Dosage and administration regimen for the treatment or prevention of Guillain-Barre syndrome with the anti-C5 antibody clovalimab

Abstract

The present invention relates to dosages and administration regimens of anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, for use in methods of treating or preventing GBS in a subject. The dosages and treatment regimens of the present invention include administering to a subject a loading dose of an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, followed by administration of a maintenance dose of the anti-C5 antibody, wherein an initial loading dose is given to the subject intravenously, and the maintenance dose is administered subcutaneously at a dosage lower than the intravenously administered loading dose.

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 of treating or preventing Guillain-Barre Syndrome (GBS). The dosages and treatment regimens of the present invention include administering to a subject a loading dose of an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, followed by a maintenance dose of the anti-C5 antibody, where an initial loading dose is given to the subject intravenously and doses are administered subcutaneously at a lower dosage than the intravenously administered loading dose. [Background technology]

[0002] The classical pathway is usually activated by the formation of antigen-antibody complexes. Independently, the first step in the activation of the lectin pathway is the binding of specific lectins such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, L-ficolin and C-type lectin CL-11. In contrast, the alternative pathway undergoes spontaneous, 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 come together at the point where complement component C3 is cleaved by active proteases to yield C3a and C3b.

[0003] Guillain-Barré syndrome (GBS) is a rare, potentially fatal disease of the peripheral nerves and nerve roots, usually caused by infection. GBS is an acute, heterogeneous, paralytic, inflammatory peripheral neuropathy characterized by rapidly progressive, symmetric limb weakness resulting in reduced or even unresponsive muscles to stimuli [1].

[0004] The prognosis of GBS is determined by the extent of axonal loss in the acute phase; if axonal damage is minimized by effective early treatment in the acute phase, sufficient nerve regeneration and collateral sprouting from surviving motor axons resulting in long-term recovery can be expected several months after the disease peak. Intravenous immunoglobulin (IVIg) (400 mg / kg body weight, daily for 5 days) and plasma exchange (PE) (50 mL plasma / kg body weight in 5 sessions over 1–2 weeks), both introduced in the 1980s, are established treatments for GBS and are considered equally effective as first-line treatments. PE and IVIg have been shown to accelerate recovery in the acute and subacute phases of the disease, initiated within 2 weeks of the onset of weakness [2, 3, 4]. Beyond these periods, there is no evidence of efficacy, and it remains unclear whether these treatments sufficiently improve long-term outcomes in patients with Guillain-Barré syndrome [3, 4]. IVIg is usually the treatment of choice, as it is easier to administer and generally more widely available than plasma exchange. Complement inhibition is a novel approach to treat GBS; complement activation appears to contribute to neurodegeneration in GBS. Early acute treatment may prevent complement-mediated long-term neurological damage. Complement activation is thought to play a key role in the pathogenesis of all GBS variants [5]. Human proof-of-concept data supporting the use of the C5 complement inhibitor (eculizumab) are available from the phase 2 JET study in patients with severe GBS [6]. The study was a 24-week, multicenter, double-blind, placebo-controlled, randomized phase 2 trial performed in Japan. In this study, the primary outcome, the proportion of patients regaining walking ability by week 4, did not exceed a predefined response threshold (50%) in the eculizumab group. However, eculizumab showed evidence of potential to improve motor function in secondary endpoints [6]. Clovalimab is a novel humanized anti-C5 monoclonal antibody that binds with high affinity to the complement protein C5, thereby inhibiting its cleavage into C5a and C5b and preventing the generation of the terminal complement complex C5b-9 (MAC) [7].Clovalimab has been demonstrated to inhibit terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH) [8].

[0005] Clovalimab is based on SMART-Ig (Recycling Antibody™) technology [7] and has pH-dependent antigen binding. Clovalimab offers efficient target disposal and improved antibody recycling efficiency resulting in enhanced neonatal fragment crystallizable receptor (FcRn) binding, prolonged half-life and complement inhibition. Furthermore, the physicochemical properties of Clovalimab support the development of highly concentrated formulations. The combination of SMART-Ig and highly concentrated formulations allows for SC dosing every 4 weeks (Q4W).

[0006] The half-lives of IVIg and crovalimab depend on recycling by the FcRn receptor in endosomes, the effect of IVIg coadministration on crovalimab PK, taking into account the competition for binding of both molecules to the FcRn receptor to maintain C5 inhibition over a 28-day period. Summary of the Invention

[0007] This need is addressed by the present invention by providing embodiments as defined in the claims.

[0008] The present invention relates to an anti-C5 antibody for use in a method of treating or preventing GBS in a subject, the method comprising: (a) administering a single intravenous dose of a 1000 mg loading dose of anti-C5 antibody to the subject; (b) subsequently administering to the subject at least one maintenance dose of 340 mg of an anti-C5 antibody subcutaneously. The present invention relates to an anti-C5 antibody for use comprising the successive steps of:

[0009] In the context of the present invention, the subject to be treated is preferably a patient having a body weight between 40 kg and 100 kg. In the context of the present invention, the subject to be treated is a subject suffering from GBS.

[0010] Furthermore, the present invention is directed to the use of anti-C5 antibodies for the treatment or prevention of GBS. In the context of the present invention, the present invention is directed to the treatment or prevention of GBS in patients treated with an anti-C5 antibody, preferably clovalimab, in combination with standard of care (SOC) intravenous immunoglobulin (IVIg). IVIg is a pool of immunoglobulins from the plasma of healthy donors, prepared by separating immunoglobulins from other components of the plasma. Examples of IVIg are Asceniv, Bivigam, Carimune, Cutaquig, Cubitol, Flebogamma, Gammaguard, GamaSTAN, Gammaked, Gammaplex, Gamnex-C, Hizentra, Hyqvia, Octagam, Panzyga, Privigen, Xembify. Thus, the dosages and administration regimens described herein for anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, are given to patients treated with a combination of anti-C5 antibodies, preferably clovalimab, and IVIg.

[0011] Accordingly, the present invention relates to an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, for use in a method of treating or preventing GBS in a subject, preferably a subject having a body weight between 40 kg and 100 kg, the method comprising: (a) administering a single intravenous dose of a 1000 mg loading dose of anti-C5 antibody to the subject; (b) subsequently administering at least one loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject. The present invention relates to an anti-C5 antibody, comprising the steps of:

[0012] "Loading dose" refers to the dose of anti-C5 antibody administered to a subject suffering from GBS at the beginning of treatment, i.e., at the beginning of a treatment regimen. In pharmacokinetics (PK), "loading dose" is the first higher dose of drug that can be given to a patient at the beginning of the course of treatment, before being reduced to a lower dose. In the context of the present invention, the loading dose is first given to the subject to be treated by intravenous administration. In the context of the present invention, the loading dose is given once at a dose of 1000 mg. Thus, in the context of the present invention, a loading dose of a composition formulated for intravenous administration is given once to a subject intravenously, and then one or more doses of a pharmaceutical composition formulated for subcutaneous administration are given subcutaneously.

