Intravenous FCRN antagonist formulations and methods of use thereof

Abstract

Provided herein are pharmaceutical compositions comprising an FcRn antagonist (e.g., efgartigimod, or a biosimilar version thereof) and methods of use thereof for reducing the serum IgG level of a subject in need thereof (e.g., a subject having an autoimmune disease such as generalized myasthenia gravis (gMG)).

Description

INTRAVENOUS FCRN ANTAGONIST FORMULATIONS AND METHODS OF USETHEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 645,349, filed May 10, 2024, the entire contents of which are hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to pharmaceutical compositions (e.g., formulations) and approved products comprising an FcRn antagonist (e.g., efgartigimod, or a biosimilar version thereof) and methods of use thereof for reducing the serum IgG level of a subject in need thereof (e.g., a subject having an autoimmune disease such as generalized myasthenia gravis (gMG)).BACKGROUND

[0003] VYVGART® (efgartigimod alfa-fcab) is a neonatal Fc receptor (FcRn) antagonist that, as of April 2024, is indicated for the treatment of gMG in adult patients who are antiacetylcholine receptor (AChR) antibody positive and for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). VYVGART was first approved with a first label in the United States by the Food and Drug Administration (FDA) in 2021 for the treatment of gMG on the basis of clinical trial data from the ADAPT study (NCT03669588). VYVGART was subsequently approved for the treatment of gMG in Japan, Europe, United Kingdom, Israel, China, and Canada during 2022-2023 and for the treatment of chronic ITP in Japan in 2024.

[0004] VYVGART, as initially approved, was described as a sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow solution supplied in a single-dose vial for infusion after dilution. Each 20 mL single-dose vial contained 400 mg of efgartigimod alfa-fcab at a concentration of 20 mg / mL. In addition, each mL of solution contained L-arginine hydrochloride (31.6 mg), polysorbate 80 (0.2 mg), sodium chloride (5.8 mg), sodium phosphate dibasic anhydrous (2.4 mg), sodium phosphate monobasic monohydrate (1.1 mg) and water for injection, USP, at a pH of 6.7.

[0005] In the pharmaceutical industry, the path from drug discovery to product approval is riddled with uncertainty. The innovations that are described in an approved product label typicallyinclude data describing the diseases / conditions suitable for use, dosing, clinical trial results, safety considerations, formulations, and the characteristics of the molecule itself. That mandatory data compilation is a product of years of effort and innovation to prove that an investigational agent is safe and effective for use to treat a given disease or condition. From time to time, as new data is generated, regulatory agencies require more evidence to establish new uses or conditions of use of a molecule. Often, these uses, or conditions of use, are reported in a product label, product insert, or summary of product characteristics. Such new and inventive concepts are exactly the kind of innovation that the patent system is designed to protect for inventors and for patients.

[0006] In clinical trials of efgartigimod as an investigational agent, hypersensitivity reactions, including rash, angioedema, and dyspnea, were mild to moderate, occurred within one hour to three weeks of administration, and did not lead to treatment discontinuation. Initial prescribing information in the original approved product label from the FDA stated to monitor patients during administration and for one hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurred during administration, it was indicated to discontinue VYVGART infusion and to institute appropriate supportive measures if needed.

[0007] No infusion-related reactions were observed and no contraindications were described in the original approved product label for VYVGART.

[0008] At the time of initial approval, immunization with vaccines during VYVGART treatment had not been studied. The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine was unknown. Because VYVGART causes a reduction in IgG levels, immunization with live-attenuated or live vaccines was not recommended during treatment with VYVGART. Initial prescribing information from the FDA stated to evaluate the need to administer age-appropriate immunizations according to immunization guidelines before initiation of a new treatment cycle with VYVGART. Similarly, patients were advised to complete age-appropriate vaccines according to immunization guidelines prior to initiation of a new treatment cycle with VYVGART.SUMMARY

[0009] The instant disclosure is directed to pharmaceutical compositions and approved products comprising an FcRn antagonist (e.g., efgartigimod, or a biosimilar version thereof) and methods of use thereof for reducing the serum IgG level of a subject in need thereof e.g., a subject having an autoimmune disease such as gMG).

[0010] These methods include new and specific monitoring for hypersensitivity reactions selected from anaphylaxis and hypotension leading to syncope, and monitoring for infusion-related reactions that have been observed since the initial approval of VYVGART in December of 2021 and taking new appropriate measures mandated by regulatory authorities to mitigate these reactions. These methods also include administration of a vaccine other than a live-attenuated or live vaccine at any time during treatment with efgartigimod, or a biosimilar version thereof, based upon postapproval studies in VYVGART-treated patients receiving vaccinations which enabled updates to the label described herein. These methods also include administration of a vaccine other than a live vaccine at any time during treatment with efgartigimod, or a biosimilar version thereof, based upon post-approval studies in VYVGART-treated patients receiving vaccinations which enabled updates to the label described herein.

[0011] In order to enhance manufacturing and improve long-term stability, a new optimized second-generation IV drug product (Efgartigimod IV Gen2) was developed as disclosed and claimed herein. Specifically, provided herein are pharmaceutical compositions of efgartigimod, or a biosimilar version thereof, in solution for injection.

[0012] Provided herein are approved products comprising: efgartigimod, or a biosimilar version thereof, in solution for injection.

[0013] Also provided herein are biological products comprising efgartigimod in a solution for injection, wherein the biological product is packaged, and wherein the package includes a label that identifies the biological product as indicated as monotherapy for the treatment of gMG.

[0014] Kits comprising the disclosed approved products or biological products are also provided.

[0015] Provided herein are methods for treating gMG in a patient, the methods comprising administering the disclosed approved products to the patient in an amount and manner that is described in a label for the approved product.

[0016] Provided herein are methods of offering for sale an approved product, said methods comprising offering for sale such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with gMG.

[0017] Thus, in one aspect, the instant disclosure provides a pharmaceutical composition comprising about 20 mg / mL of a neonatal Fc receptor (FcRn) antagonist, about 10.5 mg / mL L- arginine hydrochloride, about 1.4 mg / mL L-histidine, about 2.2 mg / mL L- histidine hydrochloridemonohydrate, about 1.5 mg / mL L-methionine, about 0.4 mg / mL polysorbate 80, about 4.1 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, at a pH of about 6.0, wherein the FcRn antagonist comprises or consists of a variant IgG Fc region, or FcRn-binding fragment thereof, wherein the variant IgG Fc region, or FcRn-binding fragment thereof, comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or a heterodimer, and wherein the first Fc domain and the second Fc domain each comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprise or consist of an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 4.

[0018] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the population consists of a dimer of a first Fc domain and a second Fc domain, and wherein the population comprises a first subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the first subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3; and at least one of: a second subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the second subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 13, respectively; a third subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the third subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 10, respectively; a fourth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the fourth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein twoasparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated; a fifth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the fifth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated; a sixth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the sixth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively; a seventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the seventh subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized; an eighth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eighth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 2; a ninth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the ninth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 7, respectively; a tenth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the tenth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized; and an eleventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eleventh subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue and a tryptophan residue, in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0019] In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0020] Also provided herein is a pharmaceutical composition comprising 20 mg / mL of an FcRn antagonist, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L- histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0, wherein the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0021] In some embodiments, the pharmaceutical composition is sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow.

[0022] In some embodiments, the pharmaceutical composition is for intravenous administration.

[0023] In some embodiments, the pharmaceutical composition is contraindicated in patients with serious hypersensitivity to efgartigimod products or to any composition excipients. In some embodiments, the hypersensitivity is anaphylaxis and / or hypotension leading to syncope.

[0024] Also provided herein is a single-dose vial comprising any pharmaceutical composition described above and herein. In some embodiments, the single-dose vial contains 20 mL of the pharmaceutical composition. In some embodiments, the single-dose vial contains 400 mg of the FcRn antagonist.

[0025] Also provided herein is a method of reducing serum IgG levels in a subject in need thereof, the method comprising administering to the subject an effective amount of any pharmaceutical composition described above and herein, or an effective amount of any pharmaceutical composition contained within the single-dose vial described above and herein.

[0026] In some embodiments, the subject has an autoimmune disease. In some embodiments, the autoimmune disease is myasthenia gravis (MG). In some embodiments, the MG is generalized MG (gMG). In some embodiments, the subject is anti -acetylcholine receptor (AChR) antibody positive. In some embodiments, the subject is anti-AChR antibody negative. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0027] In some embodiments, the pharmaceutical composition is administered to the subject at a dose of 10 mg / mL of the FcRn antagonist. In some embodiments, the pharmaceutical composition is administered to the subject once weekly or once biweekly.

[0028] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and the pharmaceutical composition is diluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical compositionrequired, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using polyethylene (PE), polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0029] Also provided herein is a method of treating MG in a subject in need thereof, the method comprising administering to the subject an effective amount of any pharmaceutical composition described above and herein, or an effective amount of the pharmaceutical composition contained within any single-dose vial described above and herein. In some embodiments, the MG is generalized MG (gMG) or ocular MG (oMG). In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject is anti-AChR antibody negative. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0030] In some embodiments, the pharmaceutical composition is administered to the subject at a dose of 10 mg / mL of the FcRn antagonist. In some embodiments, the pharmaceutical composition is administered to the subject once weekly or once biweekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0031] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0032] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within the single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0033] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion; monitoring the subject for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope; and initiating an appropriate measure to mitigate the hypersensitivity reaction when detected.

[0034] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0035] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L- histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0036] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition isdiluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0037] In some embodiments, the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the pharmaceutical composition is administered to the subject once weekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0038] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0039] In some embodiments, the anaphylaxis and / or hypotension occurs during administration or within 1 hour of administration of the pharmaceutical composition to the subject. In some embodiments, the subject is monitored during administration of the pharmaceutical composition to the subject and for 1 hour thereafter. In some embodiments, the appropriate measure comprises discontinuation of the intravenous infusion. In some embodiments, the appropriate measure comprises permanent discontinuation of treatment with the pharmaceutical composition. In some embodiments, the appropriate measure comprises seeking medical attention.

[0040] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidalimmunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0041] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion, wherein the subject has been informed of the signs and symptoms of a hypersensitivity reaction and advised to contact their healthcare provider immediately should they occur, wherein the hypersensitivity reaction is selected from the group consisting of anaphylaxis and hypotension leading to syncope.

[0042] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0043] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L- histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0044] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0045] In some embodiments, the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the pharmaceutical composition isadministered to the subject once weekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0046] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0047] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0048] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion; monitoring the subject for an infusion-related reaction; and discontinuing the infusion when an infusion-related reaction is detected. In some embodiments, the method further comprises: rechallenging the subject with the pharmaceutical composition when the infusion-related reaction is mild-to-moderate, wherein the rechallenging comprises one or more of the following: close clinical observation, slower infusion rate, and pre-m edi cation. In some embodiments, the rechallenging comprises close clinical observation, slower infusion rate, and pre-medication. In some embodiments, the method further comprises initiating appropriate therapy when the infusion-related reaction is severe. In some embodiments, the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

[0049] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0050] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0051] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L- histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of6.0.

[0052] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0053] In some embodiments, the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the pharmaceutical composition is administered to the subject once weekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0054] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequenttreatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0055] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0056] In some embodiments, the infusion-related reaction occurs during administration or within 1 hour of administration of the pharmaceutical composition to the subject. In some embodiments, the subject is monitored during administration of the pharmaceutical composition to the subject and for 1 hour thereafter.

[0057] In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0058] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion, wherein the subject has been advised of the potential risk of an infusion-related reaction. In some embodiments, the infusion-related reaction is selected from hypertension, chills, shivering, chest pain, abdominal pain, and back pain.

[0059] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0060] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L- histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0061] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition isdiluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0062] In some embodiments, the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the pharmaceutical composition is administered to the subject once weekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0063] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0064] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0065] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion; and administering to the subject a vaccine as needed at any time during treatment with the pharmaceuticalcomposition, wherein the vaccine is not a live-attenuated or live vaccine. In some embodiments, the vaccine is not a live vaccine.

[0066] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0067] In some embodiments, the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L- histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0068] In some embodiments, the pharmaceutical composition is diluted prior to use. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion. In some embodiments, the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by: calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle; diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0069] In some embodiments, the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the pharmaceutical composition is administered to the subject once weekly. In some embodiments, the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

[0070] In some embodiments, the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within1 month. Tn some embodiments, the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0071] In some embodiments, the vaccine is a COVID- 19 vaccine, an influenza vaccine, a pneumococcal vaccine, a shingles vaccine, a human papillomavirus (HPV) vaccine, or a respiratory syncytial virus (RSV) vaccine. In some embodiments, the COVID-19 vaccine is selected from tozinameran, elasomeran, NVX-CoV2373, Ad26.COV2.S, AZD1222, CoronaVac, BBV152, AD5- nCOV, MVC-COV1901, BBIBP-CorV, and Gam-COVID-Vac. In some embodiments, the influenza vaccine is selected from Audenz, Fluad Quadrivalent, Fluad, Afluria Quadrivalent, Afluria Quadrivalent Southern Hemisphere, Flucelvax Quadrivalent, Flulaval Quadrivalent, Afluria, Afluria Southern Hemisphere, FluLaval, FluMist, Fluarix, Fluvirin, Agriflu, Fluzone, Fluzone High-Dose, Fluzone Intradermal, Flucelvax, Flublok, Flublok Quadrivalent, FluMist Quadrivalent, Fluarix Quadrivalent, and Fluzone Quadrivalent. In some embodiments, the pneumococcal vaccine is selected from Pneumovax 23, Prevnar 13, VAXNEUVANCE™, and Prevnar 20. In some embodiments, the shingles vaccine is SHINGRIX. In some embodiments, the HPV vaccine is selected from GARDASIL® 9, GARDASIL®, and CERVARIX®. In some embodiments, the RSV vaccine is selected from AREXVY® and ABRYSVO™.

