Dosage and Administration Regimen for the Treatment or Prevention of C5-Related Disease with the Anti-C5 Antibody Crovalimab

Abstract

Dosages and administration regimens of anti-C5 antibodies, particularly the anti-C5 antibody crovalimab, for use in methods of treating or preventing C5-associated diseases are provided. [Solution] An anti-C5 antibody for use in a method for treating or preventing a C5-related disease in a subject, the method comprising the following consecutive steps: (a) administering a single loading dose of 1500 mg of anti-C5 antibody intravenously to the subject, followed by at least one loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject; and (b) administering at least one maintenance dose of 1020 mg of anti-C5 antibody subcutaneously to the subject.

Description

[Technical Field]

[0001] The present invention relates to dosages and administration regimens of anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, for use in methods for treating or preventing C5-related disorders in a subject, including paroxysmal nocturnal hemoglobinuria (PNH). The dosages and treatment regimens of the present invention comprise administering to a subject an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, a loading dose followed by maintenance doses of the anti-C5 antibody, wherein the first loading dose is administered intravenously to the subject, and the remaining loading and maintenance doses are administered subcutaneously at dosages lower than the intravenously administered loading dose. [Background technology]

[0002] The complement system plays a central role in the clearance of immune complexes and in the immune response to infectious agents, foreign antigens, virus-infected cells, and tumor cells. There are approximately 25–30 complement proteins, which are found as complex assemblies of plasma proteins and membrane cofactors. Complement components achieve their immune defense function by interacting in a complex series of enzymatic cleavage and membrane-binding events. The resulting complement cascade generates products with opsonic, immunoregulatory, and bacteriolytic functions.

[0003] The complement system can be activated through three distinct pathways: the classical, lectin, and alternative pathways. These pathways share many components, and although they differ in their initial steps, they converge to share the same terminal complement components (C5 through C9) that are responsible for target cell activation and destruction.

[0004] The classical pathway is typically activated by the formation of antigen-antibody complexes. Independently, the first step in lectin pathway activation is the binding of specific lectins, such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, L-ficolin, and the C-type lectin CL-11. In contrast, the alternative pathway naturally undergoes low-level turnover activation, which can be easily amplified on foreign or other abnormal surfaces (bacteria, yeast, virus-infected cells, or damaged tissue). These pathways converge at the point where complement component C3 is cleaved by activated proteases to produce C3a and C3b.

[0005] C3a is an anaphylatoxin. C3b binds to bacteria and other cells, as well as certain viruses and immune complexes, and tags them for removal from the circulation (a role known as opsonization). C3b complexes with other components to form C5 convertase, which cleaves C5 into C5a and C5b.

[0006] C5 is a 190 kDa protein found in normal serum at approximately 80 μg / ml (0.4 μM). C5 is glycosylated, with approximately 1.5–3.0% of its mass coming from carbohydrates. Mature C5 is a heterodimer of a 115 kDa α chain disulfide-linked to a 75 kDa beta chain. C5 is synthesized as a 1676 amino acid single-chain precursor protein (pro-C5 precursor) (see, e.g., US Pat. Nos. 6,355,245 and 7,432,356). The pro-C5 precursor is cleaved to yield the β chain as an amino-terminal fragment and the alpha chain as a carboxyl-terminal fragment. The alpha and beta chain polypeptide fragments are linked to each other via disulfide bonds to form the mature C5 protein.

[0007] The terminal pathway of the complement system begins with the capture and cleavage of C5. Mature C5 is cleaved into C5a and C5b fragments during complement pathway activation. C5a is cleaved from the alpha chain of C5 by C5 convertase as an amino-terminal fragment containing the first 74 amino acids of the alpha chain. The remaining portion of mature C5 is the fragment C5b, which contains the remaining portion of the alpha chain disulfide attached to the beta chain. Approximately 20% of the 11 kDa mass of C5a is attributable to carbohydrate.

[0008] C5a is another anaphylatoxin. C5b binds to C6, C7, C8, and C9 to form the membrane attack complex (MAC, C5b-9, terminal complement complex (TCC)) on the surface of target cells. When sufficient numbers of MACs insert into the target cell membrane, MAC pores are formed, mediating rapid osmotic lysis of the target cell.

[0009] As previously mentioned, C3a and C5a are anaphylatoxins. They can induce mast cell degranulation, which releases histamine and other mediators of inflammation, resulting in other inflammatory phenomena, including smooth muscle contraction, increased vascular permeability, leukocyte activation, and cell proliferation leading to hyperplasia. C5a also functions as a chemotactic peptide, attracting granulocytes, such as neutrophils, eosinophils, basophils, and monocytes, to the site of complement activation.

[0010] The activity of C5a is regulated by the plasma enzyme carboxypeptidase N, which removes the carboxy-terminal arginine from C5a forming the C5a-des-Arg derivative. C5a-des-Arg exhibits only 1% of the anaphylactic and polymorphonuclear chemotactic activity of unmodified C5a.

[0011] A properly functioning complement system provides a robust defense against infectious microorganisms; however, inappropriate complement regulation or activation has been implicated in the pathogenesis of various disorders, including paroxysmal nocturnal hemoglobinuria (PNH); rheumatoid arthritis; ischemia-reperfusion injury; atypical hemolytic uremic syndrome (aHUS); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; multiple sclerosis; and damage resulting from myocardial infarction, cardiopulmonary bypass, and hemodialysis (see, e.g., Holers et al., Immunol. Rev. (2008), Vol. 223, pp. 300-316). Therefore, inhibiting excessive or uncontrolled activation of the complement cascade can provide clinical benefits to patients with such disorders.

[0012] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder in which red blood cells (erythrocytes) are damaged and therefore destroyed more rapidly than normal red blood cells. PNH results from the clonal proliferation of hematopoietic stem cells that harbor somatic mutations in the PIG-A (phosphatidylinositol glycan class A) gene, located on the X chromosome. PIG-A mutations prematurely block the synthesis of glycosylphosphatidylinositol (GPI), a molecule required for anchoring many proteins to the cell surface. As a result, PNH blood cells lack GPI-anchored proteins, including the complement regulatory proteins CD55 and CD59. Under normal circumstances, these complement regulatory proteins block the formation of MAC on the cell surface, thereby preventing red blood cell lysis. The lack of GPI-anchored proteins causes complement-mediated hemolysis in PNH.

[0013] PNH is characterized by hemolytic anemia (a reduced red blood cell count), hemoglobinuria (the presence of hemoglobin in the urine, especially after sleep), and hemoglobinemia (the presence of hemoglobin in the bloodstream). Subjects with PNH are known to be paroxysmal, defined herein as the occurrence of dark urine. Hemolytic anemia results from the intravascular destruction of red blood cells by complement components. Other known symptoms include aphasia, fatigue, erectile dysfunction, thrombosis, and recurrent abdominal pain.

[0014] Eculizumab is a humanized monoclonal antibody against the complement protein C5 and is the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) (see, e.g., Dmytrijuk et al., The Oncologist (2008), 13(9), pp. 993-1000). Eculizumab inhibits the cleavage of C5 into C5a and C5b by C5 convertase, thereby preventing the generation of the terminal complement complex C5b-9. Both C5a and C5b-9 mediate the terminal complement-mediated events characteristic of PNH and aHUS (see, e.g., WO-A2 2005 / 074607, WO-A1 2007 / 106585, WO-A2 2008 / 069889, and WO-A2 2010 / 054403). For the treatment of PNH, the anti-C5 antibodies eculizumab or ravulizumab are commonly used. However, up to 3.5% of individuals of Asian descent carry a polymorphism in C5 affecting Arg885, which corresponds to the eculizumab and ravulizumab binding site (Nishimura et al., N Engl J Med, Vol. 370, pp. 632-639 (2014); DOI: 10.1056 / NEJMoa1311084). PNH patients with these polymorphisms represent a group with high unmet medical need because they experience poor control of intravascular hemolysis with eculizumab or ravulizumab.

[0015] Several reports have described anti-C5 antibodies. For example, WO 95 / 29697 describes an anti-C5 antibody that binds to the alpha chain of C5 but not to C5a, blocking C5 activation. WO-A2 2002 / 30985 describes an anti-C5 monoclonal antibody that inhibits C5a formation. Meanwhile, WO-A1 2004 / 007553 describes an anti-C5 antibody that recognizes the proteolytic site for C5 convertase on the alpha chain of C5 and inhibits the conversion of C5 to C5a and C5b. WO-A1 2010 / 015608 describes an anti-C5 antibody that binds to at least 1x10 7 M -1The literature described an anti-C5 antibody with an affinity constant of 1000 kJ / s. Further, WO-A1 2017 / 123636 and WO-A1 2017 / 132259 describe anti-C5 antibodies. Furthermore, WO-A 2016 / 098356 disclosed the production of an anti-C5 antibody characterized by binding to an epitope within the beta chain of C5 with higher affinity at neutral pH than at acidic pH. One of the anti-C5 antibodies disclosed in WO-A1 2016 / 098356 is the anti-C5 antibody clovalimab (see Example 1 below for details). Clovalimab is an anti-C5 antibody that binds to a distinct epitope on the beta subunit of C5, which is different from the binding epitope of eculizumab / ravulizumab. In vitro studies have demonstrated that the anti-C5 antibody clovalimab binds equally to and inhibits the activity of wild-type and Arg885-mutant C5 (Fukuzawa et al., Sci Rep, 7(1):1080. doi:10.1038 / s41598-017-01087-7(2017)). In contrast, WO-A1 2017 / 104779 reports in Figure 21 that the anti-C5 antibody eculizumab did not inhibit Arg855-mutant C5. Furthermore, WO-A1 2018 / 143266 relates to pharmaceutical compositions for use in the treatment or prevention of C5-related diseases. Furthermore, WO-A1 2018 / 143266 discloses the dosage and administration scheme of the anti-C5 antibody clovalimab used in the COMPOSER study (BP39144). The COMPOSER trial is a Phase I / II international, multicenter, open-label study to evaluate the safety and efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the anti-C5 antibody crovalimab in healthy subjects and subjects with PNH. The COMPOSER trial consists of three parts: Part 1 in healthy subjects, and Parts 2 and 3 in patients with paroxysmal nocturnal hemoglobinuria (PNH). Furthermore, patients included in Part 3 of the study had received at least 3 months of treatment with the anti-C5 antibody eculizumab.Part 1 of the COMPOSER trial was designed to include three groups of healthy patients: Group 1 received a single intravenous (IV) dose of 75 mg / body of the anti-C5 antibody crovalimab; Group 2 received a single intravenous (IV) dose of 150 mg / body of the anti-C5 antibody crovalimab; and Group 3 received a single subcutaneous (SC) dose of 170 mg / body of the anti-C5 antibody crovalimab. Because Part 1 of the COMPOSER trial is adaptive in nature (based on ongoing evaluation of safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (pD) data), the actual doses in Part 1 were as follows: Group 1 patients enrolled in Part 1 of the COMPOSER trial received 75 mg IV, Group 2 patients received 125 mg IV, and Group 3 patients received 100 mg SC.

