Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
  • A61K2039/507—Comprising a combination of two or more separate antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• the present invention relates to a dosage and administration regimen of anti-C5 antibodies, particularly of the anti-C5 antibody Crovalimab, for use in a method of treating or preventing Guillain-Barré Syndrome (GBS).
• GRS Guillain-Barré Syndrome
• the dosage and treatment regimen of the present invention include the administration of an anti-C5 antibody, preferably of the anti- C5 antibody Crovalimab, with loading doses followed by the administration of (a) maintenance dose(s) of the anti-C5 antibody to the subject, wherein the initial administered loading dose is intravenously given to the subject and the doses are subcutaneously administered in a lower dosage as the intravenously administered loading dose.
• an anti-C5 antibody preferably of the anti- C5 antibody Crovalimab
• maintenance dose(s) of the anti-C5 antibody to the subject, wherein the initial administered loading dose is intravenously given to the subject and the doses are subcutaneously administered in a lower dosage as the intravenously administered loading dose.
• the first step in 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.
• MBL mannan-binding lectin
• H-ficolin H-ficolin
• M-ficolin M-ficolin
• L-ficolin L-ficolin
• C-type lectin CL-11 C-type lectin
• GBS is an acute, heterogeneous, paralysing, inflammatory peripheral nerve disease characterized by rapidly progressive, symmetrical limb weakness which results in muscles having reduced or even absence of response to stimuli [1].
• the prognosis of GBS is determined by the extent of axonal loss in the acute phase and if axonal damage is minimized by effective early treatment in the acute phase, sufficient nerve regeneration and collateral sprouting from surviving motor axons leading to long- term recovery could be expected several months after the disease peak.
• Intravenous immunoglobulin 400 mg/kg body weight daily for 5 days
• PE plasma exchange
• IVIg were shown [2,3,4] to speed up recovery in the acute and subacute phases of the disease started within 2 weeks of the onset of weakness. Beyond these time periods, evidence on efficacy is lacking and it is still unclear whether these treatments sufficiently improve long-term outcomes in patients with Guillain-Barré syndrome [3,4].
• IVIg is easier to administer and generally more widely available than plasma exchange, it is usually the treatment of choice.
• Inhibition of complement is a novel approach for treating GBS; complement activation appear to contribute to nerve degeneration in GBS. Early acute treatment may prevent complement mediated long-term nerve damage. Complement activation is thought to play an important role in the pathogenesis of all GBS variants [5].
• Human proof of concept data supporting the use of C5 complement inhibitor (eculizumab) are available from phase 2 JET study in patients with severe GBS [6]. This study was a 24 week, multi-center, double-blind, placebo- controlled, randomized phase 2 trials conducted in Japan. In this study, the primary outcome, the proportion of patients regaining the ability to walk by week 4, did not exceed the predefined response threshold (50%) in the eculizumab group.
• Crovalimab is a novel humanized anti-C5 monoclonal antibody [7] which binds to complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9 (MAC).
• Crovalimab has been demonstrated [8] to inhibits terminal complement-mediated intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).
• Crovalimab is based on SMART-Ig (Recycling AntibodyTM) technology [7] with pH- dependent antigen binding.
• crovalimab It provides efficient target disposal and enhanced neonatal fragment crystallizable receptor (FcRn) binding, improved antibody recycling efficiency resulting in prolonged half-life and complement inhibition.
• FcRn neonatal fragment crystallizable receptor
• crovalimab support the development of high concentration formulation.
• the combination of the SMART-Ig and the high concentrated formulation enables every 4 weeks (Q4W) SC dosing.
• the half-life of IVIg and crovalimab are dependent on the recycling by FcRn receptors in the endosome, the impact of the co-administration of IVIg on crovalimab PK taking into account the binding competition of both molecules to the FcRn receptors for maintaining the C5 inhibition .over a 28 day period.
• the present invention relates to an anti-C5 antibody for use in a method of treating or preventing a GBS in a subject, wherein the method comprises the consecutive steps of: (a) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once, (b) followed by subcutaneously administering at least one maintenance dose of 340 mg of the anti-C5 antibody to the subject.
• the subject to be treated is preferably a patient with a body weight of between 40 kg and 100 kg.
• the subject to be treated is/are subject/s which suffer from GBS.
• the invention is directed to the use of the anti-C5 antibody for the treatment or prevention of GBS.
• the present invention is directed to the treatment or prevention of GBS, in patients that are treated with a combination of an anti-C5 antibody, preferably Crovalimab, and the Standard of Care (SOC) Intravenous Immunoglobulin (IVIg).
• IVIg is a pool of immunoglobulins from the plasma of healthy donors prepared by separating the immunoglobulins from the other components of the plasma.
• IVIg examples are Asceniv, Bivigam, Carimune, Cutaquig, Cuvitru, Flebogamma, Gammagard, GamaSTAN, Gammaked, Gammaplex, Gamunex-C, Hizentra, Hyqvia, Octagam, Panzyga, Privigen, Xembify.