[0072] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0073] Also provided herein is an approved product comprising efgartigimod for treatment of gMG. In some embodiments, the product is approved for treatment of gMG in adult patients who are anti-AChR antibody positive. In some embodiments, the product is approved for treatment of gMG in adult patients who do not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0074] In some embodiments, the product is provided in a single-dose vial containing 20 mg / mL efgartigimod, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0075] In some embodiments, the product is for administration via intravenous infusion. In some embodiments, the product is administered via intravenous infusion over 1 hour.

[0076] In some embodiments, the product induces an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

[0077] In some embodiments, the product induces a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope. In some embodiments, the anaphylaxis or hypotension leading to syncope occurs during or within 1 hour of administration of the product.

[0078] In some embodiments, the product is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof.

[0079] In some embodiments, the product induces an infusion-related reaction. In some embodiments, the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, one or more subsequent doses of the product are administered with close clinical observation, slower infusion rates, and pre-medications when a mild-to-moderate infusion-related reaction occurs during administration of the product.

[0080] In some embodiments, the product is co-administered with a vaccine, wherein the vaccine is not a live-attenuated or live vaccine. In some embodiments, the product is co-administered with a vaccine, wherein the vaccine is not a live vaccine.

[0081] Also provided is a biosimilar of the approved product described above and herein.

[0082] Also provided is a biological product that is bioequivalent to the approved product described above and herein.

[0083] Also provided is a kit comprising: any pharmaceutical composition described above and herein, any single-dose vial described above and herein, any approved product described above and herein, any biosimilar described above and herein, or any biological product described above and herein, and a label.

[0084] In some embodiments, the label includes a contraindication in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof. In someembodiments, the label includes a warning for hypersensitivity reactions selected from anaphylaxis and hypotension leading to syncope. In some embodiments, the label states infusion discontinuation when anaphylaxis or hypotension leading to syncope occur during or within 1 hour of administration of the product. In some embodiments, the label includes a warning for infusion-related reactions selected from hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, the label states to discontinue infusion and initiate appropriate therapy when a severe infusion-related reaction occurs during administration of the product. In some embodiments, the label states that patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications when a mild-to-moderate infusion-related reaction occurs during administration of the product. In some embodiments, the label includes data demonstrating an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

[0085] Also provided herein is a method of treating gMG in a subject in need thereof, the method comprising administering any approved product described above and herein, any biosimilar described above and herein, or any biological product described above and herein to the subject.

[0086] In some embodiments, the approved product, biosimilar, or biological product is administered to the subject once weekly. In some embodiments, the approved product, biosimilar, or biological product is administered to the subject once weekly for 4 weeks.

[0087] In some embodiments, the approved product, biosimilar, or biological product is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the approved product, biosimilar, or biological product within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the approved product, biosimilar, or biological product for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the approved product, biosimilar, or biological product for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0088] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0089] In some embodiments, the method further comprises monitoring the subject for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope; and initiating an appropriate measure to mitigate the hypersensitivity reaction when detected.

[0090] In some embodiments, the method further comprises monitoring the subject for an infusion-related reaction; and discontinuing the infusion when an infusion-related reaction is detected. In some embodiments, the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

[0091] In some embodiments, the method further comprises administering to the subject a vaccine as needed at any time during treatment with the approved product, biosimilar, or biological product, wherein the vaccine is not a live-attenuated or live vaccine. In some embodiments, the vaccine is not a live vaccine.

[0092] In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.DETAILED DESCRIPTIONDefinitions

[0093] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art in the technical field of the invention.

[0094] As used herein, the term “approved product” refers to a biological product approved by at least one regulatory agency for introduction into commerce. As used herein, the term “regulatory agency” refers to one of the following: the United States Food and Drug Administration (FDA), the European Medicines Agency of the European Union (EMA), the Pharmaceuticals and Medical Devices Agency of Japan (PMDA), and the National Medical Products Administration of China (NMPA).

[0095] As used herein, the terms “biological product” or “biologic” can be used interchangeably to refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologies can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, ormay be living entities such as cells and tissues. A biological product comprises a population of biological molecules (e.g., a population of individual protein molecules). Many therapeutic proteins are produced by recombinant DNA technology in animal or microbial host cells. During the manufacturing process, these engineered host cells make many copies of a therapeutic protein with the same amino acid sequence. Changes can occur to one or more amino acids in a given protein through post-translational modifications, such as glycosylation. Therefore, although a single protein is being manufactured, the individual protein molecules can be slightly different from each other. The resulting biological product ends up being a mix of these individual protein molecules with various sugars attached to them. Other post-translational modifications, such as oxidation or deamidation, or truncations may also be present. This is true for approved products, reference products, biosimilars, and interchangeable biosimilars.

[0096] A biological product may comprise other active or inactive ingredients. Inactive ingredients include formulation excipients. The term “dosage form,” as used herein refers to the physical form in which a biological product is produced and dispensed, such as, for example, an injectable, a tablet, or a capsule.

[0097] In some embodiments, the approved product is a biological product containing efgartigimod that has been approved for use in treating humans with generalized myasthenia gravis (gMG) and is formulated for delivery by intravenous infusion in a 10 mg / kg dose. An example of an “approved product” is the approved product described in Example 2.

[0098] In some embodiments, the approved product is provided in a single-dose vial containing 400 mg of efgartigimod at a concentration of 20 mg / mL and each milliliter of solution comprises:L-arginine hydrochloride (31.6 mg), polysorbate 80 (0.2 mg), sodium chloride (5.8 mg), sodium phosphate dibasic anhydrous (2.4 mg), sodium phosphate monobasic monohydrate (1.1 mg) and water for injection, USP, at a pH of 6.7; orL-arginine hydrochloride (10.5 mg), L-histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), L-methionine (1.5 mg), polysorbate 80 (0.4 mg), sodium chloride (4.1 mg), sucrose (20.5 mg), and water for injection, USP, at a pH of 6.0.

[0099] In some embodiments, the approved product is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any formulation excipients thereof. In some embodiments, hypersensitivity to efgartigimod alfa products is anaphylaxis or hypotension leading to syncope.

[0100] In some embodiments, the approved product induces an infusion-related reaction. In some embodiments, the infusion-related reaction is hypertension, chills, shivering, thoracic pain, abdominal pain, or back pain.

[0101] In some embodiments, when the approved product is administered in a 10 mg / kg infusion dose to subjects or a patient population having myasthenia gravis, it induces a statistically significant increase in MG-ADL response rate, and / or in QMG response rate compared to the respective response rate in a patient population receiving placebo. In some embodiments, when the approved product is administered in a 10 mg / kg infusion dose to subjects or a patient population having generalized myasthenia gravis, it induces an MG-ADL response rate of 67.7%, and a QMG response rate of 63.1%, compared to 29.7% and 14.1% response in a placebo population.

[0102] In some embodiments, when using the approved product, it is recommended to inform patients of hypersensitivity reactions and to monitor patients for hypersensitivity reactions during administration and for 1 hour after administration, where the hypersensitivity reactions are selected from the group consisting of anaphylaxis and hypotension leading to syncope. If hypersensitivity is observed in a patient during or after administration of the approved product, appropriate measures to mitigate said hypersensitivity reactions are instituted, which include discontinuing use.

[0103] In some embodiments, when using the approved product, it is recommended to monitor patients for infusion-related reactions during administration and for 1 hour after administration, where the reactions are selected from the group consisting of hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain within an hour of administration. As used herein, the terms “thoracic pain” and “chest pain” are used interchangeably. If an infusion-related reaction is severe, the patient should discontinue treatment with the approved product and initiate appropriate therapy. If an infusion-related reaction is mild to moderate, the patient should be rechallenged with the approved product with close clinical observation, slower infusion rates, and pre-medications.

[0104] In some embodiments, the approved product is further defined as follows:-is provided in a single-dose vial containing 400 mg of efgartigimod at a concentration of 20 mg / mL and each milliliter of solution comprises:L-arginine hydrochloride (31.6 mg), polysorbate 80 (0.2 mg), sodium chloride (5.8 mg), sodium phosphate dibasic anhydrous (2.4 mg), sodium phosphate monobasic monohydrate (1.1 mg) and water for injection, USP, at a pH of 6.7; orL-arginine hydrochloride (10.5 mg), L-histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), L-methionine (1.5 mg), polysorbate 80 (0.4 mg), sodium chloride (4.1 mg), sucrose (20.5 mg), and water for injection, USP, at a pH of 6.0; and-is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any formulation excipients thereof; and-when administered in a 10 mg / kg infusion dose to subjects or a patient population having myasthenia gravis, induces a statistically significant increase in MG-ADL response rate, and / or in QMG response rate compared to the respective response rate in a patient population receiving placebo; and-when administered, may induce a hypersensitivity reaction selected from anaphylaxis and hypotension leading to syncope during or within an hour of administration; and-when administered, may induce an infusion-related reaction selected from hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain during or within an hour of administration; and-when using, it is recommended to inform patients of hypersensitivity reactions and to monitor patients for hypersensitivity reactions during administration and for 1 hour after administration, where the hypersensitivity reactions are selected from the group consisting of anaphylaxis and hypotension leading to syncope, and if hypersensitivity is observed in a patient during or after administration of the approved product, appropriate measures to mitigate said hypersensitivity reactions are instituted, which include discontinuing use; and-when using, it is recommended to monitor patients for infusion-related reactions during administration and for 1 hour after administration, where the reactions are selected from the group consisting of hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain within an hour of administration, and if an infusion-related reaction is severe, the patient should discontinue treatment with the approved product and initiate appropriate therapy, and if an infusion-related reaction is mild to moderate, the patient should be rechallenged with the approved product with close clinical observation, slower infusion rates, and pre-medications.

[0105] In some embodiments, the approved product is a product approved under Biologies License Application (BLA) 761195 or European Medicines Agency (EMA) Product Number EMEA / H / C / 005849.

[0106] As used herein, the term “biosimilar” refers to a biological product approved by a regulatory agency that is highly similar to and has no clinically meaningful differences from a reference product. A biosimilar is a type of approved product. A biosimilar can be shown to be highlysimilar to the reference product by analyzing (i.e., characterizing) the structure and function of both the reference product and the proposed biosimilar and comparing characteristics of the products, such as purity, chemical identity, and bioactivity. Note that differences, such as oligosaccharide profdes, amino acid truncations or extensions, oxidation, deamidation, etc., may exist between biological products produced using different cell lines or manufacturing techniques and that a biological product may behave differently in patients if manufactured using a different cell line or a different methodology. However, differences, such as acceptable within-product variations, between the reference product and the proposed biosimilar can be present so long as the biosimilar is highly similar and has no clinically meaningful differences. Similarly, minor differences between the reference product and the proposed biosimilar in clinically inactive components are acceptable so long as the biosimilar is highly similar and has no clinically meaningful differences.

[0107] As used herein, “no clinically meaningful differences” is determined in terms of safety, purity, and potency. For example, a biosimilar is compared to and evaluated against a reference product to verify that the biosimilar has no clinically meaningful differences in terms of safety, purity, and potency from the reference product. In some embodiments, a determination of no clinically meaningful differences between a biosimilar and a reference product is based upon data derived from: (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including, for example, assessment of toxicity); and / or (c) a clinical study or studies (including, for example, assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar. A biosimilar may be an interchangeable biosimilar that may be substituted for the reference product at a pharmacy without intervention of a prescribing healthcare professional. To meet a standard of “interchangeability,” the biosimilar is expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. In some embodiments, the biosimilar utilizes the same mechanisms of action as the reference product for the proposed conditions of use, to the extent the mechanisms are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approvedfor the reference product. In some embodiments, the route of administration, the dosage form, and / or the strength of a biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure, and potent.