[0016] Part 2 of the COMPOSER trial was designed to include a cohort of patients receiving three intravenous doses of the anti-C5 antibody crovalimab: according to the original protocol design, the anti-C5 antibody crovalimab was initially administered at a dose of 300 mg / body (IV), then at 500 mg / body (IV) one week after the first dose, and finally at 1000 mg / body (IV) two weeks after the second dose. Starting two weeks after the final intravenous dose, the anti-C5 antibody crovalimab was administered subcutaneously once weekly at a dose of 170 mg / body. Based on new clinical data and PK simulations from Part 1, the starting dose for patients in Part 2 of the COMPOSER trial was changed from 300 mg to 375 mg IV. Therefore, the actual doses given in Part 2 of the COMPOSER trial were as follows: the anti-C5 antibody crovalimab was administered intravenously (IV) at 375 mg / body, followed by 500 mg / body IV one week after the first dose, and finally 1000 mg / body IV two weeks after the second dose. Starting two weeks after the final IV dose, the anti-C5 antibody crovalimab was administered subcutaneously (SC) at 170 mg / body once weekly.

[0017] Part 3 of the study included patients who had been treated with the anti-C5 antibody eculizumab for three months prior to study enrollment and were required to receive regular intravenous infusions of eculizumab. Part 3 of the study was designed to include three groups. The anti-C5 antibody crovalimab was initially administered intravenously to all groups at a single dose of 1000 mg / body. Starting one week after the first intravenous administration (day 8 after the first intravenous administration), the anti-C5 antibody crovalimab was administered subcutaneously to patients in Group 1 at a dose of 170 mg / body once weekly, to patients in Group 2 at a dose of 340 mg / body once every two weeks, and to patients in Group 3 at a dose of 680 mg / body once every four weeks. In Part 3 of COMPOSER, we detected drug-target-drug complexes (DTDCs) between crovalimab, human C5, and the antibody eculizumab in all patients with PNH who were switched from the anti-C5 antibody eculizumab to crovalimab. DTDCs cause a transient increase in crovalimab clearance, potentially increasing the risk of a temporary loss of complete inhibition of the terminal complement pathway (Roth et al., Blood (2020), Vol. 135, pp. 912–920; doi:10.1182 / blood.2019003399 and Sostelly et al., Blood (2019), Vol. 134, p. 3745).

[0018] Furthermore, WO-A1 2018 / 143266 describes the formation of immune complexes (drug-target-drug-conjugates) between clovalimab, human C5, and the antibody eculizumab in subjects treated with eculizumab. When subjects, particularly those requiring complete C5 inhibition, such as those with PNH or aHUS, switch from the anti-C5 antibody eculizumab to clovalimab, both anti-C5 antibodies bind to different epitopes on human C5, resulting in the formation of drug-target-drug-conjugates (DTDCs). These DTDCs are constructed from repeats of the eculizumab-C5-clovalimab-C5 chain of the molecule, and two DTDCs can aggregate to form larger DTDCs, allowing them to proliferate. The treatment goal for patients included in Part 3 of the COMPOSER trial with clovalimab is to ensure rapid and sustained complete inhibition of the terminal complement pathway. However, drug-target-drug complexes (DTDCs) consisting of crovalimab, human C5, and eculizumab were detected in all patients who switched from eculizumab in Part 3 of COMPOSER. DTDCs, and particularly large DTDCs, are cleared more slowly and are more likely to cause toxicity. The formation of such DTDCs should be avoided because they may pose potential risks, such as circulatory impairment, increased risk of vasculitis due to their complex size, type III hypersensitivity reactions, or abnormal activation of the complement system (Roth et al., Blood (2020), Vol., 135, pp. 912-920; see also doi:10.1182 / blood.2019003399).

[0019] Furthermore, based on its mechanism of action, the anti-C5 antibody clovalimab inhibits complement-mediated lysis of red blood cells lacking complement regulatory proteins. If the terminal complement pathway is not temporarily blocked during the treatment interval, these red blood cells may lyse, resulting in breakthrough hemolysis, a serious clinical complication in patients with PNH. Biological stressors (infection, surgery, pregnancy) lead to physiological activation of the complement pathway with upregulation of C5 (Schutte et al., Int Arch Allergy Appl Immunol. (1975), Vol. 48(5), pp. 706-720). Therefore, in patients with PNH, it is important not only to maintain complete blockade of terminal complement activity throughout the treatment period, but also to maintain a reserve of free clovalimab binding sites to minimize the occurrence of breakthrough hemolysis.

[0020] Therefore, there is a need to identify doses and administration regimens that (1) minimize DTDC formation in patients with C5-related disease, particularly in patients switched from the anti-C5 antibody eculizumab to crovalimab, (2) maximize the level of free crovalimab binding sites, and (3) ensure that patients consistently exceed the anti-C5 antibody target threshold concentration required for terminal complement inhibition, despite interindividual variability. Summary of the Invention

[0021] The present invention addresses this need by providing embodiments defined in the claims.

[0022] The present invention relates to an anti-C5 antibody for use in a method of treating or preventing a C5-associated disease in a subject, the method comprising the following sequential steps: (a) administering to the subject a single intravenous loading dose of a 1500 mg anti-C5 antibody, followed by at least one subcutaneous administration to the subject of a 340 mg loading dose of an anti-C5 antibody; and (b) administering to the subject at least one subcutaneous maintenance dose of 1020 mg of an anti-C5 antibody. 10. An anti-C5 antibody for use in a method for treating or preventing a C5-associated disease, comprising:

[0023] In the context of the present invention, the subject is preferably a patient weighing 100 kg or more. In the context of the present invention, the subject is a subject(s) suffering from a C5-related disease (e.g., PNH and aHUS) that requires inhibition of complement activity. Furthermore, the present invention is directed to the use of an anti-C5 antibody for the treatment or prevention of a C5-related disease, particularly PNH. In the context of the present invention, the present invention is directed to the treatment or prevention of a C5-related disease, preferably PNH, in a patient treated with a pharmaceutical agent useful for the treatment or prevention of a C5-related disease, preferably PNH, in which a loading dose of an intravenously administered anti-C5 antibody is administered to the subject after the final administration of the pharmacological product. Thus, the dosage and administration regimen described herein for an anti-C5 antibody, particularly the anti-C5 antibody crovalimab, is administered to a patient treated with a pharmaceutical agent useful for the treatment or prevention of a C5-related disease, preferably PNH. As explained in more detail below, the pharmaceutical agent useful for treating C5-associated diseases given to a subject prior to the initiation of the claimed dosages and treatment regimens refers to the anti-C5 antibody eculizumab or ravulizumab, preferably the anti-C5 antibody eculizumab.

[0024] As shown in the Examples, the claimed dose and treatment regimen ensure sustained and consistent blockade of terminal complement activity (maintaining levels above the target threshold of 100 μg / ml in more than approximately 95% of subjects) (see Figures 4 and 7). Furthermore, inhibition of terminal complement was achieved immediately after the first dose and generally maintained throughout the dosing interval (see Figure 8). Furthermore, the dose and treatment regimen of the present invention also ensures a sufficient reserve of free binding sites throughout the majority of the dosing interval in both treatment-naive and eculizumab-pretreated patients (see Figure 2). Because crovalimab and eculizumab bind to different C5 epitopes, DTDC formation is expected. DTDC is expected to occur if patients are simultaneously exposed to crovalimab and eculizumab during the switchover period from eculizumab to the anti-C5 antibody crovalimab (see Figure 5). DTDC formation may contribute to increased clearance of crovalimab, potentially resulting in potential risks such as type III hypersensitivity reactions, as described above. In patients switched from eculizumab to crovalimab, the claimed doses and treatment regimens are predicted to reduce the formation of DTDCs (see Figures 3 and 12). Thus, the doses and treatment regimens described herein outline new and improved dosing regimens of anti-C5 antibodies, preferably the anti-C5 antibody crovalimab, for the treatment or prevention of C5-related diseases, preferably PNH. The safety and therapeutic efficacy of the claimed doses and treatment regimens are further reported in Figures 9 to 11.

[0025] Thus, the present invention relates to an anti-C5 antibody, preferably the anti-C5 antibody crovalimab, for use in a method of treating or preventing a C5-associated disease in a subject, preferably a subject having a body weight of 100 kg or more, the method comprising the following successive steps: (a) administering to the subject a single intravenous loading dose of a 1500 mg anti-C5 antibody, followed by at least one subcutaneous administration to the subject of a 340 mg loading dose of an anti-C5 antibody; and (b) administering to the subject at least one subcutaneous maintenance dose of 1020 mg of an anti-C5 antibody. 10. An anti-C5 antibody for use in a method for treating or preventing a C5-associated disease, comprising:

[0026] "Loading dose" refers to the dose of anti-C5 antibody administered to a subject suffering from a C5-related disease, preferably PNH, at the beginning of treatment, i.e., at the beginning of a treatment regimen. In pharmacokinetics (PK), a "loading dose" is an initial, higher dose of a drug that may be administered to a patient at the beginning of a course of treatment before being reduced to a lower dose. In the context of the present invention, the loading dose is first administered to a treated subject by intravenous administration, followed by subcutaneous administration. In the context of the present invention, the loading dose is administered once at a dose of 1500 mg. Thus, in the context of the present invention, a loading dose of a composition formulated for intravenous administration is administered to a subject once intravenously, followed by subcutaneous administration of one or more loading doses of a pharmaceutical composition formulated for subcutaneous administration.