• the herein described dosage and administration regimen of the anti-C5 antibody, particularly of the anti-C5 antibody Crovalimab is given to patients who is treated with a combination of anti- C5 antibody, preferably Crovalimab, and IVIg.
• 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 GBS in a subject, preferably a subject with a body weight of between 40 kg and 100 kg, wherein the method comprises the consecutive steps of: (a) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once, (b) followed by subcutaneously administering at least one loading dose of 340 mg of the anti-C5 antibody to the subject.
• the “loading dose” refers to the dose of the anti-C5 antibody administered to the subject suffering from GBS, at the beginning of the treatment, i.e. at the start of the treatment regimen.
• a “loading dose” is an initial higher dose of a drug that may be given to a patient at the beginning of a course of treatment before dropping down to a lower dose.
• the loading dose is firstly given to subjects to be treated by intravenous administration.
• the loading dose is given once at a dose of 1000 mg.
• a loading dose of a composition formulated for intravenous administration is given intravenously once to the subject before one dose or more doses of a pharmaceutical composition formulated for subcutaneous administration is/are given subcutaneously.
• the initial dose is followed by subsequent doses of equal or smaller amounts of anti-C5 antibody at intervals sufficiently close to maintain the concentration of the anti-C5 antibody at or above an efficacious target level.
• maintenance dose(s) is (are) administered to the patients after the loading dose.
• the “maintenance dose” refers to the dose of the anti- C5 antibody that is given to a subject suffering from a C5-related disease to maintain the concentration of the anti-C5 antibody above a certain efficacious threshold of the anti-C5 antibody concentration during the treatment period.
• the target level of the anti-C5 antibody is a median of approximately 100 ⁇ g/ml or more over the treatment period.
• the target level of the anti-C5 concentration within the present invention may be determined in a biological sample of the subject to be treated.
• Means and methods for the determination of the anti-C5 concentration in a biological sample are within the common knowledge of the skilled person and can for example be determined by an immunoassay.
• the immunoassay is an ELISA.
• the maintenance dose(s) is (are) subcutaneously administered to the patients, at a dose or doses of 340 mg of the anti-C5 antibody.
• at least one maintenance, or more maintenance doses is/are given to the subject, wherein the maintenance dose(s) is (are) subcutaneously administered at a dose of 340 mg.
• At least one maintenance dose of 340 mg of the anti-C5 antibody is administered to the patients after the intravenous administration of a loading dose of 1000 mg of the anti-C5 antibody.
• the subcutaneously administered dose(s) is (are) subcutaneously administered at a dose of 340 mg of the anti-C5 antibody at least once to the subject 1 day to 3 weeks (21 days) after the start of the intravenous administration of the anti-C5 antibody.
• a dose of 340 mg of the anti-C5 antibody is subcutaneously administered 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 the intravenous administration of the anti-C5 antibody.
• a dose of 340 mg of the anti-C5 antibody is administered to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody. More preferably, one dose of 340 mg of the anti- C5 antibody is subcutaneously administered 1 day after the start of the intravenous administration. In the context of the present invention, at least one additional dose of 340 mg of the anti-C5 antibody is subcutaneously administered to the subject 1 week (7 days), 2 weeks (14 days), or 3 weeks (21 days) after the start of the intravenous administration of the anti-C5 antibody.
• additional doses of 340 mg of the anti-C5 antibody are subcutaneously administered 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of the intravenous administration of the anti-C5 antibody.
• 1, 2, 3, 4 and/or 5 doses is/are given to the subject, wherein the loading dose, is intravenously administered at a dose of 1000 mg to the subject, and wherein 1, 2, 3 or 4 doses is/are given subcutaneously at a dose of 340 mg to the patient.
• the subcutaneous administration of 4 loading doses each having a dosage of 340 mg of the anti-C5 antibody is preferred, wherein the additional doses are subcutaneously administered once 1 day after the start of the intravenous administration of the anti-C5 antibody, followed by subcutaneous administration of maintenance doses 1 week, 2 weeks and 3 weeks once weekly after the start of the intravenous administration of the anti-C5 antibody.
• the total amount of the anti-C5 antibody given via (a) maintenance dose(s) 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.
• the present invention relates to an anti-C5 antibody for use in a method of treating or preventing a C5-related disease in a subject, preferably in a subject with a body weight of between 40 kg and 100 kg, wherein the method comprises the consecutive steps of: (i) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once; (ii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody; (iii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of the intravenous administration of the anti-C5 antibody once weekly.
• intravenous administration / “intravenously administering” refer in the context of the present invention to the administration of the anti-C5 antibody into a vein of the subject such that the body of the patient to be treated receives the anti-C5 antibody in approximately 15 minutes or less, preferably 5 minutes or less.
• the anti-C5 antibody has to be formulated that it be administered via a suitable device such as (but not limited to) a syringe.
• the formulation for intravenous administration comprises 50 to 350 mg of the anti-C5 antibody, 1 to 100 mM of a buffering agent, such as histidine/aspartic acid comprising a pH of 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, such as a poloxamer.
• a buffering agent such as histidine/aspartic acid comprising a pH of 5.5 ⁇ 1.0
• an amino acid such as arginine
• a non-ionic surfactant such as a poloxamer
• 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 .
