Subcutaneous unit dosage form

Abstract

Provided herein are unit dosage forms of biologics determined based on a modeling approach in which the pharmacodynamic (PD) values ​​of the SC dose are consistent with the pharmacodynamic (PD) values ​​of a known reference IV dose, while the pharmacokinetic (PK) values ​​of the SC dose are less than the pharmacokinetic (PK) values ​​of the IV dose.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 203,856, filed August 2, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] Biologics, including antibodies and antibody fragments, are used to treat a wide range of diseases. Intravenous (IV) administration is the primary method of administering many biologics. However, patient compliance is problematic due to the requirement of IV administration. Furthermore, due to the chronic nature of many diseases and disorders treated with biologics, many patients require treatment for life, which highlights the need to improve patient compliance. Subcutaneous (SC) administration of biologics is an alternative to IV administration. Compared to IV infusion, SC administration of biologics has several advantages. For example, SC administration reduces the incidence of systemic reactions, reduces the risk of infection, and is more convenient for patients without the sometimes difficult IV access.

[0003] Previously, SC administration of biologics, especially those with high molecular weight, leads to reduced bioavailability compared to IV administration, which was considered to be common to SC administration of biologics.Generally, the bioavailability of biologics in human subjects is determined according to a single SC dose and a single IV dose.This data is then used in a model to calculate SC administration, which aims to match the pharmacokinetic (PK) parameters of safe and effective IV administration.Specifically, the goal is to achieve a similar clinical response to SC dose compared to IV dose.However, this approach may result in a high dose for SC administration, which cannot be administered to patients or may result in an increase in adverse events in patients.

[0004] Thus, there is a need in the art for improved methods for determining safe and effective SC doses of biologics. Summary of the Invention

[0005] Provided herein is a unit dosage form of a biologic determined based on a modeling approach, in which the pharmacodynamic (PD) value of the SC dose is consistent with the pharmacodynamic (PD) value of a known reference IV dose, while the pharmacokinetic (PK) value of the SC dose is less than the pharmacokinetic (PK) value of the IV dose. The unit dosage form provided herein exhibits comparable safety and efficacy compared to the reference IV dose, and is therefore non-inferior to the IV dose, thereby providing patients with a more convenient alternative method of administering the biologic.

[0006] Previously known methods for determining SC dose are based on models that aim to match the PK values ​​of SC dose and reference IV dose, which results in unit dosage forms with higher doses of biologics compared to the method used herein.Accordingly, the unit dosage forms disclosed herein contain lower doses of biologics, which may reduce adverse events in patients and may allow subcutaneous administration as an alternative to biologics that are typically administered by IV infusion.

[0007] Thus, provided herein is a unit dosage form for subcutaneous administration of a biologic, the biologic having a PK profile in a subject upon intravenous administration. iv and P.D. iv and the unit dosage form is for subcutaneous administration Sometimes PK on the target sc and P.D. sc RD of biologics sc Including PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is 0.9 to 1.1.

[0008] Provided herein is a unit dosage form for subcutaneous administration of a biologic, the biologic exhibiting PK responses in a subject upon intravenous administration. iv and B.L. iv and the unit dosage form provides PKsc and B.L. sc RD of biologics sc Including PK sc / PK iv The ratio is less than about 0.8, and the BL sc / BL iv The ratio is from about 0.9 to about 1.1.

[0009] Also provided herein is a unit dosage form for subcutaneous administration of a biologic, the amount of a subcutaneous dose of the biologic in the unit dosage form being determined by: (a) administering a subcutaneous dose of the biologic to a subject; iv and B.L. iv Bringing about, RD iv (b) BL sc (c) determining the PK of the biologic. sc and (d) determining BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv The subcutaneous dose was determined by a method including determining a subcutaneous dose that results in a ratio of less than about 0.8.

[0010] In one embodiment, BL sc and B.L. iv is the level of total serum IgG in the subject. In one embodiment, the total serum IgG in the subject is analyzed using a biological analysis method. In one embodiment, the biological analysis method is an ELISA or an automated diagnostic analyzer (IVD).

[0011] In one embodiment, the subject is a healthy volunteer or non-human animal.

[0012] In one embodiment, PD iv and P.D. sc The value is AUC. In one embodiment, the PK sc / PK iv The ratio is less than 0.7. sc / PK iv The ratio is less than 0.6. sc / PK ivThe ratio is about 0.8, about 0.7, about 0.6, or about 0.5.

[0013] In one embodiment, PD iv and P.D. sc The value is total serum IgG reduction. In one embodiment, PD sc / PD iv The ratio is 0.9 to 1.1. sc / PD iv The ratio is 0.9, 1.0, or 1.1.

[0014] In one embodiment, the biologic is selected from the group consisting of an antibody, an antibody fragment, an anticoagulant, a blood factor, a bone morphogenetic protein, an enzyme, a fusion protein, a growth factor, a hormone, an interferon, an interleukin, and a thrombolytic agent.

[0015] In one embodiment, the biologic is an antibody, e.g., an anti-FcRn antibody. In one embodiment, the antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0016] In one embodiment, the biologic comprises or consists of a variant Fc region, or an FcRn-binding fragment thereof, that binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region.

[0017] In one embodiment, the biologic antagonizes FcRn binding to the antibody Fc region.

[0018] In one embodiment, the biologic is efgartigimod.

[0019] In one embodiment, the RD iv is 10mg / kg to 25mg / kg, RD sc In one embodiment, the RD iv is 10mg / kg, RD scIn one embodiment, the RD iv is 25mg / kg, RD sc is approximately 2000 mg.

[0020] In one embodiment, the unit dosage form further comprises a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-96. In one embodiment, the hyaluronidase enzyme is rHuPH20.

[0021] In one embodiment, the unit dosage form is co-administered with a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is rHuPH20.

[0022] In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / ml to about 3000 U / ml. In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In one embodiment, the amount of hyaluronidase enzyme is 2000 U / mL.

[0023] In one embodiment, the unit dosage form is for use in treating an autoimmune disease. In one embodiment, the autoimmune disease is selected from the group consisting of pancreatic islet allograft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune disease of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura or idiopathic thrombocytopenic purpura or immune-mediated thrombocytopenia), autoimmune urticaria, Behcet's disease, bullous pemphigoid (B P), cardiomyopathy, Castleman syndrome, celiac-spruce dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré, Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic membranous neuropathies neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes mellitus, multifocal motor neuropathy (MMN), myasthenia gravis (MG), paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigus vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune Myopathy (NAM), Antisynthetase syndrome (ASyS), Primary agammaglobulinemia, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Solid organ transplant rejection, Stiff body syndrome, Systemic lupus erythematosus, Takayasu's arteritis, Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Temporal arteritis / Giant cell arteritis, Thrombotic thrombocytopenic purpura, Ulcerative colitis, Uveitis, Dermatitis herpetiformis type vasculitis,Selected from the group consisting of antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0024] Also provided herein is a method for determining a therapeutically effective dose of a biologic for subcutaneous administration, the method comprising: (a) administering to a subject a subcutaneous dose of the biologic, the biologic being a PK iv and B.L. iv Bringing about, RD iv (b) BL of a biological product sc (c) determining the PK of the biologic sc and (d) determining the BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv determining a subcutaneous dose that results in a ratio of less than about 0.8, thereby determining a therapeutically effective dose of the biologic for subcutaneous administration.

[0025] In one embodiment, the subject is a healthy volunteer or non-human animal.

[0026] Also provided herein is a method of treating a subject with a subcutaneous dose of a biologic, comprising: (a) administering to a subject a subcutaneous dose of the biologic, the biologic being a PK iv and B.L. iv Bringing about, RD iv (b) BL of a biological product sc (c) determining the PK of the biologic. sc and (d) determining BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv The subcutaneous dose was determined by a method including determining a subcutaneous dose that results in a ratio of less than about 0.8.

[0027] In one embodiment, the PK sc / PK iv The ratio is less than 0.7. sc / PK iv The ratio is less than 0.6.iv and P.K. sc Values ​​are AUC.

[0028] In one embodiment, the biologic is selected from the group consisting of an antibody, an antibody fragment, an anticoagulant, a blood factor, a bone morphogenetic protein, an enzyme, a fusion protein, a growth factor, a hormone, an interferon, an interleukin, and a thrombolytic agent.

[0029] In one embodiment, BL sc and B.L. iv is the level of total serum IgG in the subject. In one embodiment, the total serum IgG in the subject is analyzed using a biological analysis method. In one embodiment, the biological analysis method is an ELISA or an automated diagnostic analyzer (IVD).

[0030] In one embodiment, the biologic is an antibody. In one embodiment, the antibody is an anti-FcRn antibody. In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0031] In one embodiment, the biologic comprises or consists of a variant Fc region or an FcRn-binding fragment thereof that binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region. In one embodiment, the biologic antagonizes FcRn binding to an antibody Fc region. In one embodiment, the biologic is efgaltigimod.

[0032] In one embodiment, the RD iv In one embodiment, the RD iv is 25mg / kg.

[0033] In one embodiment, a therapeutically effective amount of a biologic is co-administered with a hyaluronidase enzyme. In one embodiment, a therapeutically effective amount of a biologic is administered before or after the hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-96. In one embodiment, the hyaluronidase enzyme is rHuPH20. In one embodiment, the amount of hyaluronidase enzyme is 1000 U / ml to 3000 U / ml, preferably 2000 U / mL.

[0034] Also provided herein is a unit dosage form of a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating an autoimmune disease in a human patient.

[0035] Also provided herein is a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating myasthenia gravis in a human patient.

[0036] In one aspect, the disclosure provides a variant Fc region, or FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating myasthenia gravis in a human patient, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously at a weekly dose of 950-1050 mg, regardless of the patient's weight, resulting in a reduction in total serum IgG in the patient of at least 60% compared to baseline IgG levels.

[0037] In one embodiment, the weekly dose is about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, or about 1050 mg. In one embodiment, the weekly dose is about 1000 mg.

[0038] Also provided herein is a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating pemphigus vulgaris in a human patient.

[0039] In one aspect, the disclosure provides a variant Fc region, or FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating pemphigus vulgaris in a human patient, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously at a weekly dose of 1950-2050 mg, regardless of the patient's weight, resulting in a reduction in total serum IgG in the patient of at least 60% compared to baseline IgG levels.

[0040] In one embodiment, the weekly dose is about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, or about 2050 mg. In one embodiment, the weekly dose is about 2000 mg.

[0041] In one embodiment, the treatment comprises at least 2 weekly doses. In one embodiment, the treatment comprises at least 3 weekly doses. In one embodiment, the treatment comprises at least 4 weekly doses. In one embodiment, the treatment comprises at least 5 weekly doses. In one embodiment, the treatment comprises at least 6 weekly doses. In one embodiment, the treatment comprises at least 7 weekly doses. In one embodiment, the treatment comprises at least 8 weekly doses. In one embodiment, the treatment comprises more than 8 weekly doses.

[0042] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, is administered with a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-96. In one embodiment, the hyaluronidase enzyme is rHuPH20.

[0043] In one embodiment, a reduction in total serum IgG in a patient of about 60% is obtained compared to baseline IgG levels, hi one embodiment, a reduction in total serum IgG in a patient of about 65%, about 70%, about 75%, or about 80% is obtained compared to baseline IgG levels.

[0044] In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0045] In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0046] In one embodiment, the total serum IgG level in the patient is reduced to 2000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2000-3000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 3000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2500-3500 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2750-3250 μg / mL.

[0047] In one embodiment, the total serum IgG in the patient is analyzed using a biological analytical method. In one embodiment, the total serum IgG in the patient is analyzed using an ELISA or an automated diagnostic analyzer (IVD).

[0048] In one embodiment, at least one of the IgG subtypes is reduced. In one embodiment, IgG1 is reduced. In one embodiment, IgG2 is reduced. In one embodiment, IgG3 is reduced. In one embodiment, IgG4 is reduced.

[0049] In one embodiment, the variant Fc region is efgaltigimod. [Brief description of the drawings]

[0050] [Figure 1] 1A-1B are graphs showing serum efgartigimod levels in patients from historical data after IV and SC administration of efgartigimod with or without rHuPH20 (FIG. 1A) and after SC co-administration of efgartigimod with rHuPH20 (FIG. 1B).

[0051] [Diagram 2] 2A-2C are graphs showing IgG reduction following single SC doses of 750 mg (FIG. 2A), 1250 mg (FIG. 2B), and 1750 mg (FIG. 2C) co-administered with rHuPH20 compared to background data following SC doses of 10 mg / kg without rHuPH20 and IV doses of 10 mg / kg without rHuPH20.

[0052] [Diagram 3] 3 is a graph showing a visual predictive check of efgartigimod concentrations in the study described in Example 1. The grey dots are the observed data, the solid blue line is the observed median, the dashed red lines are the 10th and 90th percentiles of the observations, and the grey areas are the 80% prediction intervals.

[0053] [Figure 4] Figure 4 is a graph showing visual predictive checks of log-scale efgartigimod concentrations in a previous study. The grey dots are observed data, the solid blue line is the median observed value, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0054] [Diagram 5] 5 is a graph showing a comparison of 10 mg / kg SC efgartigimod without (blue line) and with (red line) rHuPH20. The blue points are observations from healthy volunteers receiving 10 mg / kg SC efgartigimod without rHuPH20, the red points are observations from healthy volunteers receiving 10 mg / kg SC efgartigimod in combination with rHuPH20, the blue line is the population prediction of efgartigimod concentrations without rHuPH20, and the red line is the population prediction of efgartigimod concentrations without rHuPH20.

