adverse events and concomitant drug therapy. If a patient discontinues treatment but the study is not discontinued, the study for such a patient ends at their final visit, provided that more than 30 days have passed since their final dose. The study ends when the patient visit or the final day of safety follow-up occurs, whichever comes later.

[0282] 14. Effectiveness Assessment Blood and urine samples will be collected at the times indicated in the evaluation schedule. During the study, the following disease-related clinical laboratory parameters will be measured: (1) lactate dehydrogenase, (2) reticulocyte count, (3) paroxysmal nocturnal hemoglobinuria RBC clone size as assessed by high-sensitivity flow cytometry, and (4) estimated glomerular filtration rate (calculated using the MDRD (Modification of Diet in Renal Disease) formula).

[0283] Achieving transfusion avoidance is defined as a patient who did not require a transfusion after the initial dose of the investigational drug, meaning they did not need a transfusion.

[0284] Breakthrough hemolysis is defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN, as determined by the central laboratory (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g / dL], MAVE including thrombosis, dysphagia, or erectile dysfunction).

[0285] Stabilized hemoglobin is defined as avoiding a decrease of 2 g / dL or more from baseline in hemoglobin levels from baseline to the end of the target period without transfusions.

[0286] The principal investigator or designated investigator shall determine for each patient the signs and symptoms of PNH, which may include: fatigue, chest pain, abdominal pain, shortness of breath, dysphagia, erectile dysfunction.

[0287] Two validated HRQoL assessment scales are administered to patients before administration of the investigational drug and at the time specified in the evaluation schedule. The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, version 4.0, is a set of HRQoL questionnaires for managing fatigue symptoms caused by chronic illness (see Figure 1). FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue over the past 7 days and its impact on daily activities and functions. Patients rate each item on a 5-point scale: 0 (not at all) to 4 (very much). The total score ranges from 0 to 52, with higher scores indicating better HRQoL.

[0288] The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 Scale (QLQ-C30), version 3.0, is a questionnaire developed to assess HRQoL in cancer patients (see Figures 2A-2B). This questionnaire includes the following subscales: overall health status, functioning scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain), and single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial hardship). Thirty questions relate to HRQoL, with the first 28 questions scored on a 4-point scale (1=not at all ~ 4=very good), and the last two questions exploring the patient's overall health and HRQoL scored on a scale from 1 (very bad) to 7 (very good). Each subscale ranges from 0% to 100%, where higher scores correspond to higher levels of response. Therefore, high scores on the function scale correspond to high levels of function, while high scores on the symptom scale correspond to high levels of overall symptoms / problems.

[0289] Treatment satisfaction will also be assessed at the time it is designated for evaluation. The Treatment Administration Satisfaction Questionnaire (TASQ) is a validated questionnaire used to assess a patient's views and satisfaction with eculizumab IV, rabulizumab IV, or rabulizumab SC treatment (see Figures 3 and 4, and Theodore-Oklota et al., Patient Prefer Adherence. 2016;10:1767-1776). The TASQ scores treatment satisfaction through five domains: physical impact, psychological impact, impact on ADL, convenience, and satisfaction. Each domain provides up to five response options, with lower scores indicating more positive responses. The score is completed by adding up each of the five domains.

[0290] FACIT-Fatigue, EORTC QLQ-C30, and TASQ-IV / TASQ-SC tests are administered and documented.

[0291] 15.Safety assessment The principal investigator or designated investigator will be given the opportunity to meet with the patient and discuss the potential safety risks of ravulizumab SC, ravulizumab OBDS, and ravulizumab IV, thereby addressing any safety concerns the patient may have regarding this study.

[0292] All safety assessment points will be provided in the evaluation schedule.

[0293] Major adverse vascular events (MAVEs) are documented in the eCRF as part of the patient's medical history (pre-baseline) and throughout the study, including the diagnostic method (e.g., magnetic resonance imaging, ultrasound, angiography), date of diagnosis, and date of resolution (or ongoing).

[0294] MAVE is defined as follows: thrombophlebitis / deep vein thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis, acute peripheral vascular occlusion, mesenteric / visceral vein thrombosis or infarction, mesenteric / visceral artery thrombosis or infarction, hepatic vein / portal vein thrombosis (Budd-Chiari syndrome), cerebral artery occlusion / cerebrovascular attack, cerebral vein occlusion, renal artery thrombosis, gangrene (non-traumatic; non-diabetic), amputation (non-traumatic; non-diabetic), cutaneous thrombosis, or other (please specify).

[0295] Physical examination includes assessments of: overall appearance; skin; head, ears, eyes, nose, and pharynx; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous system; and musculoskeletal system. A simplified physical examination consists of relevant tests of each system of the body based on the judgment of the principal investigator and the patient's symptoms.

[0296] Subcutaneous or intravenous injection site evaluation will be performed at the time specified in the evaluation schedule.

[0297] Vital signs should be measured after the patient has been at rest for at least 5 minutes, and should include systolic and diastolic blood pressure (BP; mmHg), heart rate (beats / min), respiratory rate (breaths / min), and body temperature (°C or °F).

[0298] A unipolar 12-lead electrocardiogram (ECG) is obtained using an ECG machine that automatically calculates heart rate and measured values ​​such as PR, QRS, QT, and QTc intervals, as outlined in the evaluation schedule.

[0299] The patient should be in a supine position for approximately 5-10 minutes before ECG acquisition, and should remain in a supine position throughout the ECG acquisition, but must remain awake.

[0300] The principal investigator or designated investigator is responsible for interpreting the ECG, determining whether it falls within the normal range, and determining the clinical significance of the results. These determinations are directed to the eCRF.

[0301] Urine samples are analyzed for the parameters listed in Table 10. If the macroscopic analysis is abnormal, a microscopic examination of the urine sample is performed. The urine sample is also analyzed for the measurement of protein and creatinine, and the urinary protein:creatinine ratio is calculated.

[0302] [Table 10]

[0303] Prior to registration, all patients are required to undergo human immunodeficiency virus (HIV) testing for HIV-1 and HIV-2. Patients who test positive for HIV will not be registered.