• the formulation is then administered to the patient within a tolerated time period, such as 5 minutes, 15 minutes, 30 minutes, 90 minutes, or less.
• the formulation for intravenous administration is given to the patients to be treated with an injection volume of between 1 ml to 15 ml, preferably about 6 ml.
• subcutaneous administration refer in the context of the present invention to the introduction of the anti-C5 antibody under the skin of an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle.
• the pocket may be created by pinching or drawing the skin up and away from underlying tissue.
• the anti-C5 antibody has to be formulated that it may be administered via a suitable device such as (but not limited to) a syringe, a prefilled syringe, an injection device, an infusion pump, an injector pen, a needless device, or via a subcutaneous patch delivery system.
• the formulation for subcutaneous administration comprises 50 to 350 mg of the anti-C5 antibody, 1 to 100 mM of a buffering agent, such as histidine/aspartic acid comprising a pH of 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, such as a poloxamer.
• a buffering agent such as histidine/aspartic acid comprising a pH of 5.5 ⁇ 1.0
• an amino acid such as arginine
• a non-ionic surfactant such as a poloxamer
• the formulation for intravenous administration is provided in a 2.25 prefilled 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 .
• a formulation for the subcutaneous administration is provided in a prefilled syringe with a needle safety device.
• the injection devices for subcutaneous administration comprises about 1 to 15 ml or more, preferably 2.25 ml of a formulation for subcutaneous administration comprising the anti-C5 antibody.
• the injection volume to be subcutaneously administered is 1 to 15 ml, preferably either 2 ml (340 mg Crovalimab), or 4 ml (680 mg Crovalimab).
• the subcutaneous administration refers to introduction of the anti-C5 antibody under the skin of the patient to be treated by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30 minutes or less, 90 minutes or less.
• the administration may be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the patient to be treated, wherein the pump delivers a predetermined amount of the anti-C5 antibody for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.
• a drug delivery pump implanted under the skin of the patient to be treated
• the pump delivers a predetermined amount of the anti-C5 antibody for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.
• the above dosages and treatment regimens can be useful for the treatment or prevention of GBS in a subject to whom is IVIg is co- administrated.
• the treatment regimen of the present invention can be useful for treating a patient having GBS, wherein the patient also receives the Standard of Care.
• the SOC is intravenous administration of IVIg.
• the present invention also relates to a pharmaceutical composition for use in combination with IVIg for treating or preventing GBS, the composition comprises an anti-C5 antibody, preferably Crovalimab, and is administered by the following administration steps: (a) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once; and (b) subcutaneously administering at least one maintenance dose of 340 mg of the anti-C5 antibody to the subject.
• an anti-C5 antibody preferably Crovalimab
• the pharmaceutical composition comprising IVIg is administered by the following steps: (a) 400mg/kg of IVIg is intravenously administered once to the subject on the same day as the loading dose of the C5 antibody; (b) 400mg/kg of IVIg is intravenously administered to the subject daily 1 day, 2 days, 3 days and 4 days after the start of the intravenous administration of the anti-C5 antibody.
• the present invention also relates to a pharmaceutical composition for use in combination with an anti-C5 antibody, preferably Crovalimab, for treating or preventing GBS, the composition comprises IVIg and is administered by the following administration steps: (a) intravenously administered to the subject once on the same day as the loading dose of the C5 antibody (1000mg) (b) intravenously administered to the subject daily 1 day, 2 days, 3 days and 4 days after the start of the intravenous administration of the anti-C5 antibody.
• the intravenously administered dose of IVIg of a) is 400mg/kg.
• intravenously administered dose of IVIg 2 days, 3 days and 4 days after the start of the intravenous administration of the anti-C5 antibody is 400mg/kg daily.
• the pharmaceutical composition comprising the anti-C5 antibody is administered by the following steps: (i) 1000 mg of the anti-C5 antibody is intravenously administered to the subject (loading dose) once; (ii) 340 mg of the anti-C5 antibody is subcutaneously administered of to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody (maintenance dose).
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an anti-C5 antibody for use in a method of treating or preventing GBS in a subject, preferably in a subject with a body weight of between 40 kg and 100 kg, wherein the method comprises the steps of: (i) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once; (ii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody; (iii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of the intravenous administration of the anti-C5 antibody once weekly; wherein the anti-C5 antibody is used in combination with IVIg, wherein (a) 400mg/kg of IVIg is intravenously administered once to the subject on the same day as the
• the administration of initial doses of the anti-C5 antibody and IVIg may be administered together or separated. If anti-C5 antibody and IVIg are administered separately, they may administered directly subsequent one another or timely spaced. For example, the loading does of the anti-C5 antibody is given first, directly followed by the loading dose of the IVIg or, the IVIg loading dose may be administered first, directly followed by the loading of the anti-C5 antibody. Alternatively, two loading doses may be administered timely spaced, for example the two loading doses may be administered separated by time period from 5, 10, 15, 20, 30, 40, 50, 60 minutes; up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1 to 23 hours, 1 to 16hours, 1 to 8 hours, 1 to 4 hours, 1 to 2 hours.