[0055] [Figure 6] 6 is a graph showing a visual predictive check of total IgG concentrations in the study described in Example 1 obtained with a PK / PD model whose parameters were optimized using data from previous studies. The grey dots are observed data, the solid blue line is the observed median, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0056] [Figure 7]7 is a graph showing a visual predictive check of total IgG reduction in the study described in Example 1 obtained using a PK / PD model whose parameters were optimized with data from previous studies. The grey dots are observed data, the solid blue line is the median observed value, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0057] [Figure 8] 8 is a graph showing a visual predictive check of total IgG concentrations in the study described in Example 1 obtained using a PK / PD model accounting for effect compartments. The grey dots are observed data, the solid blue line is the observed median, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0058] [Figure 9] 9 is a graph showing a visual predictive check of total IgG reduction in the study described in Example 1 obtained using a PK / PD model accounting for efficacy compartments. The grey dots are observed data, the solid blue line is the observed median, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0059] [Figure 10] Figure 10 is a graph showing a visual predictive check of total IgG concentrations in historical data obtained using a PK / PD model accounting for efficacy compartments. The grey dots are observed data, the solid blue line is the observed median, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0060] [Figure 11]Figure 11 is a graph showing a visual predictive check of total IgG reduction in historical data obtained using a PK / PD model accounting for efficacy compartments. The grey dots are observed data, the solid blue line is the median observed value, the dashed red lines are the 10th and 90th percentiles of observations, and the grey areas are the 80% prediction intervals.

[0061] [Figure 12] 12 is a graph showing the area under the effect curve (AUEC) from days 22 to 29 determined from simulated total IgG reduction. The solid and dashed horizontal lines are the median and 90% CI of the AUEC from days 22 to 29 obtained with the 10 mg / kg IV QW dose of efgartigimod. The points and bars are the median and 90% CI of the AUEC from days 22 to 29 obtained with the SC QW dose of efgartigimod.

[0062] [Figure 13] Figure 13 is a graph showing simulated maximum total IgG reduction from days 22 to 29. The solid and dashed horizontal lines are the median and 90% CI of maximum total IgG reduction obtained with the 10 mg / kg IV QW dose of efgartigimod. The points and bars are the median and 90% CI of total IgG reduction obtained with the SC QW dose of efgartigimod.

[0063] [Figure 14] Figure 14 is a graph showing simulated maximum total IgG on day 29. The solid and dashed horizontal lines are the median and 90% CI of maximum total IgG reduction obtained with a 10 mg / kg IV weekly dose of efgartigimod. The points and bars are the median and 90% CI of total IgG reduction obtained with a SC weekly dose of efgartigimod.

[0064] [Figure 15]FIG. 15 is a graph showing the percentage of simulated AUEC22-29 (obtained at different efgartigimod PH20 SC weekly doses ranging from 750 mg to 1750 mg (in 25 mg increments)) that is greater than the median AUEC22-29 obtained with 10 mg / kg IV efgartigimod weekly.

[0065] [Figure 16] FIG. 16 is a graph showing the percentage of simulated maximum total IgG reductions (IgGt add) on days 22-29 (obtained with different efgartigimod PH20 SC weekly doses ranging from 750 mg to 1750 mg (in 25 mg increments)) that are less than the median maximum total IgG reductions on days 22-29 obtained with 10 mg / kg IV efgartigimod weekly. The vertical dashed line is the percentage obtained with 975 mg efgartigimod PH20 SC weekly, and the horizontal dashed line is the percentage obtained with 975 mg efgartigimod PH20 SC weekly.

[0066] [Figure 17] FIG. 17 is a graph showing the percentage of simulated total IgG reductions (IgGt add) (trough) on day 29 (obtained with different efgartigimod PH20 SC weekly doses ranging from 750 mg to 1750 mg (in 25 mg increments)) that were less than the median day 29 total IgG reduction obtained with 10 mg / kg IV efgartigimod weekly.

[0067] [Figure 18] 18 is a graph showing simulated AUEC at different time intervals obtained with 1000 mg efgartigimod PH20 SC weekly and 10 mg / kg efgartigimod IV weekly. Points and bars are the median and 5th and 95th percentiles of AUEC.

[0068] [Figure 19]19 is a graph showing simulated maximum total IgG reduction at different time intervals obtained with 1000 mg efgartigimod PH20 SC weekly and 10 mg / kg efgartigimod IV weekly. The points and bars are the median and the 5th and 95th percentiles of maximum total IgG reduction.

[0069] [Figure 20] 20 is a graph showing simulated total IgG reduction obtained with 1000 mg efgartigimod PH20 SC weekly and 10 mg / kg efgartigimod IV weekly, pre-dose on days 8, 15, 22, and 29. Points and bars are median and 5th and 95th percentiles of total IgG reduction.

[0070] [Figure 21] 21 is a graph showing simulated profiles of total IgG reduction following 1000 mg efgartigimod PH20 SC QW and 10 mg / kg IV efgartigimod QW. The solid lines and areas are the median, 5th and 95th percentiles of total IgG reduction, and the vertical dashed lines are days 22 to 29.

[0071] [Figure 22] FIG. 22 is a schematic diagram of the clinical trial protocol for subcutaneous administration of efgartigimod coformulated with rHuPH20.

[0072] [Figure 23] FIG. 23 is a graph showing the mean (SE) total IgG levels (μg / mL) over time during and after four weekly doses of 1000 mg efgartigimod-PH20 SC or 10 mg / kg efgartigimod IV.

[0073] [Figure 24]FIG. 24 is a graph showing the mean (SE) percent change from baseline in total IgG over time during and after four weekly doses of 1000 mg efgartigimod-PH20 SC or 10 mg / kg efgartigimod IV.

[0074] [Diagram 25] FIG. 25 is a graph showing the mean difference and 95% two-sided confidence intervals for the difference in change from baseline in total IgG between four weekly doses of 1000 mg efgartigimod-PH20 SC and 10 mg / kg efgartigimod IV.

[0075] [Figure 26] FIG. 26 is a graph showing the mean (SD) efgartigimod serum concentration-time profile following the fourth weekly dose of 1000 mg efgartigimod-PH20 SC or 10 mg / kg efgartigimod IV (day 22). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] Detailed Description The present disclosure provides a unit dosage form of a biologic determined based on a modeling approach in which the pharmacodynamic (PD) value of the SC dose is consistent with the pharmacodynamic (PD) value of a known reference IV dose, while the pharmacokinetic (PK) value of the SC dose is less than the pharmacokinetic (PK) value of the IV dose. The unit dosage forms provided herein exhibit comparable safety and efficacy compared to the reference IV dose, and are therefore non-inferior to the IV dose, thereby providing patients with a more convenient alternative method of administering the biologic.

[0077] Thus, provided herein is a unit dosage form for subcutaneous administration of a biologic, the biologic having a PK profile in a subject upon intravenous administration. iv and P.D. iv and the unit dosage form is for subcutaneous administration Sometimes PK on the target sc and P.D. sc RD of biologics scIncluding PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is 0.9 to 1.1.

[0078] definition As used herein, the term unit dosage form refers to a form of pharmaceutical product marketed for use, having a specific mixture of active and inactive ingredients (excipients) and apportioned to a specific dose. The unit dosage form provided herein may refer to a physically discrete unit suitable as a unitary dosage for human and / or animal subjects, each unit containing a predetermined amount of active material (e.g., about 500 mg to about 2500 mg of efgartigimod or about 500 mg to about 2500 mg of efgartigimod and about 1000 U / ml to about 3000 U / ml rHuPH20) calculated to produce a desired therapeutic effect in association with a necessary pharmaceutical diluent, carrier, or vehicle. Non-limiting examples of suitable unit dosage forms are vials, tablets, capsules, lozenges, suppositories, powder packets, wafers, cachets, ampoules, pre-filled syringes, separate multiples of any of the foregoing, and other forms described herein or generally known in the art.

[0079] As used herein, the term "biologic" refers to a product produced from a living organism or that contains a component of a living organism, e.g., an antibody or antibody fragment, or a recombinant protein. In one embodiment, the biologic is efgartigimod.

[0080] As used herein, the term "reference dose" refers to the dose-dependent change in PK and / or PD (PK iv and P.D. iv) refers to any intravenous dose of a biologic used as a reference value. In one embodiment, the reference dose may be an approved drug dose, a specific determined drug dose, or an optimal drug dose determined during clinical trial(s). In one embodiment, the reference dose of a biologic may be a dose approved by a regulatory authority (such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA)) for administration to patients.

[0081] As used herein, "RD iv " refers to a dose of a biologic for intravenous administration to a patient, generally in one single dose.

[0082] As used herein, "RD sc " refers to a dose of a biologic for subcutaneous administration to a patient, generally in one single dose.

[0083] As used herein, "PK iv The term "pharmacokinetics" refers to experimentally determined pharmacokinetic values ​​of an intravenously administered drug. These values ​​are used to describe the absorption, distribution, metabolism, and excretion of the drug in the (human) body.

[0084] As used herein, "PK sc The term "PK" refers to the pharmacokinetic values ​​of a drug administered subcutaneously. These values ​​are used to describe the absorption, distribution, metabolism, and excretion of a drug in the (human) body. In one embodiment, the PK sc can be determined based on pharmacokinetic modeling (predictive modeling methods). In one embodiment, the PK sc can be determined experimentally or empirically (eg, empirically).

[0085] As used herein, "PD ivThe term "pharmacodynamic value" refers to an experimentally determined pharmacodynamic value of an intravenously administered drug. In one embodiment, this value is used to describe the biochemical, physiological, and molecular effects (clinical effects) of a drug on the (human) body, including receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions.

[0086] As used herein, "PD sc The term "pharmacodynamics" refers to the pharmacodynamic value of a subcutaneously administered drug. In one embodiment, this value is used to describe the biochemical, physiological, and molecular effects (clinical effects) of a drug on the (human) body, including receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions. In one embodiment, the PD sc can be determined based on pharmacodynamic modeling (predictive modeling methods). In one embodiment, PD sc can be determined experimentally or empirically (eg, empirically).

[0087] As used herein, "BL iv " refers to the level of a biomarker (e.g., IgG) following intravenous administration of a biologic to a subject compared to the baseline level of the biomarker in the subject.

[0088] As used herein, "BL sc " refers to the level of a biomarker (e.g., IgG) following subcutaneous administration of a biologic to a subject compared to the baseline level of the biomarker in the subject.

[0089] As used herein, "C max " refers to the maximum serum concentration of a biologic.

[0090] As used herein, the term "AUC" refers to the area under the serum concentration versus time curve. AUC is based on the rate and extent of elimination of a biologic following administration.

[0091] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain beginning at the hinge region and ending at the C-terminus of the antibody. Thus, a complete Fc domain includes at least a portion of the hinge (e.g., upper, middle, and / or lower hinge regions), CH2, and CH3 domains.

[0092] As used herein, the term "Fc region" refers to the portion of a native immunoglobulin that is formed by the Fc domains of its two heavy chains. A native Fc region is a homodimer.

[0093] As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations (multiple alterations) compared to a native Fc region. Alterations may include amino acid substitutions, additions, and / or deletions, attachment of additional moieties, and / or alterations of native glycans. The term encompasses heterodimeric Fc regions, in which each of the constituent Fc domains is different. The term also encompasses single chain Fc regions, in which the constituent Fc domains are linked together by linker moieties.

[0094] As used herein, the term "FcRn-binding fragment" refers to a portion of an Fc region sufficient to confer FcRn binding.

[0095] As used herein, the term "hyaluronidase enzyme" refers to an enzyme that catalyzes the degradation of hyaluronic acid in the body, which may increase the permeability of tissues to fluids or drugs (e.g., biologics administered subcutaneously). In one embodiment, the hyaluronidase enzyme is recombinant human hyaluronidase PH20 enzyme (rHuPH20), which degrades hyaluronan (HA).

[0096] As used herein, the term "IgG-reduced" refers to, for example, the reduction of (disease-causing) immunoglobulin G (IgG) antibodies in a patient's serum.

[0097] As used herein, the term "baseline IgG level" refers to the level of IgG in a patient, e.g., the patient's blood, prior to the first administration (e.g., intravenous or subcutaneous administration) of a biologic.

[0098] As used herein, the term "bioanalytical method" refers to a bioanalytical assay used for quantification of molecules (e.g., proteins, antibodies such as IgG, and therapeutic agents) supporting pharmacokinetic evaluation, e.g., measuring total IgG in a serum sample. In one embodiment, the bioanalytical method is an ELISA. In one embodiment, the bioanalytical method is an automated diagnostic analyzer (IVD).

[0099] As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses variations of ±20% or ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as appropriate for practicing the methods disclosed herein.

[0100] Subcutaneous unit dosage form compositions and methods The present disclosure provides a unit dosage form of a biologic for subcutaneous administration to a subject.These unit dosage forms contain an effective amount of the biologic, and the effective amount is determined based on a modeling approach, in which the pharmacodynamic (PD) value of the SC dose is matched with the pharmacodynamic (PD) value of a known reference IV dose, while the pharmacokinetic (PK) value of the SC dose is smaller than the pharmacokinetic (PK) value of the IV dose.The unit dosage forms provided herein show comparable safety and efficacy compared to the reference IV dose, and are therefore non-inferior to the IV dose, thereby providing patients with a more convenient alternative method of administering the biologic.