[0013] According to the present invention, the initial dose is followed by subsequent doses of equal or smaller amounts of anti-C5 antibody at sufficiently close intervals to maintain the concentration of anti-C5 antibody above an effective target level. Thus, in the context of the present invention, a maintenance dose is administered to the patient after the loading dose. "Maintenance dose" refers to a dose of anti-C5 antibody given to a subject suffering from a C5-related disease to maintain the concentration of anti-C5 antibody above a certain effective threshold of anti-C5 antibody concentration during the treatment period. In the context of the present invention, the target level of anti-C5 antibody is approximately a median value of 100 μg / ml or more over the treatment period. The target level of anti-C5 concentration within the present invention can be determined in a biological sample of the subject to be treated. Means and methods for the determination of anti-C5 concentration in a biological sample are within the common knowledge of the skilled artisan and can be determined, for example, by immunoassay. Preferably, in the context of the present invention, the immunoassay is an ELISA. Preferably, the maintenance dose is administered to the patient subcutaneously in one or more doses of 340 mg of anti-C5 antibody. Thus, within the context of the present invention, at least one maintenance dose or multiple maintenance doses are given to the subject, and the maintenance dose is administered subcutaneously at a dose of 340 mg. In the context of the present invention, at least one maintenance dose of 340 mg of anti-C5 antibody is administered to the patient after intravenous administration of a loading dose of 1000 mg of anti-C5 antibody. The subcutaneously administered dose is administered subcutaneously at least once to the 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, within the context of the present invention, the dose of 340 mg of anti-C5 antibody is administered subcutaneously at least once to the subject 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, a dose of 340 mg of anti-C5 antibody is administered to the subject one day after the start of intravenous administration of anti-C5 antibody. More preferably, one dose of 340 mg of anti-C5 antibody is administered subcutaneously one day after the start of intravenous administration. In the context of the present invention, at least one additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject one week (7 days), two weeks (14 days), or three weeks (21 days) after the start of intravenous administration of anti-C5 antibody.Most preferably, the 340 mg additional dose of anti-C5 antibody is administered subcutaneously 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of intravenous administration of anti-C5 antibody. Thus, within the context of the present invention, 1, 2, 3, 4 and / or 5 doses are administered to the subject, with the loading dose being administered intravenously to the subject at a dose of 1000 mg, and 1, 2, 3 or 4 doses being administered subcutaneously to the patient at a dose of 340 mg. In the context of the present invention, subcutaneous administration of 4 loading doses, each with a dosage of 340 mg of anti-C5 antibody, is preferred, with the additional dose being administered subcutaneously once 1 day after the start of intravenous administration of anti-C5 antibody, followed by weekly subcutaneous administration of a maintenance dose 1 week, 2 weeks and 3 weeks after the start of intravenous administration of anti-C5 antibody. For example, the total amount of anti-C5 antibody provided by a maintenance dose corresponding to an intravenous administration of 1000 mg (day 1) followed by subcutaneous administration of 340 mg (day 2), 340 mg (day 8), 340 mg (day 15) and 340 mg (day 22) is 2360 mg.

[0014] In particular, the present invention relates to an anti-C5 antibody for use in a method for treating or preventing a C5-associated disease in a subject, preferably a subject having a body weight between 40 kg and 100 kg, the method comprising: (i) administering a single intravenous dose of a 1000 mg loading dose of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the start of intravenous administration of the anti-C5 antibody. The present invention relates to an anti-C5 antibody, comprising the steps of:

[0015] The term "intravenous administration" / "administering intravenously" in the context of the present invention refers to administering an anti-C5 antibody into a vein of a subject such that the body of the patient to be treated receives the anti-C5 antibody within approximately 15 minutes, preferably within 5 minutes. For intravenous administration, the anti-C5 antibody must be formulated to be administered by a suitable device, such as (but not limited to) a syringe. In the context of the present invention, a formulation for intravenous administration comprises 50-350 mg of anti-C5 antibody, 1-100 mM buffer, such as histidine / aspartic acid with pH 5.5±1.0, 1-100 mM amino acid, such as arginine, and 0.01-0.1% non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2 mL glass vial containing the following components: 170 mg / mL of clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride and 0.05% Poloxamer 188™. The formulation is then administered to the patient within an acceptable period of time, for example within 5 minutes, 15 minutes, 30 minutes, 90 minutes. Furthermore, the formulation for intravenous administration is given to the patient to be treated in an injection volume between 1 ml and 15 ml, preferably about 6 ml.

[0016] The term "subcutaneous administration" / "administering subcutaneously" in the context of the present invention refers to the introduction of an anti-C5 antibody under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow sustained delivery from a drug container. The pocket may be created by pinching or lifting the skin away from the underlying tissue. For subcutaneous administration, the anti-C5 antibody must be formulated so that it can be administered by a suitable device, such as (but not limited to) a syringe, a pre-filled syringe, an injection device, an infusion pump, an injector pen, a needleless device, or by a subcutaneous patch delivery system. In the context of the present invention, a formulation for subcutaneous administration comprises 50-350 mg of anti-C5 antibody, 1-100 mM buffer, such as histidine / aspartic acid with pH 5.5±1.0, 1-100 mM amino acid, such as arginine, and 0.01-0.1% non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml of clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride and 0.05% Poloxamer 188™. In the context of the present invention, the formulation for subcutaneous administration is provided in a pre-filled syringe with a needle-safe device. The injection device for subcutaneous administration contains about 1-15 ml or more, preferably 2.25 ml, of a formulation for subcutaneous administration comprising an anti-C5 antibody. Under normal circumstances, the injection volume to be administered subcutaneously is either 1-15 ml, preferably 2 ml (340 mg of clovalimab), or 4 ml (680 mg of clovalimab). In the context of the present invention, subcutaneous administration refers to the introduction of anti-C5 antibody under the skin of the patient to be treated by a relatively slow sustained delivery from a drug reservoir for a period of time, including but not limited to 30 minutes or less, 90 minutes or less. Optionally, administration may be performed by subcutaneous implantation of a drug delivery pump implanted under the skin of the patient to be treated, the pump delivering a predetermined amount of anti-C5 antibody for a predetermined period of time, such as 30 minutes, 90 minutes, or for a period spanning the length of the treatment regimen.

[0017] In the context of the present invention, the above dosage and treatment regimen can be useful for the treatment or prevention of GBS in subjects co-administered with IVIg.For example, the treatment regimen of the present invention can be useful for treating patients with GBS who also receive standard treatment.Preferably, SOC is intravenous administration of IVIg.

[0018] The present invention also relates to a pharmaceutical composition for use in combination with IVIg to treat or prevent GBS, the composition comprising an anti-C5 antibody, preferably clovalimab, (a) administering a single intravenous loading dose of a 1000 mg anti-C5 antibody to a subject; and (b) subcutaneously administering to the subject at least one maintenance dose of 340 mg of an anti-C5 antibody. The present invention relates to a pharmaceutical composition administered by the administration step of

[0019] In one embodiment, (i) 1000 mg of anti-C5 antibody was administered intravenously to the subject once (loading dose); (ii) 340 mg of anti-C5 antibody is administered subcutaneously to the subject one day after initiation of intravenous administration of anti-C5 antibody (maintenance dose).

[0020] In a further embodiment, the pharmaceutical composition comprising IVIg is (a) 400 mg / kg of IVIg is administered intravenously once to a subject on the same day as a loading dose of C5 antibody; (b) 400 mg / kg of IVIg is administered intravenously to the subject daily on days 1, 2, 3, and 4 following the start of intravenous administration of anti-C5 antibody. It is administered by

[0021] The present invention also provides a pharmaceutical composition for use in combination with an anti-C5 antibody, preferably clovalimab, for treating or preventing GBS, the composition comprising IVIg, (a) a single intravenous administration to a subject on the same day as a loading dose (1000 mg) of C5 antibody; (b) administering the anti-C5 antibody intravenously to the subject daily on days 1, 2, 3, and 4 after the start of intravenous administration. The present invention relates to a pharmaceutical composition administered by the administration step of

[0022] In one embodiment, the intravenously administered dose of IVIg in a) is 400 mg / kg. In a further embodiment, the intravenously administered dose of IVIg 2, 3 and 4 days after the start of intravenous administration of anti-C5 antibody (step b) is 400 mg / kg daily.

[0023] In a further embodiment, a pharmaceutical composition comprising an anti-C5 antibody is (i) 1000 mg of anti-C5 antibody is administered intravenously once to a subject (loading dose); (ii) 340 mg of anti-C5 antibody is administered subcutaneously to the subject one day after the start of intravenous administration of the anti-C5 antibody (maintenance dose). It is administered by

[0024] In particular, the present invention relates to a pharmaceutical composition comprising an anti-C5 antibody for use in a method for treating or preventing GBS in a subject, preferably a subject having a body weight between 40 kg and 100 kg, the method comprising: (i) administering a single intravenous dose of a 1000 mg loading dose of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the start of intravenous administration of the anti-C5 antibody. Including, Anti-C5 antibodies are used in combination with IVIg, (a) 400 mg / kg of IVIg was administered intravenously once to the subject on the same day as the loading dose of C5 antibody in (i). (b) 400 mg / kg of IVIg is administered intravenously to the subject daily on days 1, 2, 3, and 4 following the start of intravenous administration of anti-C5 antibody; It relates to pharmaceutical compositions.