[0108] As used herein, "bioequivalent" or "bioequivalence" is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site(s) of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

[0109] A determination of “biosimilarity” or “bioequivalence” or “interchangeability” may be made according to any of the standards defined by the FDA, EMA, PMDA, or NMPA. A company seeking approval to market a generic equivalent or biosimilar in the United States must refer to the reference product in its 35 l(k) BLA. For example, a 35 l(k) BLA applicant relies on the FDA's finding that a previously approved product, z.c., the reference product, is safe and effective, and must demonstrate, among other things, that the proposed biosimilar is the same as the reference product in certain ways. Specifically, with limited exceptions, a biological product for which an 351 (k) BLA is submitted must have, among other things, the same active ingredient(s), mechanism(s) of action for the proposed condition(s) of use (but only to the extent the mechanism(s) are known for the reference product), condition(s) of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the reference product. In Europe, a company may choose to develop and seek marketing authorisation for a “biosimilar”, wherein a biosimilar is a biological medicinal product highly similar to a reference medicinal product. The reference medicinal product is a biological product already having been granted a marketing authorisation in the European Union (EU) on the basis of a complete dossier. The legal basis for authorisation of biosimilars in Europe comes from the provisions of Article 10(4) of Directive 200I / 83 / EC and Article 6 of Regulation (EC) 726 / 2004. The legal basis of Article 10(4) of Directive 2001 / 83 / EC and Annex I, Part II, Section 4 of the Directive lays down the requirements for Marketing Authorization Applications (MAAs) based on the demonstration of the similar nature of the two biological medicinal products. Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety, and efficacy, of the similar biological medicinal product and the chosen reference medicinal product authorised in the EU.

[0110] The term “reference product” refers to a product that is approved by a regulatory agency (e.g., the approved product) against which a proposed biosimilar is compared. A reference product is approved based on, among other things, a full complement of safety and effectiveness data. A proposed biosimilar product is compared to, and evaluated against, a reference product to ensure that the product is highly similar and has no clinically meaningful differences. In some embodiments, the reference product is approved in at least one of the U.S., Europe, China, or Japan. In some embodiments, the reference product is an approved product as defined herein. In some embodiments, the reference product is a biological product, licensed in the United States under section 351(a) of the Public Health Service (PHS) Act, against which a biological product is evaluated in a BL A submitted under section 351 (k) of the PHS Act (i.e., 35 l(k) BLA).

[0111] As used herein, the terms “label,” “product label,” or “approved product label” refer to information provided to a patient and / or healthcare provider which provides relevant information regarding the approved product. Such information includes, without limitation, one or more of: the description of the approved product, clinical pharmacology, indications (uses for the approved product), contraindication (who should not take the approved product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how the approved product is supplied, safety information for the patient, or any combination thereof. In some embodiments, the label identifies efgartigimod and provides instructions for its use in a patient.

[0112] As used herein, the term “FcRn” refers to a neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as set forth in RefSeq NM 004107. The amino acid sequence of the corresponding protein is set forth in RefSeq NP 004098.

[0113] As used herein, the term “FcRn antagonist” refers to any agent that binds specifically to FcRn and inhibits the binding of immunoglobulin to FcRn (e.g., human FcRn).

[0114] As used herein, the term “Fc domain” refers to the portion of a single immunoglobulin heavy chain beginning in the hinge region and ending at the C-terminus of an antibody. Accordingly, a complete Fc domain comprises at least a portion of a hinge region (e.g., upper, middle, and / or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the term “Fc domain” refers to the portion of a single immunoglobulin heavy chain comprising both the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain comprises at least a portion of a hinge region (e.g., upper, middle, and / or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not include the hinge region.

[0115] As used herein, the term “hinge region” refers to the portion of a heavy chain molecule that joins the CHI domain to the CH2 domain. In some embodiments, the hinge region is at most 70 amino acid residues in length. In some embodiments, this hinge region comprises approximately 11- 17 amino acid residues and is flexible, thus allowing the two N-terminal antigen binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. Hinge regions can be subdivided into three distinct domains: upper, middle, and lower hinge regions. The FcRn antagonists of the instant disclosure can include all or any portion of a hinge region. In some embodiments, the hinge region is from an IgGl antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 23).

[0116] As used herein, the term “Fc region” refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region can be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is homodimeric. The Fc region can be derived from any native immunoglobulin. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the IgG heavy chain constant region is an IgGl, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed from an IgGl heavy chain constant region. In some embodiments, the IgGl heavy chain constant region comprises a Glml(a), Glm2(x), Glm3(f), or Glml7(z) allotype, see, e.g., Jefferis and Lefranc, 2009 and de Taeye et al., 2020.

[0117] As used herein, the term “variant Fc region” refers to an Fc region with one or more alteration(s) relative to a native Fc region. Alterations can include amino acid substitutions, additions and / or deletions, linkage of additional moieties, and / or alteration of the native glycans. The term encompasses heterodimeric Fc regions where each of the constituent Fc domains is different. The term also encompasses single chain Fc regions where the constituent Fc domains are linked together by a linker moiety.

[0118] As used herein the term “FcRn binding fragment” refers to a portion of an Fc region that is sufficient to confer FcRn binding.

[0119] As used herein, the term “EU position” refers to the amino acid position in the EU numbering convention for the Fc region described in Edelman, GM et al., Proc. Natl. Acad. USA,1969; 63, 78-85, and Kabat et al., in “Sequences of Proteins of Immunological Interest,” U.S. Dept. Health and Human Services, 5thedition, 1991.

[0120] As used herein, the term “baseline” refers to a measurement in a patient, e.g., in a patient’s blood, prior to the first administration (e.g., intravenous administration) of a treatment (e.g., an FcRn antagonist).

[0121] As used herein, the term “treat,” “treating,” and “treatment” refer to therapeutic or preventative measures described herein. The methods of “treatment” employ administration of a polypeptide to a subject having a disease or disorder, or predisposed to having such a disease or disorder, in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.

[0122] As used herein, the term “effective amount” in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect.

[0123] As used herein, the term “dose” or “dosing” refers to an amount of an agent administered to a subject in a single administration.

[0124] As used herein, the terms “fixed dose” or “flat dose” both refer to a dose that does not vary based upon a characteristic (e.g., body mass, e.g., within a set range; sex; age, e.g., within a set range; etc.) of the subject.

[0125] As used herein, the term “subject” or “patient” or “participant” may be used interchangeably and includes any human or non-human animal. In an embodiment, the subject or patient or participant is a human or non-human mammal. In an embodiment, the subject or patient or participant is a human.

[0126] As used herein, the term “about” or “approximately” when referring to a measurable value, such as a dosage, encompasses variations of ±5% of a given value or range, as are appropriate to perform the methods disclosed herein.

[0127] As used herein, the term “single-dose vial” refers to a vial of liquid medication intended for parenteral administration (e.g., intravenous infusion) that is meant for use in a single patient for a single administration.

[0128] As used herein, the term “preservative free” refers to compositions (e.g., pharmaceutical compositions) that do not contain amounts of preservatives that are detectable using methods known in the art.

[0129] As used herein, the term “MG-ADL response” refers to a reduction of > 2 points on MG-ADL score compared to baseline, for at least 4 consecutive weeks, where the first of the reductions occurs at the latest 1 week after the last treatment. The Myasthenia Gravis Activities of Daily Living (MG-ADL) scale is an 8-item patient-reported scale to assess MG symptoms and their effects on daily activities. It evaluates the capacity to perform different activities of daily living such as talking, chewing, swallowing, breathing, brushing the teeth / combing the hair, or arising from the chair and it also assesses double vision and eyelid droop. The 8 items of the MG-ADL were derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0-24, where higher scores indicate more severe impairments.

[0130] As used herein, the term “QMG response” refers to a reduction of > 3 points on QMG score compared to baseline, for at least 4 consecutive weeks, where the first of the reductions occurs at the latest 1 week after the last treatment. The Quantitative Myasthenia Gravis (QMG) scale is a standardized quantitative strength scoring system developed specifically for MG. The QMG has been validated and has been used by the investigators in several trials. It consists of 13 items that assess ocular, bulbar, and limb function. Out of the 13 items, 6 are timed tests of endurance measured in seconds. Each item has a possible score from 0-3. The total possible score is 39, where higher scores indicate more severe impairments.

[0131] As used herein, the term “Myasthenia Gravis Foundation of America (MGFA) clinical classification system” refers to the classification system designed by the Task Force of the Medical Scientific Advisory Board of the MGFA published in 2000 (Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Inc. Neurology 55: 16-23 (2000)). The MGFA classification system defines classes of MG based on clinical symptoms as follows: Class I- any ocular muscle weakness, all other muscle strength is normal; Class II- mild weakness affecting other than ocular muscles, may also have ocular muscle weakness of any severity; Class Ila- predominantly affecting limb muscles, axial muscles, or both, may also have lesser involvement of oropharyngeal muscles, respiratory muscles, or both; Class lib- predominantly affecting oropharyngeal muscles, respiratory muscles, or both, may also have lesser or equal involvement of limb muscles, axial muscles, or both; Class III- moderate weakness affecting other than ocular muscles, may also have ocular muscle weakness of any severity; Class Illa- predominantly affectinglimb muscles, axial muscles, or both, may also have lesser involvement of oropharyngeal muscles, respiratory muscles, or both; Class Illb- predominantly affecting oropharyngeal muscles, respiratory muscles, or both, may also have lesser or equal involvement of limb muscles, axial muscles, or both; Class IV- severe weakness affecting other than ocular muscles, may also have ocular muscle weakness of any severity; Class IVa- predominantly affecting limb muscles, axial muscles, or both, may also have lesser involvement of oropharyngeal muscles, respiratory muscles, or both; Class IVb- predominantly affecting oropharyngeal muscles, respiratory muscles, or both, may also have lesser or equal involvement of limb muscles, axial muscles, or both; Class V- defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management.FcRn Antagonists

[0132] FcRn antagonists that are useful in the compositions, methods, and uses provided herein include variant Fc regions that bind to and inhibit FcRn. Any Fc region can be altered to produce a variant Fc region for use in the methods disclosed herein. In an embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In an embodiment, the Fc region is selected from IgGl, IgG2, IgG3, and IgG4. In an embodiment, the Fc region is an IgGl Fc region (e.g., a human IgGl region). A variety of Fc region gene sequences e.g., human constant region gene sequences) are available in the form of publicly accessible deposits.

[0133] An Fc region can be further truncated or internally deleted to produce a minimal FcRn binding fragment thereof. The ability of an Fc-region fragment to bind to FcRn can be determined using any art recognized binding assay (e.g., ELISA).

[0134] To enhance the manufacturability of the FcRn antagonists disclosed herein, it is preferable that the constituent Fc regions do not comprise any non-disulfide bonded cysteine residues. Accordingly, in an embodiment, the Fc regions do not comprise a free cysteine residue.

[0135] Any variant Fc region that binds specifically to FcRn with increased affinity and reduced pH dependence relative to the native (i.e., wild-type) Fc region can be used in the methods disclosed herein. In an embodiment, the variant Fc region comprises amino acid alterations, substitutions, insertions, and / or deletions that confer the desired characteristics. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region, or FcRn binding fragment thereof, which binds to FcRn with a higher affinity at pH 5.5 as compared to a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises or consists of a variant Fcregion, or FcRn binding fragment thereof, which bind to FcRn with a higher affinity at pH 6.0 and / or at pH 7.4 as compared to a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region, or FcRn binding fragment thereof, which bind to FcRn with a higher affinity at both acidic and neutral pH.

[0136] In some embodiments, the variant Fc region is derived from the Fc region of any native immunoglobulin. In some embodiments, the native immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, the IgG is IgGl, IgG2, IgG3, or IgG4. In some embodiments, the human IgG is human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region varies from the human IgGl Fc region. In some embodiments, the human IgGl Fc region comprises a Glml(a), Glm2(x), Glm3(f), or Glml7(z) allotype.

[0137] In an embodiment, the variant Fc region, or FcRn binding fragment thereof consists of two Fc domains.

[0138] In an embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or heterodimer. In an embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In an embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0139] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of at least one Fc domain, wherein the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 22, provided below in Table 1.Table 1

[0140] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 22.

[0141] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1-21 (see Table 2 below). In some embodiments, the dimer is a heterodimer or a homodimer.Table 2

[0142] In an embodiment, the first Fc domain and / or the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 4. In an embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 4.

[0143] In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, an FcRn antagonist comprising a first Fc domain and a second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 4 is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules. In some embodiments, the predominant FcRn antagonist molecule makes up at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the population of FcRn antagonist molecules.

[0144] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1.

[0145] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2.

[0146] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0147] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 4. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 4.

[0148] In certain embodiments, the variant Fc region is a heterodimer, where the constituent Fc domains are different from each other. Methods of producing Fc heterodimers are known in the art see, e.g., US 8,216,805, which is incorporated by reference herein in its entirety). In an embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains which form a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acidsequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 4, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0149] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 1.

[0150] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 2.

[0151] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 3.

[0152] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 4.

[0153] In some embodiments, the FcRn antagonist comprises glycanation on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecules comprise glycanation at EU position 297 on one or both of the Fc domains. In some embodiments, the glycanation comprises an N-glycan. In some embodiments, the N-glycan comprises a GOF N-glycan, GIF N-glycan, G2F N- glycan, or GO N-glycan.