[0101] Previously known methods for determining SC dose are based on models that aim to match the PK values ​​of SC dose and reference IV dose, which results in unit dosage forms with higher doses of biologics compared to the method used herein.Accordingly, the unit dosage forms disclosed herein contain lower doses of biologics, which may reduce adverse events in patients and may allow subcutaneous administration as an alternative to biologics that are typically administered by IV infusion.

[0102] Thus, provided herein is a unit dosage form for subcutaneous administration of a biologic, the biologic having a PK profile in a subject upon intravenous administration. iv and P.D. iv and the unit dosage form provides PK sc and P.D. sc RD of biologics sc Including PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is 0.9 to 1.1.

[0103] Provided herein is a unit dosage form for subcutaneous administration of a biologic, the biologic exhibiting PK responses in a subject upon intravenous administration. iv and B.L. iv and the unit dosage form provides PK sc and B.L. sc RD of biologics sc Including PK sc / PK iv The ratio is less than about 0.8, and the BL sc / BL iv The ratio is from about 0.9 to about 1.1.

[0104] Also provided herein is a unit dosage form for subcutaneous administration of a biologic, the amount of a subcutaneous dose of the biologic in the unit dosage form being determined by: (a) administering a subcutaneous dose of the biologic to a subject; iv and B.L. iv Bringing about, RD iv(b) BL sc (c) determining the PK of the biologic. sc and (d) determining BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv The subcutaneous dose was determined by a method including determining a subcutaneous dose that results in a ratio of less than about 0.8.

[0105] Also provided herein is a method for determining a therapeutically effective dose of a biologic for subcutaneous administration, the method comprising: (a) administering to a subject a subcutaneous dose of the biologic, the biologic being a PK iv and B.L. iv Bringing about, RD iv (b) BL of a biological product sc (c) determining the PK of the biologic sc and (d) determining the BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv determining a subcutaneous dose that results in a ratio of less than about 0.8, thereby determining a therapeutically effective dose of the biologic for subcutaneous administration.

[0106] In one embodiment, the subject is a healthy volunteer or non-human animal.

[0107] Also provided herein is a method of treating a subject with a subcutaneous dose of a biologic, comprising: (a) administering to a subject a subcutaneous dose of the biologic, the biologic being a PK iv and B.L. iv Bringing about, RD iv (b) BL of a biological product sc (c) determining the PK of the biologic. sc and (d) determining BL sc / BL iv Ratio: 0.9 to 1.1 and PK sc / PK iv The subcutaneous dose was determined by a method including determining a subcutaneous dose that results in a ratio of less than about 0.8.

[0108] In one embodiment, PK sc / PK iv The ratio is less than 0.7. sc / PK iv The ratio is less than 0.6. iv and P.K. sc Values ​​are AUC.

[0109] In one embodiment, BL sc and B.L. iv is the level of total serum IgG in the subject. In one embodiment, the total serum IgG in the subject is analyzed using a biological analytical method. In one embodiment, the biological analytical method is an ELISA or an automated diagnostic analyzer (IVD).

[0110] In one embodiment, the biologic is an antibody molecule. In one embodiment, the antibody molecule binds to FcRn. In one embodiment, the antibody molecule comprises an engineered Fc domain for optimized binding to FcRn. In one embodiment, the antibody molecule blocks FcRn.

[0111] In one embodiment, the biologic is a variant Fc region, or an FcRn-binding fragment thereof. In one embodiment, the biologic is efgartigimod.

[0112] In one embodiment, the biologic is selected from the group consisting of an antibody, an antibody fragment, an anticoagulant, a blood factor, a bone morphogenetic protein, an enzyme, a fusion protein, a growth factor, a hormone, an interferon, an interleukin, and a thrombolytic agent.

[0113] In one embodiment, PK sc / PK iv The ratio is less than 0.7. sc / PK iv The ratio is less than 0.6. sc / PK iv The ratio is about 0.8, about 0.7, about 0.6, about 0.5, about 0.47, or about 0.4. sc / PK iv The ratio is about 0.8. sc / PK iv The ratio is about 0.7. sc / PK iv The ratio is about 0.6. sc / PK iv The ratio is about 0.5. sc / PK iv The ratio is about 0.4.

[0114] In one embodiment, PD sc / PD iv The ratio is 0.9 to 1.1. sc / PD iv The ratio is 0.9, 1.0, or 1.1. In one embodiment, PD sc / PD iv The ratio is about 0.9, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99. sc / PD iv The ratio is about 1.0, about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, or about 1.09. sc / PD iv The ratio is about 1.1, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, or about 1.19.

[0115] In one embodiment, BL sc / BL iv The ratio is 0.9 to 1.1. In one embodiment, the BL sc / BL iv The ratio is 0.9, 1.0, or 1.1. In one embodiment, the BL sc / BL iv The ratio is about 0.9, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99. sc / BL ivThe ratio is about 1.0, about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, or about 1.09. sc / BL iv The ratio is about 1.1, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, or about 1.19.

[0116] In one embodiment, PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is less than 0.7, and the PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is about 0.7, and the PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is about 0.6, and the PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is about 0.5, and PD sc / PD iv The ratio is about 0.9. sc / PK iv The ratio is about 0.4, and PD sc / PD iv The ratio is about 0.9.

[0117] In one embodiment, PK sc / PK iv The ratio is less than 0.8, and PD sc / PD ivThe ratio is about 1.0. sc / PK iv The ratio is less than 0.7, and the PD sc / PD iv The ratio is about 1.0. sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 1.0. sc / PK iv The ratio is about 0.7, and the PD sc / PD iv The ratio is about 1.0. sc / PK iv The ratio is about 0.6, and the PD sc / PD iv The ratio is about 1.0. sc / PK iv The ratio is about 0.5, and PD sc / PD iv The ratio is about 1.0. sc / PK iv The ratio is about 0.4, and PD sc / PD iv The ratio is approximately 1.0.

[0118] In one embodiment, PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is about 1.1. sc / PK iv The ratio is less than 0.7, and the PD sc / PD iv The ratio is about 1.1. sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 1.1. sc / PK iv The ratio is about 0.7, and the PD sc / PD iv The ratio is about 1.1. sc / PKiv The ratio is about 0.6, and the PD sc / PD iv The ratio is about 1.1. sc / PK iv The ratio is about 0.5, and PD sc / PD iv The ratio is about 1.1. sc / PK iv The ratio is about 0.4, and PD sc / PD iv The ratio is about 1.1.

[0119] In one embodiment, PK sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is about 0.9, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99. sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is about 1.0, about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, or about 1.09. sc / PK iv The ratio is less than 0.8, and PD sc / PD iv The ratio is about 1.1, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, or about 1.19.

[0120] In one embodiment, PK sc / PK iv The ratio is less than 0.7, and the PD sc / PD iv The ratio is about 0.9, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99. sc / PK iv The ratio is less than 0.7, and the PD sc / PDiv The ratio is about 1.0, about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, or about 1.09. sc / PK iv The ratio is less than 0.7, and the PD sc / PD iv The ratio is about 1.1, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, or about 1.19.

[0121] In one embodiment, PK sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 0.9, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99. sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 1.0, about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, or about 1.09. sc / PK iv The ratio is less than 0.6, and the PD sc / PD iv The ratio is about 1.1, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, or about 1.19.

[0122] In one embodiment, the RD iv is 10mg / kg to 25mg / kg, RD sc In one embodiment, the RD iv is 10mg / kg, RD sc In one embodiment, the RD iv is 25mg / kg, RD sc In one embodiment, the RD is about 2000 mg. ivis 10mg / kg, RD sc In one embodiment, the RD is about 2000 mg. iv is 25mg / kg, RD sc In one embodiment, the RD iv is about 10 mg / kg to about 15 mg / kg, and RD sc In one embodiment, the RD iv is 20mg / kg to about 25mg / kg, RD sc is about 1500 mg to about 2000 mg.

[0123] In one embodiment, the PK iv and P.K. sc The value is the AUC. In one embodiment, the PD iv and P.D. sc Values ​​are total serum IgG reduction in subjects.

[0124] In one embodiment, the unit dosage form further comprises a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is rHuPH20.

[0125] In one embodiment, the unit dosage form is co-administered with a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is rHuPH20.

[0126] In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / ml to about 3000 U / ml. In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In one embodiment, the amount of hyaluronidase enzyme is 2000 U / mL.

[0127] In one embodiment, the unit dosage form comprises about 1000 U / ml to about 3000 U / ml of rHuPH20. In one embodiment, the unit dosage form comprises about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises 1000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises 1500 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises 2500 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises 3000 U / mL of rHuPH20.

[0128] In one embodiment, the biologic is an antibody molecule. In one embodiment, the antibody molecule comprises an engineered Fc domain for optimized binding to FcRn. In one embodiment, the antibody molecule blocks FcRn. In one embodiment, the biologic is efgartigimod.

[0129] In one embodiment, the unit dosage form contains about 500 mg to about 2500 mg of efgartigimod. In one embodiment, the unit dosage form contains about 500 mg to about 1000 mg of efgartigimod. In one embodiment, the unit dosage form contains about 1000 mg to about 1500 mg of efgartigimod. In one embodiment, the unit dosage form contains about 1500 mg to about 2000 mg of efgartigimod. In one embodiment, the unit dosage form contains about 1500 mg to about 2000 mg of efgartigimod.

[0130] In one embodiment, the unit dosage form comprises about 500 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 750 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 1000 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 1250 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 1500 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 1750 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 2000 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 2250 mg of efgartigimod. In one embodiment, the unit dosage form comprises about 2500 mg of efgartigimod.

[0131] In one embodiment, the unit dosage form comprises about 500 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 750 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1000 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1250 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1500 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1750 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2000 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2250 mg of efgartigimod and about 2000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2500 mg of efgartigimod and about 2000 U / mL of rHuPH20.

[0132] In one embodiment, the unit dosage form comprises about 500 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 750 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1000 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1250 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1500 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 1750 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2000 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2250 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20. In one embodiment, the unit dosage form comprises about 2500 mg of efgartigimod and about 1000 U / mL to about 3000 U / mL of rHuPH20.

[0133] In one embodiment, the unit dosage form comprises the antibody molecule as a dry formulation for dissolution, such as a lyophilized powder, lyophilized powder, or water-free concentrate, In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, ampoule, or sachet.

[0134] In one embodiment, the unit dosage form comprises the antibody molecule as a liquid formulation, for example, an injection or infusion solution. In one embodiment, the liquid formulation is contained in a sealed container, such as a vial, a sachet, a pre-filled syringe, a pre-filled autoinjector, or a cartridge for a reusable syringe or applicator.

[0135] In one embodiment, a unit dose per vial may contain 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml of antibody molecule in the range of about 500 to about 2500 mg or about 1000 mg to about 2000 mg. In one embodiment, these preparations can be adjusted to the desired concentration by adding a sterile diluent to each vial.

[0136] The formulations disclosed herein include bulk drug compositions useful for the manufacture of pharmaceutical compositions (e.g., compositions suitable for administration to a subject or patient) that can be used to prepare unit dosage forms. In one embodiment, the compositions of the invention are pharmaceutical compositions. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an antibody molecule of the invention or other prophylactic or therapeutic agent) and a pharma- ceutically acceptable carrier. In one embodiment, the pharmaceutical composition is formulated to be suitable for subcutaneous administration to a subject.

[0137] Soluble hyaluronidase In the co-formulations, unit dosage forms and methods herein, soluble hyaluronidase is provided. Soluble hyaluronidase includes those that are present in soluble form upon expression and secretion from cells. Such soluble hyaluronidase includes, but is not limited to, non-human soluble hyaluronidase, bacterial soluble hyaluronidase, bovine PH20, ovine PH20, and variants thereof. Soluble hyaluronidase includes human PH20 polypeptides that are modified to be soluble. For example, hyaluronidases such as human PH20 that contain a glycophophatidylinositol (GPI) anchor can be soluble by cleavage and removal of all or part of the GPI anchor. In one embodiment, human hyaluronidase PH20, which is normally membrane anchored via a GPI anchor, is soluble by cleavage and removal of all or part of the GPI anchor at the C-terminus.

[0138] Soluble hyaluronidases also include neutral active hyaluronidases, such as soluble human PH20 polypeptides. In one embodiment, the hyaluronidase for use in the compositions, unit dosage forms, and methods herein is a soluble neutral active hyaluronidase.

[0139] Exemplary hyaluronidases include soluble forms of PH20 from any species, such as any of SEQ ID NOs: 5-40, and soluble PH20 polypeptides set forth in SEQ ID NOs: 5 and 18-23. Such soluble forms include truncated forms thereof lacking all or part of the C-terminal GPI anchor, so long as the hyaluronidase is soluble (secreted upon expression) and retains hyaluronidase activity. Such forms are also typically mature forms that lack a signal peptide when expressed in a cell. Soluble hyaluronidases also include soluble forms of any of the variants of PH20 from any species set forth in SEQ ID NOs: 5-40 that exhibit hyaluronidase activity. Variants include polypeptides having at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity with any of SEQ ID NOs: 5-40. Amino acid variants include conservative and non-conservative mutations. It is understood that residues important or otherwise required for the activity of hyaluronidase, such as any of those described above or any known to those of skill in the art, generally are in the variant and cannot be altered. These include, for example, active site residues. Thus, for example, amino acid residues 111, 113 and 176 of the human PH20 polypeptide, or a soluble form thereof (corresponding to residues in the mature PH20 polypeptide set forth in SEQ ID NO: 5), are generally in the variant and are not altered. Other residues that confer glycosylation and formation of disulfide bonds necessary for proper folding may also be invariant.