[0025] The administration of the first dose of anti-C5 antibody and IVIg may be administered together or separately. When anti-C5 antibody and IVIg are administered separately, they may be administered immediately following each other or with a time interval. For example, a loading dose of anti-C5 antibody may be given first, followed immediately by a loading dose of IVIg, or a loading dose of IVIg may be administered first, followed immediately by a loading dose of anti-C5 antibody. Alternatively, the two loading doses may be administered with a time interval between them, for example, the two loading doses may be administered with a time interval between them of 5, 10, 15, 20, 30, 40, 50, 60 minutes; up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1-23 hours, 1-16 hours, 1-8 hours, 1-4 hours, 1-2 hours. For example, a loading dose of anti-C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or the first dose of IVIg is administered in the morning and a loading dose of anti-C5 antibody is administered in the evening.

[0026] The present invention also relates to a combination of an anti-C5 antibody and IVIg for use in a method for treating or preventing GBS in a subject, preferably a subject having a body weight between 40 kg and 100 kg, the method comprising: (i) administering a single 1000 mg loading dose of anti-C5 antibody intravenously to a subject and a single 400 mg / kg intravenous dose of IVIg on the same day; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody, and administering 400 mg / kg of IVIg intravenously on the same day; (iii) administering 400 mg / kg of IVIg intravenously daily on days 2, 3, and 4 following the start of intravenous administration of anti-C5 antibody; (IV) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the start of intravenous administration of the anti-C5 antibody. The present invention relates to a combination of an anti-C5 antibody and IVIg, comprising the successive steps of:

[0027] The administration of the first dose of anti-C5 antibody and IVIg may be administered together or separately. When anti-C5 antibody and IVIg are administered separately, they may be administered immediately following each other or with a time interval. For example, a loading dose of anti-C5 antibody may be given first, followed immediately by a loading dose of IVIg, or a loading dose of IVIg may be administered first, followed immediately by a loading dose of anti-C5 antibody. Alternatively, the two loading doses may be administered with a time interval between them, for example, the two loading doses may be administered with a time interval between them of 5, 10, 15, 20, 30, 40, 50, 60 minutes; up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1-23 hours, 1-16 hours, 1-8 hours, 1-4 hours, 1-2 hours. For example, a loading dose of anti-C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or the first dose of IVIg is administered in the morning and a loading dose of anti-C5 antibody is administered in the evening.

[0028] In the context of the present invention, a "week" refers to a period of seven days.

[0029] In the context of the present invention, a "month" refers to a period of four weeks.

[0030] "Treatment", in the context of the present invention, includes a sequential series of an "induction treatment" and at least one "maintenance treatment". Typically, a treatment according to the present invention includes an "induction treatment" and at least one "maintenance treatment". Typically, a treatment according to the present invention may be for 3 weeks to 1 month, for example 28 days.

[0031] "Induction treatment" consists in intravenously administering a loading dose of anti-C5 antibody, preferably a dose of 1000 mg, to the subject. As explained herein above, "maintenance treatment" consists in (i) a succession of maintenance periods, in which one or more maintenance doses are given subcutaneously to the subject. In the context of the present invention, it is preferred that a maintenance dose of 340 mg of anti-C5 antibody is given to the subject 1 day, 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the loading dose is given to the subject to be administered intravenously. Preferably, the loading dose to be administered intravenously has a dose of 1000 mg. The maintenance dose to be given subcutaneously to the subject to be treated has a dose of 1360 mg. Thus, in the context of the present invention, a dose of 2360 mg of anti-C5 antibody is administered either intravenously or subcutaneously to the subject to be treated during the treatment period.

[0032] In the context of the present invention, the anti-C5 antibody is preferably clovalimab. Details of the sequence of the anti-C5 antibody clovalimab (CAS number: 1917321-26-6) are disclosed in the list of proposed international nonproprietary names (INN) of medicinal products, number 119, as published in WHO Drug Information (2018), volume 32, number 2, pages 302 and 303. The sequence of the anti-C5 antibody clovalimab is also shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain). The production of the anti-C5 antibody clovalimab used in the present invention is described in WO2016 / 098356 (see Example 1.1 for details). Furthermore, in the context of the present invention, the anti-C5 antibody clovalimab is administered to the patient by either a formulation for intravenous or subcutaneous administration. Intravenous or subcutaneous administration of the dosages provided herein as fixed amounts is preferred in the context of the present invention.

[0033] A formulation for intravenous administration comprises 50-350 mg of the anti-C5 antibody clovalimab, 1-100 mM of a buffer, such as histidine / aspartic acid with pH 5.5±1.0, 1-100 mM of an amino acid, such as arginine, and 0.01-0.1% of a non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2 mL glass vial containing the following components: 170 mg / ml clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% Poloxamer 188™.

[0034] A formulation for subcutaneous administration comprises 50-350 mg of the anti-C5 antibody clovalimab, 1-100 mM of a buffer, such as histidine / aspartic acid with pH 5.5±1.0, 1-100 mM of an amino acid, such as arginine, and 0.01-0.1% of a non-ionic surfactant, such as a poloxamer. Preferably in the context of the present invention, a formulation for intravenous administration is provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% Poloxamer 188™.

[0035] The patient described in the context of the present invention is a patient suffering from GBS. The preferred patient in the context of the present invention is a patient having a body weight between 40 kg and 100 kg. In the context of the present invention, the patient is preferably co-administered with IVIg.

[0036] Preferably, IVIg is administered in combination with an anti-C5 antibody to a subject suffering from GBS, and 400 mg / kg of IVIg is (a) Administered intravenously once to subjects on the same day as the loading dose (1000 mg) of C5 antibody. (b) administered intravenously to the subject daily on days 1, 2, 3, and 4 following the start of intravenous administration of anti-C5 antibody.

[0037] The present invention further provides a method for treating or preventing a C5-related disease in a subject, the method comprising: (a) administering a single intravenous loading dose of a 1000 mg anti-C5 antibody to a subject; and (b) subcutaneously administering to the subject at least one maintenance dose of 340 mg of an anti-C5 antibody. The method comprises the successive steps of:

[0038] In the context of the present invention, a method for treating or preventing a C5-related disease in a subject comprises: (i) administering a single intravenous dose of a 1000 mg loading dose of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week, 1 week, 2 weeks, and 3 weeks after the start of intravenous administration of the anti-C5 antibody. It is preferred that the administration step is carried out by

[0039] In the context of the present invention, a method for treating or preventing a C5-related disease in a subject comprises: (i) administering a single 1000 mg loading dose of anti-C5 antibody intravenously to a subject and a single 400 mg / kg intravenous dose of IVIg on the same day; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody, and administering 400 mg / kg of IVIg intravenously on the same day; (iii) administering 400 mg / kg of IVIg intravenously daily on days 2, 3, and 4 following the start of intravenous administration of anti-C5 antibody; (IV) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after the start of intravenous administration of the anti-C5 antibody. It is even more preferred that the method is carried out by the administration step of:

[0040] As explained above, in the context of the present invention, the anti-C5 antibody used in the context of dosage and administration regimen is preferably clovalimab.Furthermore, the definitions given above are equally applicable to the above method of treating or preventing C5-related disease.In the context of the present invention, it is also preferred that the subject to be treated has a body weight between 40kg and 100kg. [Brief description of the drawings]