[0027] In the context of the present invention, one or more loading doses of anti-C5 antibody are administered subcutaneously to a patient after intravenous administration of a 1500 mg loading dose of anti-C5 antibody. The subcutaneously administered loading dose(s) is / are administered subcutaneously at least once to a subject at a dose of 340 mg of anti-C5 antibody 1 day to 3 weeks (21 days) after the start of intravenous administration of anti-C5 antibody. Thus, in the context of the present invention, a 340 mg loading dose of anti-C5 antibody is administered subcutaneously to a subject at least once 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after the start of intravenous administration of anti-C5 antibody. Preferably, the 340 mg loading dose of anti-C5 antibody is administered to a subject 1 day after the start of intravenous administration of anti-C5 antibody. More preferably, one day after the start of intravenous administration, a single loading dose of 340 mg of anti-C5 antibody is administered subcutaneously. In the context of the present invention, one week (7 days), two weeks (14 days), or three weeks (21 days) after the start of intravenous administration of anti-C5 antibody, a supplemental loading dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject at least once. Most preferably, one week (7 days), two weeks (14 days), and three weeks (21 days) after the start of intravenous administration of anti-C5 antibody, a supplemental loading dose of 340 mg of anti-C5 antibody is administered subcutaneously. Thus, in the context of the present invention, one, two, three, four, and / or five loading doses are administered to the patient, wherein one loading dose, preferably the initial loading dose, is administered intravenously to the patient at a dose of 1500 mg, and one, two, three, or four loading doses are administered subcutaneously to the patient at a dose of 340 mg. In the context of the present invention, four loading doses, each with a therapeutic dose of 340 mg of anti-C5 antibody, are preferably administered subcutaneously, where a single loading dose is administered subcutaneously one day after the start of intravenous administration of anti-C5 antibody, followed by weekly loading doses administered subcutaneously one week, two weeks, and three weeks after the start of intravenous administration of anti-C5 antibody. Thus, a total of 2860 mg of anti-C5 antibody can be administered to a patient in the loading doses.The total dose refers to the total dose of anti-C5 antibody administered after 22 days of treatment, i.e., the dose reached at the end of day 22 of treatment, which is calculated by adding up the loading dose on day 1 (the first loading dose of 1500 mg administered intravenously), day 2 (the first loading dose of 340 mg administered subcutaneously to the patient one day after the start of intravenous administration of anti-C5 antibody), day 8 (the second loading dose of 340 mg administered subcutaneously one week after the start of intravenous administration), day 15 (the third loading dose of 340 mg administered subcutaneously two weeks after the start of intravenous administration), and day 22 (the fourth loading dose of 340 mg administered subcutaneously three weeks after the start of intravenous administration). For example, a total amount of anti-C5 antibody given by intravenous administration of 1500 mg (day 1) followed by loading dose(s) of 340 mg (day 2), 340 mg (day 8), 340 mg (day 15) and 340 mg (day 22) is 2860 mg.

[0028] According to the present invention, the initial dose(s) are followed by subsequent administration of equal or smaller amounts of anti-C5 antibody at intervals sufficiently short to maintain the anti-C5 antibody concentration at or above the effective target level. Therefore, in the context of the present invention, a maintenance dose(s) is administered to a patient after the loading dose. A "maintenance dose" refers to a dose of anti-C5 antibody given to a subject suffering from a C5-related disease to maintain the anti-C5 antibody concentration above a specific effective threshold of anti-C5 antibody concentration. In the context of the present invention, the target level of anti-C5 antibody is approximately 100 μg / ml or higher. The target level of anti-C5 concentration within the present invention can be determined in a biological sample from the subject to be treated. Means and methods for determining the anti-C5 concentration in a biological sample are within the general knowledge of those skilled in the art and can be determined, for example, by immunoassay. Preferably, in the context of the present invention, the immunoassay is an ELISA. Similarly, hemolytic activity can be used as a parameter for effective treatment of a patient suffering from a C5-related disease using the claimed dosage and treatment regimen. In the context of the present invention, hemolytic activity can be determined in a biological sample from a patient to be treated. In the context of the present invention, complete terminal complement inhibition (complete inhibition of the terminal pathway of the complement system) can be defined by a hemolytic activity of less than 10 U / mL. Preferably, the hemolytic activity is less than 10 U / mL, i.e., 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 U / mL. Means and methods for determining hemolytic activity in a biological sample from a patient treated with the dosage and administration regimen according to the present invention are known to those skilled in the art. Illustratively, hemolytic activity can be determined by immunoassay. Preferably, in the context of the present invention, the immunoassay is an ex vivo liposome immunoassay (LIA). In the context of the present invention, the biological sample is a blood sample. Preferably, the blood sample is a red blood cell sample. Preferably, the maintenance dose(s) are administered subcutaneously to the patient at a dose(s) of 1020 mg of anti-C5 antibody. Thus, within the context of the present invention, at least one maintenance dose, or more maintenance doses, are given to a subject, where the maintenance dose(s) are administered subcutaneously at a dose of 1020 mg.In the context of the present invention, at least one maintenance dose of 1020 mg of anti-C5 antibody is administered subcutaneously to a subject 4 weeks (28 days) after the start of intravenous administration of the anti-C5 antibody. Preferably, a single 1020 mg maintenance dose is administered subcutaneously to a subject 4 weeks after the start of intravenous administration of the anti-C5 antibody. Therefore, in the context of the present invention, at least one maintenance dose of 1020 mg is administered subcutaneously to a patient 4 weeks (28 days) after the start of intravenous administration of the anti-C5 antibody, i.e., on day 29 of the treatment regimen. Therefore, in the context of the present invention, a single 1020 mg maintenance dose is preferably administered subcutaneously 4 weeks (28 days) after the start of intravenous administration of the anti-C5 antibody. In the context of the present invention, a total of 3880 mg of anti-C5 antibody can be administered to a patient in the loading dose and maintenance doses according to the present invention. The total dose refers to the total dose of anti-C5 antibody administered after 29 days of treatment, i.e., the dose reached at the end of day 29 of treatment, which is calculated by adding up the loading dose on day 1 (a 1500 mg loading dose administered intravenously initially), day 2 (a 340 mg loading dose administered subcutaneously initially to the patient one day after the start of intravenous administration of anti-C5 antibody), day 8 (a 340 mg loading dose administered subcutaneously for the second time one week after the start of intravenous administration), day 15 (a 340 mg loading dose administered subcutaneously for the third time two weeks after the start of intravenous administration), day 22 (a 340 mg loading dose administered subcutaneously for the fourth time three weeks after the start of intravenous administration), and the 1020 mg subcutaneously administered maintenance dose (day 29). For example, the total amount of anti-C5 antibody provided by the loading and maintenance doses corresponding to an intravenous administration of 1500 mg (day 1), followed by subcutaneous administration of 340 mg (day 2), 340 mg (day 8), 340 mg (day 15), 340 mg (day 22), and 1020 mg (day 29) is 3880 mg.

[0029] The subcutaneous administration of the 1020 mg maintenance dose can be repeated several times at 4-week intervals (Q4W). In the context of the present invention, it is preferred that the 1020 mg maintenance dose be repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, and 48 months. In the context of the present invention, it is preferred that the 1020 mg maintenance dose be repeated at 4-week intervals and continued throughout the patient's lifetime.

[0030] In particular, the present invention relates to an anti-C5 antibody for use in a method of treating or preventing a C5-associated disease in a subject, preferably a subject having a body weight of 100 kg or more, the method comprising the following successive steps: (i) administering to a subject a single intravenous loading dose of 1500 mg of an anti-C5 antibody; (ii) one day after the start of intravenous administration of the anti-C5 antibody, administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject; (iii) administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the start of intravenous administration of the anti-C5 antibody; (iv) 4 weeks (28 days) after the start of intravenous administration of the anti-C5 antibody, administering to the subject a maintenance dose of 1020 mg of anti-C5 antibody subcutaneously; and (v) repeating step (iv) multiple times at time intervals of 4 weeks (28 days).

[0031] The term "intravenous administration" / "administering intravenously" in the context of the present invention refers to administering an anti-C5 antibody intravenously to a subject so that the patient's body receives the anti-C5 antibody within approximately 15 minutes or less, preferably within 5 minutes. For intravenous administration, the anti-C5 antibody must be formulated to be administered via an appropriate device, such as (but not limited to) a syringe. In the context of the present invention, a formulation for intravenous administration includes 50-350 mg of anti-C5 antibody, 1-100 mM buffer, e.g., pH 5.5±1.0, 1-100 mM histidine / aspartic acid containing an amino acid such as arginine, and 0.01-0.1% non-ionic surfactant such as poloxamer. Preferred in the context of the present invention is a formulation for intravenous administration provided in a 2 mL glass vial containing the following components: 170 mg / mL crovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188. TM The formulation is then administered to the patient within an acceptable time period, such as 5, 15, 30, or 90 minutes or less. Furthermore, the formulation for intravenous administration is administered to the patient in an injection volume of 1 ml to 15 ml, preferably about 9 ml.

[0032] The term "subcutaneous administration" / "administering subcutaneously" in the context of the present invention refers to the introduction of an anti-C5 antibody into the subcutaneous space of an animal or human patient, preferably by relatively slow, sustained delivery from a drug receptacle within a pocket between the skin and the underlying tissue. The pocket is created by pinching, lifting, or separating the skin from the underlying tissue. For subcutaneous administration, the anti-C5 antibody must be formulated so that it can be administered via a suitable device, such as (but not limited to) a syringe, prefilled syringe, injection device, infusion pump, injector pen, needleless device, or via a subcutaneous patch delivery system. In the context of the present invention, a formulation for subcutaneous administration contains 50-350 mg of anti-C5 antibody, 1-100 mM buffer, e.g., pH 5.5±1.0, 1-100 mM histidine / aspartic acid with an amino acid such as arginine, and 0.01-0.1% non-ionic surfactant, such as poloxamer. Preferred in the context of the present invention is a formulation for intravenous administration provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml crovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188. TM In the context of the present invention, the formulation for subcutaneous administration is provided in a prefilled syringe equipped with a needle safety device. The injection device for subcutaneous administration contains approximately 1 to 15 ml or more, preferably 2.25 ml, of a formulation for subcutaneous administration containing an anti-C5 antibody. Under normal circumstances, the injection volume for subcutaneous administration is 1 to 15 ml, preferably 2 ml (340 mg of crovalimab) or 6 ml (1020 mg of crovalimab). In the context of the present invention, subcutaneous administration refers to the introduction of an anti-C5 antibody into the subcutaneous tissue of a patient to be treated by relatively slow, sustained delivery from a drug receptacle over a period of time, including, but not limited to, 30 minutes or less, 90 minutes or less. Optionally, administration may be performed via the subcutaneous implantation of a drug delivery pump, which delivers a predetermined amount of anti-C5 antibody over a predetermined period of time, such as 30 minutes, 90 minutes, or the length of the treatment regimen.

[0033] In the context of the present invention, the above-described dosages and treatment regimens may be useful for the treatment or prevention of C5-related diseases in subjects previously treated with at least one pharmacological product for one or more uses in the treatment or prevention of the disease. For example, the treatment regimen of the present invention may be useful for treating patients with C5-related diseases who have been pretreated with at least one pharmacological product for use in a method for the treatment or prevention of the disease but who are predicted to respond better to a treatment regimen according to the present invention. In such cases, the medication can be switched from the pharmacological product to an anti-C5 antibody for use in the treatment or prevention of C5-related diseases according to the present invention. Preferably, the intravenously administered loading dose of the anti-C5 antibody is administered to the subject after the final dose of the pharmaceutical agent. The intravenously administered loading dose of the anti-C5 antibody preferably has a dose of 1500 mg.