[0140] In one embodiment, the soluble hyaluronidase is usually GPI anchored (such as human PH20) and is soluble by truncation at the C-terminus. Such truncation can remove all of the GPI anchor attachment signal sequence or can remove only a portion of the GPI anchor attachment signal sequence. However, the resulting polypeptide is soluble. If the soluble hyaluronidase retains a portion of the GPI anchor attachment signal sequence, it can retain 1, 2, 3, 4, 5, 6, 7 or more amino acid residues in the GPI anchor attachment signal sequence, provided that the polypeptide is soluble. A polypeptide containing one or more amino acids of the GPI anchor is referred to as an extended soluble hyaluronidase. A person skilled in the art can determine whether a polypeptide is GPI-anchored using methods well known in the art. Such methods include, but are not limited to, using known algorithms to predict the presence and location of GPI anchor attachment signal sequences and ω sites, and performing solubility analyses before and after digestion with phosphatidylinositol-specific phospholipase C (PI-PLC) or D (PI-PLD).

[0141] Extended soluble hyaluronidases, such as those set forth in SEQ ID NOs: 42-47, can be produced by making C-terminal truncations to any native GPI-anchored hyaluronidase such that the resulting polypeptide is soluble and contains one or more amino acid residues from a GPI anchor attachment signal sequence (see, e.g., U.S. Patent No. 8,927,249). These include hyaluronidases that are neutrally active, soluble, contain amino acid substitutions, and have at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more sequence identity to any of SEQ ID NOs: 42-47.

[0142] Typically, for use in the compositions, combinations, and methods herein, soluble human hyaluronidases are used, such as soluble human PH20 polypeptides of any of SEQ ID NOs: 5 and 18-23, as well as variants having at least 98% sequence identity. Hyaluronidases used in the methods herein can be recombinantly produced or purified or partially purified from natural sources, such as, for example, testis extracts. Methods for producing recombinant proteins, including recombinant hyaluronidase, are well known in the art.

[0143] (a) Soluble human PH20 An exemplary soluble hyaluronidase is soluble human PH20. Soluble forms of recombinant human PH20 have been produced and can be used in the compositions, combinations, and methods described herein. Descriptions and preparations of such soluble forms of PH20 are described, for example, in U.S. Pat. Nos. 7,767,429, 8,202,517, 8,431,380, 8,431,124, 8,450,470, 8,765,685, 8,772,246, 7,871,607, 7,846,431, 7,829,081, 8,105,586, 8,187,855, 8,257,699, 8,580,252, 9,677,061, and 9,677,062, which are incorporated herein by reference.

[0144] Recombinant soluble forms of human PH20 have been generated and can be used in the compositions, combinations, and methods provided herein. For example, see SEQ ID NO:4, which sets forth the sequence of full-length precursor PH20 and includes a signal sequence (residues 1-35), and soluble forms include those that include amino acid residues 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, Examples of such polypeptides include, but are not limited to, C-terminal truncated polypeptides of human PH20 as set forth in SEQ ID NO: 4 having amino acids 94, 495, 496, 497, 498, 499 or 500, or polypeptides that exhibit at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto, that are active at neutral pH, and that are soluble (secreted into the medium when expressed in mammalian cells). Soluble forms of human PH20 generally include those that contain amino acids 36-464 as set forth in SEQ ID NO: 4. For example, when expressed in mammalian cells, the 35 amino acid N-terminal signal sequence is cleaved during processing and the mature form of the protein is secreted. Thus, mature soluble polypeptides include those containing amino acids 36-467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482 and 483 of SEQ ID NO: 4. In one embodiment, the soluble hyaluronidase is a soluble human PH20 polypeptide that is 442, 443, 444, 445, 446 or 447 amino acids in length, such as those set forth in any of SEQ ID NOs: 5 and 18-23, and variants thereof that have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence of amino acids set forth in any of SEQ ID NOs: 5 and 18-23 and retain hyaluronidase activity.The production of such soluble forms of recombinant human PH20 is described, for example, in U.S. Patent Nos. 7,767,429, 8,202,517, 8,431,380, 8,431,124, 8,450,470, 8,765,685, 8,772,246, 7,871,607, 7,846,431, 7,829,081, 8,105,586, 8,187,855, 8,257,699, 8,580,252, 9,677,061, and 9,677,062.

[0145] Generally, soluble forms of PH20 are produced using protein expression systems that promote correct N-glycosylation to ensure that the polypeptide retains activity, as glycosylation is important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0146] (b) rHuPH20 rHuPH20 refers to a composition produced upon expression in cells, such as CHO cells, of a nucleic acid encoding residues 36-482 of SEQ ID NO:4, generally linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:4). rHuPH20 is produced by expression of a nucleic acid molecule, such as a nucleic acid molecule encoding amino acids 1-482 (set forth in SEQ ID NO:4). Post-translational processing removes the 35 amino acid signal sequence, leaving a polypeptide or mixture of polypeptides including those set forth in SEQ ID NOs:5 and 18-23. When produced in culture medium, there is heterogeneity at the C-terminus such that the product referred to as rHuPH20 includes a mixture of species that may include any one or more of SEQ ID NOs:5 and 18-23 in varying abundance. Typically, rHuPH20 is produced in cells that promote correct N-glycosylation to retain activity, such as CHO cells (e.g., DG44 CHO cells). Generally, the most abundant species is a 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO:4.

[0147] (c) Glycosylation of hyaluronidase Glycosylation, including N-linked and O-linked glycosylation, of some hyaluronidases, including soluble PH20 hyaluronidase, can be important for their catalytic activity and stability. For some hyaluronidases, removal of N-linked glycosylation can result in almost complete inactivation of hyaluronidase activity. Thus, for such hyaluronidases, the presence of N-linked glycans can be important for the generation of active enzymes.

[0148] N-linked oligosaccharides are classified into several major types (oligomannose, complex, hybrid, sulfated), all of which have a (Man)3-GlcNAc-GlcNAc-core linked through the amide nitrogen of an Asn residue contained within the -Asn-Xaa-Thr / Ser- sequence (where Xaa is not Pro). Glycosylation at -Asn-Xaa-Cys sites has been reported for coagulation protein C. In some instances, hyaluronidases, such as PH20 hyaluronidase, can contain N-glycosidic and O-glycosidic linkages. For example, PH20 has O-linked as well as N-linked oligosaccharides. There are six potential N-linked glycosylation sites at N82, N166, N235, N254, N368, and N393 of human PH20, as exemplified in SEQ ID NO:1.

[0149] (d) Variants Variants of soluble PH20 polypeptides have been produced that have altered properties, such as increased stability and / or activity. U.S. Patent Nos. 9,447,401 and 10,865,400, and granted application No. 16 / 824,572, which are incorporated by reference, describe and provide structure / function maps of human PH20 that detail the effect of amino acid substitutions at each residue in the catalytic domain of PH20. These patents provide approximately 7000 examples in which the effect of substituting each amino acid with 15 other amino acids on activity and stability is identified and described. Most variants of soluble PH20 polypeptides, including those with amino acid substitutions, deletions, and insertions, are known in the art. Those skilled in the art can easily prepare soluble hyaluronidase and its variants and learn the properties of the resulting hyaluronidase.

[0150] Other variants known to those skilled in the art are described in International PCT Application Nos. WO2020 / 022791 and WO2020197230A, which are incorporated by reference and describe modified PH20 polypeptides. These polypeptides, which are variants of the PH20 polypeptides of SEQ ID NOs: 5-40, contain substitutions, insertions, and deletions, including one or more amino acid residues S343E, M345T, K349E, L353A, L354I, N356E, and I361T. Variants containing these and other modifications are described in SEQ ID NOs: 41-96 of International PCT Application No. WO2020 / 022791.

[0151] Biologics Provided herein is a unit dosage form of a biologic determined based on a modeling approach, in which the pharmacodynamic (PD) value of the SC dose is consistent with the pharmacodynamic (PD) value of a known reference IV dose, while the pharmacokinetic (PK) value of the SC dose is less than the pharmacokinetic (PK) value of the IV dose. The unit dosage form provided herein exhibits comparable safety and efficacy compared to the reference IV dose, and is therefore non-inferior to the IV dose, thereby providing patients with a more convenient alternative method of administering the biologic.

[0152] Non-limiting examples of biologics that are useful in the unit dosage forms provided herein include antibodies, antibody fragments, anticoagulants, blood factors, bone morphogenetic proteins, enzymes, fusion proteins, growth factors, hormones, interferons, interleukins, and thrombolytic agents.Further non-limiting examples of biologics that are useful in the unit dosage forms provided herein include any biologics that have a biomarker that can be used to determine the appropriate subcutaneous administration of the biologic, for example, IgG levels can be used to determine the subcutaneous administration of FcRn antagonists.In one embodiment, the biomarker is present in healthy subjects and / or test animals, so that analysis in healthy volunteers or test animals can be used to determine the subcutaneous administration of the biologic.

[0153] In one embodiment, the biologic antagonizes FcRn binding to antibody Fc region. In one embodiment, the biologic is an antibody, for example, an anti-FcRn antibody. Any anti-FcRn antibody is suitable for use in the unit dosage form disclosed herein. In one embodiment, the antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0154] In one embodiment, the biologic comprises or consists of a variant Fc region, or an FcRn-binding fragment thereof, that binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region.

[0155] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, consists of two Fc domains. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0156] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:1.

[0157] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:2.

[0158] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:3.

[0159] In one embodiment, the biologic is efgartigimod (CAS Registry Number 1821402-21-4). [Table 1]

[0160] How to use In one aspect, the disclosure provides a method of treating a disease or disorder comprising subcutaneously administering to a subject in need thereof a unit dosage form of a biologic disclosed herein.

[0161] In certain embodiments, the present disclosure provides a method of treating an antibody-mediated autoimmune disease comprising subcutaneously administering to a subject in need thereof a unit dosage form of a variant Fc region disclosed herein, or an FcRn-binding fragment thereof.

[0162] In one embodiment, the autoimmune disease is selected from the group consisting of allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura or idiopathic thrombocytopenic purpura or immune-mediated thrombocytopenia), autoimmune urticaria, Behcet's disease, bullous pemphigoid (BP), cardiomyopathy, cytomegalovirus (CYP2), ... Jasleman syndrome, celiac-spruce dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré, Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA deficiency neuropathy, IgM polyneuropathy, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes mellitus, multifocal motor neuropathy (MMN), myasthenia gravis (MG), paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigus vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), antisynthetase syndrome (ASyS), primary agammamag The patient is selected from the group consisting of pulmonary fibrosis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-body syndrome, systemic lupus erythematosus, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, dermatitis herpetiformis type vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0163] In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once weekly. In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once every two weeks. In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once every 10-14 days. In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once every three weeks. In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once every four weeks.

[0164] In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, or about 1050 mg. In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 950 mg. In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 975 mg. In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 1000 mg. In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 1025 mg. In one embodiment, the dose of the variant Fc region, or FcRn-binding fragment thereof, is about 1050 mg.

[0165] In one embodiment, the variant Fc region or FcRn-binding fragment thereof is administered once a week. In one embodiment, the weekly dose is about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, or about 1050 mg. In one embodiment, the weekly dose is about 950 mg. In one embodiment, the weekly dose is about 975 mg. In one embodiment, the weekly dose is about 1000 mg. In one embodiment, the weekly dose is about 1025 mg. In one embodiment, the weekly dose is about 1050 mg.

[0166] In one embodiment, the treatment comprises at least 2 weekly doses. In one embodiment, the treatment comprises at least 3 weekly doses. In one embodiment, the treatment comprises at least 4 weekly doses. In one embodiment, the treatment comprises at least 5 weekly doses. In one embodiment, the treatment comprises at least 6 weekly doses. In one embodiment, the treatment comprises at least 7 weekly doses. In one embodiment, the treatment comprises at least 8 weekly doses. In one embodiment, the treatment comprises more than 8 weekly doses.

[0167] In one embodiment, the dose is an injection. In one embodiment, the dose is in a unit dosage form.

[0168] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, is administered together with recombinant enzyme human hyaluronidase. In one embodiment, the recombinant enzyme human hyaluronidase is rHuPH20. In one embodiment, the recombinant enzyme human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in the same formulation. In one embodiment, the recombinant enzyme human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in separate formulations.

[0169] In one embodiment, efgartigimod is administered together with recombinant human hyaluronidase. In one embodiment, the recombinant human hyaluronidase is rHuPH20. In one embodiment, the recombinant human hyaluronidase and efgartigimod are contained in the same formulation. In one embodiment, the recombinant human hyaluronidase and efgartigimod are contained in separate formulations.

[0170] In one embodiment, a total serum IgG reduction in about 60% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65%, about 70%, about 75%, or about 80% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 70% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 75% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 80% of patients is obtained compared to baseline IgG levels.

[0171] In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0172] In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0173] In one embodiment, the total serum IgG level in the patient is reduced to 2000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2000-3000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 3000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2500-3500 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2750-3250 μg / mL.

[0174] In one embodiment, the total serum IgG in the patient is analyzed using a biological analysis method. In one embodiment, the total serum IgG in the patient is analyzed using an ELISA or an automated diagnostic analyzer (IVD). In one embodiment, the total serum IgG in the patient is analyzed using an ELISA. In one embodiment, the total serum IgG in the patient is analyzed using an automated diagnostic analyzer (IVD).

[0175] In one embodiment, at least one of the IgG subtypes is reduced. In one embodiment, IgG1 is reduced. In one embodiment, IgG2 is reduced. In one embodiment, IgG3 is reduced. In one embodiment, IgG4 is reduced.

[0176] In one embodiment, the variant Fc region is efgaltigimod.