[0304] Prior to administration of the investigational drug, blood samples will be collected to test for the presence of radula (antibodies) against ravulizumab in the serum. Further characterization of the antibody response, including ravulizumab-binding and neutralizing antibodies, PK / PD, safety, and activity, may be performed as appropriate. Antibodies against ravulizumab will be evaluated in serum samples collected from all patients according to the evaluation schedule. Serum samples will be screened for antibodies that bind to ravulizumab, and the titers of confirmed positive samples will be reported. Detection and characterization of antibodies against ravulizumab will be performed using validated assays.

[0305] Report adverse events and serious adverse events. An adverse event (AE) is any troublesome medical event in a patient who has been administered a pharmaceutical product and is not necessarily causally related to the treatment. Therefore, an adverse event may be any undesirable or unintended sign (e.g., an abnormal clinical laboratory finding), symptom, or disease that is temporally related to the use of the drug, whether or not it is considered to be related to the drug.

[0306] Events that qualify as adverse events include: (1) any abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, X-ray scan, vital sign measurements) that are considered clinically significant (i.e., unrelated to progression of an underlying disease) in the medical and scientific judgment of the principal investigator, including worsening from baseline; (2) exacerbation of a pre-existing chronic or intermittent condition, including an increase in either the frequency or / or intensity of the condition; (3) any new condition detected or diagnosed after administration of the investigational drug, even if it may have been present before the start of the study; (4) any signs, symptoms, or clinical complications of a suspected drug interaction; or (5) any "lack of efficacy" or "lack of expected pharmacological effect" that is essentially reported as an AE or SAE. Such cases will be captured in the efficacy assessment. However, signs, symptoms, and / or clinical complications resulting from a lack of efficacy shall be reported as an AE or SAE if they meet the definition of an AE or SAE, and (6) signs, symptoms, and / or clinical complications resulting from a lack of efficacy shall be reported as an AE or SAE if they meet the definition of an AE or SAE.

[0307] Events that do not meet the definition of an adverse event include: (1) medical or surgical procedures (e.g., endoscopy, appendectomy): any medical condition leading to such a procedure is an AE; (2) situations in which no troublesome medical event occurred (e.g., hospitalization for elective surgery if planned before signing the ICF, hospitalization for social or convenience reasons); (3) expected daily fluctuations in one or more pre-existing diseases or conditions present or detectable at the start of the study that do not worsen; (4) lack of drug effect is not an AE in a clinical trial, as the purpose of the clinical trial is to establish drug effect; (5) drug error (including intentional misuse, abuse, and overdose of the product) or use other than that defined in the protocol is not considered an AE unless a troublesome medical event occurs as a result of drug error; and (6) cases of pregnancy occurring during maternal or paternal exposure to the investigational product are reported within 24 hours of becoming aware of by the principal investigator / site. Data on fetal outcomes and breastfeeding are collected for reporting to regulatory authorities and for safety assessment.

[0308] If an event does not constitute an adverse event according to the above definition, it cannot be classified as a serious adverse event (SAE), even if it is a serious condition (e.g., hospitalization due to signs / symptoms of the disease under study, or death due to disease progression). Blood transfusions administered in an inpatient or outpatient setting are not considered adverse events or serious adverse events, unless the principal investigator identifies them as such. The definition of a serious adverse event is shown in Table 11.

[0309] [Table 11]

[0310] A suspected unexpected serious adverse reaction (SUSAR) is a serious event that is not listed in the IB and is identified by the principal investigator as being related to the investigational product or procedure.

[0311] An adverse event (ADE) is an adverse event considered to be related to the use of an investigational medical device. This includes any adverse event resulting from deficiencies or inadequate use of the investigational medical device's instructions, development, installation, or operation, or from any malfunction. An ADE includes any event that is the result of misuse or intentional misuse. Misuse refers to an action or omission of an action that produces a different device response than intended by the manufacturer or user. An unexpected physiological response of the subject does not constitute misuse in itself. Dosage errors such as missed doses and underdoses that occur in connection with the use of the device are considered ADEs. Each ADE must be associated with one research device (i.e., one OBDS kit in the current study). A ravulizumab SC overdose involving multiple OBDS kits is a dosing error related to the SC drug administration route and is therefore not considered an ADE.

[0312] ADE may occur in the following cases: (1) Normal use: Injection site reactions not related to any obvious device malfunction, misuse, or abnormal use of the device; (2) Example of device malfunction: A bent needle leading to a laceration at the injection site; (3) Example of misuse: The subject, despite having the best intention to complete the required drug delivery according to the IFU, forgot to remove body hair and properly prepare the skin at the device application site, resulting in the device detaching during delivery and leading to partial delivery; (4) Example of misuse (abnormal use): The subject used the device to administer a substance other than the investigational drug, contrary to the instructions for use of the device designated for ravulizumab OBDS IB, resulting in toxicity from that substance.

[0313] Two OBDS kits are used to deliver the prescribed 490 mg dose of ravulizumab SC. Dosage errors such as missed doses (non-dosing) and partial doses (underdosing) related to research equipment or the use of research equipment are considered adverse drug reactions (ADEs). Any missed or undelivered doses related to ravulizumab SC administration using OBDS are also considered ADEs. Along with the ADE, the kit number associated with the undelivered ADE must be recorded. After partial dosing, there may be one ADE associated with one device. Therefore, one partial dosing ADE is associated with one OBDS unit, and one kit number is required in the recording of the partial dosing ADE.

[0314] A serious adverse event caused by a device (SADE) is an ADE that results in one of the consequences specific to SAE.

[0315] Unexpected device-induced serious adverse events (USADEs) are, by their nature, not identified as events with a predicted incidence, severity, or outcome in the current version of ravulizumab OBDS IB.

[0316] An equipment malfunction is an inadequacy of an investigational medical device relating to its identifiability, quality, durability, reliability, safety, or performance. This may result from a malfunction, misuse, user error, inadequate labeling, or insufficient information provided by the manufacturer. If a drug administration error is related to an equipment malfunction / malfunction, it is considered an ADE (Advanced Drug Application).