[0034] In the context of the present invention, a pharmacological product contains an active substance other than the anti-C5 antibody administered intravenously or subcutaneously in accordance with the present invention. The active substance of the pharmacological product, in the context of the present invention, may be an siRNA targeting C5 mRNA or an anti-C5 antibody other than the anti-C5 antibody administered subcutaneously or intravenously to a subject treated in accordance with the present invention. The pharmacological product may contain an anti-C5 antibody other than the anti-C5 antibody administered to a patient in the context of the present invention. The antibody contained in the pharmaceutical used for pretreatment may be ravulizumab, or eculizumab, or a variant thereof. Preferably, the antibody contained in the pharmacological product used for prior art treatment is eculizumab or a variant thereof. Exemplary sequence variants of the anti-C5 antibody eculizumab are shown in SEQ ID NOs: 11 and 12.

[0035] An antibody variant in the context of the present invention can be an anti-C5 antibody containing an Fc region variant in which one or more amino acid modifications have been introduced into the native sequence Fc region of the antibody. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions. In the context of the present invention, the antibody variant retains some, but not all, effector functions, making the variant a desirable candidate for applications in which in vivo antibody half-life is important but certain effector functions (e.g., complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / depleted CDC and / or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to confirm that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcR gamma III, whereas monocytes express Fc gamma RI, Fc gamma RII, and Fc gamma RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for assessing ADCC activity of a molecule of interest are described in US Pat. No. 5,500,362 (e.g., Hellstrom et al., Proc. Nat'l Acad. Sci. USA (1983), Vol. 83, pp. 7059-7063) and Hellstrom et al., Proc. Nat'l Acad. Sci. USA (1985), Vol. 82, pp. 1499-1502; see US Pat. No. 5,821,337 (see Bruggemann et al., J. Exp. Med. (1987), Vol. 166, pp. 1351-1361). Alternatively, non-radioactive assays may be used (e.g., ACTI for flow cytometry). TMSee non-radioactive cytotoxicity assays (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assays (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo in an animal model, e.g., as disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA (1998), Vol. 95, pp. 652-656. C1q binding assays can also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CDC activity. See, e.g., C1q and C3c binding ELISAs in WO-A2 2006 / 029879 and WO-A1 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods (1996), Vol. 202, pp. 163; Cragg et al., Blood (2003), Vol. 101, pp. 1045-1052 and Cragg et al., Blood (2004), Vol. 103, pp. 2738-2743). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, for example, Petkova et al., Int'l. Immunol. (2006), Vol. 18(12), pp. 1759-1769).

[0036] Antibodies with reduced effector function include those with substitutions at one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (US-B1 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant with substitutions of residues 265 and 297 to alanine (US-B1 7,332,581).

[0037] Certain antibody variants have been described with improved or diminished binding to FcRs (see, e.g., US Pat. No. 1,673,7056; WO-A2 Publication No. 2004 / 056312; and Shields et al., J. Biol. Chem. (2001), Vol. 9(2), pp. 6591-6604).

[0038] In certain embodiments, the antibody variant comprises an Fc region comprising one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0039] In some embodiments, modifications are made in the Fc region that result in altered (i.e., improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in US-B1 6,194,551, WO 1999 / 51642, and Idusogie et al., J. Immunol. (2000), Vol. 164, pp. 4178-4184.

[0040] Antibodies with improved binding to the neonatal Fc receptor (FcRn), which has a prolonged half-life and is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. (1976), Vol. 117, pp. 587 and Kim et al., J. Immunol. (1994), Vol. 24, pp. 249), are described in US 2005 / 0014934. These antibodies comprise an Fc region with one or more substitutions that improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., substitution of Fc region residue 434 (US Pat. No. 7,371,826). For other examples of Fc region variants, see also Guyer et al., J. Immunol. (1976), Vol. 117, pp. 587 and Kim et al., J. Immunol. (1994), Vol. 24, pp. 249.

[0041] In the context of the present invention, the initial dose of the intravenous infusion composition of the present invention is administered to the patient to be treated on the same day as the last dose of the pharmacological product, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days (1 week), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days (2 weeks), 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days (3 weeks) or more after said last dose. Preferably, in the context of the present invention, the intravenously administered loading dose of the anti-C5 antibody is administered on the 3rd day after the last dose of the pharmacological product, or 3 days, 4 days, 5 days, 6 days, 7 days (1 week), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days (2 weeks), 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days (3 weeks) or more after said last dose. Preferably, the intravenously administered loading dose of anti-C5 antibody is given to the patient 7 days (1 week) or more after the last dose of the pharmacological preparation. Also preferred in the context of the present invention is intravenously administering the loading dose 14 days (2 weeks) or more after the last dose of the pharmacological product. Most preferred in the context of the present invention is intravenously administering the anti-C5 antibody 21 days (3 weeks) after the last dose of the pharmacological product.

[0042] In the context of the present invention, a "week" refers to a period of 7 days.

[0043] In the context of the present invention, a "month" refers to a period of four weeks.

[0044] "Treatment" in the context of the present invention includes a sequential series of "induction treatment" and at least one "maintenance treatment". Typically, treatment according to the present invention includes an "induction treatment" and at least one "maintenance treatment". Typically, treatment according to the present invention lasts for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year (12 months), 2 years (24 months), 3 years (36 months), or 4 years (48 months). Preferred in the context of the present invention is treatment that continues for the entire life of the patient.

[0045] "Induction therapy" consists of (i) the intravenous administration of a loading dose, preferably a 1500 mg dose, of an anti-C5 antibody to a subject, and (ii) at least one subsequent loading dose, preferably a 340 mg dose, of an anti-C5 antibody to a subject. As noted above, within the context of the present invention, it is preferred that the 340 mg loading dose of anti-C5 antibody be administered 1 day, 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the intravenously administered loading dose has been administered to the subject. Preferably, the intravenously administered loading dose has a dose of 1500 mg. The loading dose administered subcutaneously to the treated subject has a dose of 1360 mg. Thus, within the context of the present invention, a loading dose of 2860 mg is administered intravenously or subcutaneously to the treated subject during induction therapy. "Maintenance therapy" consists of (i) a sequential series of maintenance periods during which one or more maintenance doses are administered subcutaneously to the subject. In the context of the present invention, a maintenance dose of 1020 mg of anti-C5 antibody is preferably given to the subject once, 4 weeks (1 month) after the start of intravenous administration of the loading dose of anti-C5 antibody. As mentioned above, the subcutaneous administration of the maintenance dose of 1020 mg can be repeated several times at 4-week intervals (Q4W). In the context of the present invention, it is preferred to repeat the maintenance dose of 1020 mg at 4-week intervals and continue it throughout the patient's life.

[0046] In the context of the present invention, the C5-related disease is a complement-mediated disease or condition involving excessive or uncontrolled activation of C5. In certain embodiments, the C5-related disease is at least one selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis (RA), lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), dense deposition disease (DDD), macular degeneration, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, thrombotic thrombocytopenic purpura (TTP), spontaneous fetal loss, Pauci-immune vasculitis, epidermolysis bullosa, recurrent fetal loss, multiple sclerosis (MS), traumatic brain injury, myocardial infarction, injury due to cardiopulmonary bypass or hemodialysis, refractory generalized myasthenia gravis (gMG), and neuromyelitis optica (NMO). Preferably, in the context of the present invention, the C5-related disease is at least one selected from the group consisting of PNH, aHUS, gMG, and NMO. Most preferably, the C5-related disease is PNH. Furthermore, in the context of the present invention, subjects suffering from the C5-related disease PNH can be tested for the presence of the C5 Arg885 mutation. Therefore, the dosing regimen disclosed herein can also be used for the treatment and / or prevention of subjects suffering from PNH, characterized in that the subjects have the C5 Arg855 mutation. In this context, the Arg885 mutation refers to a genetic mutation in C5 in which Arg at position 885 is replaced with His. In this context, the term "C5" refers to the protein having the amino acid sequence set forth in SEQ ID NO: 13.

[0047] In the context of the present invention, the anti-C5 antibody is preferably clovalimab. The sequence details of the anti-C5 antibody clovalimab (CAS number: 1917321-26-6) are disclosed in the International Non-proprietary Names for Pharmaceutical Substances (INN) draft list No. 119, published on pages 302 and 303 of WHO Drug Information (2018), Vol. 32, No. 2. The sequence of the anti-C5 antibody clovalimab is also shown in SEQ ID NO: 3 (heavy chain) and SEQ ID NO: 4 (light chain). The production of the anti-C5 antibody clovalimab used in the present invention is described in WO 2016 / 098356 (see Example 1 for details). Furthermore, in the context of the present invention, the anti-C5 antibody clovalimab is administered to patients in a formulation for intravenous or subcutaneous administration. Intravenous or subcutaneous administration of a fixed dose is preferred in the context of the present invention.

[0048] A formulation for intravenous administration comprises 50 to 350 mg of the anti-C5 antibody crovalimab, 1 to 100 mM of a buffer, e.g., pH 5.5±1.0, 1 to 100 mM of an amino acid, such as arginine, and 0.01 to 0.1% of a non-ionic surfactant, e.g., poloxamer. Preferred in the context of the present invention is that the formulation for intravenous administration is provided in a 2 mL glass vial containing the following components: 170 mg / mL crovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188. TM .

[0049] A formulation for subcutaneous administration comprises 50 to 350 mg of the anti-C5 antibody crovalimab, 1 to 100 mM of a buffer, e.g., pH 5.5±1.0, 1 to 100 mM of an amino acid, such as arginine, and 0.01 to 0.1% of a non-ionic surfactant, e.g., poloxamer. Preferred in the context of the present invention is a formulation for intravenous administration provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml crovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188. TM .

[0050] The anti-C5 antibody eculizumab is sold under the trade name Soliris® by Alexion Pharmaceuticals, Inc. The sequences of the anti-C5 antibody eculizumab are shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain). Additionally, sequence variants of the anti-C5 antibody eculizumab are shown in SEQ ID NOs: 11 and 12.

[0051] The sequence of the anti-C5 antibody clovalimab is sold under the trade name Ultomiris® by Alexion Pharmaceuticals, Inc. The sequence of the anti-C5 antibody (CAS number: 1803171-55-2) is disclosed in the proposed list of International Non-proprietary Names for Pharmaceutical Substances (INN) No. 117, published on pages 319 and 320 of WHO Drug Information (2017), Vol. 31, No. 2. The sequence of the anti-C5 antibody ravulizumab is also shown in SEQ ID NO: 5 (heavy chain) and SEQ ID NO: 6 (light chain).