[0041] [Figure 1] Graph of pharmacokinetics of radiolabeled IVIg in serum and total radioactivity as a percentage of the injected dose. Kendrick F, Evans ND, Berlanga O, Harding SJ, Chappell MJ. Parameter identification for a model of neonatal Fc receptor-mediated recycling of endogenous immunoglobulin G in humans. Front Immunol. 10. (2019) Figure 2A. [Diagram 2] Graph of mean (SEM) M281 PK profile from single ascending doses in a first-in-human study in healthy volunteers for five different doses. Figure extracted from Momenta R&D Day 2018 presentation. [Diagram 3] Graph of mean serum IgG concentrations as a percentage (%) of baseline according to M281 dose in single ascending dose (SAD) and multiple ascending dose (MAD) studies. Figure adapted from Ling LE, Hillson JL, Tiessen RG, et al., M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study. Clin Pharmacol Ther. (2018). [Figure 4]PK / PD model for clovalimab, C5, IgG, M281 in serum and their recycling in endosomes by FcRn. Each box corresponds to the concentration (nM) of the entity defined in Table 4. [Ab1], [Ab1Ag], [AgAb1Ag], [Ag], [IgG], [IgG*], [M281] are the concentrations in the central compartment. [Ab1]p, [Ab1Ag]p, [AgAb1Ag]p are the concentrations in the peripheral compartment. CLAb1 and CLAg are the clearances (L / day / kg) of free Ab1 and free Ag. CLe,Ab1, CLe,Ab1Ag, CLe,AgAb1Ag, CLe,IgG, CLe,M281 are the clearances of Ab1, Ab1Ag, AgAb1Ag, IgG, and M281 into endosomes (L / day / kg). CLe,Ab1 recy, CLe,IgG recy, CLe,M281 recy are the clearances of Ab1, IgG, and M281 from endosomes back to plasma (L / day / kg). Ab1, IgG, and M281 that are not bound to FcRn are cleared at rates defined by the elimination constants ke,Ab1, ke,IgG, and ke,M281 (1 / day). Vc, Vc IgG, and Vc M281 are the volumes of the central compartment for Ab1 / Ag, IgG, and M281 (L / kg). VpAb1, Vp Ab1Ag, Vp AgAb1Ag and Vp IgG are the peripheral compartment volumes (L / kg). Q Ab1 and Q IgG are the intercompartmental clearances (L / day / kg). kinAg is the production rate of Ag (nmol / day). konAb1 (nM / day) and koffAb1 (1 / day) are the binding and dissociation rates of Ab1 with Ag. [Diagram 5] 1 is an ODE equation for a model of binding of Ab1 to Ag in serum. [Figure 6] ODE equations for IgG, IgG* and M281 in serum. [Figure 7] ODE equations for Ab1, IgG, IgG*, and M281 in endosomes. [Figure 8]Equations for Ab1 disposal term from serum to endosomes and Ab1 recycling term from endosomes to serum. [Figure 9] Equation for Ab1 in endosomes. [Figure 10] Graph of model individual fit for total Ab1, total Ag and free Ag for composer part 1 (healthy volunteer subjects 11001-11007). Each column corresponds to a subject and rows correspond to total Ab1 (red alias [Ab1]total=[Ab1]+[Ab1Ag]+[AgAb1Ag]), total Ag (green alias [Ag]total=[Ag]+[Ab1Ag]+2[AgAb1Ag]) and free Ag (blue alias [Ag]). Concentrations observed in the composer study (Example 2.1) are shown as black dots and the continuous lines are simulations performed using empirical Bayes model parameter estimates for each subject. [Figure 11] Graph of model individual fit for total Ab1, total Ag and free Ag for composer part 1 (healthy volunteer subjects 11008-11015). Each column corresponds to a subject and rows correspond to total Ab1 (red alias [Ab1]total=[Ab1]+[Ab1Ag]+[AgAb1Ag]), total Ag (green alias [Ag]total=[Ag]+[Ab1Ag]+2[AgAb1Ag]) and free Ag (blue alias [Ag]). Concentrations observed in the composer study (Example 2.1) are shown as black dots and the continuous lines are simulations performed using empirical Bayes model parameter estimates for each subject. [Figure 12]2 is a graph of model individual fit for total Ab1, total Ag and free Ag for composer part 2 (naive PNH patients). Each column corresponds to a subject and rows correspond to total Ab1 (red alias [Ab1]total=[Ab1]+[Ab1Ag]+[AgAb1Ag]), total Ag (green alias [Ag]total=[Ag]+[Ab1Ag]+2[AgAb1Ag]) and free Ag (blue alias [Ag]). Concentrations observed in the composer study (Example 2.1) are shown as black dots and the continuous lines are simulations performed using empirical Bayes model parameter estimates for each subject. [Figure 13] 2 is a graph of model individual fit for total Ab1, total Ag and free Ag for composer part 4 (naive PNH patients). Each column corresponds to a subject and rows correspond to total Ab1 (red alias [Ab1]total=[Ab1]+[Ab1Ag]+[AgAb1Ag]), total Ag (green alias [Ag]total=[Ag]+[Ab1Ag]+2[AgAb1Ag]) and free Ag (blue alias [Ag]). Concentrations observed in the composer study (Example 2.1) are shown as black dots and the continuous lines are simulations performed using empirical Bayes model parameter estimates for each subject. [Figure 14] Graph of model individual fit for radiolabeled IgG* in serum (top panel) and total body radioactivity (bottom panel) normalized by injected dose. Each column corresponds to a subject, and rows correspond to dose-normalized IgG* in serum (i.e., [IgG*]*Vc IgG / dose), total radioactivity (i.e., [Vc IgG*[IgG*]+Vp IgG*[IgG*]p+Ve*([IgG*]e+[IgG*-FcRn]e)] / dose). Observations from the radiolabeling study (Example 2.2) are shown as black dots, and the continuous lines are simulations performed using the empirical Bayes model parameter estimates for each subject. [Figure 15]2 is a graph of model individual fit for M281PK and endogenous IgG normalized by baseline IgG levels. Each column corresponds to the average data for each SAD and MAD trial arm, and the rows correspond to M281 PK (aka [M281]) and the ratio of endogenous IgG to its baseline value (aka [IgG] / [IgG] baseline). Observations from the M281 SAD and MAD studies (Example 2.3) are shown as black dots, and the continuous lines are simulations performed using the empirical Bayes model parameter estimates for each study arm. [Figure 16] Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 17]Sensitivity analysis #1: [FcRn]total concentration divided by 2. Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 18]Sensitivity analysis #2: Ve multiplied by 10. Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 19]Sensitivity analysis #3: IgG baseline multiplied by 2. Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 20]Sensitivity analysis #4: C5 baseline multiplied by 2. Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 21]Graph of simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Median (solid line) and min / max (dotted line) simulated time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model, i.e., Total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], Total C5 = [Ag] + [Ab1Ag] + 2 [AgAb1Ag], Total IgG = [IgG], Crova free paratope = 2 [Ab1] + [Ab1Ag], Free crova = [Ab1], Free C5 = [Ag], Endo:Free IgG = [IgG]e, Endo:Free Crova = [Ab1]e, Endo:Crova-FcRn = [Ab1-FcRn]e, Endo:Free IgG = [IgG]e, Endo:IgG-FcRn = [IgG-FcRn]e. All concentrations are expressed in uM. [Figure 22]Graph of simulated individual, median and min / max time profiles for 33 subjects receiving clovalimab alone. All concentrations are in uM. Individual (continuous thick purple line), median (continuous thick black line) and min / max (dotted line) simulated time profiles for 33 subjects receiving clovalimab alone; clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Diagram 23] Graph of simulated individual, median and min / max time profiles for 33 subjects receiving clovalimab and IVIg. All concentrations are in uM. Individual (continuous thick purple line), median (continuous thick black line) and min / max (dotted line) simulated time profiles for 33 subjects receiving clovalimab and IVIg; clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg for patients >100kg, followed by 340mg SC on days 2, 8, 15 and 22. IVIg regimen: 400mg / kg daily on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. EXAMPLES

[0042] The following examples illustrate the invention.

[0043] Example 1: Antibodies and Clinical Trials 1.1 Clovalimab The sequence of the anti-C5 antibody clovalimab is shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain). Furthermore, the generation of the anti-C5 antibody clovalimab used in the present invention is described in WO2016 / 098356. Briefly, the gene encoding the heavy chain variable domain (VH) (SEQ ID NO: 3) of 305LO15 was combined with the gene encoding the modified human IgG1 heavy chain constant domain (CH) variant SG115 (SEQ ID NO: 4). The gene encoding the light chain variable domain (VL) (SEQ ID NO: 5) of 305LO15 was combined with the gene encoding the human light chain constant domain (CL) (SK1, SEQ ID NO: 6). The antibody was expressed in HEK293 cells co-transfected with the combination of heavy and light chain expression vectors and purified by protein synthesis.

[0044] 1.2 Clinical Trials BN43118 is a phase 3, randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of clovalimab compared to placebo as add-on therapy to standard of care (SOC) for the treatment of patients with Guillain-Barré syndrome (GBS). The study will enroll approximately 136 participants randomized to double-blind treatment in a 1:1 ratio to receive either clovalimab or placebo in addition to background therapy. Blinded study medication (clovalimab or placebo) will be administered intravenously on day 1 and subcutaneously on days 2, 8, 15 and 22 in addition to SOC (IVIg). Patients who receive background therapy before study day 1 must be able to receive their first dose of blinded study medication before their final dose of background therapy. The study will consist of four periods: a 5-day screening period, a 4-week treatment period, and a 24-week post-treatment follow-up period.