[0317] The principal investigator will assess the severity of each AE and SAE reported during the study and assign it to one of the following classifications according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03, published on June 14, 2010. Each CTCAE term is a Lowest Level Term (LLT) according to MedDRA. Each LLT will be coded into a MedDRA basic term: (1) Grade 1: Mild (asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated), (2) Grade 2: Moderate (minimal, local or non-invasive intervention indicated; age-appropriate instrumental ADL limitation), (3) Grade 3: Severe (severe or medically significant but not immediately life-threatening; hospitalization or extended hospitalization indicated; physical disability present; limitation of self-care ADL), (4) Grade 4: Life-threatening (emergency intervention indicated), and (5) Grade 5: Fatal (death related to AE). Any changes in the severity of an AE must be documented in accordance with the specific guidelines of the eCRF Completion Guidelines. Severity and severity must be distinguished: severity refers to the intensity of the AE, while severity refers to an AE that meets the specific criteria for SAE as described above.

[0318] The principal investigator is obligated to determine the relationship between the investigational drug and the occurrence of each AE / SAE, and between the research device and the occurrence of each ADE / SADE. The principal investigator's causal determination must be provided for all AEs and ADEs (both non-serious and serious). This determination must be recorded as appropriate in the eCRF and any additional forms. The definitions of causal determination are as follows: (1) No relationship: There is no evidence to suggest that there was a reasonable possibility that the drug caused the adverse event, and (2) Relationship: There is evidence to suggest that there was a reasonable possibility that the drug caused the adverse event. The principal investigator will use clinical judgment to determine the relationship with the investigational drug or medical device. Other causes, such as one or more underlying conditions, combination therapies, and other risk factors, as well as the temporal relationship between the event and the administration of the investigational drug, will be considered and investigated. This protocol uses the current IB as the Reference Safety Document. The predictability and reporting criteria for SAEs are determined by the sponsor based on the Reference Safety Document. It is possible that an SAE may occur and the principal investigator may only have the minimum information necessary for the initial report. However, it is crucial that the principal investigator always determines the causal relationship for all events before the initial submission of SAE data.

[0319] We collect all events, from the signing of the ICF as specified in the evaluation schedule to follow-up contact.

[0320] As with any terminal complement antagonist, ravulizumab increases patient susceptibility to meningococcal infection (N meningitidis). To reduce the risk of meningococcal infection, all patients must have been vaccinated against meningococcal infection within three years prior to or at the time of initiation of the investigational drug. Patients initiating investigational drug treatment less than two weeks after meningococcal vaccination must receive appropriate prophylactic antibiotic treatment for up to two weeks after vaccination.

[0321] Where available, vaccines against serotypes A, C, Y, W135, and B are recommended for the prevention of common pathogenic meningococcal serotypes. Patients should be vaccinated or revaccinated in accordance with current national vaccination guidelines or local vaccine use practices with complement inhibitors (e.g., eculizumab).

[0322] Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given in accordance with official guidance and local practices regarding the appropriate use of antibiotics. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary.

[0323] To enhance patients' awareness of the risk of infections they may experience during the study and to encourage prompt disclosure of any potential signs or symptoms, patients will be provided with a safety card to carry at all times. At each visit, further discussion and explanation regarding potential risks, signs, and symptoms will take place as part of a review of the patient safety card, as outlined in the evaluation schedule. One or more meningococcal (N. meningitidis) vaccinations will be recorded in the patient's eCRF.

[0324] Injection site reactions are localized to the site of SC or IV administration and may include erythema, itching, and subcutaneous hemorrhage. Injection-related reactions may be systemic in nature and generally immune-mediated or non-immune-mediated, occurring within a few hours of drug administration. Immune-mediated reactions may include allergic reactions (e.g., anaphylaxis), while non-immune-mediated reactions are nonspecific (e.g., headache, dizziness, nausea). Monitoring of these reactions will be performed as part of the routine safety assessment in this study.

[0325] Infusion-related reactions are defined as systemic adverse events (e.g., fever, chills, flushing, changes in heart rate and blood pressure, dyspnea, nausea, vomiting, diarrhea, and generalized skin rash) that occur during or within 24 hours of infusion, and which the principal investigator determines to be related to the investigational drug.

[0326] Device performance is determined in accordance with IFU requirements, using reported outcomes (including device malfunctions / errors) for the intended prescribed dose.

[0327] In the event of equipment malfunction, ravulizumab OBDS may be sent to the central laboratory for analysis, regardless of whether it is related to medication leakage or not.

[0328] For this study, any IV or SC ravulizumab dose higher than specified / required in the protocol will be considered a medication error of overdose. Overdose is a medication error that is not considered an AE or ADE unless it results in a serious medical event.

[0329] An overdose related to ravulizumab SC administration via OBDS is defined as the administration of ravulizumab SC in amounts exceeding the total dose contained in two full-volume OBDS cartridges. This definition is made due to the practical consideration that a standard dose of ravulizumab SC administration involves the use of multiple OBDS units, each containing a fixed dose / volume of ravulizumab. This definition is based on the definition of overdose for the investigational drug and the broad safe dose range of ravulizumab previously clinically tested (up to 5400 mg IV, equivalent to ravulizumab in 10 or fewer standard-volume OBDS cartridges).

[0330] 16. Pharmacokinetic assessment The timing of sample collection for PK is critically important for the primary endpoint of this study. The initiation time of the dose administered on day 1 is the nominal time for all subsequent doses and associated samples. Samples obtained outside the assigned PK visit window will be considered a protocol deviation. Subsequent sample collection timing remains the same as the nominal time of dose initiation on day 1.

[0331] Blood samples for determining serum drug concentration will be collected before administration of the investigational drug at the points and within the window indicated in the evaluation schedule. For day 1 of the SC group and days 1 and 15 of the IV group, post-administration blood samples will be collected within 30 minutes of the end of infusion. For day 57 of the IV group, the blood sample will be collected upon arrival at the facility; no dose will be administered on day 57. The date and time (24-hour format) of each sample acquisition will be recorded.

[0332] If breakthrough hemolysis occurs, additional PK samples will be required. Unused samples may be kept for up to 5 years to perform additional ravulizumab-related assessments as needed.

[0333] Primary endpoint (C on day 71) トラフ The serum ravulizumab concentration over time is evaluated using the target primary PK parameter. Other PK parameters may also be explored.