[0052] The patient described in the context of the present invention is a patient suffering from a C5-related disease. In the context of the present invention, a preferred patient is a patient with a body weight of 100 kg or more. In the context of the present invention, a C5-related disease is a complement-mediated disease or condition involving excessive or uncontrolled activation of C5. In certain embodiments, the C5-related disease is at least one selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis (RA), lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), dense deposition disease (DDD), macular degeneration, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, thrombotic thrombocytopenic purpura (TTP), spontaneous fetal loss, Pauci-immune vasculitis, epidermolysis bullosa, recurrent fetal loss, multiple sclerosis (MS), traumatic brain injury, myocardial infarction, injury due to cardiopulmonary bypass or hemodialysis, refractory generalized myasthenia gravis (gMG), and neuromyelitis optica (NMO). Preferably, in the context of the present invention, the C5-related disease is at least one selected from the group consisting of PNH, aHUS, gMG, and NMO. Most preferably, the C5-related disease is PNH.

[0053] Furthermore, the present invention relates to a method for treating or preventing a C5-related disease in a subject, the method comprising the following sequential steps: (a) administering to the subject a single intravenous loading dose of a 1500 mg anti-C5 antibody, followed by at least one subcutaneous administration to the subject of a 340 mg loading dose of an anti-C5 antibody; and (b) administering to the subject at least one subcutaneous maintenance dose of 1020 mg of an anti-C5 antibody. 10. An anti-C5 antibody for use in a method for treating or preventing a C5-associated disease, comprising:

[0054] In the context of the present invention, the method for treating or preventing a C5-related disease in a subject is preferably carried out by the following administration steps: (i) administering to a subject a single intravenous loading dose of 1500 mg of an anti-C5 antibody; (ii) one day after the start of intravenous administration of the anti-C5 antibody, administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject; (iii) administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject 1 week, 2 weeks, and 3 weeks after the start of intravenous administration of the anti-C5 antibody; (iv) 4 weeks after the start of intravenous administration of the anti-C5 antibody, administering a maintenance dose of 1020 mg of anti-C5 antibody subcutaneously to the subject; and (v) repeating step (iv) several times at intervals of 4 weeks.

[0055] As mentioned above, in the context of the present invention, it is preferred that the anti-C5 antibody used in the context of the dosage and administration regimen is clovalimab. Furthermore, the above definitions also apply to the above method for treating or preventing C5-related diseases. Also, in the context of the present invention, it is preferred that the body weight of the treated subject is 100 kg or more. [Brief explanation of the drawings]

[0056] [Figure 1] Relationship of the anti-C5 antibody crovalimab and hemolytic activity measured by liposome immunoassay (LIA) in healthy subjects and subjects with the C5-related disorder paroxysmal nocturnal hemoglobinuria (PNH). Exposure-response assessment demonstrates that approximately 100 μg / mL of crovalimab is required to achieve complete terminal complement inhibition. Complete terminal complement inhibition (complete inhibition of the terminal pathway of the complement system) is defined as hemolytic activity <10 U / mL. The vertical dotted line indicates the pharmacodynamic (PD) threshold of 100 μg / mL of crovalimab. [Figure 2] Available free binding sites for the anti-C5 antibody clovalimab. The grey lines correspond to simulations of 15 individuals based on parameters estimated from COMPOSER (BP39144) data. Data from the COMPOSER trial were used for the simulations. The y-axis shows the concentration of the anti-C5 antibody clovalimab (RO7112689; SKY59). The x-axis shows time (days). The dark grey line corresponds to the median value for these 15 patients. S0: COMPOSER Part 3 regimen. S5: Proposed regimen for Part 4 and Phase III of the COMPOSER trial. [Figure 3]Time profile of drug-target-drug-conjugate (DTDC). The gray line corresponds to a simulation of 15 individuals based on parameters estimated from COMPOSER (BP39144) data. Data from the COMPOSER trial were used for the simulation. The dark gray line corresponds to the median of these 15 patients. S0: COMPOSER Part 3 regimen; S5: Proposed regimen for COMPOSER Part 4 and Phase III (RO7112689): crovalimab (SKY59). [Figure 4] Simulation of the concentration-time profile of crovalimab in a treatment-naïve patient (top panel) and in a patient with PNH who switched from eculizumab to crovalimab (bottom panel). The gray interval corresponds to the 90% prediction interval, and the gray line corresponds to the median prediction. The dotted black line corresponds to the target concentration level of 100 μg / mL for the anti-C5 antibody crovalimab. [Figure 5]A model describing how drug-target-drug complexes (DTDCs) between crovalimab, human C5, and the antibody eculizumab are cleared, recycled, and continuously assembled from smaller DTDCs. When a patient switches from the anti-C5 antibody eculizumab to crovalimab, both anti-C5 antibodies bind to different epitopes on human C5, resulting in the formation of DTDCs in the circulation. These DTDCs are constructed from repeated eculizumab-C5-crovalimab-C5 chains and grow over time when two DTDCs assemble to form larger DTDCs. This model (Figure 5) reports how DTDCs are cleared and recycled by the FcRn receptor of the anti-C5 antibody crovalimab. (1) DTDCs arise when a patient is simultaneously exposed to crovalimab and eculizumab during the switch from one drug to the other, due to the antibody's recognition of different epitopes on C5. DTDCs are internalized in endosomes via phagocytosis. (2) The clovalimab antibody, which binds to human C5 in a pH-dependent manner, dissociates from soluble human C5 (bound to the anti-C5 antibody clovalimab) under acidic conditions (pH 6.0) in endosomes, where the anti-C5 antibody eculizumab still binds to soluble human C5 under acidic conditions in endosomes. (3) The anti-C5 antibody (clovalimab and the C5-eculizumab complex) is taken up by cells by binding to FcRn expressed on the cell membrane. The C5-eculizumab complex is transported to lysosomes and degraded or recycled along with the C5 protein still bound to the antibody. In contrast, the anti-C5 antibody clovalimab dissociates from FcRn in endosomes under acidic conditions and is released back into the plasma without the C5 protein, improving its functionality and efficacy. (4), (5) The released anti-C5 antibody clovalimab can then re-bind to human C5 and be used to construct even smaller DTDCs. This has the effect of "recycling" the anti-C5 antibody crovalimab: DTDC and especially the C5-eculizumab complex are then degraded again by the endosome, while the anti-C5 antibody crovalimab is recycled again to assemble a smaller DTDC. [Figure 6]COMPOSER Part 4 included patients with PNH. COMPOSER Part 4 evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) effects of an optimized clovalimab regimen in patients with PNH who had not previously received anti-C5 therapy, preferably clovalimab, or who had switched from eculizumab, with a primary evaluation at week 20. Of the 15 patients enrolled, 8 (53%) had not previously received C5 inhibitor therapy, and 7 (47%) had switched from eculizumab to clovalimab. [Figure 7] Crovalimab exposure in patients enrolled in Part 4 of the COMPOSER trial. In all patients, crovalimab levels were maintained above a Ctrough value of approximately 100 μg / mL, which is associated with terminal complement inhibition. Lines indicate the mean and shaded areas indicate the 95% confidence interval. [Figure 8] Liposome immunoassay (LIA) time course showing median complement activity in patients enrolled in Part 4 of the COMPOSER trial. Terminal complement inhibition was achieved shortly after the first dose and was generally maintained throughout the study. Lines represent median values, and whiskers indicate 95% confidence intervals. The lower limit of quantitation for the LIA assay is 10 U / mL. LIA, liposome immunoassay. [Figure 9] Measurement of total and free C5 levels in patients enrolled in Part 4 of the COMPOSER trial. (A) Limited total C5 accumulation was observed in treatment-naive patients, with a decline in switched patients. (B) Free C5 levels declined rapidly after the first dose and remained low throughout follow-up. [Figure 10] Measurement of normalized lactate dehydrogenase (LDH) in patients enrolled in Part 4 of the COMPOSER trial. In treatment-naive patients, median lactate dehydrogenase (LDH) levels decreased to ≤1.5 × upper limit of normal (ULN) by Day 15 and remained below that level throughout the observation period. In patients switched from eculizumab to crovalimab, median baseline LDH was ≤1.5 × ULN and remained there throughout the observation period. LDH: lactate dehydrogenase; ULN: upper limit of normal. [Figure 11]Summary of Clovalimab Treatment-Related Adverse Events (AEs) Clovalimab was well tolerated, and no serious treatment-related adverse events (AEs) were observed. [Figure 12] DTDC profiles over time observed for the clovalimab regimens in Parts 3 and 4 of the COMPOSER study. The solid lines represent the sum of the median percentages of clovalimab eluted in size-exclusion chromatography (SEC) fractions 1–4 (left panel) and fractions 5–6 (right panel). The dosing regimen for Part 3 of the COMPOSER study is shown in light gray, and the dosing regimen for Part 4 is shown in dark gray. [Figure 13] Normalized LDH levels in PNH patients carrying the C5 Arg885His mutation treated with clovalimab. Clovalimab achieved sustained terminal complement inhibition in PNH patients with the Arg885 polymorphism. All patients achieved complete terminal complement inhibition as measured by liposome immunoassay (LIA). LIA levels ranged from 32 to 42 U / mL at study entry, decreased to ≤10 U / mL by day 2, and were maintained thereafter. The lower limit of quantification for the LIA assay is 10 U / mL. LIA, liposome immunoassay.

[0057] The following examples illustrate the invention. Example 1: Anti-C5 antibody The sequences of the anti-C5 antibody clovalimab are shown in SEQ ID NO: 3 (heavy chain) and SEQ ID NO: 4 (light chain). Furthermore, the production of the anti-C5 antibody clovalimab used in the present invention is described in WO 2016 / 098356. Briefly, the gene encoding the heavy chain variable domain (VH) of 305LO15 (SEQ ID NO: 7) was combined with the gene encoding the modified human Ig1 heavy chain constant domain (CH) mutant SG115 (SEQ ID NO: 8). The gene encoding the light chain variable domain (VL) of 305LO15 (SEQ ID NO: 9) was combined with the gene encoding the human light chain constant domain (CL) (SK1, SEQ ID NO: 10). The antibody was expressed in HEK293 cells co-transfected with a combination of heavy and light chain expression vectors, and the protein was purified.

[0058] Example 2: Dosages and Administration Regimen Used in the COMPOSER Trial (BP39144; ClinicalTrials.gov Identifier: NCT03157635) To determine the appropriate dose and administration regimen, the Phase I / II COMPOSER trial (BP39144) was initiated. The trial initially consisted of three parts: Part 1 in healthy participants, and Parts 2 and 3 in patients with paroxysmal nocturnal hemoglobinuria (PNH). Furthermore, patients included in Part 3 of the trial had to have received at least 3 months of treatment with the anti-C5 antibody eculizumab.

[0059] Part 1 of this study was designed to include three groups of healthy patients. Group 1 received a single intravenous (IV) dose of 75 mg / body of the anti-C5 antibody crovalimab. Group 2 received a single intravenous (IV) dose of 150 mg / body of the anti-C5 antibody crovalimab. Group 3 received a single subcutaneous (SC) dose of 170 mg / body of the anti-C5 antibody crovalimab. Because Part 1 of the COMPOSER study is adaptive in nature (based on ongoing evaluation of safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (pD) data), the actual doses in Part 1 were as follows: Group 1 patients enrolled in Part 1 of the COMPOSER study received 75 mg IV, Group 2 patients received 125 mg IV, and Group 3 patients received 100 mg SC.