[0045] As the half-lives of IVIg and clovalimab depend on recycling by the FcRn receptor in endosomes [9], a mathematical model was constructed to describe the impact of IVIg coadministration on clovalimab PK, taking into account the binding competition of both molecules to the FcRn receptor. The model is an extension of the clovalimab PK / PD model developed for PNH-naive patients and reported in

[10] , which describes the binding of clovalimab to C5, with the addition of FcRn competition between IVIg and clovalimab in endosomes. This report details the various components and assumptions of this model, as well as its calibration based on clovalimab composer clinical data

[11] and literature data on the pharmacokinetics (PK) of IVIg. Simulations were performed to measure the impact of IVIg infusion on the PK / PD of clovalimab and to evaluate whether full C5 inhibition could be maintained over a period of 28 days.

[0046] Example 2: Data used for modeling To calibrate the combined IVIg PK and crovalimab PK / PD model, three data sets were pooled: Clovalimab Composer Clinical Study PK / PD Data: Individual patient data were used to estimate Clovalimab PK and, in addition, Clovalimab binding parameters to C5 were estimated. IVIg PK data: Radiolabeled PK time-course profiles for IVIg

[12] were used to estimate IVIg PK parameters in serum and endosomes. M281 PK / PD data: The PK time course of the monoclonal anti-FcRn antibody M281

[13] and its effect on endogenous IgG were used to estimate endosomal volume and FcRn receptor concentration.

[0047] Clovalimab composer data, IVIg PK data and M281 PK / PD data are provided in Example 2.1, Example 2.2 and Example 2.3, respectively. Values ​​for binding of clovalimab, IVIg and M281 to FcRn were required to establish the model and were fixed to their in vitro values ​​measured by surface plasmon resonance (SPR) as detailed in Example 2.4. Finally, the baseline value for IgG was fixed to a value representing the average levels reported in the literature and described in Example 2.5.

[0048] The data validation and aggregation process is identical to that described in

[10] .

[0049] 2.1 Composer Research BP39144 Composer is a four-part, first-in-human study designed to evaluate the safety, tolerability, PK, and PD of clovalimab in healthy volunteers (HV; part 1), as well as the safety, tolerability, PK, PD, and efficacy of clovalimab in eculizumab-naive PNH patients (parts 2 and 4) and in PNH patients switched from eculizumab to clovalimab (parts 3 and 4)

[11] . Further details regarding the study design, doses and regimens used, and samples collected are given in

[10] .

[0050] Data for HV and naive PNH patients (not previously treated with eculizumab) available in the clinical database at the cutoff date of January 29, 2020 were included in this analysis. Of note, GBS patients enrolled in the BN43118 study were not treated with C5 inhibitors

[10] , so data from patients who switched from eculizumab to clovalimab (parts 3 and 4) were not used in this analysis. Concentrations of clovalimab, total C5, and free C5 were converted to molar units (i.e., nM) using molecular weights of 190 kDa and 149 kDa for C5 and clovalimab, respectively. Dosage and administration rates were normalized by each subject's body weight at baseline and converted to molar units (i.e., amounts are in nmol / kg and infusion rates for IV administration are in nmol / day / kg).

[0051] The number of samples available for analysis from the COMPOSER trial for total crovalimab, free and total C5 in serum is given in Table 1. [Table 1]

[0052] 2.2 IVIG PK profile over time The IVIg PK time profiles of six individuals, shown in Figure 1, were extracted from the literature on the IVIg radiolabeled study by Kendrik et al.

[12] . Data for individual subjects consisted of the percentage of the injected dose of IVIg that remained in the serum over time and the percentage of the dose that remained in the body over time. Some individuals have health conditions that may result in different PK half-lives and increased or decreased serum IgG concentration levels. However, the health conditions of the subjects were not considered in this analysis.

[0053] 2.3 M281 PK / PD time course profile To quantify endosomal volume and the number of available FcRn receptors in endosomes, data from M281 monoclonal IgG1 anti-FcRn antibody, a high affinity FcRn binder (Kd=28.7 pM at pH=6.0)

[13] , were used for model calibration. Mean PK profiles from a first-in-human (FIH) single ascending dose (SAD) study in healthy volunteers for doses of 3 mg / kg (n=3), 10 mg / kg (n=6), 30 mg / kg (n=6) and 60 mg / kg (n=6) were extracted from Figure 2 (reported in

[14] ). As the PK profile in the M281 MAD study was not available in the literature, only the SAD study provided information on the PK of IgG. Since M281 has high affinity for FcRn at endosomal pH=6.0, it blocks the binding of endogenous IgG to FcRn and reduces serum IgG concentrations. Figure 3 shows the reduction in the mean serum endogenous IgG profile for increasing doses of M281 in the SAD and MAD studies. These data provide information on the mean levels of FcRn receptors available for IgG recycling in endosomes. Mean serum IgG concentrations (as a percentage of baseline) were extracted from this figure for SAD doses of 3 mg / kg (n=3), 10 mg / kg (n=6), 30 mg / kg (n=6) and 60 mg / kg (n=5) and for MAD doses of 15 mg / kg (n=3), 30 mg / kg (n=3).

[0054] We note that although the PK profile in the M281 MAD study was not available, the MAD time profile for IgG was used for model calibration. Because individual subject data was not available for M281, we assumed that each mean profile for different dose arms in the SAD and MAD studies corresponds to a different "individual" in the data set used for model calibration (including individual data for clovalimab and individual radiolabeled IgG PK profiles).

[0055] 2.4 Clovalimab, IVIG and M281 FcRn binding To model the interaction of clovalimab, IgG, and M281 with FcRn receptor in endosomes, the in vitro association rate constants k and dissociation rate constants k between clovalimab, IgG, M281, and FcRn were obtained from the literature and reported in Table 2. [Table 2]

[0056] 2.5 IgG baseline concentration Because endogenous baseline IgG concentrations were not available in any of the data sets, we assume that all patients had the same baseline IgG concentration for model calibration and simulations. As the normal IgG concentration range in adults has been reported to be between 0.767 g / dL and 1.59 g / dL

[17] , we fixed this concentration at 1 g / dL (i.e., 66.7 uM assuming a molecular weight of 150e3 g / mol for IgG).

[0057] Example 3: Modeling 3.1 Methodology a) Model calibration strategy A pooled dataset (described in Example 2) consisting of the clovalimab composer data, the IVIg PK data and the M281 PK / PD data was used for the simultaneous calibration of the clovalimab PK / PD, the IVIg PK and the M281 PK / PD models. A nonlinear mixed effects (NLME) approach was used to obtain population parameter estimates and empirical Bayes estimation (EBE) was used to obtain individual parameter estimates as described in

[10] .

[0058] 3b) Software To obtain parameter estimates, nonlinear mixed-effects analyses were performed using the Monolix software system, version 2019R2 (Lixoft, Paris, France). Simulations were performed using the R package mlxR, version 4.1.5 in the R environment, version 3.6.3.

[0059] c) Patient data inclusion criteria All available subject / patient data from composer parts 1, 2 and 4 listed in Table 1 are included in this analysis.