[0334] 17. Pharmacodynamics Evaluate free C5 concentration over time. Blood samples will be collected before administration of the investigational drug at the points and within the windows specified in the evaluation schedule. For day 1 in the SC group and days 1 and 15 in the IV group, post-administration blood samples will be collected within 30 minutes of the end of infusion. For day 57 in the IV group, a blood sample will be collected upon facility visit; no dose will be administered on day 57. Samples obtained outside the assigned visit window will be considered a protocol deviation. If breakthrough hemolysis occurs, additional PD samples will be required. Unused samples may be retained for up to 5 years for additional evaluation as needed.

[0335] Further details regarding sample collection, including blood volume requirements, are provided in the clinical laboratory manual.

[0336] 18. Statistical methods and planned analysis The statistical hypothesis is that patients treated with ravulizumab SC by OBDS will show a 71-day C トラフ The concentration is non-inferior to that of patients treated with ravulizumab IV.

[0337] C トラフAssuming a geometric mean ratio (SC / IV) of 1.03 and a coefficient of variation of 0.4, 62 patients in the ravulizumab SC group and 31 patients in the ravulizumab IV comparison group achieved 90% power to detect non-inferiority using a one-sided test at an alpha level of 0.05 and a non-inferiority boundary (NIB) of 0.8. The alpha level and NIB are based on the recommendations in the "Standard Approaches to Establishing Bioequivalence" and "Guideline on the Investigation of Bioequivalence" guidelines from the U.S. Food and Drug Administration and the European Medicines Agency, respectively. To account for the possibility that up to 10% of patients may not meet the inclusion criteria for the PK analysis population, this sample size is increased to 105 patients (70 patients in the ravulizumab SC group and 35 patients in the ravulizumab IV group). An interim analysis will be conducted to assess futility and perform a sample size reestimation. This sample size reestimation could result in an increase of up to 144 patients (up to 96 patients in the ravulizumab SC group and 48 patients in the ravulizumab IV comparison group).

[0338] The analysis population is defined in Table 12. Table 13 shows the drug administration window for inclusion in the PK analysis population.

[0339] [Table 12]

[0340] [Table 13]

[0341] The primary analysis uses the population targeted for PK analysis.

[0342] All data and all outcomes derived from the data will be presented in a detailed data list or summary table. Graphs may also be provided where appropriate. All analyses will be performed using SAS® release, version 9.4 or later (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables will be summarized using descriptive statistics, including observation count and mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by patient frequency and percentage.

[0343] Prior to database fixation and analysis, a separate statistical analysis plan (SAP) shall specify the details of the statistical analysis described below. Any changes to the data analysis methods described in the protocol are only required if they alter the primary objective or the conduct of the study. Any other changes to the data analysis methods described in the protocol or SAP, and the reasons for making such changes, shall be documented in the clinical research report. Further exploratory data analysis may be performed where deemed appropriate.

[0344] After all assessments required by the protocol during the randomization treatment period have been completed for all patients, serum C12 of ravulizumab SC compared to ravulizumab IV was performed. トラフ A primary analysis will be conducted to evaluate the non-inferiority of [the product / feature].

[0345] The primary analysis will be conducted on the population targeted for PK analysis.

[0346] The primary endpoint was serum ravulizumab C at day 71. トラフ The geometric mean C from ravulizumab group IV is... トラフ Geometric mean C from the ravulizumab SC group トラフ The ratio is calculated along with the two-sided 90% CI. If the lower limit of the 90% CI for the geometric mean ratio (labulizumab SC / labulizumab IV) is higher than the 80% NIB, then labulizumab SC treatment is concluded to be non-inferior to labulizumab IV treatment.

[0347] To obtain the aforementioned 90% CI, the C under consideration is トラフ The data will be analyzed using analysis of variance. In addition to the formulation (SC or IV), this statistical analysis model will take body weight into account. The data will be transformed using logarithmic transformation before analysis. Point estimates and CIs will be calculated and created for the mean of the differences in the logarithmically transformed parameters. These will then be inversely transformed and presented on a ratio scale.

[0348] Sensitivity analysis is performed by repeating this primary analysis on the largest analysis population (FAS) and the protocol-compliant population (PPS) for which evaluable PK data is available.

[0349] Secondary analyses will be conducted on the largest analysis population (FAS). Where applicable, results from the randomization treatment period will be presented in parallel by treatment group, although no formal comparisons will be made. Summarization of data over time during patients receiving ravulizumab SC is based on the time elapsed since initial exposure to ravulizumab SC. At the start of the extension period, patients randomized to the SC group will have received their initial dose of ravulizumab SC 56 days prior, while patients initially randomized to the IV group will receive their initial dose of ravulizumab SC. Taking this difference in exposure into account, for example, the summary at day 183 (from the initial dose of ravulizumab SC) will use data from patients randomized to the SC group at day 183 of the study and data from patients randomized to the IV group at day 239 of the study.

[0350] Pharmacokinetic analysis will be performed on all patients in the PK analysis population who have evaluable PK data from FAS as described above. Since this is a multicenter patient study, censoring of PK or PD data may be considered if sample collection or handling errors are suspected.

[0351] A graph of the mean serum ravulizumab concentration over time will be created. Graphs of serum concentration over time for individual patients may also be provided. Actual dose administration and sample collection times will be used for all calculations. Descriptive statistics will be calculated for serum concentration data at each sample collection time, as needed.

[0352] Pharmacodynamic analysis will be performed for all patients with evaluable PD data from FAS. The PD effect of ravulizumab will be evaluated by determining the absolute value of free serum C5 concentration over time. Descriptive statistics of PD data will be calculated for each sample collection time as appropriate. Further determination of serum free C5 concentration may be considered as appropriate.

[0353] Quality of life is assessed using the FACIT-Fatigue 4th Edition Questionnaire and the EORTC QLQ-C30 3.0 Edition Questionnaire. Data from these questionnaires are summarized at baseline, at day 183, and at each applicable time point after baseline using descriptive statistics for continuous variables of observed values, as well as changes from baseline.

[0354] Patient satisfaction with the procedure will be assessed using the TASQ score. These data will be summarized at baseline, at day 183, and at each applicable time point after baseline using descriptive statistics for the continuous variable of the observed value, as well as the change from baseline. Any safety data generated from this questionnaire will be documented as adverse events in the AE eCRF at the medical discretion of the principal investigator.