• the loading dose of the anti- C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or first dose of IVIg is administered in the morning and the loading dose of the anti-C5 antibody is administered in the evening.
• the present invention also relates to a combination of an anti-C5 antibody and IVIg for use in a method of treating or preventing a GBS in a subject, preferably in a subject with a body weight of between 40 kg and 100 kg, wherein the method comprises the consecutive steps of: (i) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once and intravenously administering 400mg/kg of IVIg once on the same day; (ii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody and intravenously administering 400mg/kg of IVIg on the same day; (iii) intravenously administering 400m
• the administration of initial doses of the anti-C5 antibody and IVIg may be administered together or separated. If anti-C5 antibody and IVIg are administered separately, they may administered directly subsequent one another or timely spaced. For example, the loading does of the anti-C5 antibody is given first, directly followed by the loading dose of the IVIg or, the IVIg loading dose may be administered first, directly followed by the loading of the anti-C5 antibody. Alternatively, two loading doses may be administered timely spaced, for example the two loading doses may be administered separated by time period from 5, 10,15, 20, 30, 40, 50, 60 minutes; up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1 to 23 hours, 1 to 16hours, 1 to 8 hours, 1 to 4 hours, 1 to 2 hours.
• the loading dose of the anti-C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or first dose of IVIg is administered in the morning and the loading dose of the anti-C5 antibody is administered in the evening.
• a “week” refers to a period of time of 7 days.
• a “month” refers to a period of time of 4 weeks.
• “Treatment” in the context of the present invention comprises the sequential succession of an “induction treatment“ and at least a “maintenance treatment”.
• a treatment according to the invention comprises an “induction treatment” and at least one “maintenance treatment”.
• a treatment according to the invention may be 3 weeks to 1 month, e.g.28 days.
• An “induction treatment” consists in an intravenous administration of a loading dose, preferably a dose of 1000 mg, of the anti-C5 antibody to the subject.
• a “maintenance treatment” consists in the sequential succession of (i) a maintenance period wherein one or more maintenance dose(s) is (are) subcutaneously given to the subjects.
• a maintenance dose of 340 mg of the anti-C5 antibody is given to the subject is given 1 day, 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the intravenously administered loading dose was given to the subject.
• the loading dose to be administered intravenously has a dose of 1000 mg.
• the maintenance dose which is subcutaneously given to the subject to be treated has a dose of 1360 mg.
• a dose of 2360 mg of the anti-C5 antibody is either intravenously, or subcutaneously administered to the subject to be treated during the treatment period.
• the anti-C5 antibody is preferably Crovalimab.
• the sequence details of the anti-C5 antibody Crovalimab (CAS number: 1917321-26-6) are disclosed in List No. 119 of proposed International Non-proprietary Names for Pharmaceutical Substances (INN) as published at pages 302 and 303 of WHO Drug Information (2016), Vol.32, No.2.
• the sequences of the anti-C5 antibody Crovalimab is also shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain).
• the generation of the anti-C5 antibody Crovalimab used in the present invention is described in WO 2016/098356 (see Example 1.1 for details).
• the anti-C5 antibody Crovalimab is administered to the patients by a formulation either for intravenous administration, or for subcutaneous administration.
• Preferred in the context of the present invention is the intravenous or subcutaneous administration of the herein provided dosages as (a) fixed-dose(s).
• the formulation for intravenous administration comprises 50 to 350 mg of the anti-C5 antibody Crovalimab, 1 to 100 mM of a buffering agent, such as histidine/aspartic acid comprising a pH of 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, such as a poloxamer.
• a buffering agent such as histidine/aspartic acid comprising a pH of 5.5 ⁇ 1.0
• an amino acid such as arginine
• a non-ionic surfactant such as a poloxamer.
• 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 .
• the formulation for subcutaneous administration comprises 50 to 350 mg of the anti-C5 antibody Crovalimab, 1 to 100 mM of a buffering agent, such as histidine/aspartic acid comprising a pH of 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, such as a poloxamer.
• a buffering agent such as histidine/aspartic acid comprising a pH of 5.5 ⁇ 1.0
• an amino acid such as arginine
• a non-ionic surfactant such as a poloxamer.
• the formulation for intravenous administration is provided in a 2.25 prefilled 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 .
• Patients described in the context of the present invention are patients suffering from GBS.
• Preferred patients in the context of the present invention are patients with a body weight of between 40 kg and 100 kg.
• patients preferably are co-administered IVIg.
• IVIg is administered in combination with an anti-C5 antibody to the subject suffering from GBS, wherein 400mg/kg of IVIg is (a) intravenously administered to the subject once on the same day as the loading dose of the C5 antibody (1000mg) (b) intravenously administered to the subject daily 1 day, 2 days, 3 days and 4 days after the start of the intravenous administration of the anti-C5 antibody Moreover, the present invention relates to a method of treating or preventing a C5-related disease in a subject, wherein the method comprises the consecutive steps of: (a) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once,; and (b) subcutaneously administering at least one maintenance dose of 340 mg of the anti- C5 antibody to the subject.