[0060] d) Notation In the remainder of this document, the concise notation defined in Table 3 is used to represent serum concentrations for clovalimab, C5, endogenous IgG or IVIg, radiolabeled IVIg, M281, and the complex formed by binding of clovalimab to C5. Some of these quantities are also estimated in the peripheral compartment (with the suffix p) and endosomes (with the suffix e). [Table 3]

[0061] 3.2. Model for Ab1, Ag, IVIg, and M281 with FcRn recycling in endosomes a) Model description A model illustrating the binding of Ab1 (Clovalimab) to Ag(C5) and competition with IgG for FcRn recycling in endosomes is shown in Figure 4. It includes the following components: Ab1 PK / PD model in serum: The top part of Figure 4 contains two binding submodels describing the sequential binding process of one Ag protein to one arm of the free Ab1 antibody to form the complex Ab1Ag, followed by a second Ag protein binding to the second arm of the same antibody to form the complex AgAb1Ag (as described in

[10] ). A peripheral distribution compartment was included for free and bound Ab1, along with two different distribution volumes for free Ab1 and complexes Ab1Ag and AgAb1Ag. During the modeling process, it was observed that the data did not support the addition of a peripheral compartment for Ag. The ordinary differential equations (ODEs) describing the concentration of free Ab1 (i.e. [Ab1]), the concentration of free Ag (i.e. [Ag]) and the concentration of Ab1 bound to one Ag (i.e. [Ab1Ag]) and the concentration of Ab1 bound to two Ags (i.e. [AgAb1Ag]) are given in Figure 5. IgG PK model in serum: The lower left part of Figure 4 is a two-compartment linear kinetic model for endogenous IgG or IVIg and radiolabeled IVIg (annotated with an asterisk, i.e. IgG*). The distribution volume and clearance are assumed to be identical for IgG and IgG*. The ODEs describing the concentrations of IgG and IgG* in serum are given in Figure 6 M281 PK model in serum: A one compartment linear kinetic model is used to describe M281 PK. The ODE describing the concentration of M281 in serum is given in Figure 6. · Endosome model: After internalization into endosomes, clovalimab, IgG, IgG* and M281 antibodies bind to FcRn and can be recycled back to serum. Antibodies that are not bound to FcRn are removed from endosomes. Since Ab1 is engineered with pH-dependent recycling technology (i.e. SMART-Ig Recycling®), we assume that Ag dissociates from antibody complexes Ab1Ag and AgAb1Ag when the antibody is internalized into endosomes due to a 1000-fold increase in the dissociation constant KdAb1 (see [7]). Therefore, only free Ab1 is present in endosomes. The ODE describing the binding to FcRn in endosomes is given in Figure 7.

[0062] The definitions and descriptions of the model parameters are given in Table 4. [Table 4]

[0063] The binding constants konAb1-Ag and koffAb1-Ag describe the binding of one arm of the Ab1 antibody to an Ag. Thus, a free antibody with two free Fab arms available has a two times higher probability of binding to a free Ag than an antibody with one arm already bound to one Ag. This is reflected in the model equation as 2konAb1-Ag in the binding equation for free Ab1 in FIG. 5. Similarly, an antibody bound to two Ags has a two times higher probability of losing an Ag molecule than an antibody bound to only one Ag. This is reflected in the equation describing the dissociation of two Ags bound to an antibody (i.e., AgAb1Ag) by a factor of 2 in the dissociation rate in FIG. 5, i.e., 2koffAb1.

[0064] To account for endosomal internalization and FcRn recycling for Ab1, a clearance term CLe,Ab1 is added with a minus sign to the ODE equation for Ab1 in serum, as shown in FIG. 8. The same term appears with a plus sign (and after adjusting for the different distribution volumes between serum Vc and endosomes Ve) in the equation describing free Ab1 in endosomes, as shown in FIG. 9. After binding to FcRn, Ab1 is recycled back to serum through the clearance term CLe,Ab1 recy, which appears with a minus sign in the ODE equation for the complex Ab1-FcRn in endosomes in FIG. 9 and with a plus sign in the serum equation for Ab1 in FIG. 8. Ab1 antibody not bound to FcRn in endosomes is removed with the term ke,Ab1 in FIG. 9.

[0065] Similar parameters and equations were introduced into the model to describe the internalization and recycling of IgG, IgG* and M281, as shown in FIG.

[0066] b) Overview of model assumptions The main hypotheses of the model are: The binding rate of Ag to Ab1 (konAb1-Ag and koffAb1-Ag) is identical when the second arm of the Ab1 antibody is free or already bound to another Ag protein koffAb1 was set to a fixed value for each subject, assuming that in vitro surface plasmon resonance (SPR) estimates of this constant reflect the in-vivo situation. Binding of Ag to Ab1 occurs only in the central compartment (not in peripheral tissues) · The rates of endogenous Ag production (kinAg) and clearance (CLAg) are constant over time. The clearance process to the endosome is linear and not saturable We hypothesize that due to the pH-dependent recycling technology SMART-Ig Recycling®, Ab1 is not bound to Ag in endosomes, and therefore only free Ab1 antibodies are recycled (i.e. Ab1Ag and AgAb1Ag are recycled as Ab1). Total [FcRn] concentration is assumed to be constant over time. We hypothesize that the FcRn recycling process from endosomes to serum is linear and not saturable (after binding to FcRn). Because albumin binds to a different FcRn epitope than IgG, we believe that albumin is not involved in the FcRn recycling saturation process of IgG antibodies. Only free Ab1, IgG, IgG* and M281 are cleared from endosomes (i.e. all molecules bound to FcRn are recycled back to serum) We assume the same clearance constant in the endosome for Ab1, IgG, IgG* and M281, i.e. ke Ab1 = ke IgG = ke M281 · We hypothesize that clearance of antibodies from the body occurs exclusively in endosomes.

[0067] Therefore, other parallel processes that require the addition of other loss constants are not taken into account.

[0068] Example 4: Simulation and sensitivity analysis 4.1 Base case simulation Simulations of patients receiving either clovalimab alone or clovalimab co-administered with IVIg (both treatments starting on the same day) were performed using the following regimens: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22. IVIg: 400mg / kg daily on days 1, 2, 3, 4 and 5 Simulations were performed using EBEs obtained from the 33 subjects from the Composer study included in the model calibration. EBEs for subjects from the radiolabeled IVIg and M281 studies were not used in the simulations because they do not contain information on C5 inhibition. For each subject, a baseline C5 concentration of 70ug / mL and an IgG concentration of 1g / dL were assumed. The primary outputs of these simulations are median and min / max time-varying profile values ​​for: Total Ab1 drug concentration (in uM) Total IgG concentration (in uM) Free Ab1 (in uM) Free Ab1 paratope concentration (in uM), i.e. the number of free Ab1 arms available for binding to Ag. This amount is given by the sum 2 × [Ab1] + [Ab1Ag]

[0069] Additionally, endosomal time course profiles for free FcRn, free IgG, free clovalimab and complexed FcRn-clovalimab, FcRn-IgG are provided in the Appendix.

[0070] The primary metrics used to compare simulations between crovalimab alone and crovalimab with IVIg are the maximum reduction in median PK concentrations at trough (upon administration of crovalimab) and the duration of complete C5 inhibition.

[0071] 4.2 Sensitivity analysis To assess the robustness of the base case simulations, a sensitivity analysis was performed to lower the threshold for saturating FcRn recycling using the following scenarios: Divide the concentration of FcRn receptors in endosomes by 2 Multiply the endosome volume by 10 Multiply the baseline IgG concentration by 2

[0072] Furthermore, because GBS is an acute condition, the individual variation in C5 levels is unknown; therefore, a simulation assuming an increase in baseline C5 concentration from 70 ug / mL to 140 ug / mL was performed in this sensitivity analysis.

[0073] All simulations were performed using the same dosing regimen described in Example 4.1, the same set of parameters representing the same 33 patients, and sensitivity analyses with and without IVIg co-administration were compared using the same metrics.

[0074] Example 5: Results 5.1 Modeling Data from 15 healthy volunteers in composer part 1, 10 and 8 naive PNH patients from parts 2 and 4, respectively, and the radiolabeled IgG* and M281 data described in Example 2 were used to calibrate a model (see FIG. 4 ) describing the binding of Ag (i.e., C5) to Ab1 (i.e., clovalimab) and its competition with IgG for endosomes. The number of samples available from composer parts 1, 2 and 4 for total Ab1, total Ag, free Ag are given in Table 1.

[0075] To reduce uncertainties regarding the estimations due to the introduction of the endosomal part of the model, the population parameters for the central distribution volume, the volume and intercompartmental clearance of Ab1 and its competition with Ag, as well as the production and clearance rates of Ag, were fixed to the values ​​obtained without the endosomal model and described in

[10] . These values ​​are reported in Table 5.

[0076] The ensemble parameter values ​​obtained from the model calibration are reported in Table 6.

[0077] The individual fitness plots reported in Figures 10, 11, 12, and 13 show that the concentration time courses for Total [Ab1], Total [Ag], and Free [Ag] from the Composer study are well explained by the model.

[0078] The individual fit plots in FIG. 14 show that the model adequately described dose-normalized radiolabeled IgG* in serum in the top panel and whole body radioactivity in the bottom panel.