[0060] Part 2 of the study was designed to include a cohort of patients receiving three intravenous doses of the anti-C5 antibody crovalimab: according to the original protocol design, the anti-C5 antibody crovalimab was initially administered at a dose of 300 mg / body (IV), then at 500 mg / body (IV) one week after the first dose, and finally at 1000 mg / body (IV) two weeks after the second dose. Two weeks after the final intravenous dose, the anti-C5 antibody crovalimab was administered subcutaneously (SC) once weekly at a dose of 170 mg / body. Based on new clinical data and PK simulations from Part 1, the starting dose for patients in Part 2 of the COMPOSER study was changed from 300 mg to 375 mg IV. Therefore, the actual doses given in Part 2 of the COMPOSER trial were as follows: the anti-C5 antibody crovalimab was administered intravenously (IV) at 375 mg / body, followed by 500 mg / body IV one week after the first dose, and finally 1000 mg / body IV two weeks after the second dose. Starting two weeks after the final IV dose, the anti-C5 antibody crovalimab was administered subcutaneously (SC) at 170 mg / body once weekly.

[0061] Part 3 of the study included patients who had been treated with the anti-C5 antibody eculizumab for at least 3 months prior to study enrollment. These patients were required to receive regular intravenous infusions of eculizumab. Part 3 of the study was designed to include three groups. The anti-C5 antibody crovalimab was initially administered intravenously at a single dose of 1000 mg / body weight to all patients. Starting one week after the first intravenous dose (day 8 after intravenous administration), crovalimab was administered subcutaneously at 170 mg / body weight once weekly to patients in Group 1, 340 mg / body weight once every two weeks to patients in Group 2, and 680 mg / body weight once every four weeks to patients in Group 3. Part 1 of the COMPOSER study enrolled 15 healthy patients. Because of the randomization of Part 1, only 9 of the initial 15 patients received crovalimab. Part 3 of the COMPOSER trial enrolled 19 patients, of whom 3 withdrew.

[0062] Details of patients included in the COMPOSER trial (Part 1, Part 2, and Part 3) can be summarized as follows:

[0063] TIFF0007748311000001.tif92170

[0064] Following the completion of the above details of patients included in Parts 1 to 3 of the COMPOSER trial, one additional patient from COMPOSER Part 3 discontinued the study.

[0065] Example 3: Determining a dosing regimen to achieve complete and sustained terminal complement inhibition through treatment with the anti-C5 antibody crovalimab The therapeutic goal of clovalimab, preferably in C5-related diseases such as paroxysmal nocturnal hemoglobinuria (PNH), is to ensure rapid, sustained, and complete inhibition of the terminal complement pathway. In patients switched from eculizumab to clovalimab, a drug-free period is clinically inappropriate. Therefore, by design, residual concentrations of eculizumab are present when clovalimab treatment is initiated. Drug-target-drug complexes (DTDCs) consisting of clovalimab, human C5, and eculizumab were detected in all patients switched from eculizumab in COMPOSER Part 3 using a multispecies assay combining enzyme-linked immunosorbent assay (ELISA) and size-exclusion chromatography (SEC). SEC is a separation technique based on differences in Stokes radii and protein geometry: SEC separates molecules by size as they pass through a gel filtration medium packed into a column to form a packed bed. Unlike ion exchange or affinity chromatography, molecules do not bind to the chromatographic medium, so the buffer composition does not directly affect resolution (resolution between peaks). The medium is a porous matrix of spherical particles that is chemically and physically stable and inert (lacking reactivity and adsorption properties). SEC was used in fractionation mode to separate multiple components in a sample based on their size differences. For complex sample compositions with different proteins, such as serum, the combination of SEC with an analyte (crovalimab)-specific ELISA provided the desired specificity and sensitivity for detecting the concentration of crovalimab in each separated fraction. To enable detection of crovalimab concentration by ELISA, the SEC separation was fractionated into eight fractions. This approach was used to describe the DTDC profile over time for each individual. To determine the dosing regimen expected to achieve complete and sustained terminal complement inhibition throughout the treatment period and to recommend the dose (Phase III dose) to be used in clinical trials, two complementary model-informed drug development (MIDD) approaches were developed: • An empirical population pharmacokinetic model used to recommend a subcutaneous (SC) dose and regimen that maintains crovalimab concentrations above a target threshold concentration of 100 μg / ml throughout the dosing interval in patients. A biochemical model that simultaneously describes total and free C5 kinetics, crovalimab and eculizumab pharmacokinetics, and DTDC kinetics, used to recommend doses and regimens that minimize the formation of large DTDCs in patients switched from eculizumab to crovalimab, while maximizing the levels of free crovalimab binding sites in all patients.

[0066] 3.1 Population pharmacokinetic model The concentration-time profile of the anti-C5 antibody crovalimab was best described using a two-compartment open model with first-order elimination and first-order absorption, accounting for subcutaneous (SC) administration (see Betts A. et al., mAbs (2018), Vol. 10, No. 5, pp. 751-764). The pharmacokinetic (PK) profile in patients switched from eculizumab in COMPOSER Part 3 demonstrates transient, rapid elimination not observed in healthy volunteers and treatment-naïve patients with PNH. To describe the pharmacokinetics (PK) of patients switched from eculizumab to the anti-C5 antibody crovalimab, we modeled the elimination of crovalimab as a combination of first-order elimination, as used in treatment-naïve patients, and a faster clearance that exponentially decreases over time. Body weight (median: 72.3 kg (40.6-131.5 kg)) was tested as a covariate for clearance and volume and was found to significantly affect these parameters when incorporated using nonproportional scaling with a fixed coefficient of 0.75 for clearance and a fixed coefficient of 1 for volume. The parameter "clearance" is a measure of the body's ability to excrete a drug. Clearance is expressed as volume per unit time. The parameter "volume" represents the volume of distribution, a measure of the apparent space in the body that can contain the anti-C5 antibody clovalimab. Age was also considered a covariate for absorption rate and was introduced into the model as a categorical covariate. Patients aged 50 years or older appeared to have a lower absorption rate than younger patients. Bioavailability after subcutaneous (SC) administration is estimated to be approximately 100%.

[0067] The model was able to accurately estimate PK parameters and had good predictive performance qualifying it for use for simulation purposes.

[0068] 3.2 Drug-Target-Drug Complexes (DTDC) Biochemical Model A biochemical mathematical model was developed to investigate the kinetics of DTDC formation and disappearance under the assumption that complexes of increasing size are formed by the reversible binding of smaller complexes (see Figure 5). This model accounts for all complexes made from Ab1-Ag-Ab2 unit repeats (antibody 1 (Ab1), antibody 2 (Ab2), and antigen (Ag) represent clovalimab, eculizumab, and C5, respectively), starting with the smallest complex (Ab1-Ag-Ab2) and continuing to the largest complex containing 4 Ab1, 4 Ab2, and 8 Ags observed in an in vitro SEC assay (e.g., complex Ab1-Ag-Ag-Ab2-Ag-Ab1-Ag-Ab2-Ag-Ab1-Ag-Ab2-Ag-Ab2-Ag). A ligand-binding model was used to describe each possible biochemical reaction that explains the formation of a complex via the binding of two smaller complexes. The clearance of the complex and the recycling of free crovalimab from DTDC (due to the release of C5 from crovalimab under the acidic conditions of the lysosome by SMART-Ig Recycling®) were also accounted for in each binding reaction. Details of the SMART-Ig Recycling® system are described by Fukuzawa et al., Sci Rep. (2017), Vol. 7(1):1080; doi:10.1038 / s41598-017-01087-7. Model parameters were estimated using a nonlinear mixed-effects approach using data collected in the COMPOSER study. The model was developed using total crovalimab, total C5, and 8 SEC fractions, where DTDC is detected according to its molecular weight. Assessment of model adequacy was satisfactory for simulation purposes. The model was calibrated using eculizumab concentrations at the time of switch and chromatography-based measurements of total crovalimab time profile, total C5 concentration, and DTDC size distribution from the Phase I / II COMPOSER trial (see Roth et al., Blood (2020), Vol., 135, pp. 912–920; doi:10.1182 / blood.2019003399).

[0069] 3.3 Phase III dose determination By using both models—a population pharmacokinetic model and a DTDC biochemistry model—in parallel, we aim to (1) minimize the formation of larger DTDCs in patients switching from eculizumab to crovalimab, (2) maximize the level of free crovalimab binding sites, and (3) ensure that patients achieve a target concentration above the target threshold concentration required for complement inhibition (target C trough This allowed for the identification of a fixed dose and dosing regimen that ensures a therapeutically effective dose (>approximately 100 μg / mL of crovalimab).

[0070] Based on its mechanism of action, clovalimab inhibits complement-mediated lysis of red blood cells lacking complement regulatory proteins. If the terminal complement pathway is not temporarily blocked during the treatment interval, these red blood cells may lyse, resulting in breakthrough hemolysis, a serious clinical complication in patients with PNH. Biological stressors (infection, surgery, pregnancy) lead to physiological activation of the complement pathway with upregulation of C5 (Schutte et al., Int Arch Allergy Appl Immunol. (1975), Vol. 48(5), pp. 706-720). Therefore, in patients with PNH, it is important not only to maintain complete blockade of terminal complement activity throughout the treatment period, but also to maintain a reserve of free clovalimab binding sites to minimize the occurrence of breakthrough hemolysis.

[0071] Available pharmacokinetic (PK) and pharmacodynamic (PD) data from Parts 1, 2, and 3 of the COMPOSER trial were integrated to characterize the PK / PD relationship of crovalimab after IV and SC administration and to identify the exposure level required to fully inhibit terminal complement system activity. Pooling PK and PD data from nine healthy volunteers in Part 1, ten patients with PNH in Part 2, and 16 patients with PNH in Part 3 demonstrated that crovalimab induces a concentration-dependent inhibition of serum hemolytic activity as measured by ex vivo liposome immunoassay (LIA). Assessment of the exposure-response relationship demonstrated that approximately 100 μg / mL of crovalimab was required to achieve complete terminal complement inhibition, defined as hemolytic activity <10 U / mL (see Figure 1).

[0072] In a population PK model, body weight was tested as a covariate for the clearance and volume of distribution of crovalimab and was found to statistically affect these parameters when incorporated using non-proportional scaling. As a result, for a given dose, larger patients tend to have lower exposures that are underexposed compared to smaller patients. To compensate for the effect of body weight, a weight-based tiered dosing approach is proposed to ensure all patients receive equivalent crovalimab exposure throughout the dosing interval.