• the method of treating or preventing a C5-related disease in a subject is carried out by the following administration steps: (i) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once; (ii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody; (iii) subcutaneously administering a loading dose of 340 mg of the anti-C5 antibody to the subject 1 week, 2 weeks and 3 weeks after the start of the intravenous administration of the anti-C5 antibody once weekly.
• the method of treating or preventing a C5-related disease in a subject is carried out by the following administration steps: (i) intravenously administering a loading dose of 1000 mg of the anti-C5 antibody to the subject once and intravenously administering 400mg/kg of IVIg once on the same day; (ii) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 day after the start of the intravenous administration of the anti-C5 antibody and intravenously administering 400mg/kg of IVIg on the same day; (iii) intravenously administering 400mg/kg of IVIg daily 2 days, 3 days and 4 days after the start of the intravenous administration of the anti-C5 antibody (IV) subcutaneously administering a maintenance dose of 340 mg of the anti-C5 antibody to the subject 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of the intravenous administration of the anti-C5
• the anti-C5 antibody used in the context of the dosage and administration regiment is Crovalimab. Further, the definition given above apply likewise to the above methods of treating or preventing a C5-related disease. It is also preferred in the context of the present invention that the subject to be treated has a body weight of between 40 kg and 100 kg.
• FIGURES The Figures show: Figure 1 Radiolabeled IVIg pharmacokinetic in serum and total radioactivity as proportion of injected dose Figure 2A from 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.
• CLe, Ab1, CLe, Ab1Ag, CLe, AgAb1Ag, CLe, IgG, CLe,M281 are the clearance (L/day/kg) of Ab1, Ab1Ag, AgAb1Ag, IgG and M281 into the endosome.
• CLe,Ab1 recy, CLe, IgG recy, CLe, M281 recy are the clearance (L/day/kg) of Ab1, IgG and M281 from the endosome back to plasma.
• Ab1, IgG and M281 not bound to FcRn are eliminated with a rate defined by the elimination constant ke, Ab1, ke, IgG and ke, M281 (1/day).
• Vc, Vc IgG and Vc M281 are the are the volume (L/kg) of the central compartment for Ab1/Ag, IgG and M281.
• VpAb1, Vp Ab1Ag, Vp AgAb1Ag and Vp IgG are the volume (L/kg) of the peripheral compartments.
• Q Ab1 and Q IgG are the inter-compartmental clearance (L/day/kg).
• kinAg is the production rate (nmol/day) of Ag.
• konAb1 (nM/day) and koffAb1 (1/day) are the association and dissociation rate of Ab1 with Ag.
• the concentrations observed in the COMPOSER study are displayed as black dots and the continuous lines are the simulations performed using the empirical Bayes model parameter estimates for each subject Figure 12 Model Individual Goodness Fit for Total Ab1, Total Ag and Free Ag for COMPOSER Part 2 (Na ⁇ ve PNH Patients)
• the observations from the radiolabeled studies are displayed as black dots and the continuous lines are the simulations performed using the empirical Bayes model parameter estimates for each subject.
• Figure 15 Model Individual Goodness Fit for M281PK, and endogenous IgG normalized by baseline IgG level
• Each column corresponds to the average data for each SAD and MAD trial arm and the rows to M281 PK (aka [M281]) and the ratio of endogenous IgG to its baseline value (aka [IgG]/[IgG]baseline).
• the observations from the M281 SAD and MAD studies are displayed as black dots and the continuous lines are the simulations performed using the empirical Bayes model parameter estimates for each study arm.
• FIG. 16 Simulated Median and Min/Max Time Profiles for 33 Subjects Receiving Only Crovalimab (in black) or Crovalimab with IVIg (in blue). All Concentrations are in uM Median (continuous lines) and min/max (dotted lines) simulated time profiles for 33 subjects receiving either crovalimab alone (black lines) or crovalimab with IVIg (blue lines); Crovalimab regimen: 1000 mg IV on Day 1 for patient below 100 kg and 1500 mg for patients above 100 kg, followed by 340 mg SC on Days 2, 8, 15, and 22. IVIg regimen: 400 mg/kg daily on Day 1, 2, 3, 4 and 5 Each panel corresponds to a different output of the model, i.e.
• the generation of the anti- C5 antibody Crovalimab used in the present invention is described in WO 2016/098356. Briefly, the genes encoding the heavy chain variable domain (VH) of 305LO15 (SEQ ID NO: 3)) were combined with the genes encoding a modified human IgG1 heavy chain constant domain (CH) variant SG115 (SEQ ID NO: 4). The genes encoding the light chain variable domain (VL) of 305LO15 (SEQ ID NO: 5) were combined with the genes encoding a human light chain constant domain (CL) (SK1, SEQ ID NO: 6). Antibodies were expressed in HEK293 cells co- transfected with the combination of heavy and light chain expression vectors, and were purified by protein.