[0079] Similarly, FIG. 15 shows that M281 PK and its effect on baseline normalized endogenous IgG concentrations are well described by the model for each arm of the SAD and MAD studies. [Table 5] [Table 6]

[0080] Example 6: Simulation and sensitivity analysis 6.1 Base Case Simulation Simulations were performed using individual parameter estimates (i.e., EBE) for the 33 subjects from the composer study used for model calibration.

[0081] The results of the simulation for subjects receiving either clovalimab alone or clovalimab with IVIg are shown in FIG. 16, where time 0 corresponds to day 1 when treatment is initiated.

[0082] The median and min / max simulated profiles for the concentrations of clovalimab and IgG in serum and endosomes are presented in Figure 21 in Appendix 1. Thirty-three individual profiles for subjects receiving clovalimab only or both clovalimab and IVIg are depicted in Figures 22 and 23, respectively.

[0083] When coadministered with IVIg at the recommended dose in GBS, a decrease in serum concentrations of clovalimab is observed because it competes for FcRn recycling. Median clovalimab trough concentrations were decreased by 19% on day 8 in the presence of IVIg.

[0084] The median clovalimab concentration over the simulated time period remains above a threshold concentration of approximately 100ug / mL, which is the value used as a reference to achieve complete C5 activity inhibition. Looking at the expected free C5 profile, where complete inhibition is observed, complete inhibition is confirmed. Furthermore, the minimum value for clovalimab free paratope always remains above 0, indicating that there is always clovalimab binding capacity to capture free C5 molecules over the 72-day period.

[0085] 6.2 Sensitivity analysis To assess the robustness of the assumptions made in the model, we performed sensitivity analyses with respect to model parameters that affect the efficiency of FcRn recycling. Furthermore, because GBS is an acute condition, individual variability in C5 levels is unknown; therefore, we performed simulations assuming an increase in baseline C5 concentrations.

[0086] This analysis represents a possible "worst case scenario" for reduced C5 inhibition induced by alterations in clovalimab PK. The following model parameters were purposefully altered one by one as follows: 1. Divide the total concentration of FcRn in the endosome [FcRn]total by 2. 2. Multiply the volume of the endosome Ve by 10. 3. Increase the rate of endogenous IgG production by 2-fold, resulting in a doubling of baseline IgG concentrations to 2 g / dL 4. Baseline C5 concentrations were increased two-fold, from 70 μg / mL to 140 μg / mL

[0087] The results of sensitivity analysis number 1 are shown in Figure 17. The impact of IVIg on the PK of clovalimab is higher when the concentration of FcRn in the endosomes [FcRn]total is divided by 2; in this scenario, the clovalimab median concentration is reduced by 27% at day 8 at the trough in the presence of IVIg. Of note, in the base case simulation, this reduction was approximately 19%. Over the 40 day period, the median profile remains above the 100ug / ml threshold and the minimum of clovalimab free paratope always remains strictly positive, ensuring full C5 inhibition.

[0088] The results of sensitivity analysis #2 in Figure 18 demonstrate that a 10-fold increase in endosomal volume alters the PK profile of clovalimab, but no difference can be observed in the median clovalimab concentrations with or without IVIg co-administration.

[0089] In analysis #3, as shown in Figure 19, a two-fold increase in baseline endogenous levels of IgG (from 1 g / dL to 2 g / dL) results in a reduction in median crovalimab concentrations of 22% at day 8; however, crovalimab free paratope values ​​are always strictly positive over the 40 day period. Of note, in base case simulations, this reduction was approximately 19%.

[0090] Finally, in sensitivity analysis #4, a simulation was performed assuming a two-fold increase in baseline C5 concentrations (140 ug / mL), with the results provided in Figure 20. Median clovalimab trough concentrations decreased by 22% on day 8.

[0091] Even when taking into account uncertainties regarding several key parameters driving clovalimab repurposing by FcRn, these sensitivity analyses demonstrate that the proposed clovalimab dosing strategy is expected to provide sufficient inhibition of C5 over a period of at least 40 days based on the median PK profile.

[0092] Example 7 Observations A previously developed model for clovalimab reported in

[10] was extended to account for the saturation of FcRn recycling when IVIg is co-administered. A key assumption of the model is that antibody clearance occurs only in endosomes when the antibody is not bound to FcRn (as is typically assumed in literature [9]). Thus, the half-life of the antibody is driven by the extent to which the antibody can bind to FcRn receptors in endosomes and be recycled. Thus, the concentration of FcRn receptors and the volume of the endosomes are important parameters to be estimated to quantify when FcRn recycling is saturated and affects clovalimab serum concentrations. As shown in Figure 3, M281 binding to FcRn clearly saturates IgG recycling from endosomes to serum, so the addition of the M281 PK / PD profile in our dataset provided the necessary information to estimate these two parameters. We note that the population estimate for FcRn receptor concentration in endosomes, [FcRn]total=42.3 μM reported in Table 6, is comparable to the value of 41.2 uM reported in Kendrik's publication

[12] (i.e., [FcRn]tot=Rtot / v3=14 umol / 0.34 L). However, the estimated volume of the endosome, Ve=0.14 L (assuming a body weight of 70 kg), is 2.4 lower (i.e., v3=0.34 L) than reported in the same publication, motivating the use of the M281 data to estimate this parameter.

[0093] After calibration, the model provided a sufficient goodness of fit for the PK of IVIg in Figure 14 and for the PK / PD of clovalimab with C5 inhibition as shown in Figures 10, 11, 12 and 13. However, as seen in the second row of Figures 10, 11, 12 and 13, it was not able to capture part of the variability for total [Ag] at the individual level. Because the production rate of Ag (i.e. kinAg) is assumed constant over time in the model, the model does not have the ability to fit the variability of total Ag. This is particularly highlighted in Figures 10 and 11 for six healthy volunteers receiving placebo (i.e. subjects 11002, 11003, 11006, 11010, 11012, 11015) who have a constant predicted total Ag concentration (i.e. horizontal green line) but whose measured total Ag varies within a 300 nM range.

[0094] Due to limited individual data for IgG and M281, at the population level, parameters were usually estimated with insufficient precision (ie, RSE >50%), as given in Table 6.

[0095] These findings justified why, during the model building process, the model parameters describing the PK / PD of clovalimab and C5 in serum were fixed to the population values ​​given in Table 5 in order to reduce the estimation uncertainty regarding the parameters describing the FcRn recycling process. The values ​​in Table 5 were obtained using the model given in

[10] , which does not explicitly describe the processes occurring in the endosomes.

[0096] To avoid propagating uncertainties regarding population parameter estimates, we only performed simulations using individual EBE parameters. These EBEs were obtained for the 33 subjects receiving clovalimab in the Composer clinical study. EBE parameters obtained for subjects from the radiolabeled IVIg and M281 studies were not used in the simulations because they did not carry information on the PK / PD of clovalimab.

[0097] Simulations showed that the selected clovalimab dosing regimen (1000 mg IV on day 1 for patients under 100 kg and 1500 mg for patients over 100 kg, followed by 340 mg SC on days 2, 8, 15 and 22) when coadministered with IVIg at a dose of 400 mg / kg for 5 consecutive days provides a median clovalimab PK profile above the reference threshold of 100 ug / mL (for full C5 inhibition). The maximum effect of IVIg coadministration occurs on day 8, with a reduction in median serum clovalimab concentration of 19%. Even when considering the minimum of the predictions (corresponding to a small number of subjects), the levels of free paratope always remain strictly positive over a period of 72 days, as can be observed in the individual profiles in Figure 23.

[0098] Sensitivity analyses demonstrated the robustness of the results by evaluating the effects of reducing the concentration of FcRn receptors by a factor of 2, increasing endosomal volume by a factor of 10, and increasing baseline levels of IgG by a factor of 2. In all these cases, median clovalimab serum concentrations remained above 100ug / mL over the 40 day period, and the minimum values ​​of free paratope remained strictly positive over the 40 day period.

[0099] The increase in C5 baseline from 70ug / mL to 140ug / mL had a modest impact on median PK levels, as the reduction in median serum clovalimab concentrations increased from 19% to 22% on day 8. This increase was driven by faster endosomal internalization of clovalimab-C5 complexes compared to free clovalimab (i.e., CLe,Ab1=0.00696L / day / kg and CLe,Ab1Ag=CLe,AgAb1Ag=0.0103L / day / kg), resulting in an overall faster clearance of clovalimab.