[0073] Two medication regimens were established: ● Patients weighing >40kg to <100kg Loading dose: 1000 mg crovalimab intravenously (IV) on day 1, followed by 340 mg crovalimab subcutaneously (SC) on days 2, 8, 15, and 22.

[0074] Maintenance dose: crovalimab 680 mg SC on day 29, followed by crovalimab 680 mg SC every four weeks (Q4W) thereafter. ● Patients weighing > / =100 kg Loading dose: crovalimab 1500 mg IV on day 1, followed by crovalimab 340 mg SC on days 2, 8, 15, and 22.

[0075] Maintenance dose: crovalimab 1020 mg SC on day 29, followed by crovalimab 680 mg SC every four weeks (Q4W) thereafter.

[0076] Example 4: DTDC model simulation results Simulations based on this model aimed to identify doses and dosing regimens that minimize the formation of larger DTDCs in patients switched from eculizumab to crovalimab and provide sufficient reserves of free crovalimab binding sites in patients switched from eculizumab or treatment-naïve PNH patients. The latter criterion provides an objective assessment of the margin of hemolysis control within which a dosing regimen provides protection from breakthrough hemolysis. Simulations were performed using only parameter estimates derived from COMPOSER Part 3 patients who switched from eculizumab to crovalimab. A dosing regimen that provides a sufficient reserve of free crovalimab epitopes in patients previously treated with eculizumab would also be appropriate for treatment-naïve patients. As shown in Figures 2 and 3, the dosing regimen described above is expected to minimize the formation of the largest DTDCs while maximizing free epitope availability.

[0077] Example 5: Results of population pharmacokinetic model simulations Simulations based on population PK modeling were performed to recommend doses and dosing regimens that would ensure that trough concentrations above 100 μg / mL were maintained throughout the dosing interval and that steady-state concentrations were rapidly established in the majority of patients in both treatment-naive and eculizumab-pretreated PNH patients.

[0078] We simulated the concentration-time profile of crovalimab in 20,000 treatment-naïve patients with PNH and 20,000 patients with PNH who switched from eculizumab to crovalimab, with a median body weight of 75.6 kg (standard deviation ±20.3 kg; 5th and 95th percentiles of 42.2 kg and 109.0 kg, respectively). The simulations accounted for age effects, with 50% of the simulation population aged 50 years or older and 50% of the simulation population aged 50 years or older. The choice of weight distribution was based on the distribution observed in the COMPOSER trial.

[0079] Based on the simulation results (Figure 4), the above dose and treatment regimen rapidly established steady-state concentrations throughout the dosing interval, with sustained C concentrations above 100 μg / mL in approximately 95% of individuals, regardless of body weight. trough With this dosing regimen, concentrations above 100 μg / mL are predicted to be maintained in both treatment-naive patients and patients switched from eculizumab, despite the observed transient increase in crovalimab clearance and the resulting longer time to reach steady-state concentrations.

[0080] The proposed dose and dosing regimen is expected to ensure complete and consistent blockade of terminal complement activity (maintained above the target threshold in approximately 95% of patients) and to ensure a sufficient reserve of free binding sites for the majority of the dosing interval in both treatment-naive and eculizumab-pretreated patients. It is also expected to reduce the formation of larger DTDCs in patients switched from eculizumab. The dose was confirmed in Part 4 of the COMPOSER trial in seven patients switched from eculizumab to crovalimab. In Part 4, the safety, pharmacokinetic (PK), and pharmacodynamic (PD) effects of the optimized crovalimab regimen were evaluated in 15 patients (data cutoff January 29, 2020), including 8 (53%) anti-C5 therapy-naïve PNH patients (8 (53%)) or 7 (47%) previously treated with the anti-C5 antibody eculizumab. The baseline characteristics of patients enrolled in Part 4 of the COMPOSER study are shown in Figure 6. The most appropriate dose to reduce DTDC, especially the persistence of large DTDC, was determined to be a series of loading doses (1000 mg crovalimab intravenously (IV) on Day 1, followed by 340 mg crovalimab subcutaneously (SC) on Days 2, 8, 15, and 22) followed by maintenance doses (29 days). The COMPOSER Part 4 study consisted of 680 mg of crovalimab administered SC to one eye, followed by 680 mg of crovalimab administered subcutaneously every four weeks (Q4W). Data from COMPOSER Part 4 confirmed that the size distribution of DTDCs was shifted to smaller complexes with the claimed optimized dosing regimen. Further results of the above crovalimab dose and regimen (1000 mg of crovalimab administered intravenously (IV) on day 1, followed by 340 mg of crovalimab administered subcutaneously (SC) on days 2, 8, 15, and 22) and the subsequent maintenance dose (680 mg of crovalimab administered SC on day 29, followed by 680 mg of crovalimab administered subcutaneously every four weeks (Q4W)) are reported in Figures 7 through 11.

[0081] As shown in Figure 7, this optimal dosing regimen resulted in a C of approximately 100 μg / mL (a level associated with complement inhibition) over the 20-week (140-day) follow-up period. through was sustained above the value.

[0082] Furthermore, terminal complement inhibition was achieved immediately after the first dose and was maintained throughout the study period (see Figure 8).

[0083] Furthermore, limited accumulation of total C5 was observed in anti-C5 therapy-naive PNH patients (n=8, Figure 9(A)), while decreased C5 levels were observed in switched PNH patients (n=7, Figure 9(B)) who had previously been treated with the anti-C5 antibody eculizumab.

[0084] Furthermore, Figure 10 reports that intravascular hemolysis was controlled, and the majority of patients had hemoglobin stabilization and avoided transfusions: In total, 10 patients (67%) achieved hemoglobin stabilization (avoidance of a decrease in hemoglobin of ≥2 g / dL from baseline in the absence of transfusions) at week 20, including 5 of 8 untreated patients and 5 of 7 switched patients. From baseline to week 20, 11 patients (73%) were transfusion-free, including 5 of 8 untreated patients and 6 of 7 switched patients. Over a total of 7.2 patient-years at risk, no patients experienced a breakthrough hemolysis (BTH) event as defined by Kulasekararaj et al., Blood (2019), Vol. 33, pp. 540-549.

[0085] Furthermore, it was revealed that the dose and treatment regimen of the anti-C5 antibody crovalimab described above was well tolerated, and no serious treatment-related adverse events (AEs) were observed (see Figure 11).

[0086] Thus, the modeling approach described herein demonstrates that the claimed dosing regimen is superior in treating or preventing C5-related diseases such as PNH in both untreated subjects and, particularly, subjects pretreated with eculizumab.

[0087] Example 6: Comparison of DTDC size distribution results between Part 3 and Part 4 of the COMPOSER study In Part 3 of the COMPOSER study, drug-target-drug complexes (DTDCs) between clovalimab, human C5, and the antibody eculizumab were detected in all PNH patients who were switched from the anti-C5 antibody eculizumab to clovalimab. This example describes the comparison of DTDC size distribution between the dosing regimens in Parts 3 and 4 of the COMPOSER study. In Part 3 of the COMPOSER study, subjects were initially administered the anti-C5 antibody clovalimab intravenously at a single dose of 1000 mg / body. Starting one week after the first intravenous dose (8 days after IV administration), the anti-C5 antibody clovalimab was administered subcutaneously (SC) at a dose of 170 mg / body weekly, 340 mg / body every two weeks, or 680 mg / body every four weeks. In Part 4 of the COMPOSER trial, patients received clovalimab according to the dose and treatment regimen described above: the optimized dose and regimen consisted of a loading series of 1000 mg SC on day 1 and 340 mg SC on days 2, 8, 15, and 22, followed by a maintenance series of 680 mg SC every 4 weeks starting on day 29 (week 5). The loading series increased the total dose of clovalimab received during the first month of treatment to reduce the formation of larger DTDC complexes, in line with the lattice theory of complex formation. This optimized dosing strategy was investigated in patients in Part 4 who were switching treatments and compared with 19 PNH patients enrolled in Part 3 who switched from eculizumab to clovalimab. DTDC size distribution was measured using size exclusion chromatography (SEC) coupled with ELISA. SEC separated DTDC complexes into fractions according to their size: larger DTDC complexes were found in fractions 1–4, while smaller complexes, such as single motif complexes and non-DTDC complexes, were found in fractions 5–6. DTDCs were observed in all patients in Part 3 (Figure 12; larger DTDCs were found in fractions 1–4, while smaller complexes, including single motifs and non-DTDCs, were found in fractions 5–6). Two patients in Part 3 experienced clinical symptoms consistent with a type III hypersensitivity reaction due to DTDC. The DTDC size distribution in patients in Part 4 who received the optimal dosing strategy evolved differently from patients in Part 3, consistent with model predictions.In patients who switched in Part 4 (n = 7; data cutoff January 29, 2020), the sum of DTDC in fractions 1–4 began to decrease on day 8 and continued to decrease, in contrast to patients in Part 3. At day 22, the mean percentage of maximum DTDC was reduced by 56% in patients in Part 4 compared with patients in Part 3. Additionally, serum crovalimab concentrations in patients in Part 4 remained above 100 μg / mL, a level associated with complement inhibition. Despite the observation of DTDC in all patients switched from eculizumab in Part 4, no adverse events suggestive of type III hypersensitivity reactions occurred. In conclusion, patients receiving the optimized crovalimab regimen had lower concentrations of DTDC than patients receiving the Part 3 regimen.

[0088] Example 7: Outcome of response to crovalimab in PNH patients with C5 polymorphism Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the loss of the endogenous complement regulators CD59 and CD55 on hematopoietic cells. Peripheral blood elements are susceptible to complement-mediated destruction, resulting in intravascular hemolysis and thrombosis. Standard treatment is terminal complement inhibition with eculizumab, an anti-C5 monoclonal antibody (mAb). However, up to 3.5% of individuals of Asian descent harbor a polymorphism in C5 affecting Arg885, which corresponds to the binding site for eculizumab and ravulizumab (see Nishimura et al., N Engl J Med, Vol. 370, pp. 632–639 (2014); DOI: 10.1056 / NEJMoa1311084). PNH patients with these polymorphisms constitute a group with high unmet medical need because they experience poor control of intravascular hemolysis with eculizumab. Clovalimab is a novel anti-C5 mAb that binds to a distinct epitope on the beta subunit of C5. In vitro studies demonstrated that clovalimab binds equally to wild-type and Arg885 mutant C5 and inhibits their activity (Fukuzawa et al., Sci Rep, 7(1):1080. doi:10.1038 / s41598-017-01087-7(2017)).

[0089] Objective: The objective of this example is to describe the response to crovalimab in PNH patients with C5 polymorphisms.