[0154] In some embodiments, the FcRn antagonist comprises or consists of a population of FcRn antagonists, wherein at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, or at least 57% of the population of Fc domains of the FcRn antagonists comprise galactose. In some embodiments, the population comprises or consists of FcRn antagonists, wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the population of Fc domains of the FcRn antagonists comprise fucose.

[0155] In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both Fc domains. In some embodiments, the FcRn antagonist comprises glycine and lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441. In some embodiments, the FcRn antagonist comprises amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441 and comprises amidated proline at EU position 439.

[0156] In some embodiments, the FcRn antagonist comprises aspartate, lysine, threonine, histidine, threonine, and cysteine at EU positions 221, 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 221, and comprises lysine, threonine, histidine, threonine, and cysteine at EU positions 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221 and 222, and comprises threonine, histidine, threonine, and cysteine at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221- 224, and comprises threonine and cysteine at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

[0157] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consistsof multiple subpopulations of FcRn antagonist molecules. Tn some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 subpopulations.

[0158] In some embodiments, a first subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3.

[0159] In some embodiments, a second subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 13, respectively.

[0160] In some embodiments, a third subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 10, respectively.

[0161] In some embodiments, a fourth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated.

[0162] In some embodiments, a fifth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation are deaminated.

[0163] In some embodiments, a sixth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively.

[0164] In some embodiments, a seventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0165] In some embodiments, an eighth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2.

[0166] In some embodiments, a ninth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 7, respectively.

[0167] In some embodiments, a tenth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0168] In some embodiments, an eleventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domaincomprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue or a tryptophan residue, in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0169] In some embodiments, a first subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0170] In some embodiments, a second subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 13, respectively.

[0171] In some embodiments, a third subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 10, respectively.

[0172] In some embodiments, a fourth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated.

[0173] In some embodiments, a fifth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated.

[0174] In some embodiments, a sixth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2 and 3, respectively.

[0175] In some embodiments, a seventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domainand a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0176] In some embodiments, an eighth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0177] In some embodiments, a ninth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 7, respectively.

[0178] In some embodiments, a tenth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0179] In some embodiments, an eleventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue or a tryptophan residue in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0180] In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with one of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with two of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with three of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonistmolecules comprises or consists of the first subpopulation combined with four of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with five of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with six of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with seven of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with eight of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with nine of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with all of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations.

[0181] In some embodiments, the population comprises or consists of the first and second subpopulations. In some embodiments, the population comprises or consists of the first and third subpopulations. In some embodiments, the population comprises or consists of the first and fourth subpopulations. In some embodiments, the population comprises or consists of the first and fifth subpopulations. In some embodiments, the population comprises or consists of the first and sixth subpopulations. In some embodiments, the population comprises or consists of the first and seventh subpopulations. In some embodiments, the population comprises or consists of the first and eighth subpopulations. In some embodiments, the population comprises or consists of the first and ninth subpopulations. In some embodiments, the population comprises or consists of the first and tenth subpopulations. In some embodiments, the population comprises or consists of the first and eleventh subpopulations. In some embodiments, the populations listed above further comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, or 9 additional subpopulations. In some embodiments, these additional subpopulations are one or more of those described above.

[0182] In some embodiments, the population comprises or consists of the first and seventh, ninth, or eleventh subpopulations. In some embodiments, the population comprises or consists of the first, seventh, ninth, and eleventh subpopulations.

[0183] In some embodiments, the first subpopulation makes up at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation makes up about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation makes up 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation makes up 40%-90%, 50%-80%, or 55%-70% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation makes up 56.9%-68.3% or 59.5%-67.9% of the population of FcRn antagonist molecules.

[0184] In some embodiments, the second subpopulation makes up less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation makes up about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation makes up 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation makes up 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation makes up 0.8%-2.0% or 0.8%-2.1% of the population of FcRn antagonist molecules.

[0185] In some embodiments, the third subpopulation makes up less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation makes up about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation makes up 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation makes up 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation makes up 1. l%-2.1% or 1.0%-1.9% of the population of FcRn antagonist molecules.

[0186] In some embodiments, the fourth subpopulation makes up less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up about 5%, about 4%, about 3%, about 2%, or about 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 5%, 4%, 3%, 2%, or 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up l%-5%, 2%-4%, or 2%-3% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 2. l%-3.2% or 2.0%-3.1% of the population of FcRn antagonist molecules.

[0187] In some embodiments, the fifth subpopulation makes up less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up 5%-12%, 6%-10%, or 7%-8% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up 6.8%-9.4% or 6.9%-8.7% of the population of FcRn antagonist molecules.

[0188] In some embodiments, the sixth subpopulation makesup less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, or less than 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation makes up about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, or about 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation makes up 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation makes up 7%-17%, 10%- 15%, or 11%-12% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation makes up 7.0%-14.0% or 10.0%-14.4% of the population of FcRn antagonist molecules.

[0189] In some embodiments, the seventh subpopulation makes up less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up about 6.0%, about 5.5%, about5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1 .5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up O.5%-5.5%, 1.0%-3.0%, or 1.5%-2.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up 1.5%-5.5% or 1.4%-4.9% of the population of FcRn antagonist molecules.

[0190] In some embodiments, the eighth subpopulation makes up less than 7.5%, less than 7.0%, less than 6.5%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, or less than 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation makes up about 7.5%, about 7.0%, about 6.5%, about 6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, or about 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation makes up 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, or 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation makes up 2.5%-7.5%, 3.0%- 5.0%, or 3.5%-4.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation makes up 2.9%-7.4% or 3.0%-6.3% of the population of FcRn antagonist molecules.

[0191] In some embodiments, the ninth subpopulation makes up less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation makes up about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation makes up 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation makes up 0.5%-3.5%, 1.5%-2.0%, or 1.0%-1.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation makes up 0.4%-3.2% or 0.5%- 2.6% of the population of FcRn antagonist molecules.

[0192] In some embodiments, the tenth subpopulation makes up less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation makes up about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation makes up 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In someembodiments, the tenth subpopulation makes up 0.5%-2.0%, 0.5%-l .5%, or 1.0%-1.5% of the population of FcRn antagonist molecules.

[0193] In some embodiments, the eleventh subpopulation makes up less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation makes up about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation makes up 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation makes up 0.5%-2.0%, 0.5%-l .5%, or 1.0%-1.5% of the population of FcRn antagonist molecules.

[0194] In some embodiments, the population of FcRn antagonist molecules comprises one or more of the FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in International Patent Application No. PCT / IB2023 / 000696, fded on November 14, 2023, incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a population of FcRn antagonists as described in International Patent Application No. PCT / IB2023 / 000696, filed on November 14, 2023, incorporated herein by reference in its entirety.

[0195] In an embodiment, the FcRn antagonist is efgartigimod (CAS Registry No. 1821402- 21-4). Efgartigimod is described in further detail herein below. The term “efgartigimod” as used herein is interchangeable with “efgartigimod alfa”. In some embodiments, efgartigimod is efgartigimod alfa-fcab.Pharmaceutical Compositions

[0196] The instant disclosure provides pharmaceutical compositions comprising an FcRn antagonist.

[0197] In an embodiment, the FcRn antagonist is efgartigimod, or a biosimilar version thereof. Efgartigimod (ARGX-113) is a modified human immunoglobulin (Ig) gamma (IgG) 1- derived Fc of the za allotype that binds with nanomolar affinity to human FcRn. Efgartigimod encompasses the IgGl Fc region (encompassing residues of SEQ ID NO: 2) and has been engineered using ABDEG™ technology to increase its affinity for FcRn at both physiological and acidic pH, see Vaccaro C et al., Nat Biotechnol. 2005; 23(10): 1283. See also U.S. Pat. No. 10,316,073, the contents of which are incorporated by reference herein in their entirety. The increased affinity for FcRn ofefgartigimod at both acidic and physiological pH results in a blockage of FcRn -mediated recycling of IgGs.

[0198] Efgartigimod alfa is a human recombinant immunoglobulin G1 (IgGl)-derived Fc fragment produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Efgartigimod alfa is a human IgGl antibody fragment engineered for increased affinity to the neonatal Fc Receptor (FcRn).

[0199] Efgartigimod alfa-fcab is a human immunoglobulin G1 (IgGl)-derived Fc fragment (fragment, crystallized) of the za allotype. The efgartigimod alfa-fcab Fc fragment is a homodimer consisting of two identical peptide chains each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity for FcRn. The molecule weight of efgartigimod alfa-fcab is approximately 54 kDa.

[0200] Efgartigimod is a prescription medicine registered as VYVGART®, which is approved in the United States, Europe, United Kingdom, China, Canada and Israel for the treatment of adults with gMG who are anti-AChR antibody positive, and in Japan for the treatment of adults with gMG who do not have sufficient response to steroids or non-steroidal immunosuppressive therapies (ISTs). Efgartigimod is also approved in Japan for the treatment of chronic ITP. Efgartigimod is under development for both the intravenous (IV) and subcutaneous (SC) administration route in multiple indications.

[0201] In an embodiment, the pharmaceutical composition is a biological product that is highly similar to and has no clinically meaningful differences from efgartigimod. In some embodiments, the pharmaceutical composition is a biological product that is highly similar to and has no clinically meaningful differences from efgartigimod alfa-fcab.

[0202] In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from about 20 mg to about 2,000 mg. In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from about 300 mg to about 500 mg. In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from about 500 mg to about 1200 mg.

[0203] In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from 20 mg to 2,000 mg. In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from 300 mg to 500 mg. In some embodiments, the pharmaceutical composition comprises an FcRn antagonist in an amount from 500 mg to 1200 mg.

[0204] In some embodiments, the pharmaceutical composition comprises about 400 mg of an FcRn antagonist. In some embodiments, the pharmaceutical composition comprises 400 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0205] In some embodiments, the pharmaceutical composition comprises about 412 mg of an FcRn antagonist. In some embodiments, the pharmaceutical composition comprises 412 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0206] In some embodiments, the pharmaceutical composition comprises from about 10 mg / mL to about 200 mg / mL of an FcRn antagonist. In some embodiments, the pharmaceutical composition comprises from 10 mg / mL to 200 mg / mL of an FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0207] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist. In some embodiments, the pharmaceutical composition comprises 20.0 ± 2.0 mg / mL of an FcRn antagonist. In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0208] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 10.5 mg / mL L-arginine hydrochloride, about 1.4 mg / mL L-histidine, about 2.2 mg / mL L- histidine hydrochloride monohydrate, about 1.5 mg / mL L-methionine, about 0.4 mg / mL polysorbate 80, about 4.1 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0209] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L- histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, and 20.5 mg / mL sucrose, at a pH of 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0210] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 20 mM L-histidine / L -histidine hydrochloride, about 70 mM sodium chloride, about 50 mM L-arginine hydrochloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w / ) polysorbate 80, at a pH of about 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0211] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 20 mM L-histidine / L -histidine hydrochloride, 70 mM sodium chloride, 50 mM L- arginine hydrochloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w / ) polysorbate 80, at a pH of 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0212] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 31.6 mg / mL L-arginine hydrochloride, about 0.2 mg / mL polysorbate 80, about 5.8 mg / mL sodium chloride, about 2.4 mg / mL sodium phosphate dibasic anhydrous, about 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0213] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0214] In some embodiments, the pharmaceutical composition comprises 0.02-0.06% w / v polysorbate 80.

[0215] In some embodiments, the pH of the pharmaceutical composition is 6.0 ± 0.3.

[0216] In some embodiments, the osmolality of the pharmaceutical composition is from 280-450 mOsmol / kg H2O.

[0217] In some embodiments, the pharmaceutical composition is less colored than or equal to color standard Y5. In some embodiments, the pharmaceutical composition comprises a clarity and degree of opalescence of < 18 NTU (nephelometric turbidity unit). In some embodiments, the pharmaceutical composition comprises a clarity and degree of opalescence of less than or equal to Ph. Eur. Reference Suspension III. In some embodiments, the pharmaceutical composition is essentially free of visible particles. In some embodiments, the pharmaceutical composition contains < 6000 particles having a size of > 10 pM per container. In some embodiments, the pharmaceutical composition contains < 600 particles having a size of > 25 pM per container.

[0218] In some embodiments, the potency of the pharmaceutical composition is from 70- 135% activity relative to a reference standard. In some embodiments, potency is measured by competitive binding to FcRn in the presence of human IgG3. In some embodiments, potency is measured by human IgG3 competition ELISA.

[0219] In some embodiments, the pharmaceutical composition comprises >55.0% of the main isoform of the FcRn antagonist, from 10.0-27.0% of acidic isoforms of the FcRn antagonist, and <24.0% of basic isoforms of the FcRn antagonist. In some embodiment, charge-related variants are measured using imaged capillary isoelectric focusing (icIEF).