[0177] In one aspect, also provided herein is a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating myasthenia gravis in a human patient.

[0178] In one aspect, the disclosure provides a variant Fc region, or FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating myasthenia gravis in a human patient, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously at a weekly dose of 950-1050 mg, regardless of the patient's weight, resulting in a reduction in total serum IgG in the patient of at least 60% compared to baseline IgG levels.

[0179] In one embodiment, the weekly dose is about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, or about 1050 mg. In one embodiment, the weekly dose is about 950 mg. In one embodiment, the weekly dose is about 975 mg. In one embodiment, the weekly dose is about 1000 mg. In one embodiment, the weekly dose is about 1025 mg. In one embodiment, the weekly dose is about 1050 mg.

[0180] In one embodiment, the treatment comprises at least 2 weekly doses. In one embodiment, the treatment comprises at least 3 weekly doses. In one embodiment, the treatment comprises at least 4 weekly doses. In one embodiment, the treatment comprises at least 5 weekly doses. In one embodiment, the treatment comprises at least 6 weekly doses. In one embodiment, the treatment comprises at least 7 weekly doses. In one embodiment, the treatment comprises at least 8 weekly doses. In one embodiment, the treatment comprises more than 8 weekly doses.

[0181] In one embodiment, the dose is an injection. In one embodiment, the dose is in a unit dosage form.

[0182] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, is administered together with recombinant enzymatic human hyaluronidase. In one embodiment, the recombinant enzymatic human hyaluronidase is rHuPH20. In one embodiment, the recombinant enzymatic human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in the same formulation. In one embodiment, the recombinant enzymatic human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in separate formulations. In one embodiment, the recombinant enzymatic human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are co-administered. In one embodiment, the recombinant enzymatic human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are administered sequentially. In one embodiment, the recombinant enzymatic human hyaluronidase is administered before the variant Fc region, or FcRn-binding fragment thereof. In one embodiment, the recombinant enzyme human hyaluronidase is administered after the variant Fc region, or an FcRn-binding fragment thereof.

[0183] In one embodiment, efgartigimod is administered together with recombinant enzyme human hyaluronidase. In one embodiment, the recombinant enzyme human hyaluronidase is rHuPH20. In one embodiment, the recombinant enzyme human hyaluronidase and efgartigimod are contained in the same formulation. In one embodiment, the recombinant enzyme human hyaluronidase and efgartigimod are contained in separate formulations. In one embodiment, the recombinant enzyme human hyaluronidase and efgartigimod are administered simultaneously. In one embodiment, the recombinant enzyme human hyaluronidase and efgartigimod are administered sequentially. In one embodiment, the recombinant enzyme human hyaluronidase is administered before efgartigimod. In one embodiment, the recombinant enzyme human hyaluronidase is administered after efgartigimod.

[0184] In one embodiment, a total serum IgG reduction in about 60% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65%, about 70%, about 75%, or about 80% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 70% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 75% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 80% of patients is obtained compared to baseline IgG levels.

[0185] In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0186] In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within 31, 30, 29, 28, 27, 26, or 25 days of the first administration.

[0187] In one embodiment, the total serum IgG level in the patient is reduced to 2000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2000-3000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 3000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2500-3500 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2750-3250 μg / mL.

[0188] In one embodiment, the total serum IgG in the patient is analyzed using a biological analysis method. In one embodiment, the total serum IgG in the patient is analyzed using an ELISA or an automated diagnostic analyzer (IVD). In one embodiment, the total serum IgG in the patient is analyzed using an ELISA. In one embodiment, the total serum IgG in the patient is analyzed using an automated diagnostic analyzer (IVD).

[0189] In one embodiment, at least one of the IgG subtypes is reduced. In one embodiment, IgG1 is reduced. In one embodiment, IgG2 is reduced. In one embodiment, IgG3 is reduced. In one embodiment, IgG4 is reduced.

[0190] In one embodiment, the variant Fc region is efgaltigimod.

[0191] Also provided herein is a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating pemphigus vulgaris in a human patient.

[0192] In one aspect, the disclosure provides a variant Fc region, or FcRn-binding fragment thereof, wherein the Fc domain of the Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively, for use in treating pemphigus vulgaris in a human patient, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously at a weekly dose of 1950-2050 mg, regardless of the patient's weight, resulting in a reduction in total serum IgG in the patient of at least 60% compared to baseline IgG levels.

[0193] In one embodiment, the weekly dose is about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, or about 2050 mg. In one embodiment, the weekly dose is about 1950 mg. In one embodiment, the weekly dose is about 1975 mg. In one embodiment, the weekly dose is about 2000 mg. In one embodiment, the weekly dose is about 2025 mg. In one embodiment, the weekly dose is about 2050 mg.

[0194] In one embodiment, the treatment comprises at least 2 weekly doses. In one embodiment, the treatment comprises at least 3 weekly doses. In one embodiment, the treatment comprises at least 4 weekly doses. In one embodiment, the treatment comprises at least 5 weekly doses. In one embodiment, the treatment comprises at least 6 weekly doses. In one embodiment, the treatment comprises at least 7 weekly doses. In one embodiment, the treatment comprises at least 8 weekly doses. In one embodiment, the treatment comprises more than 8 weekly doses.

[0195] In one embodiment, the dosage is in a unit dosage form.

[0196] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, is administered together with recombinant enzyme human hyaluronidase. In one embodiment, the recombinant enzyme human hyaluronidase is rHuPH20. In one embodiment, the recombinant enzyme human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in the same formulation. In one embodiment, the recombinant enzyme human hyaluronidase and the variant Fc region, or FcRn-binding fragment thereof, are contained in separate formulations.

[0197] In one embodiment, efgartigimod is administered together with recombinant human hyaluronidase. In one embodiment, the recombinant human hyaluronidase is rHuPH20. In one embodiment, the recombinant human hyaluronidase and efgartigimod are contained in the same formulation. In one embodiment, the recombinant human hyaluronidase and efgartigimod are contained in separate formulations.

[0198] In one embodiment, a total serum IgG reduction in about 60% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65%, about 70%, about 75%, or about 80% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 65% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 70% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 75% of patients is obtained compared to baseline IgG levels. In one embodiment, a total serum IgG reduction in about 80% of patients is obtained compared to baseline IgG levels.

[0199] In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration.

[0200] In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within one month of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks, three weeks, four weeks, five weeks, or six weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within two weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within three weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within four weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within five weeks of the first administration. In one embodiment, the maximum percentage of total serum IgG reduction in the patient is achieved within six weeks of the first administration.

[0201] In one embodiment, the total serum IgG level in the patient is reduced to 2000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2000-3000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 3000-4000 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2500-3500 μg / mL. In one embodiment, the total serum IgG level in the patient is reduced to 2750-3250 μg / mL.

[0202] In one embodiment, the total serum IgG in the patient is analyzed using a biological analysis method. In one embodiment, the total serum IgG in the patient is analyzed using an ELISA or an automated diagnostic analyzer (IVD). In one embodiment, the total serum IgG in the patient is analyzed using an ELISA. In one embodiment, the total serum IgG in the patient is analyzed using an automated diagnostic analyzer (IVD).

[0203] In one embodiment, at least one of the IgG subtypes is reduced. In one embodiment, IgG1 is reduced. In one embodiment, IgG2 is reduced. In one embodiment, IgG3 is reduced. In one embodiment, IgG4 is reduced.

[0204] In one embodiment, the variant Fc region is efgaltigimod. EXAMPLES

[0205] The following examples are offered by way of illustration and not by way of limitation.

[0206] Example 1: Study to compare the PK / PD and safety of subcutaneous doses of efgartigimod + rHuPH20 Efgartigimod (UNII:961YV2O515) is a human IgG1-derived Fc fragment of the za allotype (variant Fc region) that binds to human FcRn with nanomolar affinity. A randomized, open-label, clinical trial was conducted to evaluate the safety and pharmacokinetic (PK) / pharmacodynamic (PD) parameters of a subcutaneous (SC) dose of efgartigimod.

[0207] A SC formulation containing recombinant human hyaluronidase PH20 enzyme (rHuPH20) was developed for SC administration of efgartigimod as an alternative to IV infusion. The enzyme rHuPH20 locally degrades hyaluronan (HA) within the SC space, which allows for increased dispersion and absorption of co-administered therapies. A ready-to-use liquid SC formulation containing efgartigimod and rHuPH20 (efgartigimod-PH20) was injected as a fixed dose. This formulation and administration method is expected to increase patient convenience compared to IV formulation and administration.

[0208] Healthy volunteers aged 18-70 years with body weights ranging from 50-100 kg were screened for 21 days and then randomized into four treatment groups (n=8 for each group) as follows: a. Treatment A: A single SC dose of 750 mg efgartigimod co-administered with 2000 U / mL hyaluronidase enzyme rHuPH20; b. Treatment B: A single SC dose of 1250 mg efgartigimod coadministered with 2000 U / mL rHuPH20; c. Treatment C: A single SC dose of 1750 mg efgartigimod coadministered with 2000 U / mL rHuPH20; and d. Treatment D: A single SC dose of 10 mg / kg efgartigimod co-administered with 2000 U / mL rHuPH20.

[0209] Analysis of pharmacokinetic parameters Interim analyses of several pharmacokinetic parameters were performed based on the PK population (randomized patients with at least one plasma concentration value available for efgartigimod). Plasma concentrations of efgartigimod at each sample time point were analyzed by the following summary statistics: mean calculated using untransformed data, standard deviation (SD) calculated using untransformed data, minimum, median, maximum, number of observations, and number of observations greater than the lower limit of quantification (LLOQ).

[0210] Geometric mean plasma concentrations versus protocol time were presented by patient on both linear and logarithmic scales, respectively.

[0211] The following summary statistics are available: max All PK parameters except:G mean , GCV, mean calculated using untransformed data, SD calculated using untransformed data, minimum, median, maximum, and number of observations were assessed.

[0212] The following summary statistics are used to calculate the PK parameter t max : Number of observations, median, minimum, and maximum were evaluated.

[0213] Analysis of pharmacodynamic parameters Continuous PD parameters, including analysis of total IgG, were summarized with descriptive statistics including geometric means.

[0214] result An interim analysis was performed 22 days after dosing to evaluate PK and PD parameters. Serum levels of efgartigimod after a single SC dose in patients in treatment groups A-D were compared to background data from administration of 10 mg / kg IV or SC efgartigimod (without rHuPH20) (Figure 1A and Figure 1B). The PK data show that the addition of rHuPH20 resulted in increased bioavailability of efgartigimod after SC administration compared to SC administration without rHuPH20 (see Table 2). [Table 2]

[0215] PD results from interim analyses were also compared to historical data. Total IgG reduction after 750 mg SC efgartigimod was inferior to 10 mg / kg IV (Figure 2A), whereas maximum IgG reduction after 1250 mg SC efgartigimod was equivalent to 10 mg / kg IV (Figure 2B). Both the onset of total IgG reduction after 1750 mg SC efgartigimod and the long-term effect of total IgG reduction were equivalent to 10 mg / kg IV (Figure 2C). No significant adverse events were observed in treatment groups A-D.

[0216] This single-dose study demonstrated the safety of SC administration of efgartigimod co-administered with rHuPH20 and showed that SC administration can result in total IgG reductions that are equivalent to IV administration in healthy volunteers.

[0217] Example 2: Calculation of subcutaneous dose of efgartigimod from pharmacokinetic (PK) and pharmacodynamic (PD) data To determine a safe and effective SC dose of the biologic, PK / PD modeling was used to match the reduction in total IgG (a PD parameter) for IV and SC doses of the biologic, based on data from a single SC dose of the biologic, using the known IV dose as a benchmark.

[0218] A previously determined PK / PD model was used to construct a simulation of total IgG reduction following different subcutaneous doses of efgartigimod with and without the hyaluronidase enzyme rHuPH20. Using preliminary PK / PD data from human subjects treated with a single subcutaneous dose of efgartigimod (study described in Example 1 above), the PK / PD model was used to simulate the reduction in total IgG following different subcutaneous doses of efgartigimod with and without rHuPH20. max and AUC, as well as median trends in IgG reduction across treatment groups, were reported.

[0219] Covariate analysis of body weight showed no statistically significant effect of body weight on PK or IgG, suggesting that a fixed dose is feasible for subcutaneous administration.

[0220] Previous PK model for efgartigimod in healthy volunteers Previously, a population PK analysis was performed to evaluate the effects of efgartigimod in a study of efgartigimod in healthy volunteers. This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending IV dose study to evaluate the safety, tolerability, PK, PD, and immunogenicity of efgartigimod in healthy male and healthy female volunteers of non-childbearing potential. In summary, the PK model adequately captured the concentration-time characteristics of efgartigimod after single ascending doses of 0.2, 2, 10, 25, and 50 mg / kg, as well as multiple ascending doses. Multiple doses of efgartigimod or placebo were administered every 4 days (q4d) for six doses (10 mg / kg alone) or every 7 days (q7d) for four doses (10 and 25 mg / kg). The final PK model consisted of a three-compartment model with linear clearance and included the assumption that the second marginal volume (V3) was equal to the first marginal volume (V2). Inter-individual variability (IIV) was determined for clearance (CL), median volume of distribution (V1), intercompartmental clearance (Q), and marginal compartment volume (V2=V3). In addition, covariance of IIV was implemented in the model for CL, V1, and V2=V3. An additive residual error model was used, standard for log-transformed data.