[0355] Lactate dehydrogenase levels are summarized at baseline and each applicable time point after baseline using descriptive statistics for the continuous variable of the observed value, as well as the change from baseline.

[0356] The number and proportion of patients with breakthrough hemolysis are summarized over time by presenting the number and proportion of patients with breakthrough hemolysis, along with two-sided 95% confidence intervals, for each applicable time point after baseline. The number and proportion of patients not requiring transfusion, as well as the number and proportion of patients with stabilized hemoglobin, are summarized similarly.

[0357] All safety analyses will be conducted on the safety target population, which is defined as all patients receiving at least one dose of ravulizumab.

[0358] The following definitions apply to AEs and ADEs: A pre-treatment adverse event is any adverse event that begins after informed consent has been given but before the first infusion of the investigational drug. A treatment-induced AE (TEAE) is any adverse event that begins during or after the first infusion of the investigational drug. By definition, all ADEs occur during or after the first infusion.

[0359] The incidence of TEAEs is summarized overall by organ system classification (SOC) and basic terminology, by severity, and by relationship to treatment. The incidence of SAEs is also summarized. Similarly, the incidence of ADEs and SADEs is summarized by SOC, basic terminology, and severity. All AEs and ADEs are coded using the Medical Dictionary for Regulatory Activities, 18th edition or later.

[0360] Adverse changes in physical examination findings from baseline are classified as adverse events and analyzed accordingly.

[0361] For all applicable study visits, summarize the observed values ​​and changes from baseline (last assessment before ravulizumab) of ECG, vital signs, and laboratory findings. For all applicable study visits, summarize the shift from baseline in classification for laboratory results that can be classified as normal, low, or high based on normal range values.

[0362] For all applicable study visits, summarize the change from baseline in ECG intervals (PR, RR, QT, and QTcF). The QT interval is corrected for heart rate using Fridericia's formula (QTcF).

[0363] Regarding immunogenicity data, summarize the number, proportion, and potency of patients who develop ADA to ravulizumab. You may also examine the proportion of patients with at least one positive ADA result over time (formerly positive) and the proportion of patients who remain consistently negative.

[0364] Device performance is evaluated by the number and percentage of doses successfully administered completely out of all intended doses. The reasons for unsuccessful dose administration are summarized. Reasons reported as "device-related technical failures" are further summarized by category.

[0365] Where deemed necessary, further exploration of PK, PD, ravulizumab OBDS performance data, and patient-reported outcomes may be conducted.

[0366] An interim analysis will be conducted when 50% of the planned patients (n=105) have completed the primary endpoint assessment (i.e., 34 patients in the ravulizumab SC group and 17 patients in the ravulizumab IV comparison group). This is expected to result in at least 45 patients meeting the inclusion criteria for the PK analysis population.

[0367] The initial part of the analysis is to determine futility so that the sponsor can terminate the study early if the likelihood of a significant final outcome is low. This protects resources when the likelihood of non-inferiority appears very low, preventing further patient exposure to the investigational drug.

[0368] After determining futility, an interim analysis will also be conducted to re-evaluate the sample size, using the same set of patients and data, based on estimates of the primary endpoint, to re-determine the size necessary for the study.

[0369] Patient registration will continue without interruption while this analysis is underway.

[0370] At the time of the interim analysis, there are no plans to discontinue the study in order to demonstrate non-inferiority.

[0371] If a nonbinding futility boundary is used based on a 20% non-inferiority conditional power (CPni), and the sponsor decides to continue the study, the crossing of the futility boundary will not affect the Type I error rate in the primary analysis.

[0372] Sample size reestimation (SSR) analysis is also based on CPni, which is calculated using the results obtained in this interim analysis. CPni is calculated assuming an “observed effect” value; i.e., the population mean C トラフ This is the sample mean C at the time of sample size reestimation. トラフ This is equal to the maximum total number of patients, which is 144. The sample size will never be reduced from the planned sample size of 105 patients. The sample size will not be increased if the CPni is at least 90% of the total sample size of the planned 105 patients.

[0373] The decisions made based on this sample size reestimation analysis follow the following rules (see Table 14):

[0374] If CPmin ≤ CPni < 0.9, the sample size is increased by exactly the amount needed to raise CPni to 90%, with an upper limit of 144 patients. The range CPmin ≤ CPni < 0.9 is called the promising zone. Specifically, when CPni is in this promising zone, this decision rule increases the sample size to the smaller of 144 patients or the number needed to raise CPni to 90%.

[0375] [Table 14]

[0376] The lower limit of the promising area, CPmin, was determined according to the methodology described in Mehta et al. (Mehta et al., Stat Medicine. 2011;30:3267-3284) and is not explicitly stated here to avoid the possibility of research bias arising after any decisions made based on this sample size reestimation analysis. Further details are provided to SAP.

[0377] If the judgment for day 1 is missing, the screening judgment will be used as the baseline judgment.

[0378] Missing data from HRQoL instruments will be handled as specified in the documentation for each instrument.

[0379] Example 2: Interim results of a Phase 3 clinical trial In adult PNH patients who had been stable for more than 3 months on eculizumab (SOLIRIS®), a phase 3, randomized, parallel-group, multicenter, open-label, PK non-inferiority study (referred to as "ALXN1210-PNH-303") was conducted to compare subcutaneously administered ravulizumab (ULTOMIRIS®) (RAV-SC) with intravenously administered ravulizumab (RAV-IV), substantially following the protocol shown in Example 1 above.

[0380] Specifically, this study is a phase 3, randomized, parallel-group, open-label, PK non-inferiority study comparing RAV-SC with RAV-IV. Adult PNH patients who had been stable on eculizumab for at least 3 months were included in the switch. Randomization (2:1, SC vs. IV) was stratified by baseline weight category (40kg to <60kg and 60kg to <100kg). The randomization-treatment period was 10 weeks, with patients randomized to a treatment arm in a 2:1 ratio (ravRAV-SC vs. RAV-IV).

[0381] 136 participants were enrolled and received at least one dose. All seven participants from facility 0657 were excluded from the primary analysis population due to deviations from source data management. One participant discontinued treatment before completion of the randomization period. 113 patients were included in the primary analysis population (PK analysis population).