[0220] In some embodiments, the pharmaceutical composition comprises >97% full-length FcRn antagonist molecules and <1.8% total fragments of FcRn antagonist molecules as measured by reducing CE-SDS. In some embodiments, the pharmaceutical composition comprises >95% full- length FcRn antagonist molecules and <2.2% total fragments of FcRn antagonist molecules as measured by non-reducing CE-SDS.

[0221] In some embodiments, the pharmaceutical composition comprises >97.0% monomeric FcRn antagonist molecules and <3.0% aggregates of FcRn antagonist molecules. In some embodiments, monomers and aggregates are measured using GP-HPLC.

[0222] In some embodiments, the pharmaceutical composition is sterile and comprises <3.60 EU / mL endotoxin. In some embodiments, endotoxin levels are measured using a Limulus amebocyte lysate method.

[0223] In any of the above embodiments, the pharmaceutical composition may be a unit dosage form.

[0224] In an embodiment, the unit dosage form comprises the FcRn antagonist as a dry formulation for dissolution such as a lyophilized powder, freeze-dried powder, or water-free concentrate. In an embodiment, the dry formulation is comprised in a hermetically sealed container such as a vial, an ampoule, or a sachet.

[0225] In an embodiment, the unit dosage form comprises the FcRn antagonist as a liquid formulation, e.g., injection or infusion solution. In an embodiment, the liquid formulation is comprised in a hermetically 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. In an embodiment, the liquid formulation is comprised in a single-dose vial.

[0226] In an embodiment, the single-dose vial may contain 20 mL of a liquid formulation comprising an FcRn antagonist in an amount of 400 mg. In some embodiments, the single-dose vial is overfilled to allow withdrawal of 20 mL or more of the liquid formulation from the vial. In some embodiments, the single-dose vial is overfilled by 2-5%. In some embodiments, the single-dose vial is overfilled by 3%. In some embodiments, the single-dose vial contains 20.6 mL of a liquidformulation comprising an FcRn antagonist in an amount of 412 mg. Tn some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0227] In some embodiments, the single-dose vial contains 20.6 mL of a liquid formulation comprising 412 mg of an FcRn antagonist, 28.8 mg L-histidine, 45.3 mg L-histidine hydrochloride monohydrate, 84.5 mg sodium chloride, 216.3 mg L-arginine hydrochloride, 30.9 mg L-methionine, 422.3 mg sucrose, 8.2 mg polysorbate 80, and water for injection, USP, at a pH of 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0228] In some embodiments, the single-dose vial contains 400 mg of an FcRn antagonist at a concentration of 20 mg / mL and each mL of solution in the vial contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg sodium phosphate dibasic anhydrous, 1.1 mg sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0229] In some embodiments, the pharmaceutical composition is stable when subjected to up to 3 freeze / thaw cycles. In some embodiments, the pharmaceutical composition has a shelf-life of 36 months when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition has a shelflife of up to 60 months when stored at 5 °C ± 3 °C.

[0230] In some embodiments, the pharmaceutical compositions described herein are contraindicated in patients with serious hypersensitivity to the FcRn antagonist (e.g., efgartigimod) or to any of the excipients in the compositions. In some embodiments, the hypersensitivity is anaphylaxis and / or hypotension leading to syncope.

[0231] In an embodiment, the pharmaceutical compositions are diluted prior to administration to a subject. In some embodiments, the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP, prior to administration to a subject. In some embodiments, the pharmaceutical composition is diluted to a total volume of 125 mL prior to administration to a subject.

[0232] In some embodiments, the pharmaceutical composition is diluted prior to administration to a subject by: (a) calculating the dose (mg), total drug volume (mL) of the composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight; (b) withdrawing the calculated dose of the composition from the vial(s) with a sterile syringe and needle; (c) diluting the withdrawn composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion; (d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and (e) administering the diluted composition using polyethylene (PE), polyvinyl chloride(PVC), ethylene vinyl acetate (EVA), or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.Kits

[0233] The present disclosure provides kits comprising an FcRn antagonist and a label. In some embodiments, the kit comprises a pharmaceutical composition comprising an FcRn antagonist and a label. Any FcRn antagonist described herein, or pharmaceutical composition thereof, may be included in the kits provided herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0234] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 10.5 mg / mL L-arginine hydrochloride, about 1.4 mg / mL L-histidine, about 2.2 mg / mL L-histidine hydrochloride monohydrate, about 1.5 mg / mL L-methionine, about 0.4 mg / mL polysorbate 80, about 4.1 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0235] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L- histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, and 20.5 mg / mL sucrose, at a pH of 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0236] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 20 mM L-histidine / L-histidine hydrochloride, about 70 mM sodium chloride, about 50 mM L-arginine hydrochloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w / ) polysorbate 80, at a pH of about 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0237] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 20 mM L-histidine / L-histidine hydrochloride, 70 mM sodium chloride, 50 mM L- arginine hydrochloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w / ) polysorbate 80, at a pH of 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0238] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an FcRn antagonist, about 31.6 mg / mL L-arginine hydrochloride, about 0.2 mg / mL polysorbate 80, about 5.8 mg / mL sodium chloride, about 2.4 mg / mL sodium phosphate dibasic anhydrous, about 1.1mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0239] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0240] In some embodiments, the kit comprises a single dose vial comprising the FcRn antagonist as a liquid formulation, and a label.

[0241] In some embodiments, the single-dose vial contains 20.6 mL of a liquid formulation comprising 412 mg of an FcRn antagonist, 28.8 mg L-histidine, 45.3 mg L-histidine hydrochloride monohydrate, 84.5 mg sodium chloride, 216.3 mg L-arginine hydrochloride, 30.9 mg L-methionine, 422.3 mg sucrose, 8.2 mg polysorbate 80, and water for injection, USP, at a pH of 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0242] In some embodiments, the single-dose vial contains 400 mg of an FcRn antagonist at a concentration of 20 mg / mL and each mL of solution in the vial contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg sodium phosphate dibasic anhydrous, 1.1 mg sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0243] In some embodiments, the label identifies efgartigimod and provides instructions for its use in a patient. In some embodiments, the label includes an indication for the treatment of gMG in adult patients who are anti-AChR antibody positive. In some embodiments, the label includes an indication for the treatment of adults with gMG who do not have sufficient response to steroids or non-steroidal immunosuppressive therapies (ISTs). In some embodiments, the label includes data demonstrating an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

[0244] In some embodiments, the label includes an indication for the treatment of ITP in adult patients. In some embodiments, the label includes data demonstrating a sustained platelet count response rate of 21.8% in a population of ITP patients with more than 12 months since diagnosis who received 10 mg / mg efgartigimod, compared with a sustained platelet count response rate of 5.0% ofa population of ITP patients with more than 12 months since diagnosis who received placebo. In some embodiments, the label includes data demonstrating a sustained platelet count response rate of 25.6% in a population of ITP patients with more than 3 months since diagnosis who received 10 mg / mg efgartigimod, compared with a sustained platelet count response rate of 6.7% of a population of ITP patients with more than 3 months since diagnosis who received placebo. As used herein, a “sustained platelet count response” refers to a platelet count of at least 50,000 / pL for at least 4 out of 6 consecutive weeks.

[0245] In some embodiments, the label includes a contraindication in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof. In some embodiments, the label includes a warning for hypersensitivity reactions selected from anaphylaxis and hypotension leading to syncope. In some embodiments, the label states infusion discontinuation when anaphylaxis or hypotension leading to syncope occur during or within 1 hour of administration of the product. In some embodiments, the label includes a warning for infusion-related reactions selected from hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, the label states to discontinue infusion and initiate appropriate therapy when a severe infusion-related reaction occurs during administration of the product. In some embodiments, the label states that patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications when a mild-to-moderate infusion-related reaction occurs during administration of the product. In some embodiments, the label includes a combination of any of the features described above or elsewhere herein.Methods

[0246] The present disclosure provides methods of reducing serum IgG levels in a subject in need thereof comprising administering to the subject an effective amount of an FcRn antagonist according to the disclosure or a pharmaceutical composition comprising the same. The disclosure also provides methods for treating an antibody-mediated disorder (e.g., an autoantibody-mediated disorder) in a subject comprising administering to the subject an effective amount of an FcRn antagonist according to the disclosure or a pharmaceutical composition comprising the same. In some embodiments, the antibody-mediated disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from myasthenia gravis (e.g., gMG) or ITP (e.g., chronic ITP).

[0247] Approximately 80% of all MG patients, but only about 50% of ocular MG (oMG) patients, test positive for the presence of anti-AChR autoantibodies (i.e., are anti-AChR antibody positive). AChR autoantibodies can be measured using one or more art-recognized methods, including radioimmunoprecipitation and cell-based assays (see Jacob et al., Arch. Neurol., 2012; 69:994-1001), as well as ELISA and fluorescence assays based on immunoprecipitation (see Yang et al., J Neurol. Sci., 2011; 301 :71-76). In some embodiments, the subject has gMG and is anti-AChR antibody positive. In some embodiments, the subject has gMG and is anti-AChR antibody negative. In some embodiments, the subject has gMG and does not have sufficient response to steroids or nonsteroidal immunosuppressive therapies as determined by a health care provider.Dosins

[0248] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0249] In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 300 mg to 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1200 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0250] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 500 mg, about750 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0251] In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1200 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11,000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg, or 20,000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0252] In some embodiments, the FcRn antagonist is administered at a dose of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0253] In some embodiments, the FcRn antagonist is administered at a dose of 0.2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 2 mg / kg to 120 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 3 mg / kg to 60 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0254] In some embodiments, the FcRn antagonist is administered at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, or about 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0255] In some embodiments, the FcRn antagonist is administered at a dose of 0.2 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0256] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once monthly, or once every 6 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0257] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0258] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, or about 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0259] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 0.2 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, or200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0260] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 10 mg / kg to about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every 2 weeks at a dose of 30 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0261] In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 10 mg / kg as an intravenous infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 10 mg / kg as an intravenous infusion over about 1 hour. Incertain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 10 mg / kg as an intravenous infusion over about 1 hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 10 mg / kg as an intravenous infusion over about 1 hour once weekly for about 4 weeks. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 10 mg / kg as an intravenous infusion in a total volume of about 125 mL over about 1 hour once weekly for about 4 weeks. As used herein, the term “over about 1 hour” means the infusion lasts about 1 hour from the start of the infusion to the end of the infusion.

[0262] In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of 10 mg / kg as an intravenous infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of 10 mg / kg as an intravenous infusion over 1 hour. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of 10 mg / kg as an intravenous infusion over 1 hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod, or a biosimilar version thereof, is administered at a dose of 10 mg / kg as an intravenous infusion in a total volume of 125 mL over 1 hour once weekly for 4 weeks. As used herein, the term “over 1 hour” means the infusion lasts 1 hour from the start of the infusion to the end of the infusion.

[0263] In certain embodiments, for patients weighing 120 kg or more, efgartigimod, or a biosimilar version thereof, is administered at a dose of about 1200 mg per intravenous infusion. In certain embodiments, for patients weighing 120 kg or more, efgartigimod, or a biosimilar version thereof, is administered at a dose of 1200 mg per intravenous infusion.

[0264] In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously at fixed dose of 100 mg to 10,000 mg once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once monthly, or once every 6 weeks. In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously at fixed dose of 1000 mg or 2000 mg once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once monthly, or once every 6 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0265] In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously at fixed dose of 100 mg to 10,000 mg once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once monthly, or once every 6 weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously at fixed dose of 1000 mg or 2000 mg once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once monthly, or once every 6 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0266] In some embodiments, the FcRn antagonist is administered using a phased dosing schedule comprising multiple treatment cycles. In some embodiments, the phased dosing schedule comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or more treatment cycles. In some embodiments, each treatment cycle independently comprises or consists of administration of 1-5 doses of the FcRn antagonist within 1 month. In some embodiments, at least one treatment cycle comprises or consists of weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, each treatment cycle comprises or consists of weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0267] In some embodiments, the phased dosing schedule comprises a first treatment cycle and one or more subsequent treatment cycles. In some embodiments, the first treatment cycle and the one or more treatment cycles each independently comprise or consist of administration of 1-5 doses of the FcRn antagonist within 1 month. In some embodiments, the first treatment cycle comprises or consists of weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, at least one of the one or more subsequent treatment cycles comprises or consists of weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles comprise or consist of weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subj ect based on clinical evaluation by a health care provider. In some embodiments, each of the one or more subsequent treatment cycles is administered > 50 days from the start of the previous treatment cycle. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0268] In some embodiments, treatment according to any of the dosing regimens described herein is followed by a period wherein the subject does not receive any further FcRn antagonist.Subjects receiving an FcRn antagonist according to any of the dosing regimens described herein may achieve clinical response such that treatment can be withdrawn. In some embodiments, clinical response is defined as MG-ADL response, QMG response, or both MG-ADL response and QMG response. The subject may remain untreated during a period wherein clinical response has been achieved, optionally with a period of further treatment if clinical deterioration occurs. In some embodiments, clinical deterioration refers to new or worsening respiratory / bulbar symptoms or at least a 2-point increase of individual non-ocular MG-ADL items. If, further to treatment according to any of the dosing regimens described herein, clinical response is not achieved or relapse occurs, the subject may undergo a further period of treatment with the FcRn antagonist in accordance with any of the dosing regimens described herein. In some embodiments, a subsequent treatment cycle is administered when the subject exhibits one or more of the following: a total MG-ADL score of > 5; a total MG-ADL score of > 5 with more than 50% of the score due to non-ocular symptoms; a loss of MG-ADL response; and a reduction of total MG-ADL score of < 2 points compared to the score at the previous treatment cycle baseline. In some embodiments, loss of MG-ADL response is defined as no longer showing a decrease of > 2 points on the total MG-ADL score compared to the corresponding treatment cycle baseline. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.Hypersensitivity and Infusion-Related Reactions

[0269] Efgartigimod, an FcRn antagonist according to the instant disclosure, was approved by the United States FDA in 2021 for the treatment of gMG in adult patients who are anti-AChR antibody positive. The recommended dosage of efgartigimod, as listed in the original label was 10 mg / kg administered as an intravenous infusion over 1 hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose of efgartigimod was 1200 mg (3 vials) per infusion. Subsequent treatment cycles were indicated based on clinical evaluation by a healthcare provider.[00270J Approval was based upon data establishing the efficacy of efgartigimod in adult patients with gMG who are anti-AChR antibody positive in clinical trial NCT03669588. A total of 167 patients were enrolled in NCT03669588 and were randomized to receive either VYVGART (efgartigimod alfa-fcab) lOmg / kg (1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83). Baseline characteristics were similar between treatment groups. Patients had a median age of 46 years at screening (range: 19 to 81 years) and a median time since diagnosis of 9 years. Seventy-one percent were female, and 84% were White. Median MG-ADL total score was 9, and median Quantitative Myasthenia Gravis (QMG) total score was 16. The majority of patients (n=65 for VYVGART; n=64 for placebo) were positive for AChR antibodies.