• VH heavy chain variable domain
• CH heavy chain constant domain
• CL human light chain constant domain
• Clinical trial BN43118 is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical study which will evaluate the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of crovalimab compared with placebo as add-on therapy to standard of care (SOC) for the treatment of patients with Guillain-Barré syndrome (GBS).
• SOC standard of care
• This study will enroll approximately 136 participants randomized to double-blinded treatment in a 1:1 ratio to receive either crovalimab or placebo in addition to background therapy.
• Blinded study drug crovalimab or placebo
• the patients who received background therapy prior to study day 1 must be able to receive the first dose of blinded study drug before the last dose of background therapy.
• the study will be composed of 4 periods: 5-day screening period, 4-week treatment period, 24-week post-treatment follow up.
• 5-day screening period 4-week treatment period
• 24-week post-treatment follow up As the half-life of IVIg and crovalimab are dependent on the recycling by FcRn receptors in the endosome [9], a mathematical model was built to describe the impact of the co-administration of IVIg on crovalimab PK taking into account the binding competition of both molecules to the FcRn receptors.
• This model is an extension of the crovalimab PK/PD model describing the binding of crovalimab to C5 developed for PNH na ⁇ ve patients and reported in [10] with the addition of the FcRn competition between IVIg and crovalimab in the endosome.
• the present report details the different components and assumptions of this model as well as the calibration based on crovalimab 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 crovalimab and to assess if complete C5 inhibition can be maintained over a 28-day period.
• Example 2 DATA USED FOR MODELING To calibrate the combined IVIg PK and crovalimab PK/PD model, three sets of data were pooled: • Crovalimab COMPOSER clinical study PK/PD data: individual patient’s data were used to estimate crovalimab PK as well as to estimate the binding parameters of crovalimab to C5 • IVIg PK data: radiolabeled PK time course profiles for IVIg [12] were used to estimate IVIg PK parameters in serum and in the endosome • M281 PK/PD data: the PK time course of the monoclonal anti-FcRn antibody M281 [13] and its impact on endogenous IgG were used to estimate the volume of endosome and the concentration of FcRn receptors.
• Crovalimab COMPOSER data, IVIg PK data and M281 PK/PD data are described in Example 2.1, Example 2.2 and Example 2.3, respectively.
• Values for the binding of crovalimab, IVIg and M281 with 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.
• SPR Surface Plasmon Resonance
• baseline value for IgG was fixed to values representing average level reported in the literature and described in Example 2.5. The data checking and assembly process is identical to the one described in [10].
• COMPOSER Study BP39144 COMPOSER is a first-in-human study [11] consisting of four sequential parts, designed to evaluate the safety, tolerability, PK and PD of crovalimab in healthy volunteers (HVs; Part 1) and the safety, tolerability, PK, PD and efficacy of crovalimab in PNH patients na ⁇ ve to eculizumab (Parts 2 and 4) and PNH patients switching from eculizumab to crovalimab (Parts 3 and 4). Further details on the study designs, dose and regimen used and samples collected are given in [10].
• data from patients switching from eculizumab to crovalimab (Parts 3 and 4) were not used in this analysis as GBS patients enrolled in the BN43118 study will be C5 inhibitor treatment na ⁇ ve [10].
• the concentration of crovalimab, total C5 and free C5 were converted in molar unit (i.e. nM) using the molecular weights of 190 kDa, 149 kDa respectively for C5 and crovalimab.
• the dose amount and dose rate were normalized by each subject body weight at baseline and converted in mole units (i.e. amounts are in nmol/kg and infusion rates for the IV administration are in nmol/day/kg).
• the number of samples available for analysis from the COMPOSER trial for total crovalimab, free and total C5 in serum are given on Table 1.
• the data for an individual subject consist of the time course of the proportion of injected dose of IVIg remaining in serum and the time course of the proportion of dose remaining in the body.
• Several individuals have health conditions which may result in different PK half-lives and an increased or decreased serum IgG concentration levels. However, subject health status was not taken into account in this analysis.
• Figure 3 displays the reduction of the average serum endogenous IgG profiles for increasing doses of M281 in the SAD and MAD studies. These data provides information on the average level of FcRn receptors available for IgG recycling in the endosome.
• the MAD time profiles for IgG were used in the model calibration even though the PK profiles in the M281 MAD study were not available.
• Example 3 MODELING 3.1 Methodology a) Model Calibration Strategy A pooled dataset consisted of Crovalimab COMPOSER data, IVIg PK data and M281 PK/PD data (and described in Example 2) was used for the simultaneous calibration of the crovalimab PK/PD, IVIg PK and M281 PK/PD model. Population parameters estimates were obtained using a Non-Linear Mixed Effect (NLME) approach and individual parameter estimates were derived using empirical Bayes estimates (EBEs) as described in [10]. 3b) Software The non-linear mixed effect analyses were performed using the Monolix software system, version 2019R2 (Lixoft, Paris, France) to obtain parameter estimates.
• NLME Non-Linear Mixed Effect
• EBEs empirical Bayes estimates
• Ab1 PK/PD model in serum contains two binding sub-models 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 the second arm of the same antibody to form the complex AgAb1Ag (as described in [10]).