[0382] All patients received a body-weight-based IV loading dose on day 1. Days 15–71: Patients received either a QW SC dose (490 mg via two RAV-OBDS) or a single Q8W RAV IV maintenance dose. For the extension period, all patients self-administered the QW SC dose (490 mg via two RAV-OBDS) for up to 182 weeks. The sample size was 105 patients (70 SC and 35 IV). When 50% of the planned total sample size completed the primary endpoint assessment, a futility analysis and sample size reestimation analysis were performed (in January 2020). There were no dropouts. The study scheme is shown in Figure 5. Patient allocation and the analysis population are summarized in Figure 6. Patient demographic information and baseline characterization are shown in Figures 7A–7B.

[0383] The specific medications prescribed are as follows: Labulizumab SC dosage: Day 1 loading dose (IV) = 2400 mg for patients weighing 40 kg to less than 60 kg and 2700 mg for patients weighing 60 kg to less than 100 kg; Day 15 and maintenance dose (SC) = 490 mg qw for all patients.

[0384] Rabulizumab IV dosage: Day 1 loading dose (IV) = 2400 mg for patients weighing 40 mg or more but less than 60 kg, and 2700 mg for patients weighing 60 kg or more but less than 100 kg; Day 15 maintenance dose (IV) = 3000 mg for patients weighing 40 kg or more but less than 60 kg, and 3300 mg for patients weighing 60 kg or more but less than 100 kg.

[0385] Extended maintenance dose (SC) = 490 mg qw for all patients.

[0386] A. Objectives and Evaluation Items The primary objective was to demonstrate the non-inferiority of subcutaneous ravulizumab trough concentration compared to intravenous administration. The primary endpoint was serum ravulizumab trough concentration (C trough) at day 71. Data were included from a 10-week randomized treatment period for all patients who had not previously discontinued this study.

[0387] The safety objective was to evaluate the safety of ravulizumab and ravulizumab on-body delivery systems (OBDS) administered subcutaneously. Safety endpoints included physical examinations, vital signs, clinical laboratory findings, and adverse events (AEs), including adverse device effects (ADEs).

[0388] Secondary objectives and endpoints include (1) characterizing the PK, PD, and immunogenicity of ravulizumab SC (i.e., C over time). トラフ (1) assessing health-related quality of life and treatment satisfaction with ravulizumab SC (i.e., FACIT-fatigue, EORTC QLQ-30, treatment satisfaction questionnaire), (2) assessing the efficacy of ravulizumab SC (i.e., LDH, breakthrough hemolysis, transfusion avoidance, stable hemoglobin, overall PNH symptoms), and (4) determining the performance of ravulizumab OBDS (i.e., reported outcomes of intended dose administration). Interim endpoints are up to June 2020 and are limited to data from the randomization treatment period (10 weeks).

[0389] B. Primary analysis A primary analysis was performed on the PK analysis population. This included all patients with evaluable PK data who met the following criteria: (1) all doses up to day 64 adhered to the planned dose and the administration time window specified in the protocol, and (2) the pre-administration PK sample on day 71 was collected within ±3 hours of the nominal time of the first dose on day 1.

[0390] The geometric mean ratio (labulizumab SC / labulizumab IV) has a 90% confidence interval (CI). This was done using a weighted test statistic to account for interim analysis of sample size reestimation and to avoid the inflated risk of Type I errors. Non-inferiority was claimed when the lower limit of the CI was higher than the 80% non-inferiority threshold (NIB).

[0391] The analysis included: (1) ANOVA controlling for treatment (SC and IV) and weight categories, and (2) C data that had been logarithmically transformed before the analysis. トラフ The data includes (3) point estimates and CIs obtained for the difference in mean values ​​of the logarithmically transformed data, and (4) the inversely transformed data presented on a ratio scale.

[0392] C. Other populations analyzed: All patients in the protocol-compliant group and the PK group who also meet all of the following criteria: (1) Meets the following inclusion criteria: #1: The patient was treated with eculizumab according to the recommended dose indication for PNH (900 mg every 14 ± 2 days) for at least 3 months prior to study enrollment, did not skip any doses within 2 months prior to study enrollment, and did not exceed 2 doses outside the visit window. #2: At the time of screening, according to the central laboratory, lactate dehydrogenase levels ≤ 1.5 × ULN. Samples must be obtained within 24 hours prior to or immediately before the scheduled eculizumab dose administration (i.e., at trough eculizumab levels). #3: There is a documented record of a diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation. #4: The participant weighs between 40kg and 100kg, and the principal investigator expects them to remain within this weight range throughout the study period. #5: Patients must be willing and capable of submitting written informed consent and complying with all study visits and procedures, including self-administration of ravulizumab SC doses and use of any one or more data collection devices to directly record patient data. (2) None of the following exclusion criteria were met: #1: LDH levels > 2×ULN more than once within 3 months prior to study registration. #2: MAVE for the 6 months prior to study registration. #3: Platelet count <30,000 / mm³ at screening 3 (30×10 9 / L). #4: Neutrophil absolute count <500 / μL (0.5 × 10) at screening 9 / L) The PD analysis population included all patients who received at least one dose of ravulizumab and had evaluable PD data. The maximum analysis population and safety population included all registered patients in the analysis population who received at least one dose of ravulizumab (excluding those from facility 0657). The modified maximum analysis population and modified safety population included all patients in the FAS and safety population, but also included patients from facility 0657 who received at least one dose of ravulizumab.

[0393] D. Results: The primary PK non-inferiority analysis is shown in Figure 8. The Stage 1 population consists of all patients included in the sample size reestimation analysis. The Stage 2 population consists of all patients not analyzed as part of the sample size reestimation analysis. The mixed model is performed with logarithmically transformed parameters and includes treatment and stratified weight groups as fixed effects. The geometric least squares mean is the least squares mean from the mixed model after inverse transformation to the original scale. The 90% confidence interval is presented after inverse transformation to the original scale. The z-score is calculated for each stage and presented as a composite score using pre-specified weights of 0.5 and 0.5. Statistical significance was reached when the weighted overall z-score was greater than 1.645. The PK non-inferiority forest plot is shown in Figure 9. Mean serum ravulizumab concentrations are shown in Figure 10. Free C5 concentrations are shown in Figure 11.