[0271] At baseline, over 80% of patients in each group received AChE inhibitors, over 70% in each treatment group received steroids, and approximately 60% in each treatment group received NSISTs, at stable doses.

[0272] Patients were treated with VYVGART at the recommended dosage regimen described above.

[0273] The efficacy of VYVGART was measured using the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. In this study, an MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle.

[0274] The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders during the first treatment cycle between treatment groups in the AChR-Ab positive population. A statistically significant difference favoring VYVGART was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the VYVGART -treated group vs 29.7% in the placebo-treated group (p <0.0001)].

[0275] The efficacy of VYVGART was also measured using the Quantitative Myasthenia Gravis (QMG) total score which is a 13 -item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. In this study, a QMG responder was defined as a patient who had a 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after last infusion of the cycle.

[0276] The secondary endpoint was the comparison of the percentage of QMG responders during the first treatment cycle between both treatment groups in the AChR-Ab positive patients. A statistically significant difference favoring VYVGART was observed in the QMG responder rateduring the first treatment cycle [63.1% in the VYVGART-treated group vs 14.1% in the placebo- treated group (p <0.0001)].

[0277] VYVGART was initially approved with no contraindications. Hypersensitivity reactions, including rash, angioedema, and dyspnea, were observed in the clinical trials. These hypersensitivity reactions were mild-to-moderate, occurred within 1 hour to 3 weeks of administration, and did not lead to treatment discontinuation. No infusion-related reactions were reported.

[0278] Since approval in 2021, the following unexpected new adverse reactions have been studied: hypersensitivity reactions including anaphylaxis and hypotension, and infusion-related reactions. Unexpectedly, anaphylaxis and hypotension leading to syncope occurred during or within an hour of administration and led to infusion discontinuation and in some cases to permanent discontinuation.

[0279] Thus, in some embodiments, subjects treated in accordance with the methods described herein, particularly subjects receiving the FcRn antagonist via an intravenous route of administration, are monitored for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope, and appropriate measures are instituted if needed. In some embodiments, the subjects are monitored during administration of the FcRn antagonist and for 1 hour after administration. In some embodiments, the FcRn antagonist is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the appropriate measure to be initiated following detection of anaphylaxis and / or hypotension leading to syncope is discontinuation of the intravenous infusion. In some embodiments, the appropriate measure to be initiated following detection of anaphylaxis and / or hypotension leading to syncope is permanent discontinuation of treatments with the FcRn antagonist. In some embodiments, the subject is informed of the signs and symptoms of a hypersensitivity reaction, such as anaphylaxis and / or hypotension leading to syncope, and is advised to contact a healthcare provider immediately should they occur. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0280] Infusion-related reactions reported following initial approval (z.e., postmarketing) include hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. Infusion-related reactions occurred during or within an hour of administration and led to infusion discontinuation.

[0281] Thus, in some embodiments, subjects treated in accordance with the methods described herein, particularly subjects receiving the FcRn antagonist via an intravenous route of administration, are monitored for an infusion-related reaction, and the infusion is discontinued if aninfusion-related reaction is detected. Tn some embodiments, the subjects are monitored during administration of the FcRn antagonist and for 1 hour after administration. In some embodiments, the FcRn antagonist is administered to the subject via intravenous infusion over 1 hour. In some embodiments, the subject is rechallenged with the FcRn antagonist when the infusion-related reaction is mild-to-moderate as determined by a health care provider. In some embodiments, rechallenging comprises one or more of close clinical observation, slower infusion rate, and pre-medication. In some embodiments, rechallenging comprises close clinical observation, slower infusion rate, and premedication. In some embodiments, the infusion is discontinued when the infusion-related reaction is severe and appropriate therapy is initiated. In some embodiments, the FcRn antagonist is readministered following a severe infusion-related reaction if the benefit is determined to justify the potential risk. In some embodiments, a determination of a mild-to-moderate infusion-related reaction or a severe infusion-related reaction is made by a health care provider based upon guidance in the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, published November 27, 2017 (evs.nci.nih.gov / ftpl / CTCAE / CTCAE_5.0 / ). In some embodiments, the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, the subject is advised of the potential risk of an infusion-related reaction. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0282] In any of the above methods, the FcRn antagonist may be comprised in a pharmaceutical composition as described herein. In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 20 mM L-histidine / L-histidine hydrochloride, 70 mM sodium chloride, 50 mM L-arginine hydrochloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w / ) polysorbate 80, at a pH of 6.0. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0283] In some embodiments, the pharmaceutical composition comprises 20 mg / mL of an FcRn antagonist, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.Vaccination

[0284] Immunization with vaccines during VYVGART treatment had not been studied when it was initially approved for the treatment of gMG in adult patients who are anti-AChR antibody positive. Thus, the safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine was unknown upon initial approval. Because VYVGART causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines was not recommended during treatment with VYVGART. It was initially recommended to evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART.

[0285] Since approval, it was determined that any vaccine, other than live vaccines, may be administered as needed at any time during treatment with VYVGART.

[0286] Thus, in some embodiments, subjects treated in accordance with the methods described herein, particularly subjects receiving the FcRn antagonist via an intravenous route of administration, are administered a vaccine as needed at any time during treatment with the FcRn antagonist, wherein the vaccine is not a live or live-attenuated vaccine. In some embodiments, the vaccine is not a live vaccine. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof. In some embodiments, the FcRn antagonist is comprised in a pharmaceutical formulation as described herein. In some embodiments, the FcRn antagonist is administered intravenously in a dose of 10 mg / kg over 1 hour. In some embodiments, the FcRn antagonist is administered intravenously in a dose of 10 mg / kg once weekly. In some embodiments, the FcRn antagonist is administered intravenously in a dose of 10 mg / kg once weekly for 4 weeks. In some embodiments, the FcRn antagonist is administered intravenously in a dose of 10 mg / kg over 1 hour once weekly for 4 weeks. In some embodiments, further treatment cycles are administered based on clinical evaluation. In some embodiments, a further treatment cycle comprises or consists of once weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, a further treatment cycle is initiated > 50 days from the start of a previous treatment cycle. In some embodiments, a further treatment cycle is initiated > 50 days from the start of the most recent treatment cycle.

[0287] The methods described herein may include an additional step of administering to the subject an effective amount of one or more vaccines.

[0288] As used herein, the term “vaccine” refers to a biological preparation that improves immunity in the context of a particular disease, disorder, or condition.

[0289] Vaccines that are useful in the methods and uses provided herein include, but are not limited to, any recombinant vaccine, toxoid vaccine, or inactivated vaccine. In some embodiments,the vaccine is not a live attenuated vaccine or a live vaccine. In some embodiments, the vaccine is not a live vaccine.

[0290] Recombinant vaccines that are useful in the methods and uses provided herein include, but are not limited to an mRNA vaccine, a viral vector vaccine, and a subunit vaccine. Examples of subunit vaccines include, but are not limited to, a polysaccharide vaccine, a conjugate vaccine, and a protein-based vaccine.

[0291] In some embodiments, the vaccine is a T-cell dependent vaccine. Examples of T-cell dependent vaccines include, but are not limited to, a COVID-19 vaccine. Examples of COVID-19 vaccines are provided below.

[0292] In some embodiments, the vaccine is a seasonal vaccine. In some embodiments, the vaccine is not a seasonal vaccine.

[0293] In some embodiments, the vaccine is an adenovirus vaccine, an anthrax vaccine, a cholera vaccine, a COVID-19 vaccine, a cytomegalovirus (CMV) vaccine, a dengue vaccine, a diphtheria vaccine, an Ebola vaccine, a hepatitis A vaccine, a hepatitis B vaccine, a hepatitis C vaccine, a Haemophilus influenzae type B (Hib) vaccine, a human immunodeficiency virus (HIV) vaccine, a human papillomavirus (HPV) vaccine, a seasonal influenza vaccine, a Japanese encephalitis vaccine, a malaria vaccine, a measles vaccine, a meningococcal vaccine, a mumps vaccine, a pertussis vaccine, a pneumococcal vaccine, a polio vaccine, a rabies vaccine, a respiratory syncytial virus (RSV) vaccine, a rotavirus vaccine, a rubella vaccine, a shingles vaccine, a smallpox vaccine, a tetanus vaccine, a tuberculosis vaccine, a typhoid vaccine, a varicella vaccine, a yellow fever vaccine, or any combination thereof. In some embodiments, the vaccine is a COVID-19 vaccine, an influenza vaccine, a pneumococcal vaccine, a shingles vaccine, an HPV vaccine, or an RSV vaccine.

[0294] In some embodiments, the vaccine is a COVID-19 vaccine. Any suitable COVID- 19 vaccine can be used. In some embodiments, the COVID- 19 vaccine comprises one or more SARS- CoV-2 antigens selected from the group consisting of spike protein S2, nucleocapsid, spike protein SI, full-length spike protein, and spike protein receptor-binding domain. Examples of COVID-19 vaccines that may be used in the methods and uses provided herein include, but are not limited to, tozinameran (BNT162b2; Comirnaty; Pfizer), elasomeran (mRNA- 1273; Spikevax; Moderna), NVX- CoV2373 (Nuvaxovid / Covovax; Novavax), Ad26.COV2.S (Jcovden; Johnson & Johnson / Janssen), AZD1222 (Vaxzevria; AstraZeneca), CoronaVac (Sinovac), BBV152 (Bharat Biotech), AD5-nCOV(CanSino), MVC-COV1901 (Medigen), BBIBP-CorV (Sinopharm), and Gam-COVID-Vac (Gamaleya).

[0295] In some embodiments, the vaccine is an influenza vaccine. Any suitable influenza vaccine can be used. In some embodiments, the influenza vaccine is a seasonal influenza vaccine. Examples of influenza vaccines that may be used in the methods and uses provided herein include, but are not limited to, Audenz, Fluad Quadrivalent, Fluad, Afluria Quadrivalent, Afluria Quadrivalent Southern Hemisphere, Flucelvax Quadrivalent, Flulaval Quadrivalent, Afluria, Afluria Southern Hemisphere, FluLaval, FluMist, Fluarix, Fluvirin, Agriflu, Fluzone, Fluzone High-Dose, Fluzone Intradermal, Flucelvax, Flublok, Flublok Quadrivalent, FluMist Quadrivalent, Fluarix Quadrivalent, and Fluzone Quadrivalent.

[0296] In some embodiments, the vaccine is a pneumococcal vaccine. Any suitable pneumococcal vaccine can be used. Examples of pneumococcal vaccines that may be used in the methods and uses provided herein include, but are not limited to, Pneumovax 23, Prevnar 13, VAXNEUVANCE™, and Prevnar 20.

[0297] In some embodiments, the vaccine is a shingles vaccine. Any suitable shingles vaccine can be used. An example of a shingles vaccine that may be used in the methods and uses provided herein includes, but is not limited to, SHINGRIX® (Zoster Vaccine Recombinant, Adjuvanted).

[0298] In some embodiments, the vaccine is an HPV vaccine. Any suitable HPV vaccine can be used. Examples of HPV vaccines that may be used in the methods and uses provided herein include, but are not limited to, GARDASIL® 9 (Human Papillomavirus 9-valent Vaccine, Recombinant), GARDASIL® (Human Papillomavirus Quadrivalent Vaccine, Recombinant), and CERVARIX® (Human Papillomavirus Bivalent Vaccine, Recombinant).