[0221] This model was extended to describe the PK of efgartigimod in healthy volunteers in another efgartigimod study. This was a randomized, open-label, parallel-group study to compare the PK, PD, safety, and tolerability of the SC formulation with the intravenous (IV) formulation of efgartigimod in healthy male subjects. In this study, subjects were assigned to either Treatment A (single dose of 10 mg / kg IV) or B (single dose of 10 mg / kg SC) or Treatment C (two IV doses of 20 mg / kg followed by eight weekly SC doses of 300 mg). To describe the PK of the compounds in this study, zero-order absorption was added to the existing PK model to estimate the duration of the zero-order process (DUR) as well as absolute bioavailability (F). The final model included IIV, V2=V3, V1, Q2, and F on the CL. To increase model stability, only the covariance between IIV and V2=V3 on the CL was estimated.

[0222] Current modeling approach and assumptions for efgaltigimod co-administered with rHuPH20 The focus of the analysis was modeling of data from 32 subjects treated with a single SC injection of either 750 mg, 1250 mg, 1750 mg, or 10 mg / kg efgartigimod + rHuPH20 (study described in Example 1). For data on IV and SC dosing without rHuPH20, PK and historical IgG data from Treatments A (single IV dose of 10 mg / kg) and B (single SC dose of 10 mg / kg) from a previous study were included in the analysis.

[0223] First, parameters from an existing PK model for healthy volunteers were used to predict the healthy volunteer data in the study described in Example 1. The model did not adequately predict the PK of efgartigimod co-administered with rHuPH20, especially in the absorption phase. Therefore, absorption-related parameters (i.e., absolute bioavailability and duration of the zero-order absorption process) were estimated for the study described in Example 1, along with the residual error. In this way, the description of the PK of efgartigimod in the new study was improved. However, the absorption phase was still not adequately described. To improve the description of the absorption of the compound when co-administered with rHuPH20, the first-order absorption rate constant kA was also estimated for the study described in Example 1 (i.e., 0.24 1 / hr in Table 3), while in the previous PK model, the parameter kA was fixed at 99 to resemble zero-order absorption. In this way, a sequential zero-first-order absorption model could be identified, which improved the description of the PK of efgartigimod + rHuPH20. Furthermore, the duration of the zero-order process was estimated to be shorter in the study described in Example 1 compared to the historical data (ie, 83.7 hours vs. 131 hours, as reported in Table 3).

[0224] As a final step, all PK parameters were optimized in the data from the background data and study described in Example 1. Parameter estimates showed that the relative bioavailability and the period of zero-order processes were found to be higher and lower, respectively, in the study described in Example 1 compared to the background data (see Table 3). In addition, the inter-individual variability at Q2 (IIV) and the correlation between the IIV at clearance (CL) and the IIV at the first peripheral volume (V2) were removed because they were not accurately estimated (i.e., RSE%>50%). To improve model stability, the inter-individual variability on kA was removed and estimated for the period of zero-order absorption. As shown in the visual prediction check, the PK model adequately captured the typical characteristics of efgartigimod concentrations in the study described in Example 1 (see Figure 3) and the background data (see Figure 4) as well as the inter-individual variability between treatment groups. The effect of body weight on the PK parameters was examined but found to be not statistically significant. [Table 3]

[0225] Comparison of efgartigimod 10 mg / kg SC with and without coadministration of rHuPH20 showed that the observed max But the prediction t max The results suggest that the absorption model for the study described in Example 1 can still be improved since the relative bioavailability appears to be smaller than the dose (Figure 5). Different absorption models were investigated to improve the description of the PK of efgartigimod in the study described in Example 1, such as parallel zero-order zero-order absorption (with and without lag time) and parallel zero-order absorption (with and without lag time). However, none of these examined models were found to be better than the current model with continuous zero-order absorption. Therefore, the potential dependence between PK parameters and dose was investigated. In the study described in Example 1, bioavailability appeared to increase with dose. Nevertheless, including a dose function in the relative bioavailability did not significantly improve the description of the population and individual PK characteristics.

[0226] In conclusion, the population PK model of efgartigimod + rHuPH20 was considered appropriate for PK / PD analysis.

[0227] PK / total IgG model The PK / total IgG model is based on the relationship between the concentration of efgartigimod and the rate of degradation of total IgG (k out The study consisted of an indirect response model in which efgartigimod was stimulated with the FcRn receptor. This model reflects the mechanism of action for efgartigimod, which binds to the FcRn receptor, reduces total IgG recycling, and causes increased degradation of total IgG. The total IgG-reducing effect of efgartigimod was found to be saturable, so E max A model was used to quantify the PK / PD relationships (E fixed to estimates from a pooled analysis of previous studies). max parameters). Effect compartments were included in the model to allow for accurate accounting of the delay in the decline of total IgG concentrations. Baseline total IgG levels and efficacy (EC 50 ) was determined and the residual variability was described by a proportional error model.

[0228] In particular, model parameters derived from a previous combined analysis of the previous efgartigimod studies were used to predict total IgG concentrations in the study described in Example 1. To do so, it was assumed that the baseline of total IgG in the study described in Example 1 was the same as the baseline in one of the previous studies (i.e., 8570 mg / L). Overall, the model was able to predict the 750 mg, 1750 mg, and 10 mg / kg dose groups reasonably well. However, it did not adequately predict the 1250 mg treatment group. By estimating the baseline of total IgG in the study described in Example 1, the model improved its description of total IgG across dose groups (parameter estimates are reported in Table 4). However, it still underpredicted the total IgG concentration in the 1250 mg group. As a further step, E maxAll parameters except for were optimized against total IgG data from the previous study and the study described in Example 1. The baseline inter-individual variability in the 1250 mg SC group appeared to be lower relative to the other treatment groups in the study described in Example 1. A visual predictive check showed that the model over-predicted the inter-individual variability in the 1250 mg SC treatment group (Figure 6). Additionally, the model under-predicted the median total IgG reduction in the 750 mg and 1750 mg SC dose groups (Figure 7).

[0229] The inclusion of an effect compartment in the model structure allowed for a better capture of the total IgG concentrations of the SC-treated group in both the historical data and the study described in Example 1. In this new model structure, the EC50 was estimated to be higher because it represents the concentration in the effect compartment (i.e., 33636 ng / mL vs. 20900 ng / mL in Table 4). A visual predictive check confirmed that the model captured both the typical total IgG concentrations (Figure 8) and declines (Figure 9) over time as well as the inter-individual variability in the study described in Example 1. Furthermore, the inclusion of an effect compartment provided a reasonable explanation for the total IgG concentrations (Figure 10) and declines (Figure 11) in the historical data. Therefore, we consider this model suitable for exploring the predicted total IgG declines in future studies.

[0230] The effect of body weight was examined on baseline total IgG and EC50 parameters and was found to be not statistically significant. In conclusion, the population PK / total IgG model of efgaltigimod + rHuPH20 was deemed adequate to simulate typical PK and IgG reduction and its uncertainty for assessing dose in future studies. [Table 4]

[0231] Modeling Conclusions An available population PK model previously developed to describe efgartigimod concentrations in previous studies was modified to adequately capture the PK of the compound plus rHuPH20 in the study described in Example 1. More specifically, the absorption model was modified because the SC treatment group of efgartigimod + rHuPH20 required the implementation of sequential zero-first order processes. Furthermore, administration of efgartigimod with rHuPH20 resulted in a higher relative bioavailability compared to the 10 mg / kg SC group in the historical data (0.764 vs. 0.560 with and without rHuPH20, respectively).

[0232] The final PK / total IgG model previously developed to describe total IgG in a healthy population consisted of an indirect response model in which the concentration of efgartigimod stimulated the degradation rate of the biomarker of interest. This model was refined by the inclusion of an effect compartment to adequately capture the total IgG concentration and decline in healthy volunteers treated with efgartigimod + rHuPH20 in the study described in Example 1. The effect of body weight on any of the PK or PD parameters was found to be not statistically significant.

[0233] Simulation methods and assumptions Simulations were performed using R (version 3.4.4, The R foundation for Statistical Computing) and RStudio (version 1.1.463, RStudio Inc, Boston, USA) in combination with a custom-built simulation package.

[0234] Simulations were performed using the PK and PK / Total IgG models developed to describe efgartigimod and total IgG concentrations in healthy volunteers from the study described in Example 1. Efgartigimod concentrations and total IgG time profiles were simulated based on the typical PK and total IgG parameter estimates reported in Tables 5 and 6, respectively. Different scenarios based on efgartigimod PH20 SC ranging from 750 mg to 1750 mg (in 25 mg increments) QW for 12 weeks were simulated in addition to 10 mg / kg IV efgartigimod weekly (QW) for a 12 week scenario, which represented the benchmark for these simulations. For each scenario, 500 simulations including parameter uncertainties were performed. For the benchmark dose of 10 mg / kg IV QW, a 1 hour infusion and a body weight of 70 kg were assumed. For each scenario, the median, 5th percentile, and 95th percentile of the following three indices were calculated based on the simulated total IgG concentration-time profile after efgartigimod administration: (a) Area under the effect curve (AUEC D22-D29 ), (b) Maximum total IgG reduction after the fourth dose on days 22-29; and (c) Trough reduction in total IgG on day 29 (i.e., resulted in a reduction in total IgG before dosing on day 29). [Table 5] [Table 6]

[0235] Simulation results The median and 5th and 95th percentiles of metrics obtained with efgartigimod QW at 10 mg / kg IV were: (a) AUEC D22-D29(b) maximum total IgG reduction after the fourth dose on days 22-29: -66.59% (-68.96%; -64.38%), and (c) trough reduction in total IgG on day 29: -65.75% (-68.43%; -63.42%).

[0236] AUEC from 22nd to 29th days D22-D29 The simulated metrics following administration of different dose levels of efgartigimod PH20 SC for maximum total IgG reduction, maximum total IgG reduction, and total IgG reduction on day 29, respectively, are shown in Figures 12, 13, and 14. The efgartigimod PH20 SC doses that produced medians equivalent to the benchmark scenario for these three metrics were 925 mg (Figure 12), 900 mg (Figure 13), and 825 mg (Figure 14), respectively. These simulations showed the SC dose of efgartigimod to be non-inferior to the benchmark IV dose.

[0237] For each dose, the percentage of simulated values ​​above the target levels (derived for the benchmark scenario) was calculated for each of the three metrics (see Figures 15, 16, and 17). D22-D29 ) dose of efgartigimod PH20 SC produced median values ​​equivalent to the benchmark scenario for the three selected metrics.

[0238] The 825 mg efgartigimod PH20 SC dose achieved the median AUEC D22-D29 Above 34.2%AUEC D22-D29 values, resulting in a 32.8% maximum total IgG reduction on days 22 to 29 below the corresponding median value obtained with efgartigimod QW at 10 mg / kg IV, and a 46.4% trough total IgG reduction on day 29 below the corresponding median value obtained in the benchmark scenario.

[0239] Furthermore, the 900 mg efgartigimod PH20 SC dose achieved a median AUEC D22-D29 Above 47.6%AUEC D22-D29 values, 56.4% of the maximum total IgG reduction on days 22 to 29 below the corresponding median value obtained with efgartigimod QW at 10 mg / kg IV, and 72.4% of the trough total IgG reduction on day 29 below the corresponding median value obtained in the benchmark scenario.

[0240] Furthermore, the 925 mg efgartigimod PH20 SC dose achieved a median AUEC D22-D29 Above 51.4%AUEC D22-D29 values, 65.4% of the maximum total IgG reduction on days 22 to 29 below the corresponding median value obtained with efgartigimod QW at 10 mg / kg IV, and 78.4% of the trough total IgG reduction on day 29 below the corresponding median value obtained in the benchmark scenario.

[0241] A summary of the results obtained with several doses of efgartigimod PH20 SC is shown in Table 7 below. [Table 7]

[0242] These results suggested that a dose of at least 975 mg efgartigimod PH20 SC was required to obtain greater than 75% of the maximum total IgG reduction on days 22-29, which exceeded the median maximum total IgG reduction on days 22-29 in the benchmark scenario (see Table 7).

[0243] SC Dose Selection This dose is AUEC D22-D29 The 1000 mg efgartigimod PH20 SC dose was selected for further clinical development because it predicted near the 5th percentile of the benchmark scenario for maximum total IgG reduction on days 22 to 29 and the 95th percentile of the benchmark scenario for maximum total IgG reduction on days 22 to 29 and trough total IgG reduction on day 29.

[0244] Specifically, the simulations demonstrated that (a) a dose of 1000 mg efgartigimod PH20 SC produced an AUEC equivalent to the 5th percentile achieved with efgartigimod 10 mg / kg IV once weekly; D22-D29 (b) a dose of 950 mg efgartigimod PH20 SC resulted in the 95th percentile of maximum total IgG reduction on days 22-29 equivalent to the 95th percentile obtained with efgartigimod 10 mg / kg IV once weekly (FIG. 13), and (c) a dose of 900 mg efgartigimod PH20 SC resulted in the 95th percentile of trough total IgG reduction on day 29 equivalent to the 95th percentile obtained with efgartigimod 10 mg / kg IV once weekly (FIG. 14).

[0245] Furthermore, the simulations showed that 1000 mg of efgartigimod PH20 SC achieved the median AUEC D22-D29 Above 59.8%AUEC D22-D29 values ​​(FIG. 15), 84.0% of the maximum total IgG reduction on days 22-29 below the corresponding median obtained with efgartigimod 10 mg / kg IV once weekly (FIG. 16), and 92.6% of the trough total IgG reduction on day 29 below the corresponding median obtained with the benchmark scenario of efgartigimod 10 mg / kg IV once weekly (FIG. 17) (see also Table 7).