[0394] Non-inferiority of subcutaneous traflabrizumab concentrations compared to intravenous concentrations was demonstrated in the PK analysis population. The geometric mean ratio (GMR) was 1.257 with a 90% CI (1.160, 1.361) and p-value < 0.0001. Regarding pharmacokinetics (PK) and pharmacodynamics (PD), in both treatment groups, all free C5 results obtained throughout the randomized treatment period after the initial dose were ≤ 0.5 μg / mL (i.e., the defined threshold for complete terminal complement inhibition). For all subjects without unexpected PK findings, subcutaneous administration resulted in ravulizumab exposure ≥ 175 μg / mL, the defined threshold for complete complement inhibition. No ADA-positive results were observed in any participant under treatment.

[0395] Regarding efficacy, mean lactate dehydrogenase is shown in Figure 12, breakthrough hemolysis / transfusion avoidance in Figure 13, and hemoglobin stability / overall PNH symptoms in Figure 14. Breakthrough hemolysis was low in both arms (i.e., no events in the subcutaneous arm, compared to one event in the intravenous arm). Transfusion avoidance was maintained in 94% and 87% of participants in both the subcutaneous and intravenous groups, respectively. Transfusion avoidance is defined as patients who remained transfusion-free and did not require a transfusion after the initial dose of the investigational drug. Stable hemoglobin results were maintained in 94% and 82% of participants in both the subcutaneous and intravenous groups, respectively. PNH symptoms were observed in 45% and 47% of participants in both the subcutaneous and intravenous groups, respectively.

[0396] Regarding safety, no ADA-positive results were observed in any participant during treatment. A summary of AEs that occurred during treatment is shown in Figure 15, and a summary of serious adverse events is shown in Figure 16. The proportion of patients with at least one adverse event (AE) was higher in the subcutaneous arm (81%) and 60% compared to the intravenous arm. When device-induced adverse events (ADEs) were excluded, the proportions were similar: subcutaneous (64%) vs. intravenous (60%). Of the ADEs, 23% were injection-related and 4% were contact-related. Regarding serious adverse events (SAEs), the subcutaneous result was 5 / 84 cases (6%), compared to 1 / 45 cases (2%) in the intravenous group. No serious device-induced adverse events (SADEs) were reported. There were no cases of meningococcal disease.

[0397] Regarding safety, there are two main areas of focus: (1) TEAEs (not related to ADE) and (2) ADEs. TEAs had a higher incidence in the subcutaneous arm: (1) fever - 6 patients, all G1, all unrelated; (2) asthenia - 4 patients, the majority G1, 2 related, and 2 unrelated; (3) fatigue - 6 patients (2 cases of worsening fatigue), the majority G1, 1 related; and (4) diarrhea - 10 patients (11 events), all G1, 3 related events. Regarding ADEs, n: 38 cases (45.2%) E=107. (1) Application site events: n=3 cases (3.6%) E=3; (2) Injection site events: n=19 cases (22.6%) E=73; and (3) Device use: n=20 cases (23.8%) E=31.

[0398] E. Summary: In summary, the primary results demonstrated non-inferiority of subcutaneous traflabulizumab concentrations compared to intravenous administration in the PK analysis population, with a geometric mean ratio (GMR) of 1.257, 90% CI (1.160, 1.361), and p-value < 0.0001. Regarding PK / PD, in both treatment groups, all free C5 results obtained throughout the randomized treatment period after the initial dose were below 0.5 μg / mL; the defined threshold for complete terminal complement inhibition. For all subjects without unexpected PK findings, subcutaneous administration resulted in ravulizumab exposure ≥ 175 μg / mL, the defined threshold for complete complement inhibition. No ADA-positive results were observed in any participant under treatment. Regarding safety, the proportion of patients with at least one adverse event (AE) was higher in the subcutaneous arm (81%) and 60% (60%) compared to the intravenous arm. Excluding adverse drug reactions (ADEs), the ratios were similar: SC 64% vs. IV 60%. Regarding ADEs, 26% had site-related complications (injection-related: 23%, contact-related: 4%). Regarding SAEs: SC 5 / 84 cases (6%) vs. IV 1 / 45 cases (2%). No SADEs were reported, and there were no meningococcal cases.

[0399] Regarding efficacy, breakthrough hemolysis was low in both arms: SC (no events) vs. IV (1 event). Transfusion avoidance was maintained in 94% and 87% of participants in the SC and IV groups, respectively. Stable hemoglobin results were maintained in 94% and 82% of participants in the SC and IV groups, respectively. Symptoms of PNH were observed in 45% and 47% of participants in the SC and IV groups, respectively.

[0400] [Table A-1]

[0401] [Table A-2]

[0402] [Table A-3]

[0403] Table A-4

[0404] Table A-5

[0405] Table A-6

Claims

1. A composition for treating a human patient having a complement-associated condition, comprising an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the composition is administered to the patient during an administration cycle, and the anti-C5 antibody or antigen-binding fragment thereof is administered subcutaneously (SC).

2. The composition of claim 1, wherein the composition is administered subcutaneously with a device, e.g., an on-body delivery system (OBDS), comprising an effective amount of the anti-C5 antibody, e.g., ravulizumab or eculizumab or a biosimilar antibody thereof.

3. The composition of claim 1 or 2, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 490 mg every week thereafter.

4. 2. The composition of claim 1, wherein the human patient receives an intravenous loading dose prior to subcutaneous administration.

5. The loading dose is a weight-based dose, i. A dose of 2400 mg is administered to a patient weighing 40 kg or more and less than 60 kg; or ii. A dose of 2700 mg is administered to a patient weighing 60 kg or more and less than 100 kg; The composition of claim 4.

6. 2. The composition of claim 1, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and 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, respectively, of a native human IgG Fc constant region, according to EU numbering.

7. 5. The composition of claim 4, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 490 mg q1w on day 15 of the administration cycle and for at least 7 weeks thereafter.

8. 8. The composition of claim 7, wherein the administration cycle is for a total of 10 weeks of treatment.

9. 4. The composition of claim 3, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 490 mg q1w for up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, or chronically for the life of the patient.