[0299] In some embodiments, the vaccine is an RSV vaccine. Any suitable RSV vaccine can be used. Examples of RSV vaccines that may be used in the methods and uses provided herein include, but are not limited to, AREXVY® (Respiratory Syncytial Virus Vaccine, Adjuvanted) and ABRYSVO™ (Respiratory Syncytial Virus Vaccine).

[0300] In certain embodiments, the vaccines provided herein are in admixture with one or more adjuvants. Many different adjuvants can be used with the vaccine compositions disclosed herein. The vaccine composition(s) and adjuvant(s) may be mixed together in the same fluid volume, and the vaccine composition(s) can comprise one or more adjuvant(s).

[0301] A variety of adjuvants may be employed, including, for example, systemic adjuvants and mucosal adjuvants. A systemic adjuvant is an adjuvant that can be delivered parenterally.Systemic adjuvants include adjuvants that create a depot effect, adjuvants that stimulate the immune system and adjuvants that do both. An adjuvant that creates a depot effect is an adjuvant that causes the antigen to be slowly released in the body, thus prolonging the exposure of immune cells to the antigen. This class of adjuvants includes alum (e.g., aluminum hydroxide, aluminum phosphate); or emulsion-based formulations including mineral oil, non-mineral oil, water-in-oil or oil-in-water-in oil emulsion, oil-in-water emulsions such as Seppic ISA series of Montanide adjuvants (e.g, Montanide ISA 720; Air Liquide, Paris, France); MF59 (a squalene-in-water emulsion stabilized with Span 85 and Tween 80; Chiron Corporation, Emeryville, Calif.); PROVAX (an oil-in-water emulsion containing a stabilizing detergent and a micelle-forming agent; IDEC, Pharmaceuticals Corporation, San Diego, Calif); and Matrix-M adjuvant.

[0302] Other adjuvants stimulate the immune system, for instance, cause an immune cell to produce and secrete cytokines or IgG. This class of adjuvants includes immunostimulatory nucleic acids, such as CpG oligonucleotides; saponins purified from the bark of the Q. saponaria tree, such as QS-21; poly[di(carboxylatophenoxy)phosphazene] (PCPP polymer; Virus Research Institute, USA); RNA mimetics such as polyinosinic:polycytidylic acid (poly I:C) or poly I:C stabilized with poly-lysine (poly-ICLC [Hiltonol®; Oncovir, Inc.]); derivatives of lipopolysaccharides (LPS) such as monophosphoryl lipid A (MPL; Ribi ImmunoChem Research, Inc., Hamilton, Mont.); muramyl dipeptide (MDP; Ribi) and threonyl -muramyl dipeptide (t-MDP; Ribi); OM-174 (a glucosamine disaccharide related to lipid A; OM Pharma SA, Meyrin, Switzerland); and Leishmania elongation factor (a purified Leishmania protein; Corixa Corporation, Seattle, Wash.).

[0303] Other systemic adjuvants are adjuvants that create a depot effect and stimulate the immune system. These compounds have both of the above-identified functions of systemic adjuvants. This class of adjuvants includes but is not limited to ISCOMs (Immunostimulating complexes which contain mixed saponins, lipids and form virus-sized particles with pores that can hold antigen; CSL, Melbourne, Australia); ASOl (a liposome based formulation containing MPL and QS-21; GlaxoSmithKline, Belgium); AS02 (an oil-in-water emulsion containing MPL and QS-21; GlaxoSmithKline, Rixensart, Belgium); AS04 (contains alum and MPL; GlaxoSmithKline, Belgium); AS 15 (a liposome based formulation containing CpG oligonucleotides, MPL and QS-21; GlaxoSmithKline, Belgium); non-ionic block copolymers that form micelles such as CRL 1005 (these contain a linear chain of hydrophobic polyoxypropylene flanked by chains of polyoxyethylene; Vaxcel, Inc., Norcross, Ga.); and Syntex Adjuvant Formulation (SAF, an oil-in-water emulsion containing Tween 80 and a nonionic block copolymer; Syntex Chemicals, Inc., Boulder, Colo.).

[0304] The mucosal adjuvants are adjuvants that are capable of inducing a mucosal immune response in a subject when administered to a mucosal surface. Mucosal adjuvants include CpG nucleic acids (e.g., PCT published patent application WO 99 / 61056, incorporated herein by reference in its entirety), bacterial toxins: e.g., Cholera toxin (CT), CT derivatives including but not limited to CT B subunit (CTB); CTD53 (Vai to Asp); CTK97 (Vai to Lys); CTK104 (Tyr to Lys); CTD53 / K63 (Vai to Asp, Ser to Lys); CTH54 (Arg to His); CTN107 (His to Asn); CTE114 (Ser to Glu); CTE112K (Glu to Lys); CTS61F (Ser to Phe); CTS 106 (Pro to Lys); and CTK63 (Ser to Lys), Zonula occludens toxin (zot), Escherichia coli heat-labile enterotoxin, Labile Toxin (LT), LT derivatives including but not limited to LT B subunit (LTB); LT7K (Arg to Lys); LT61F (Ser to Phe); LT112K (Glu to Lys); LT118E (Gly to Glu); LT146E (Arg to Glu); LT192G (Arg to Gly); LTK63 (Ser to Lys); and LTR72 (Ala to Arg), Pertussis toxin, PT including PT-9K / 129G; Toxin derivatives; Lipid A derivatives (e.g., monophosphoryl lipid A, MPL); Muramyl Dipeptide (MDP) derivatives; bacterial outer membrane proteins (e.g., outer surface protein A (OspA) lipoprotein of Borrelia burgdorferi, outer membrane protein of Neisseria meningitidis); oil-in-water emulsions (e.g., MF59; aluminum salts (Isaka et al., 1998, 1999)); and Saponins (e.g., QS-21, e.g., QS-21 Stimulon®, Antigenics LLC, Lexington, Mass.), ISCOMs, MF59 (a squalene-in- water emulsion stabilized with Span 85 and Tween 80; Chiron Corporation, Emeryville, Calif.); the Seppic ISA series of Montanide adjuvants (e.g., Montanide ISA 720; Air Liquide, Paris, France); PROVAX (an oil-in-water emulsion containing a stabilizing detergent and a micelle-forming agent; IDEC Pharmaceuticals Corporation, San Diego, Calif.); Syntext Adjuvant Formulation (SAF; Syntex Chemicals, Inc., Boulder, Colo.); poly[di(carboxylatophenoxy)phosphazene] (PCPP polymer; Virus Research Institute, USA) and Leishmania elongation factor (Corixa Corporation, Seattle, Wash.).

[0305] Adjuvant(s) that can be added to the vaccine compositions disclosed herein include, for example, saponins, and immunostimulatory nucleic acids.

[0306] Pharmaceutical compositions for vaccines can be optionally prepared as lyophilized product, which may then be formulated for oral administration or reconstituted to a liquid form for parenteral administration.

[0307] Pharmaceutical compositions for vaccines can additionally be formulated to contain other agents as pharmaceutically acceptable carriers or excipients, including bulking agents, stabilizing agents, buffering agents, sodium chloride, calcium salts, surfactants, antioxidants, chelating agents, other excipients, and combinations thereof.

[0308] Bulking agents are preferred in the preparation of lyophilized formulations for vaccines. Such bulking agents form the crystalline portion of the lyophilized product and may be selected from the group consisting of mannitol, glycine, alanine, and hydroxyethyl starch (HES).

[0309] Stabilizing agents may be selected from the group consisting of sucrose, trehalose, raffinose, and arginine. These agents are preferably present in amounts between 1-4%.

[0310] Sodium chloride can be included in the present vaccine formulations preferably in an amount of 100-300 mM, or if used without the aforementioned bulking agents, can be included in the formulations in an amount of between 300-500 mM NaCl. Calcium salts include calcium chloride, calcium gluconate, calcium glubionate, or calcium gluceptate.

[0311] Buffering agents can be any physiologically acceptable chemical entity or combination of chemical entities which have a capacity to act as buffers, including but not limited to histidine, potassium phosphate, TRIS [tris-(hydroxymethyl)-aminomethane], BIS-Tris Propane (l,3-bis-[tris- (hydroxymethyl)methylamino]-propane), PIPES [piperazine-N,N'-bis-(2-ethanesulfonic acid)], MOPS [3-(N-morpholino)ethanesulfonic acid], HEPES (N-2-hydroxyethyl-piperazine-N'-2- ethanesulfonic acid), MES [2-(N-morpholino)ethanesulfonic acid], and ACES (N-2-acetamido-2- aminoethanesulfonic acid). Typically, the buffering agent is included in the vaccine formulation in a concentration of 10-50 mM. Specific examples of base buffers include (i) PBS; (ii) 10mMKPO.sub.4, 150 mM NaCl; (iii) 10 mM HEPES, 150 mM NaCl; (iv) 10 mM imidazole, 150 mM NaCl; and (v) 20 mM sodium citrate. Excipients that can be used include (i) glycerol (10%, 20%); (ii) Tween 50 (0.05%, 0.005%); (iii) 9% sucrose; (iv) 20% sorbitol; (v) 10 mM lysine; or (vi) 0.01 mM dextran sulfate.

[0312] Surfactants, if present, are preferably in a concentration of 0.1% or less, and may be chosen from the group including but not limited to polysorbate 20, polysorbate 80, pluronic polyols, and BRIJ 35 (polyoxyethylene 23 laurel ether). Antioxidants, if used, must be compatible for use with a pharmaceutical preparation, and are preferably water soluble. Suitable antioxidants include homocysteine, glutathione, lipoic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), methionine, sodium thiosulfate, platinum, glycine-glycine-histidine (tripeptide), and butylatedhydroxytoluene (BHT). Chelating agents should preferably bind metals such as copper and iron with greater affinity than calcium, if a calcium salt is being used in the composition. A preferred chelator is deferoxamine.

[0313] The vaccines disclosed herein may be administered using any desired route of administration. Many methods may be used to introduce the vaccines described herein, including butnot limited to, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, mucosal, intranasal, intra-tumoral, and intra-lymph node routes. Non-mucosal routes of administration include, but are not limited to, intradermal and topical administration. Mucosal routes of administration include, but are not limited to, oral, rectal, and nasal administration. Advantages of intradermal administration include use of lower doses and rapid absorption, respectively. Advantages of subcutaneous or intramuscular administration include suitability for some insoluble suspensions and oily suspensions, respectively.

[0314] Solubility and the site of the administration are factors which should be considered when choosing the route of administration of the vaccines. The mode of administration can be varied between multiple routes of administration, including those listed above.

[0315] If the vaccines are water-soluble, then they may be formulated in an appropriate buffer, for example, phosphate buffered saline or other physiologically compatible solutions, preferably sterile. Alternatively, if a vaccine has poor solubility in aqueous solvents, then it may be formulated with a non-ionic surfactant such as Tween, or polyethylene glycol. Thus, the compositions may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral, or rectal administration.

[0316] The vaccines may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The preparation may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the vaccine may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0317] The vaccine may also be formulated in a rectal preparation such as a suppository or retention enema, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0318] In addition, the vaccine may also be formulated as a depot preparation. Such long- acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the preparation may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophilic drugs.Approved Products

[0319] The present disclosure also provides approved products containing efgartigimod for the treatment of gMG. Methods of treating gMG comprising administering an approved product containing efgartigimod are also provided. Use of an approved product containing efgartigimod for the treatment of gMG is also provided.

[0320] In some embodiments, the approved product is for intravenous administration. In some embodiments, the approved product is for intravenous administration over 1 hour.

[0321] In some embodiments, the approved product is provided in a single-dose vial containing 20 mg / mL efgartigimod, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

[0322] In some embodiments, the product is approved for treatment of gMG in adult patients who are anti-AChR antibody positive. In some embodiments, the product is approved for treatment of gMG in adult patients who do not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0323] In some embodiments, the approved product is a reference product.

[0324] In some embodiments, the approved product induces an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

[0325] In some embodiments, the approved product induces a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope. In some embodiments, anaphylaxis or hypotension leading to syncope occurs during or within 1 hour of administration of the product. In some embodiments, the approved product is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof.

[0326] In some embodiments, the approved product induces an infusion-related reaction. In some embodiments, the infusion-related reaction is one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, one or more subsequent doses of the approved product are administered with close clinical observation, slower infusion rates, and pre-medications when a mild-to-moderate infusion-related reaction occurs during administration of the approved product.

[0327] In some embodiments, the approved product is co-administered with a vaccine. In some embodiments, the vaccine is not a live-attenuated or live vaccine. In some embodiments, the vaccine is not a live vaccine. In some embodiments, the vaccine is administered on the same day as the approved product. In some embodiments, the vaccine is administered at any time during treatment with the approved product.