[0246] Additionally, the AUEC (Figure 18) and maximum total IgG reduction (Figure 19) obtained with efgartigimod PH20 SC QW 1000 mg and efgartigimod QW 10 mg / kg IV were calculated for i) days 1 to 8, ii) days 8 to 15, iii) days 15 to 22, and iv) days 22 to 29. Pre-dose total IgG reduction on days 8, 15, 22, and 29 with efgartigimod PH20 SC QW 1000 mg and efgartigimod QW 10 mg / kg IV was also derived (Figure 20). At each time interval, the percentage of simulated AUECs obtained with 1000 mg efgartigimod PH20 SC QW above the median AUECs obtained with efgartigimod QW 10 mg / kg IV was predicted to be (Figure 18): i) 0% (days 1-8), ii) 25% (days 8-15), iii) 53.6% (days 15-22), iv) 59.8% (days 22-29) (see Table 8).

[0247] At each time interval, the percentage of simulated maximum total IgG reduction achieved with 1000 mg efgartigimod PH20 SC QW below the median maximum total IgG reduction achieved with efgartigimod QW 10 mg / kg IV was predicted to be (Figure 19): i) 9.6% (days 1-8), ii) 78.2% (days 8-15), iii) 88.4% (days 15-22), and iv) 84.0% (days 22-29) (see Table 8). The percentage of simulated total IgG reduction achieved with 1000 mg efgartigimod PH20 SC QW below the median total IgG reduction achieved with efgartigimod QW 10 mg / kg IV was predicted to be i) 9.6% (before dosing on day 8), ii) 78.2% (before dosing on day 15), iii) 92.0% (before dosing on day 22), and iv) 92.6% (before dosing on day 29) (see Figure 20 and Table 8).

[0248] Simulated total IgG profiles obtained with 10 mg / kg IV efgartigimod QW and 1000 mg efgartigimod PH20 SC QW are shown in FIG. [Table 8]

[0249] conclusion Based on comparable PD parameters of total IgG reduction, a dose of 1000 mg efgartigimod administered subcutaneously with rHuPH20 was proposed for weekly administration in clinical trials.

[0250] Using previously developed PK and PK / PD models to describe efgartigimod and total IgG concentrations in healthy volunteers from the study described in Example 1, simulations were performed to support dose selection of efgartigimod PH20 SC once weekly to provide similar effects on total IgG as efgartigimod 10 mg / kg IV once weekly. Simulation results showed that efgartigimod PH20 SC doses of 925 mg, 900 mg, and 825 mg each provided median AUEC values ​​on days 22-29 equivalent to efgartigimod 10 mg / kg IV QW. D22-D29 These results suggest that IFN-α resulted in a maximal total IgG reduction, and a trough total IgG reduction on day 29.

[0251] The dose of 1000 mg of efgartigimod PH20 SC was D22-D29 The study was selected for future clinical development because it predicted near the 5th percentile of the benchmark scenario for maximum total IgG reduction on days 22 to 29 and the 95th percentile of the benchmark scenario for maximum total IgG reduction on days 22 to 29 and trough total IgG reduction on day 29.

[0252] Example 3: A study to compare the pharmacodynamics, pharmacokinetics, safety, and tolerability of multiple intravenous infusions of efgartigimod with the pharmacodynamics, pharmacokinetics, safety, and tolerability of multiple subcutaneous injections of efgartigimod-PH20 SC in healthy subjects This example describes the protocol and results of a Phase I clinical trial to demonstrate the pharmacodynamic (PD) effect of subcutaneous (SC) injections of 1000 mg efgartigimod co-formulated with rHuPH20 (efgartigimod-PH20) four times per week is non-inferior to the pharmacodynamic (PD) effect of intravenous (IV) infusions of efgartigimod at a dose of 10 mg / kg four times per week (see schematic of study protocol in FIG. 15).

[0253] In this study, subjects were randomized 1:1 to receive open-label efgartigimod IV or efgartigimod-PH20 SC, respectively. We hypothesized that equivalent PD efficacy would result in equivalent efficacy in patients, and investigated the non-inferiority of efgartigimod PD efficacy when administered SC compared with IV.

[0254] The efgartigimod IV 10 mg / kg dose selected for this study is a dose that has been shown to be well tolerated, safe, and associated with clinical efficacy in patients with generalized myasthenia gravis. The efgartigimod-PH20 SC 1000 mg dose was predicted to produce similar PD effects as the efgartigimod IV 10 mg / kg dose and was selected based on the modeling and simulations described in Example 2.

[0255] Inclusion and Exclusion Criteria A total of 54 healthy subjects were randomized in a 1:1 ratio to either efgartigimod IV (27 subjects) or efgartigimod-PH20 SC (27 subjects). Subjects were selected based on the inclusion and exclusion criteria listed below. Inclusion and Exclusion Criteria Inclusion criteria: 1. Subjects are aged 18-65 years, inclusive, on the date of signing the ICF. 2. Subjects are males or females of non-childbearing potential (postmenopausal [defined as follicle-stimulating hormone (FSH) > 33.4 IU / L and continuous amenorrhea for at least 1 year without alternative medical cause; in subjects receiving hormone replacement therapy, a pre-treatment background value > 33.4 IU / L is accepted as evidence of menopausal status]) or have undergone documented permanent sterilization (i.e., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 3. Female subject has a negative pregnancy test on day -1. 4. Subjects were those with a body weight of ≥ 50kg and ≤ 100kg at screening, inclusively 18-30kg / m 2 have a body mass index (BMI) of. 5. Subject is able to understand the requirements of the study and is able to provide written informed consent (including agreement for uses and disclosures of health information related to the study), willingness and ability to comply with the procedures of the study protocol (including required study visits). 6. Subject is in good physical and mental health, in the opinion of the Investigator, based on medical history, physical examination, ECG, and vital signs findings, and biochemistry, hematology, virology, and urinalysis results prior to the first IMP dose. 7. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use effective contraception. Male subjects who practice true sexual abstinence (if consistent with the participant's preferred usual lifestyle) may also be included. Sterilized male subjects who have undergone vasectomy and have documented postoperative azoospermia may also be included. In addition, male subjects will not be allowed to donate sperm from the time of signing the ICF, throughout the duration of the study, and until 90 days after the last dose of IMP. 8. The condition of the subject's abdominal skin tissue must allow assessment of absorption and local safety of the planned SC injections, as determined by the Investigator. 9. Subject agrees to discontinue and refrain from all medications (including over-the-counter and / or prescription medications) except for occasional use of paracetamol (maximum dose 2 g / day and maximum 10 g / 2 weeks), antacid use, and ibuprofen (maximum dose 400 mg / day and not coadministered with antacids) from at least 2 weeks prior to the first efgartigimod dose until the final follow-up visit on day 78. 10. Subject agrees to refrain from strenuous exercise from at least 2 weeks prior to the first dose of efgartigimod until the final follow-up visit on Day 78. 11. Subjects are non-smokers and do not use nicotine-containing products. Non-smokers are defined as individuals who have quit smoking for at least 1 year prior to screening. 12. Subject has a negative nicotine analyte test at screening and on day -1. 13. Subject has a negative urine drug screen (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, sedatives, methadone, and tricyclic antidepressants) at screening and on day -1. 14. Subject has a negative alcohol urine test at screening and on day -1. 15. Subject has a body temperature of 35.2°C to 37.6°C at screening and day -1. Exclusion criteria 16. Subject previously participated in a clinical trial of efgartigimod and received efgartigimod. 17. Subject has known hypersensitivity or a history of severe allergic or anaphylactic reaction to one of the components of the efgartigimod formulation, in the opinion of the Investigator. 18. Subject tests positive at screening for any of the following conditions: a. Subjects have active Hepatitis B infection (acute or chronic) as determined by Hepatitis B serology (https: / / www.cdc.gov / hepatitis / hbv / pdfs / SerologicChartv8.pdf) at the time of screening. b. Subject is seropositive for Hepatitis C virus antibody (HCV Ab). c. The subject has positive human immunodeficiency virus (HIV) serology. 19. Subject has a clinically significant active or chronic uncontrolled bacterial, viral, or fungal infection at screening. 20. Subject with clinical evidence of other significant serious illness, subject who has undergone recent major surgery, or any other reason that may confound the results of the trial or expose the subject to undue risk. 21. Subject has total IgG<6g / L at screening. 22. Subject has the presence or sequelae of gastrointestinal, hepatic, renal, or any other condition known to potentially interfere with the absorption, distribution, metabolism, or excretion of efgartigimod. 23. Subject has a history of malignancy for ≥3 years prior to first dose of efgartigimod, unless deemed cured by appropriate treatment, with no evidence of recurrence. Subjects with the following cancers may be included at any time: A. Adequately treated basal cell or squamous cell skin cancer B. Carcinoma of the cervix in situ c. Carcinoma in situ of the breast or d. Incidental histologic findings of prostate cancer (TNM stage T1a or T1b) 24. Subject has a clinically significant abnormality detected on ECG recording in either rhythm or conduction (e.g., QTcF>450ms for males, QTcF>470ms for female subjects, or known long QT syndrome). First degree heart block or sinus arrhythmia is not considered a significant abnormality. 25. Subject has clinically relevant abnormalities detected in pre-dose vital sign measurements. 26. Subject has had significant blood loss (including blood donation >500 mL) or has received a transfusion of any blood product within 12 weeks prior to the (first) efgartigimod dose or has received a scheduled blood transfusion within 4 weeks after the end of the study. 27. Subject has been treated with any drug known to have a distinct potential for toxicity to major organs within the past 3 months prior to the first efgartigimod dose. 28. Subjects have a history of consuming more than 21 units of alcoholic drinks per week or a history of alcoholism or drug / chemical / substance abuse within 2 years prior to screening (Note: 1 unit = 330 mL of beer, 110 mL of wine, or 28 mL of spirits). Regular consumption of large amounts of coffee, tea (>6 cups per day), or equivalent within 3 weeks prior to the first dose will also be excluded. 29. Subject has received an investigational drug within 3 months or 5 half-lives of the drug (whichever is longer) prior to the first efgartigimod dose. 30. Subject has received a vaccination (e.g., influenza vaccine) within the past 4 weeks prior to screening. 31. Subject has received any systemic immunosuppressant within 6 months prior to the first efgartigimod dose. 32. Subject has received any systemic steroids within 3 months prior to the first efgartigimod dose. 33. Subject has received any monoclonal antibody within 6 months prior to the first efgartigimod dose. 34. Subject is an employee of the investigator or research center and will be directly involved in the proposed study or other studies under the direction of that investigator or research center, as well as a family member of the employee or research center. 35. Subject has any condition or situation which, in the opinion of the Investigator, makes the subject unlikely or unable to complete the study or to comply with study procedures and requirements. 36. Subject has any condition that impairs hemolysis. 37. Subject is a pregnant or lactating female, or intends to become pregnant during the study or within 90 days after the final dose. 38. Subject has a positive nasopharyngeal PCR test for SARS-CoV-2 on day -2 or day -1. 39. Subject has had any contact with a SARS-CoV-2 positive or COVID-19 patient within the past 2 weeks prior to admission to the Clinical Research Center.

[0256] Investigational drug, dose, and method of administration The efgartigimod IV formulation is available in a 20R vial with an extractable volume of 20 mL. Each vial can deliver 400 mg of efgartigimod.

[0257] The Efgartigimod-PH20 SC product is a 10R vial with an extractable volume of 10 mL and a concentration of 165 mg / mL. The vial is ready to use and can deliver 1650 mg of Efgartigimod.

[0258] Combination therapy From 2 weeks prior to the first dose of efgartigimod until the end of the study, subjects were prohibited from using any treatments or medications (including over-the-counter and / or prescription drugs, dietary supplements, nutritional supplements, vitamins, and / or herbal supplements such as ginkgo biloba and St. John's wort) except for paracetamol (maximum dose 2 g / day, maximum dose 10 g / 2 weeks), antacids, and ibuprofen (maximum dose 400 mg / day, not co-administered with antacids) as approved in consultation with the investigator.

[0259] All medications initiated from receipt of signed informed consent to the end of the study or during the study will be recorded.

[0260] Any medications started, stopped, increased, or decreased in response to an AE will also be recorded.

[0261] Objectives and Evaluation Items The primary objective of the study is to demonstrate that the PD efficacy of 1000 mg efgartigimod-PH20 SC injections four times per week is non-inferior to the PD efficacy of efgartigimod intravenous (IV) infusions at a dose of 10 mg / kg four times per week by comparing the percentage reduction in total immunoglobulin G (IgG) levels after 4 weeks (day 29), i.e., 1 week after the fourth dose, using a non-inferiority margin of 10%.

[0262] The secondary objectives of the study are as follows: To compare the PD efficacy of efgartigimod IV and efgartigimod-PH20 SC over time. To evaluate the PK of efgartigimod IV and efgartigimod-PH20 SC; and To evaluate the safety, tolerability, and anti-drug antibodies (ADA) of efgartigimod IV and efgartigimod-PH20 SC.

[0263] The primary endpoint of the study was the percent reduction in total IgG levels compared to baseline at Day 29 (Week 4), 7 days after the fourth IV or SC administration of efgartigimod.