[0100] The selected crovalimab dosing regimen is therefore expected to encompass the therapeutic objective of maintaining sustained complete C5 inhibition over 28 days despite co-administration of IVIg.

[0101] Example 8 Summary / Conclusion The effect of IVIg infusion on the PK and PD profiles of crovalimab in subjects receiving both treatments simultaneously was investigated using a mechanistic mathematical model that accounts for the binding of crovalimab to C5 and predicts the concentrations of free C5 and free crovalimab paratope over time (thereby quantifying the spare free crovalimab sites available to bind to C5 molecules).

[0102] The model also includes a PK model of endogenous IgG in serum, as well as the competition of IgG and clovalimab for binding to the FcRn receptor in endosomes. This part of the model allows for the quantification of the effect of the recommended therapeutic dose of IVIg on clovalimab PK concentrations. The model also includes a description of the M281 anti-FcRn antibody PK and PD, which are used to estimate the concentration of FcRn receptors and the volume of endosomes.

[0103] Ensemble methods were used to simultaneously calibrate the clovalimab PK / PD model, the IVIg PK model and the M281 PK / PD model.A pooled dataset including clovalimab composer data in 33 healthy volunteers and naïve PNH patients, radiolabeled IgG data from the literature

[12] in six subjects, and published PK / PD SAD and MAD data for the M281 monoclonal anti-FcRn antibody [13, 14] was constructed and used for model calibration.

[0104] Simulation and sensitivity analyses were then performed to quantify the impact of IVIg coadministration on the PK and PD profiles of crovalimab using individual parameter estimates obtained from 33 subjects from the Clinical Study Composer. These data were included in the calibration dataset.

[0105] The following doses and dosing regimens for clovalimab and IVIg were used in these simulations: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22. IVIg: 400mg / kg daily on days 1, 2, 3, 4 and 5

[0106] IVIg dose and administration regimen was based on standard treatment for acute GBS (400 mg / kg QD for 5 consecutive days).

[0107] The main conclusions of this modelling and simulation analysis are: · The maximum predicted reduction in median crovalimab serum concentrations was 19% on day 8 when receiving concomitant IVIg. · Median crovalimab serum concentrations remained above approximately 100ug / mL, the reference threshold expected to provide full C5 activity, for 72 days, which encompasses the expected target treatment period for the BN43118 study of 28 days. · The level of free paratope always remains strictly positive, indicating that there is always spare clovalimab binding capacity available. Sensitivity analyses demonstrated that full C5 inhibition was maintained over the 40-day period even when model parameters, such as FcRn receptor concentration, baseline levels of IgG and C5, and endosomal volume, were altered in ways that reduced clovalimab recycling by FcRn.

[0108] Overall, the simulation results and sensitivity analysis indicate that the selected clovalimab dosing regimen provides complete C5 inhibition for at least 40 days.

[0109] In summary, the presented modeling approach provides a tool to understand the interactions of IVIg and crovalimab in FcRn recycling and to quantify through simulation the effects of IVIg on crovalimab PK levels, crovalimab free binding sites and free C5.

[0110] Based on the results of this study, the following dosing regimens will be selected for testing in clinical study BN43118: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22.

[0111] However, to ensure that the dose selected is sufficient to achieve full C5 inhibition, a dose confirmation step is planned in Study BN43118; actual PK data from 10 GBS subjects will be evaluated to confirm that the dose selected is sufficient.

[0112] [Table 7] TIFF2025510490000008.tif124161

[0113] [Table 8] TIFF2025510490000010.tif72161

[0114] [Table 9]

Claims

1. A pharmaceutical composition comprising an anti-C5 antibody for use in a method for treating or preventing Guillain-Barré syndrome (GBS) in a subject, wherein the method is a) A step of administering a 1000 mg loading dose of anti-C5 antibody intravenously once, and b) The next step is to subcutaneously administer at least one dose of 340 mg of anti-C5 antibody to the target population. A pharmaceutical composition containing the above.

2. The pharmaceutical composition according to claim 1, wherein a subcutaneous dose of 340 mg is administered to the subject at least once between one day and three weeks after the start of intravenous administration of the anti-C5 antibody.

3. The pharmaceutical composition according to claim 2, for use in combination with intravenous immunoglobulin (IVIg).

4. The pharmaceutical composition according to claim 3, wherein a dose of 400 mg / kg of IVIg is administered intravenously to the subject at least once.

5. The pharmaceutical composition according to claim 4, wherein a dose of 400 mg / kg of IVIg is administered intravenously to the subject daily on days 1, 2, 3, 4, and 5.

6. The pharmaceutical composition according to claim 2, wherein a subcutaneous dose of 340 mg of anti-C5 antibody is administered to the subject once, one day after the start of intravenous administration of the anti-C5 antibody.

7. The pharmaceutical composition according to claim 2, wherein at least one additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject one week or two weeks after the start of intravenous administration of the anti-C5 antibody.

8. The pharmaceutical composition according to claim 2, wherein an additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject once a week, one week and two weeks after the start of intravenous administration of the anti-C5 antibody.

9. The pharmaceutical composition according to claim 6, wherein a dose of 340 mg of anti-C5 antibody is administered subcutaneously to a target several times at intervals of at least four weeks.

10. The pharmaceutical composition according to claim 7, wherein a dose of 340 mg of anti-C5 antibody is administered subcutaneously to a target several times at time intervals of at least 4 weeks.

11. The method comprises the following administration steps: (i) A step of administering a 1000 mg loading dose of anti-C5 antibody intravenously as a single dose; (ii) A step of administering a 340 mg dose of anti-C5 antibody subcutaneously one day after the start of intravenous administration of anti-C5 antibody; (iii) A procedure in which a 340 mg dose of anti-C5 antibody is administered subcutaneously once a week, one week (7 days), two weeks (14 days), and three weeks (21 days) after the start of intravenous administration of anti-C5 antibody. The pharmaceutical composition according to claim 1, as implemented by [method].

12. A pharmaceutical composition according to claim 11 for use in combination with IVIg, wherein, (a) 400 mg / kg of IVIg was administered intravenously to the subject once on the same day as a loading dose of 1000 mg of anti-C5 antibody, and (b) A pharmaceutical composition comprising 400 mg / kg of IVIg administered intravenously to the subject daily, one day, two days, three days, and four days after the start of intravenous administration of an anti-C5 antibody.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has been pre-treated with at least one pharmacological product useful for the treatment or prevention of GBS, and an intravenous loading dose of 1000 mg of anti-C5 antibody is administered to the subject after the final dose of the pharmacological product.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has a body weight between 40 kg and 100 kg.

15. The pharmaceutical composition according to any one of claims 1 to 12, wherein the concentration of the anti-C5 antibody determined in the target biological sample is 100 μg / ml or more.

16. The pharmaceutical composition according to any one of claims 1 to 12, wherein the anti-C5 antibody is clobarimab.

17. A combination of an anti-C5 antibody and IVIg for use in a method for treating or preventing GBS in a subject, wherein the method is (i) A single intravenous dose of 1000 mg of anti-C5 antibody is administered to the target patient, followed by a single intravenous dose of 400 mg / kg of IVIg on the same day; (ii) One day after initiating intravenous administration of anti-C5 antibody, a maintenance dose of 340 mg of anti-C5 antibody is administered subcutaneously, followed by intravenous administration of 400 mg / kg of IVIg on the same day; (iii) The step of intravenously administering 400 mg / kg of IVIg daily, two, three, and four days after the start of intravenous administration of anti-C5 antibody; and (iv) Subcutaneous administration of a maintenance dose of 340 mg of anti-C5 antibody once a week, one week (7 days), two weeks (14 days), and three weeks (21 days) after the start of intravenous administration of anti-C5 antibody. A combination of anti-C5 antibody and IVIg, including a series of steps.

18. The combination for use according to claim 17, wherein the subject has been pre-treated with at least one pharmacological product useful for the treatment or prevention of GBS, and an intravenous loading dose of 1000 mg of anti-C5 antibody is administered to the subject after the final dose of the pharmacological product.

19. The combination for use according to claim 17, wherein the subject has a body weight between 40 kg and 100 kg.

20. The combination for use according to claim 17, wherein the concentration of the anti-C5 antibody determined in the target biological sample is 100 μg / ml or more.

21. The combination for use according to claim 17, wherein the anti-C5 antibody is clobalimab.

Images