10. The composition of any one of claims 1 to 9, wherein the patient has previously been treated with eculizumab.

11. 11. The composition of claim 10, wherein the administration cycle is initiated at least two weeks after the patient's last dose of eculizumab.

12. The composition of claim 1 , wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 12 and a light chain variable region of SEQ ID NO:

8.

13. The composition of claim 1 , wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO:

13.

14. The composition of claim 1 , wherein the antibody or antigen-binding fragment thereof 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.

15. The anti-C5 antibody or antigen-binding fragment thereof has a K binding affinity of 0.1 nM or less to human C5 at pH 7.4 and 25° C. Ｄ Affinity dissociation constants (K Ｄ The composition according to any one of claims 1 to 14, wherein the bond is at least one of the following:

16. The anti-C5 antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25° C. Ｄ The composition of any one of claims 1 to 15, which binds with ≧10 nM.

17. The composition of any one of claims 1 to 16, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 100 µg / mL during the administration cycle.

18. 18. The composition of any one of claims 1 to 17, wherein the complement-related disorder is selected from the group consisting of atypical hemolytic uremic syndrome (aHUS), complement-mediated thrombotic microangiopathy (CM-TMA), paroxysmal nocturnal hemoglobinuria (PNH), neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), amyotrophic lateral sclerosis (ALS), pre-eclampsia-hemolysis, high liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), generalized myasthenia gravis (gMG), dermatomyositis, and Guillain-Barre syndrome (GBS).

19. The composition of any one of claims 1 to 18, wherein the treatment results in terminal complement inhibition.

20. The composition of any one of claims 1 to 19, wherein the treatment results in a reduction in hemolysis as measured by lactate dehydrogenase (LDH) levels.

21. 10. The composition of claim 1, wherein the treatment results in at least one therapeutic effect selected from the group consisting of reduction or cessation of fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, and erectile dysfunction.

22. 2. The composition of claim 1, wherein the treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones, and D-dimer.

23. 2. The composition of claim 1, wherein the treatment results in a shift toward normal levels of chronic disease-associated biomarkers selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine: albumin: creatinine and plasma brain natriuretic peptide (BNP).

24. 10. The composition of claim 1, wherein the treatment results in a reduction in transfusion requirements and / or major adverse vascular events (MAVEs).

25. 2. The composition of claim 1, wherein the treatment results in a change from baseline in quality of life as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, 4th edition, and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 scale.

26. The composition according to any one of claims 1 to 25, characterized in that the composition is administered subcutaneously using an on-body delivery system (OBDS).

27. 27. The composition of claim 26, wherein the OBDS comprises the SMARTDOSE Gen I delivery platform.

28. 27. The composition of claim 26, wherein the OBDS comprises a pharmaceutical formulation comprising ravulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.

29. The composition of any one of claims 1 to 28, wherein the SC administration results in a serum ravulizumab trough concentration (C trough) of about 200 μg / ml to about 1000 μg / ml; preferably about 400 μg / ml to about 800 μg / ml; in particular about 550 μg / ml to about 650 μg / ml.

30. The composition of any one of claims 1 to 29, wherein SC administration of an effective amount results in an increase in serum ravulizumab trough concentration (C trough) compared to an intravenous formulation containing ravulizumab; preferably the increase in C trough is from about 5% to about 50%, preferably from about 15% to about 35%.

31. 31. The composition of any one of claims 1 to 30, wherein said SC administration reduces free C5 levels in said patient; preferably reduces said free C5 levels below a defined threshold for complete terminal complement inhibition in said patient, e.g., ≦0.5 μg / ml.

32. 32. The composition of any one of claims 1-31, wherein said SC administration results in a full complement inhibition threshold level of ravulizumab in said patient, e.g., an in vivo ravulizumab level of >= 175 μg / ml.

33. The composition of any one of claims 1 to 32, wherein administration of an effective amount of the SC results in: (a) attenuating breakthrough hemolysis in the patient; (b) avoiding transfusion in the patient; (c) stabilizing the hemoglobin level in the patient; and (d) reducing at least one PNH symptom in the patient.

34. The composition according to any one of claims 1 to 33, characterized in that the composition is administered in an injection of 5 to 9 minutes.

35. The composition according to any one of claims 1 to 34, characterized in that the composition is administered by a tandem subcutaneous (SC) device.

36. A composition according to any one of claims 1 to 35, characterized in that the composition is administered at a constant flow rate, for example by means of a plurality of electromechanical pins.

37. The composition of any one of claims 1 to 36, wherein the patient is an adult patient weighing between 40 kg and 100 kg.

38. 1. A device for subcutaneous administration of an anti-C5 antibody or an antigen-binding fragment thereof, comprising: a) On-Body Delivery Systems (OBDS); b) A subcutaneous formulation of the anti-C5 antibody or antigen-binding fragment thereof. Including, equipment.

39. 40. The device of claim 38, wherein the OBDS comprises the SMARTDOSE Gen I delivery platform.

40. 39. The device of claim 38, wherein the subcutaneous formulation of the anti-C5 antibody or antigen-binding fragment thereof comprises avulizumab (70 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.

41. 40. The device of claim 38, wherein the device delivers a dose of 490 mg to a human patient over a one week period.

42. 1. A device, particularly an on-body delivery system (OBDS), comprising an effective amount of a subcutaneous (SC) formulation for treating a complement-mediated condition, said SC formulation comprising an anti-C5 antibody, e.g., ravulizumab or eculizumab or a biosimilar antibody thereof, or an antigen-binding fragment of said anti-C5 antibody; particularly, said SC formulation comprises ravulizumab.

43. 43. The device of claim 42, comprising: (a) an injection device (platform) for delivery of the anti-C5 antibody; (b) a pre-filled cartridge (PFC) containing the anti-C5 antibody attached to the platform; and (c) a telescoping screw assembly (TSA).

44. 43. The device of claim 42, wherein the PFC comprises about 3.5 ml ravulizumab at a concentration of about 70 mg / ml.

45. 1. A kit for treating a complement-related disease or disorder, comprising: (a) a device according to any one of claims 38 to 44; and (b) instructions for use of the device for subcutaneous administration of the anti-C5 antibody or antigen-binding fragment thereof; Kit including:

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