• Peripheral distribution compartments were included for free and bound Ab1 with two different volumes of distribution for free Ab1 and the complexes Ab1Ag and Ag Ab1Ag.
• ODEs Ordinary Differential Equations
• IgG PK model in serum the lower left part of Figure 4 is a two-compartment linear disposition model for endogenous IgG or IVIg and radiolabeled IVIg (annotated with a star, i.e. IgG*). The volumes of distribution and the clearances are assumed 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 disposition model is used to described M281 PK.
• the ODE describing the concentrations of M281 in serum isgiven in Figure 6 • Endosome model: after internalization into the endosome, crovalimab, IgG, IgG* and M281 antibodies can bind to FcRn and being recycled back into serum. The antibodies not bound to FcRn are eliminated from the endosome. Since Ab1 has been designed with pH dependent recycling technology (i.e.
• a free antibody which has two free Fab arms available has a two-times higher probability to bind a free Ag than an antibody where one arm is already bound to one Ag. This is reflected in the model equation as 2konAb1-Ag in the binding equation of free Ab1 on Figure 5.
• an antibody bound to two Ag has 2-times higher probability to lose an Ag molecule than an antibody bound to only one Ag. This is reflected in the equation describing the dissociation of two Ag bound to an antibody (i.e. AgAb1Ag) by a factor of 2 on the dissociation rate, i.e.2 koffAb1 on Figure 5.
• a clearance term CLe,Ab1 is added with a negative sign to the ODE equation for Ab1 in serum as shown on Figure 8.
• the same term appears with a positive sign (and after adjustment for the different volume of distribution between serum Vc and endosome Ve) in the equation describing free Ab1 in the endosome as displayed in Figure 9.
• Ab1 is recycled back to serum through the clearance term CLe,Ab1 recy which appears with a negative sign on the ODE equation for the complex Ab1-FcRn in Figure 9 in the endosome and with a positive sign in the serum equation for Ab1 in Figure 8.
• Example 4 SIMULATIONS AND SENSITIVITY ANALYSIS 4.1 Base case simulation Simulations of patients receiving either crovalimab alone or co-administered with IVIg (with both treatment starting on the same day) were performed in using the following regimen: • Crovalimab: 1000 mg IV on Day 1 for patient below 100 kg and 1500 mg for patients above 100 kg, followed by 340 mg SC on Days 2, 8, 15, and 22 • IVIg: 400 mg/kg daily on Day 1, 2, 3, 4 and 5 • The simulations were performed using the EBEs obtained from the 33 subjects from the COMPOSER study which were included in the model calibration.
• the EBEs for the subjects from the radiolabeled IVIg and M281 studies were not used in the simulations since they do not contain any information on C5 inhibition.
• a C5 baseline concentration of 70 ug/mL and an IgG baseline concentration of 1g/dL was assumed.
• the main outputs of these simulations are the median and min/max time-course profiles values for: • Total Ab1 drug concentrations (in uM) • Total IgG concentrations (in uM) • Free Ab1 (in uM) • Free Ab1 paratope concentrations (in uM), i.e. the number of free Ab1 arms available for binding to Ag.
• Example 5 RESULTS 5.1 MODELING The model (see Figure 4) describing the binding of Ag (i.e. C5) with Ab1 (i.e. crovalimab) and its competition with IgG in the endosome was calibrated using the data from the 15 healthy volunteers in COMPOSER Part 1, 10 and 8 na ⁇ ve PNH patients from Parts 2 and 4, respectively and the radiolabeled IgG* and M281 data described in Example 2. The number of available samples from COMPOSER Parts 1, 2 and 4 for total Ab1, total Ag, free Ag are given in Table 1.
• Figure 14 Individual goodness-of-fit plots on Figure 14 shows that the model described adequately the dose normalized radiolabeled IgG* in serum on the upper panel and total body radioactivity on the lower panel.
• Figure 15 shows that M281 PK and its impact on baseline normalized endogenous IgG concentrations is adequately described by the model for each arm of the SAD and MAD studies.
• Table 5 Model Population Parameters Estimates Obtained from the Model Without The Endosome and Reported in [10] and Fixed in the Endosome Model.
• the following model parameters were purposely modified one-by-one, as follows: 1.
• the total concentration of FcRn in the endosome [FcRn]total is divided by a factor of 22.
• the volume of the endosome Ve is multiplied by a factor 10 3.
• the production rate of endogenous IgG is increased by a factor of 2 resulting in a doubling of the baseline concentration of IgG to a value of 2 g/dL 4.
• the concentrations of C5 at baseline was increased by a factor of 2 from 70 ⁇ g/mL to 140 ⁇ g/mL
• the results of the sensitivity analysis No.1 is shown on Figure 17.
• crovalimab dosing strategy is expected to provide adequate inhibition of C5 for at least a 40-day period based on the median PK profile even when taking into account uncertainty on some key parameters driving the recycling of crovalimab by FcRn.
• Example 7 DISCUSSION A previously developed model of crovalimab, reported in [10], was extended to account for the saturation of FcRn recycling when IVIgs are co-administered. A key assumption of the model is that antibody elimination happens only in the endosome (as it is usually hypothesized in the literature [9]) when antibodies are not bound to FcRn.