[0090] Methods: The above-mentioned crovalimab dose and regimen (1000 mg crovalimab intravenously (IV) on day 1, followed by 340 mg crovalimab subcutaneously (SC) on days 2, 8, 15, and 22) followed by a maintenance dose (680 mg crovalimab SC on day 29, followed by 680 mg crovalimab subcutaneously every 4 weeks (Q4W) thereafter) was administered to patients with PNH harboring a C5 polymorphism (C5 Arg885 mutation (SEQ ID NO: 13)). Plasma concentrations of crovalimab, lactate dehydrogenase (LDH), free and total C5, and complement activity were determined at each visit. Patients were followed for transfusions, breakthrough hemolysis (BTH) events, and safety.

[0091] Results: Of 44 patients enrolled in Part 2 (n = 10), Part 3 (n = 19), and Part 4 (n = 15) of the COMPOSER trial (ClinicalTrials.gov Identifier: NCT03157635), four had the c.2654G->A nucleotide polymorphism predictive of the Arg885His substitution. At the data cutoff in September 2019, follow-up ranged from 12.4 to 98.3 weeks. All four patients were male and had been diagnosed 44 to 734 weeks prior to enrollment. PNH granulocyte clone size ranged from 89 to 95%. At enrollment, one patient was switched from ongoing eculizumab therapy, and three had previously discontinued eculizumab. All patients had LDH levels >3x the upper limit of normal (ULN) at enrollment, which rapidly declined and remained below 1.5x the ULN throughout follow-up (Figure 13). One patient required transfusion after enrollment (12 units of red blood cells (RBCs) in 6 months); this patient had an underlying diagnosis of aplastic anemia and required 198 units of RBCs in the 12 months prior to enrollment. None of the four patients experienced a breakthrough hemolysis (BTH) event. All four patients achieved complete terminal complement inhibition as measured by liposome immunoassay (LIA). LIA levels ranged from 32 to 42 U / mL at study enrollment, decreased to ≤10 U / mL by Day 2 (low-level quantification), and remained thereafter. Similarly, free C5 levels remained <0.5 μg / mL after Week 6 (Day 43). The safety profile of these patients was similar to that of the remaining participants. Three serious adverse events (SAEs) were reported, none of which were related to the study. One patient had two SEAs, bile duct stones, and cholelithiasis. The second patient had an SEA of upper respiratory tract infection at the time of admission, which developed 20 months later and resolved during treatment.

[0092] CONCLUSIONS: Clovalimab achieved complete and sustained terminal complement inhibition in PNH patients with the Arg885 polymorphism. Therefore, clovalimab is a promising anti-C5 antibody for the treatment and / or prevention of patients with PNH, characterized by the C5 Arg885His mutation. <Further embodiments of the present disclosure> [Embodiment 1] 1. An anti-C5 antibody for use in a method of treating or preventing a C5-related disease in a subject, said method comprising the following successive steps: (a) administering to the subject a single intravenous loading dose of a 1500 mg anti-C5 antibody, followed by at least one subcutaneous administration to the subject of a 340 mg loading dose of an anti-C5 antibody; and (b) administering to the subject at least one subcutaneous maintenance dose of 1020 mg of an anti-C5 antibody. an anti-C5 antibody, [Embodiment 2] 2. The anti-C5 antibody for use according to embodiment 1, wherein a loading dose of 340 mg of the antibody administered subcutaneously is administered to the subject at least once, from 1 day to 3 weeks after the start of intravenous administration of the anti-C5 antibody. [Embodiment 3] 3. The anti-C5 antibody for use according to embodiment 2, wherein a loading dose of 340 mg of the antibody administered subcutaneously is administered to the subject once, one day after the start of intravenous administration of the anti-C5 antibody. [Embodiment 4] 4. The anti-C5 antibody for use according to embodiment 2 or embodiment 3, wherein at least one booster loading dose of 340 mg of the anti-C5 antibody is administered subcutaneously to the subject one week or two weeks after initiation of intravenous administration of the anti-C5 antibody. [Embodiment 5] An anti-C5 antibody for use according to any one of embodiments 2 to 4, wherein a booster loading dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject once a week, one week and two weeks after initiation of intravenous administration of the anti-C5 antibody. [Embodiment 6] An anti-C5 antibody for use according to any one of embodiments 1 to 4, wherein at least one maintenance dose of 1020 mg of anti-C5 antibody is administered subcutaneously to the subject four weeks after initiation of intravenous administration of the anti-C5 antibody. [Embodiment 7] 7. The anti-C5 antibody for use according to embodiment 6, wherein a maintenance dose of 1020 mg of the anti-C5 antibody is administered subcutaneously once to the subject four weeks after the start of intravenous administration of the anti-C5 antibody. [Embodiment 8] 8. The anti-C5 antibody for use according to embodiment 6 or embodiment 7, wherein a maintenance dose of 1020 mg of the anti-C5 antibody is administered subcutaneously to the subject multiple times at time intervals of at least 4 weeks. [Embodiment 9] 9. The anti-C5 antibody for use according to any one of embodiments 1 to 8, wherein the method is carried out by administering: (i) administering to a subject a single intravenous loading dose of 1500 mg of an anti-C5 antibody; (ii) one day after the start of intravenous administration of the anti-C5 antibody, administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject; (iii) administering a loading dose of 340 mg of anti-C5 antibody subcutaneously once weekly to the subject 1 week, 2 weeks, and 3 weeks after the start of intravenous administration of the anti-C5 antibody; (iv) 4 weeks after the initiation of intravenous administration of the anti-C5 antibody, administering to the subject a maintenance dose of 1020 mg of anti-C5 antibody subcutaneously; and (v) repeating step (iv) multiple times at time intervals of 4 weeks. [Embodiment 10] An anti-C5 antibody for use according to any one of embodiments 1 to 9, wherein the subject has undergone pre-treatment with at least one pharmacological product useful for the treatment or prevention of a C5-related disease, and a loading dose of 1500 mg of anti-C5 antibody administered intravenously is administered to the subject after the final dose of the pharmacological product. [Embodiment 11] 11. The anti-C5 antibody for use according to embodiment 10, wherein a loading dose of 1500 mg of the anti-C5 antibody administered intravenously is administered to the subject on the third day or three days after the administration of the last dose of the pharmacological product. [Embodiment 12] 12. The anti-C5 antibody for use according to embodiment 10 or embodiment 11, wherein the pharmacological product comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from the anti-C5 antibody contained in the composition for subcutaneous or intravenous injection. [Embodiment 13] 13. The anti-C5 antibody for use according to any one of embodiments 10 to 12, wherein the pharmacological product comprises eculizumab, ravulizumab or a variant thereof. [Embodiment 14] 14. An anti-C5 antibody for use according to any one of embodiments 1 to 13, wherein the subject has a body weight of 100 kg or more. [Embodiment 15] 15. An anti-C5 antibody for use according to any one of embodiments 1 to 14, wherein the anti-C5 antibody concentration determined in a biological sample of the subject is 100 μg / ml or more. [Embodiment 16] 15. An anti-C5 antibody for use according to any one of embodiments 1 to 14, having a hemolytic activity determined in a biological sample of the subject of less than 10 U / mL. [Embodiment 17] 17. An anti-C5 antibody for use according to embodiment 15 or embodiment 16, wherein the biological sample is a blood sample, preferably a red blood cell sample. [Embodiment 18] 18. The anti-C5 antibody for use according to any one of embodiments 1 to 17, wherein the anti-C5 antibody is clovalimab. [Embodiment 19] 19. The anti-C5 antibody for use according to any one of embodiments 1 to 18, wherein the C5-related disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis (RA), lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), dense deposition disease (DDD), macular degeneration, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, thrombotic thrombocytopenic purpura (TTP), spontaneous fetal loss, Pauci-immune vasculitis, epidermolysis bullosa, recurrent fetal loss, multiple sclerosis (MS), traumatic brain injury, myocardial infarction, injury due to cardiopulmonary bypass or hemodialysis, refractory generalized myasthenia gravis (gMG), and neuromyelitis optica (NMO).

Claims

1. A pharmaceutical composition comprising crovalimab for treating or preventing a C5-related disease in a subject, wherein a loading dose of 1500 mg of crovalimab is administered intravenously to the subject on day 1, a loading dose of 340 mg of crovalimab is administered subcutaneously to the subject on days 2, 8, 15, and 22, and a maintenance dose of 1020 mg of crovalimab is administered subcutaneously to the subject once every four weeks starting on day 29, and wherein the subject has a body weight of 100 kg or more.

2. A medicament for treating or preventing a C5-related disease in a subject, comprising clovalimab, the medicament comprising the following administration steps: (i) administering to a subject a single intravenous loading dose of 1500 mg of crovalimab; (ii) one day after the initiation of intravenous administration of crovalimab, the subject is administered a 340 mg loading dose of crovalimab subcutaneously; (iii) one week, two weeks, and three weeks after the start of intravenous administration of crovalimab, the subject is administered a loading dose of 340 mg crovalimab subcutaneously once weekly; (iv) 4 weeks after initiation of intravenous administration of crovalimab, the subject is administered a subcutaneous maintenance dose of 1020 mg crovalimab; and (v) repeating step (iv) multiple times at intervals of 4 weeks; and the subject has a body weight of 100 kg or more.

3. 3. The method of claim 1, wherein the subject has undergone prior treatment with at least one pharmacological product useful for the treatment or prevention of a C5-related disease, and wherein a loading dose of 1500 mg of crovalimab administered intravenously is administered to the subject after the final dose of the pharmacological product.

4. 4. The method of claim 3, wherein a loading dose of 1500 mg of crovalimab administered intravenously is administered to the subject on or more than three days after the administration of the last dose of the pharmacological product.

5. 5. The medicament of claim 3 or claim 4, wherein the pharmacological product comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from clovalimab for subcutaneous or intravenous injection.

6. 6. The medicament of any one of claims 3 to 5, wherein the pharmacological product comprises eculizumab, ravulizumab or variants thereof.

7. 7. The method of claim 1, wherein the concentration of crovalimab determined in a biological sample of the subject is 100 μg / ml or more.

8. The pharmaceutical of any one of claims 1 to 7, wherein the hemolytic activity determined in a biological sample of the subject is less than 10 U / mL.

9. The pharmaceutical composition according to claim 7 or 8, wherein the biological sample is a blood sample.

10. The pharmaceutical composition of claim 9, wherein the biological sample is a red blood cell sample.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the C5-related disease is selected from the group consisting of rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; atypical hemolytic uremic syndrome (aHUS); dense deposition disease (DDD); macular degeneration; hemolysis; elevated liver enzymes; low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; multiple sclerosis (MS); traumatic brain injury; injury due to myocardial infarction, cardiopulmonary bypass, or hemodialysis; refractory generalized myasthenia gravis (gMG); and neuromyelitis optica (NMO).

12. The pharmaceutical composition of claim 11, wherein the C5-related disease is selected from the group consisting of aHUS, gMG, and NMO.

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