[0264] Secondary endpoints of the study were: Percentage reduction in total IgG levels at week 4 compared to all other time points assessed; Percentage reduction in levels of IgG subtypes (IgG1, IgG2, IgG3, and IgG4) at all evaluation time points; Absolute values ​​and changes from baseline in total IgG levels and IgG subtype (IgG1, IgG2, IgG3, and IgG4) levels at all assessment times; Percentage reduction in total IgG levels and AUEC for each subtype at weekly intervals after each dose (weeks 1, 2, 3, and 4) for weeks 1 through 4 and throughout the study period (weeks 1 through 11); Serum levels of efgartigimod and derived PK parameters, and Clinical laboratory assessments, vital signs measurements, ECG recordings, and incidence and characterization of TEAEs.

[0265] Sample collection and analysis Pharmacokinetics / Pharmacodynamics Efgartigimod concentrations in serum were determined using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 300 ng / mL. Concentrations were calculated by interpolation from a calibration curve. Quality control samples were analyzed throughout the study. Their measured concentrations were used to determine the inter-run, overall precision, and accuracy of the assay.

[0266] Blood samples were taken on study days 1, 8, 15, 22, 23–27, 29, 36, 50, 64, and 78 (taken prior to each IV or SC efgaltigimod administration on treatment days) to determine levels of total IgG and IgG subtypes (IgG1, IgG2, IgG3, and IgG4).

[0267] Anti-drug antibody (ADA) evaluation For subjects in the SC treatment group, individual serum and plasma titers of ADA to efgartigimod and rHuPH20 were measured before and after SC injection of efgartigimod-PH20, respectively. For subjects in the IV treatment group, individual serum titers of ADA to efgartigimod were measured before and after IV infusion of efgartigimod.

[0268] Samples for ADA determination were taken on days 1, 15, 29, 50, and 78 of the study.

[0269] Primary endpoint analysis based on PD analysis The primary endpoint of the study was defined as the percent reduction in total IgG levels compared to baseline at day 29 (week 4), ie, 7 days after the fourth IV or SC administration of efgartigimod.

[0270] The hypotheses for non-inferiority assessment, with a 10% non-inferiority margin comparing SC with IV administration, were: H0:μ iv -μ sc ≧10 H1:μ iv -μ sc <10

[0271] μ iv and μ sc are the estimated mean % reduction in total IgG after 4 weeks (day 29) in subjects receiving efgartigimod as an IV or SC dose, respectively.

[0272] An analysis of covariance model (ANCOVA) was used to estimate the mean percentage reduction at week 4 for each treatment group as well as two-sided 95% CIs for the difference between both treatment groups. The model included the factors of treatment and baseline IgG levels as covariates.

[0273] The SC formulation was considered non-inferior to the IV formulation if the upper limit of the 95% CI (mean reduction with IV minus mean reduction with SC) was below a margin of 10%.

[0274] Primary endpoint analysis based on PD analysis Secondary PD outcomes included: Percentage reduction in total IgG levels at week 4 compared to all other time points assessed; Percentage reduction in levels of IgG subtypes (IgG1, IgG2, IgG3, and IgG4) at all evaluation time points; Absolute values ​​and changes from baseline in total IgG levels and IgG subtype (IgG1, IgG2, IgG3, and IgG4) levels at all assessment times; Percentage reduction in total IgG levels and AUEC for each subtype at weekly intervals after each dose (weeks 1, 2, 3, and 4) for weeks 1-4 and for the entire study period (weeks 1-11).

[0275] The same ANCOVA model was used for all secondary endpoints. All endpoints were summarized by time point or interval and by treatment group.

[0276] result Pharmacology An interim analysis of data from the study shows that absolute values ​​for total IgG and percent change from baseline in IgG levels over time for the efgartigimod-PH20 SC and efgartigimod IV groups are presented in Figure 16 and Figure 17, respectively.

[0277] The pattern of total IgG reduction was comparable between both treatment groups, achieving maximum reduction approximately 1 week after the last dose. Thereafter, mean total IgG slowly increased and returned to baseline by day 64 (i.e., 42 days after the last dose). Note that the number of observations after day 29 gradually declines due to the data cutoff (see Table 9). [Table 9]

[0278] The primary endpoint of the study was defined as the percentage reduction in total IgG from baseline one week after the fourth dose of study drug (i.e., day 29). Analysis of covariance (ANCOVA), including factors of treatment group and baseline IgG as covariates, was used to derive confidence intervals (CIs) for the difference in percent change from baseline in total IgG between the two treatment groups. From this model, 95% two-sided CIs were derived for the difference in percent change from baseline on day 29 versus the preceding weekly visit.

[0279] Based on this model, the difference in reduction of total IgG on day 29 was 1.23 percentage points (PP) (see Table 10), which means a slightly higher reduction in total IgG with efgartigimod-PH20 SC compared to efgartigimod IV. Although non-inferiority assessment was not an objective of the interim analysis, the results met the non-inferiority criteria, and the lower limit of the 95% CI of the difference between the treatment groups on day 29 (-2.68 PP) was already above the pre-specified non-inferiority margin of -10%. Indeed, the lower limits of the confidence intervals for the difference in reduction of total IgG on days 8, 15, and 22 were all found to be above this pre-specified non-inferiority margin (see Figure 18 and Table 10). [Table 10]

[0280] Results of the interim analysis suggest that the effect of four weekly SC injections of 1000 mg efgartigimod-PH20 SC was non-inferior to the effect of four weekly IV infusions with 10 mg / kg efgartigimod IV on percent change from baseline to day 29 in total IgG.

[0281] Following administration of efgartigimod-PH20 SC and efgartigimod IV, the mean percent change from baseline in total IgG levels decreased after each dose of efgartigimod, respectively, to a maximum reduction of 67.5% on day 29 (7 days after the last injection) and 68.0% on day 26 (4 days after the last infusion).

[0282] Baseline levels of total IgG, as well as levels at maximum reduction, were comparable between both treatment groups, i.e., 8003 μg / mL and 8968 μg / mL at baseline, and 2600 μg / mL and 2829 μg / mL at maximum reduction after efgartigimod-PH20 SC and efgartigimod IV, respectively (see Table 11). [Table 11]

[0283] Pharmacokinetics (PK) The PK profile following four weekly doses of 1000 mg efgartigimod-PH20 SC or 10 mg / kg efgartigimod IV is shown in Figure 19 and PK parameters are summarized in Table 12. For this interim evaluation, PK parameters were estimated based on scheduled sample collection times. [Table 12]

[0284] After multiple injections of 1000 mg efgartigimod-PH20 SC, a plateau phase consisting of one or more peaks was observed 24 to 120 hours after administration, suggesting a prolonged absorption phase with the SC route of administration. max The median was 48 hours, with individual values ​​ranging from 8 to 96 hours. Mean (SD) efgartigimod C after the fourth SC injection trough and C max were 19.9 (7.11) μg / mL and 46.6 (11.9) μg / mL, respectively.

[0285] Based on the average, C max and AUC 0-168h were approximately 80% and 15% lower, respectively, whereas C trough was approximately 50% higher after 1000 mg efgartigimod-PH20 SC compared with 10 mg / kg efgartigimod IV. 1 / 2 ) were comparable to the mean (SD) values ​​of 83.2 (16.3) and 75.6 (13.2) hours after 1000 mg efgartigimod-PH20 SC and 10 mg / kg efgartigimod IV, respectively.

[0286] conclusion The 1000 mg efgartigimod-PH20 SC fixed dose resulted in similar total IgG reduction and was therefore non-inferior to the 10 mg / kg efgartigimod IV dose. This was surprising because, when using a classical PK model to calculate an efgartigimod SC dose with equivalent bioavailability to the effective IV dose, the dose was twice the weight-based IV dose (efgartigimod SC bioavailability is approximately 47% of that of efgartigimod IV). Instead, the PK / PD modeling approach, based on matching PD parameters to a reference IV dose as described in Example 2, identified a fixed dose that was safe, effective, and likely to lead to increased patient compliance. * * *

[0287] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to be included within the scope of the appended claims.

[0288] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. 1. A unit dosage form for subcutaneous administration of a biologic, comprising: (a) the biologic exhibits PK responses in a subject upon intravenous administration; ｉｖ and P.D. ｉｖ RD ｉｖ and (b) the unit dosage form exhibits PK responses in a subject upon subcutaneous administration ｓｃ and P.D. ｓｃ RD of the biologic ｓｃ and (c) Said PK ｓｃ / PK ｉｖ The ratio is less than 0.8, and the PD ｓｃ / PD ｉｖ The unit dosage form, wherein the ratio is 0.9 to 1.

1.

2. 1. A unit dosage form for subcutaneous administration of a biologic, comprising: (a) the biologic exhibits PK responses in a subject upon intravenous administration; ｉｖ and B.L. ｉｖ RD ｉｖ and (b) the unit dosage form exhibits PK responses in a subject upon subcutaneous administration ｓｃ and B.L. ｓｃ RD of the biologic ｓｃ and (c) Said PK ｓｃ / PK ｉｖ The ratio is less than about 0.8, and the BL ｓｃ / BL ｉｖ The unit dosage form, wherein the ratio is from about 0.9 to about 1.

1.

3. 1. A unit dosage form for subcutaneous administration of a biologic, wherein the amount of a subcutaneous dose of the biologic in said unit dosage form is: (a) administering a subcutaneous dose of the biologic to a subject, wherein the biologic has a PK ｉｖ and B.L. ｉｖ RD ｉｖ administering, (b) the BL of the biological product ｓｃ determining (c) PK of the biologic ｓｃ determining (d) a BL of about 0.9 to about 1.1 ｓｃ / BL ｉｖ Ratio and PK less than about 0.8 ｓｃ / PK ｉｖ determining a subcutaneous dose that results in a ratio of

4. The unit dosage form according to any one of claims 1 to 3, wherein the subject is a healthy volunteer or a non-human animal.

5. A unit dosage form according to any one of claims 1 to 3 for use in the treatment of autoimmune diseases.

6. 1. A pharmaceutical composition for use in a method of treating a subject, comprising a subcutaneous dose of a biologic, wherein the subcutaneous dose of the biologic comprises: (a) administering a subcutaneous dose of the biologic to a subject, wherein the biologic has a PK ｉｖ and B.L. ｉｖ RD ｉｖ administering, (b) the BL of the biological product ｓｃ determining (c) PK of the biologic ｓｃ determining (d) a BL of about 0.9 to about 1.1 ｓｃ / BL ｉｖ Ratio and PK less than about 0.8 ｓｃ / PK ｉｖ determining a subcutaneous dose that results in a ratio of

7. The BL ｓｃ and the BL ｉｖ is the level of total IgG in a serum sample of the subject.

8. 8. The pharmaceutical composition of claim 6 or 7, wherein the biologic comprises or consists of a variant Fc region or an FcRn-binding fragment thereof that binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region.

9. 9. The pharmaceutical composition of claim 8, wherein the biological agent is efgartigimod.

10. Said RD ｉｖ The pharmaceutical composition of claim 9, wherein the dose is 10 mg / kg.

11. Said RD ｉｖ The pharmaceutical composition of claim 9, wherein the dose is 25 mg / kg.

12. 7. The pharmaceutical composition of claim 6, wherein the therapeutically effective amount of the biologic is (a) co-administered with a hyaluronidase enzyme, or (b) administered before or after the hyaluronidase enzyme.

13. 13. The pharmaceutical composition of claim 12, wherein the hyaluronidase enzyme comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-96 or is rHuPH20.

14. 14. The pharmaceutical composition of claim 13, wherein the amount of hyaluronidase enzyme is 1000 U / mL to 3000 U / mL, preferably 2000 U / mL.

15. 1. A pharmaceutical composition for use in treating myasthenia gravis in a human patient, comprising a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of said Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively; - the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously as a weekly dose of 950-1050 mg, regardless of the patient's weight; and - a reduction in total serum IgG in said patient of at least 60% compared to baseline IgG levels is obtained; Optionally, the weekly dose is about 1000 mg.

16. 1. A pharmaceutical composition for use in treating pemphigus vulgaris in a human patient, comprising a variant Fc region, or an FcRn-binding fragment thereof, wherein the Fc domain of said Fc region comprises amino acids Y, T, E, K, F, and Y at EU Kabat positions 252, 254, 256, 433, 434, and 436, respectively; - the variant Fc region, or FcRn-binding fragment thereof, is administered subcutaneously as a weekly dose of 1950 to 2050 mg, regardless of the patient's weight; and - a reduction in total serum IgG in said patient of at least 60% compared to baseline IgG levels is obtained; Optionally, the weekly dose is about 2000 mg.

17. 17. The pharmaceutical composition of claim 15 or 16, wherein the treatment comprises at least four weekly doses.

18. 17. The pharmaceutical composition of claim 15 or 16, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered in conjunction with a hyaluronidase enzyme, and optionally the hyaluronidase enzyme comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-96, or is rHuPH20.

19. 19. The pharmaceutical composition of claim 18, wherein the variant Fc region, or FcRn-binding fragment thereof, is administered before or after a hyaluronidase enzyme.

20. 17. The pharmaceutical composition of claim 15 or 16, wherein said percentage of total serum IgG reduction is achieved within one month of the first administration.

21. 17. The pharmaceutical composition of claim 15 or 16, wherein the maximum percentage of total serum IgG reduction is achieved within one month of the first administration.

22. 17. The pharmaceutical composition of claim 15 or 16, wherein the total IgG level is reduced to 2500-3500 μg / mL.

23. 17. The pharmaceutical composition of claim 15 or 16, wherein the total serum IgG in the patient is analyzed using a bioanalytical method, preferably ELISA or an automated diagnostic analyzer (IVD).

24. 17. The pharmaceutical composition of claim 15 or 16, wherein at least one of the IgG subtypes is reduced.

25. 17. The pharmaceutical composition of claim 15 or 16, wherein the variant Fc region is efgartigimod.

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