• the half- life of the antibody is driven by how much an antibody can bind the FcRn receptors in the endosome and being recycled. Therefore, the concentration of FcRn receptors and the volume of the endosome are key parameters to be estimated to quantify when FcRn recycling will be saturated and will impact crovalimab serum concentration.
• the addition of the M281 PK/PD profile in our dataset provided the necessary information to estimate these two parameters since M281 binding to FcRn clearly saturates the recycling of IgG from the endosome to serum as shown on Figure 3.
• the model After calibration, the model provided adequate goodness-of-fit for the PK of IVIg on Figure 14 and the PK/PD of crovalimab on C5 inhibition as displayed on Figure 10, Figure 11, Figure 12 and Figure 13. However, part of the variability on total [Ag] could not be captured at the individual level as can be seen on the second rows of Figure 10, Figure 11, Figure 12 and Figure 13.
• the model does not have the ability to match the variation of total Ag as the production rate of Ag (i.e. kinAg) is assumed constant over time in the model. This is in particular highlighted on of Figure 10 and Figure 11 for the 6 heathy volunteers receiving a placebo (i.e. subjects 11002, 11003, 11006, 11010, 11012, 11015) who have a constant predicted total Ag concentration (i.e.
• the median crovalimab serum concentration remains above the 100 ug/mL over a period of 40 days, and the minimum value of the free paratopes remains strictly positive over a 40-day period.
• An increase in the C5 baseline from 70 ug/mL to 140 ug/mL had a mild impact on the median PK level as the reduction of the median serum crovalimab concentration on Day 8 was increased from 19% to 22%. This increase is driven by the faster endosome internalization of the crovalimab-C5 complexes compared with free crovalimab (i.e.
• This PK/PD model describes the binding of crovalimab with C5 and predicts the concentrations over time of free C5 and free crovalimab paratopes (which quantify the reserve of free crovalimab sites available to bind C5 molecules).
• the model also includes a PK model of endogenous IgG in serum as well as the competition of IgG and crovalimab to bind the FcRn receptor in the endosome. This part of the model allows quantifying the impact of the recommended therapeutic dose of IVIg on crovalimab PK concentration.
• the model also includes a description of the M281 anti- FcRn antibody PK and PD used to estimate the concentration of FcRn receptors and the volume of the endosome.
• a population approach was used to calibrate simultaneously the crovalimab PK/PD model, the IVIg PK model and the M281 PK/PD model.
• a pooled dataset comprising crovalimab COMPOSER data in 33 healthy volunteers and na ⁇ ve PNH patients, radiolabeled IgG data from literature [12] in six subjects and published PK/PD SAD and MAD data for the M281 monoclonal anti-FcRn antibody [13,14] was built and used for model calibration. Simulations and sensitivity analyses were then conducted to quantify the impact of IVIg co-administration on the PK and PD profiles of crovalimab using the individual parameter estimates obtained from 33 subjects from the clinical study COMPOSER. These data wereincluded in the calibration dataset.
• the following dose and dosing regimen for crovalimab and IVIg were used in these simulations: • Crovalimab: 1000 mg IV on Day 1 for patient below 100 kg and 1500 mg for patientsabove 100 kg, followed by 340 mg SC on Days 2, 8, 15, and 22 • IVIg: 400 mg/kg daily on Day 1, 2, 3, 4 and 5 IVIg dose and dosing regimen are based on the standard treatment of acute GBS (400mg/kg QD for 5 consecutive days). The main conclusions of this modeling & simulation analyses are: • The predicted maximum reduction of the median crovalimab serum concentrationwas 19% on Day 8 when receiving simultaneously IVIg.
• Crovalimab median serum concentrations remain over 72 days above approximately 100 ug/mL, the reference threshold expected to provide complete C5 activity. This period is covering the expected targeted therapeutic duration for the BN43118 study of 28 days. • The level of free paratopes remains always strictly positive indicating that there is always a crovalimab binding reserve available. • Sensitivity analysis demonstrated that complete C5 inhibition is maintained over a 40-day period even when model parameters such as the concentration of FcRn receptors, baseline level of IgG and C5 and the volume of the endosome are changed in the direction of reducing the recycling of crovalimab by FcRn.
• the selected crovalimab dosing regimen provides complete C5 inhibition for at least for 40 days.
• the modeling approach presented provides a tool to understand the interaction of IVIg and crovalimab on FcRn recycling and to quantify through simulations the impact of IVIg on crovalimab PK level, crovalimab free binding sites and free C5.
• the following dosing regimen is selected to be tested in the clinical study BN43118 • Crovalimab: 1000 mg IV on Day 1 for patient below 100 kg and 1500 mg for patients above 100 kg, followed by 340 mg SC on Days 2, 8, 15, and 22 However, to ensure that the selected dose is adequate to achieve complete C5 inhibition, a dose confirmation step is planned in the study BN43118; actual PK data from 10 GBS subjects will be assessed to confirm the adequacy of the selected dose.

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