[0328] In some embodiments, the label for the approved product includes a contraindication in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof. In some embodiments, the label for the approved product includes a warning for hypersensitivity reactions selected from anaphylaxis and hypotension leading to syncope. In some embodiments, the label for the approved product states infusion discontinuation when anaphylaxis or hypotension leading to syncope occur during or within 1 hour of administration of the product. In some embodiments, the label for the approved product includes a warning for infusion-related reactions selected from hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain. In some embodiments, the label for the approved product states to discontinue infusion and initiate appropriate therapy when a severe infusion-related reaction occurs during administration of the product. In some embodiments, the label of the approved product states that patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications when a mild- to-moderate infusion-related reaction occurs during administration of the product.

[0329] In some embodiments, the label of the approved product includes data demonstrating an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of patients who received placebo. In some embodiments, the label of the approved product includes a combination of any of the features described above or elsewhere herein.

[0330] Biosimilars and bioequivalents of the approved product described herein are also encompassed by the instant disclosure.

[0331] Methods of treating gMG comprising administering an approved product containing efgartigimod, a biosimilar of an approved product containing efgartigimod, or a bioequivalent of an approved product containing efgartigimod to a subject are also provided. Use of an approved product containing efgartigimod, a biosimilar of an approved product containing efgartigimod, or a bioequivalent of an approved product containing efgartigimod for the treatment of gMG in a subject is also provided.

[0332] In some embodiments, the approved product, biosimilar, or bioequivalent is administered to the subject once weekly. In some embodiments, the approved product, biosimilar, or bioequivalent is administered to the subject once weekly for 4 weeks.

[0333] In some embodiments, the approved product, biosimilar, or bioequivalent is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the approved product, biosimilar, or bioequivalent within 1 month. In some embodiments, the first treatment cycle comprises weekly administration of the approved product, biosimilar, or bioequivalent for 4 weeks. In some embodiments, the one or more subsequent treatment cycles each comprise weekly administration of the approved product, biosimilar, or bioequivalent for 4 weeks. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation. In some embodiments, each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

[0334] In some embodiments, treatment according to any of the dosing regimens described herein is followed by a period wherein the subject does not receive any further treatment with the approved product, biosimilar, or bioequivalent. Subjects receiving an approved product, biosimilar, or bioequivalent according to any of the dosing regimens described herein may achieve clinical response such that treatment can be withdrawn. In some embodiments, clinical response is defined as MG-ADL response, QMG response, or both MG-ADL response and QMG response. The subject may remain untreated during a period wherein clinical response has been achieved, optionally with a period of further treatment if clinical deterioration occurs. In some embodiments, clinical deterioration refers to new or worsening respiratory / bulbar symptoms or at least a 2-point increase of individual non-ocular MG-ADL items. If, further to treatment according to any of the dosing regimens described herein, clinical response is not achieved or relapse occurs, the subject may undergo a further period of treatment with the approved product, biosimilar, or bioequivalent in accordance with anyof the dosing regimens described herein. In some embodiments, a subsequent treatment cycle is administered when the subject exhibits one or more of the following: a total MG-ADL score of > 5; a total MG-ADL score of > 5 with more than 50% of the score due to non-ocular symptoms; a loss of MG-ADL response; and a reduction of total MG-ADL score of < 2 points compared to the score at the previous treatment cycle baseline. In some embodiments, loss of MG-ADL response is defined as no longer showing a decrease of > 2 points on the total MG-ADL score compared to the corresponding treatment cycle baseline.

[0335] In some embodiments, the subject is anti-AChR antibody positive. In some embodiments, the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

[0336] In some embodiments, the methods or uses described herein further comprise monitoring the subject for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope; and initiating an appropriate measure to mitigate the hypersensitivity reaction when detected.

[0337] In some embodiments, the methods or uses described herein further comprise monitoring the subject for an infusion-related reaction; and discontinuing the infusion when an infusion-related reaction is detected. In some embodiments, the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

[0338] In some embodiments, the methods and uses described herein further comprise administering to the subject a vaccine as needed at any time during treatment with the approved product, biosimilar, or biological product, wherein the vaccine is not a live-attenuated or live vaccine. In some embodiments, the vaccine is not a live vaccine.

[0339] In some embodiments, the subject is a human, such as, for example, an adult human.EXAMPLES

[0340] The invention will be further understood with reference to the following non-limiting examples.Example 1: Development of Second Generation Efgartigimod IV Formulation

[0341] First-generation formulations of efgartigimod for intravenous use (Efgartigimod IV Genl; VYVGART®) and for subcutaneous use (Efgartigimod PH20 SC Genl; VYVGART® HYTRULO) have been approved by the FDA under BLA 761195 and BLA 761304, respectively, for the treatment of gMG in adult patients who are anti-AChR antibody positive.

[0342] Efgartigimod IV Genl, as initially approved, was formulated as a concentrate for solution for intravenous infusion presented in single-dose vials containing 20.0 mg / mL efgartigimod; 1.1 mg / mL sodium phosphate monobasic monohydrate and 2.4 mg / mL sodium phosphate dibasic anhydrous (25 mM sodium phosphate); 5.8 mg / mL sodium chloride (100 mM sodium chloride); 31.6 mg / mL L-arginine hydrochloride (150 mM L-arginine hydrochloride); and 0.2 mg / mL polysorbate 80 (0.02% (w / v) polysorbate 80), at a pH of 6.7. Additional information on the approved Efgartigimod IV Genl formulation is provided in Example 2.

[0343] Efgartigimod IV Genl and Efgartigimod PH20 SC Genl were manufactured by separate upstream processes. In order to enhance manufacturing and improve long-term stability, a new optimized drug substance formulation was developed as described below, which feeds into both a second-generation IV drug product (Efgartigimod IV Gen2) and a second-generation SC drug product (Efgartigimod PH20 SC Gen2).

[0344] Stability of Efgartigimod at Low Concentration (20 mg / mL) in Histidine Buffer containing Methionine

[0345] An important adaptation to the second generation (Gen2) drug substance formulation is the requirement for it to feed into both the 20 mg / mL Efgartigimod IV Gen2 and the 200 mg / mL Efgartigimod PH20 SC Gen2 drug product formulations. Since the risk for physical and chemical incompatibilities is the largest at high concentration, the L-histidine buffer of the current Efgartigimod SC Genl 180 mg / mL drug substance was selected for this new 200mg / mL Gen2 drug substance. In addition to the change in buffer composition for IV administration (L-histidine at pH 6.0 instead of phosphate at pH 6.7), the composition of other excipients (L-arginine HC1, sucrose, L-methionine and surfactant) was optimized to deliver the best possible high concentration formulation. To demonstrate that this change has no negative impact on efgartigimod, stability of L-histidine-based formulations (20 mM L-histidine / L -histidine HC1) containing 20 mg / mL efgartigimod, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, 2000 U / mL rHuPH20, and either 0.02% (w / v) polysorbate 80 (PS80) or 0.02% (w / v) polysorbate 20 (PS20), pH 6.0, was evaluated up to 24 months at +5°C ± 3°C, +25°C ± 2°C and +40°C ± 2°C.

[0346] The results demonstrated that formulations containing either 0.02% (w / v) PS80 or 0.02% (w / v) PS20 have comparable stability behavior and are also comparable to the 20 mg / mL Efgartigimod IV Genl formulation with exception of methionine oxidation. Methionine oxidation remained stable in both histidine-based formulations tested due to the presence of L-methionine as oxidation scavenger in the formulation buffer. The difference in oxidation behavior when formulated in the L-histidine formulation containing L-methionine versus the phosphate buffer of the IV Genl formulation is therefore considered an improvement of the long-term stability behavior.

[0347] Overall, comparable and good stability behavior was observed for both L-histidine- based formulations containing 20 mg / mL efgartigimod. The L-histidine / PS20-containing formulation demonstrated an apparent slightly higher surfactant degradation compared to the L-histidine / PS80- containing formulation over the 24-month time period at +5°C.

[0348] Formulation Improvements to Reduce Polysorbate Degradation and Fatty Acid Mediated Particle Formation

[0349] A correlation between PS20 concentration in efgartigimod formulations and onset of subvisible particle formulation due to degradation of PS20 in free fatty acids had previously been observed. Therefore, a stability study was conducted using the Efgartigimod 180 mg / mL PH20 SC Gen 1 formulation with varying concentrations of PS20 and PS80.

[0350] Nine formulations differing in type of surfactant (PS20 versus PS80), surfactant grade, surfactant concentrations, and efgartigimod concentration and DS source were stored at +5°C ± 3 °C and +25°C ± 2°C for up to 24 months (Table 3). The samples were analyzed for degree of opalescence, pH, protein concentration by OD280, subvisible particles by light obscuration, purity by GP-HPLC, PS concentration by HPLC-FMA and free fatty acid concentration by LC-MS.Table 3: Formulations Evaluated During Surfactant Stability Study

[0351] For the PS20-containing formulations, results demonstrated an improved stability profile with increasing PS20 concentration. Increasing the PS20 concentration delays the onset of subvisible particle formation due to the increased solubility of the generated free fatty acids in the PS20 micelles. All PS20-containing formulations demonstrated a decrease in PS20 content over the course of the study.

[0352] For the PS80-containing formulations, no increase in subvisible particles was observed together with a lower increase in % aggregates compared to the PS20-containing formulations. In addition, no decrease in PS80 content was observed over the course of the study. Therefore, PS80 was concluded to be the preferred surfactant to be used in the 200 mg / mL Gen2 drug substance formulation.

[0353] Furthermore, the stability study revealed that the stability behavior of the nine formulations was comparable for degree of opalescence, pH, protein concentration and purity.

[0354] Formulation Development to Counter Soluble-Gel Transitions

[0355] Soluble-gel transitions were observed in L-histidine (pH 6.0) formulations containing high concentration (180 mg / mL) efgartigimod upon storage at +5°C ± 3°C, which were reversible at ambient temperature. As this could potentially impact the pre-dilution (200 mg / mL efgartigimod) Gen2 drug substance formulation that will be used to prepare the Efgartigimod Gen2 IV formulation, an investigation was performed to avoid the soluble-gel transitions.

[0356] First, in Part A of the study, the impact of various concentrations of L-arginine HC1 to the 200 mg / mL formulation on gel formation was evaluated after a hold time at +5°C ±3 °C. The different formulations (Table 4) were exposed to +25°C ±2°C and +40°C ±2°C for up to 4 weeks. Methods applied during the study were visual inspection (only after hold time at +5°C), osmolality (only at TO), purity by GP-HPLC, non-reduced and reduced CE-SDS and icIEF.

[0357] In Part B of the study, aggregation in the presence or absence of L-arginine HC1 at different pH values (Table 5) were compared following agitation stress for 2 weeks at 150 rpm at +37°C. Samples were analyzed by GP-HPLC and non-reduced and reduced CE-SDS.

[0358] For both studies, the L-histidine-based formulation with 0.04% (w / v) PS80 was used since this was the optimal determined surfactant.Table 4: Formulations Evaluated During Part A of Soluble-Gel Transition StudyTable 5: Formulations Evaluated During Part B of Soluble-Gel Transition Study

[0359] The osmolality of the formulations studied in Part A is reported in Table 6. The osmolality increased with increasing concentrations of L-arginine HC1. Upon storage at +5°C ± 3°C, the soluble-gel transition, which was reversible at ambient temperature, was only observed for the formulation containing no L-arginine HC1 (Fl). All Part A formulations containing L-arginine HC1, F2 to F6, prevented gel formation.

[0360] No impact was observed on the stability profile of efgartigimod after the addition of L-arginine HC1 to the formulation. Similar levels of aggregation (as determined by GP-HPLC), fragmentation (as determined by reduced and non-reduced CE-SDS) and charge variants (as determined by icIEF) were observed.Table 6: Osmolality of Formulations with Various Concentrations of L-Arginine HC1

[0361] All formulations studied in Part B showed a minor increase in aggregation (as determined by GP-HPLC) and fragmentation (as determined by CE-SDS) after 2 weeks agitation stress at +37°C. No difference in intact efgartigimod levels following agitation was observed between the different formulations as shown by CE-SDS (both non-reduced and reduced). The GP-HPLC results demonstrated higher levels of aggregates for the formulations at pH 6.3 and 6.5 compared to the formulations at pH 6.0. Overall, all results were comparable to the formulation without L-arginine HC1, showing the addition of L-arginine HC1 does not impact the level of aggregation.

[0362] Based on the above studies, the soluble-gel transition of a 200 mg / mL efgartigimod formulation could effectively be prevented by the addition of L-arginine HC1 at a concentration within the range of 20 mM to 200 mM. The addition of L-arginine HC1 did not impact the stability behavior of efgartigimod.

[0363] To prevent the soluble-gel transition and to limit the increase in osmolality, an L- arginine HC1 concentration of 50 mM was selected, resulting in a formulation containing 200 mg / mL efgartigimod, 20 mM L-histidine / L-histidine HC1, 100 mMNaCl, 60 mM sucrose, 0.04% polysorbate 80, and 50 mM L-arginine HC1, at pH 6.0.

[0364] Formulation Development to Limit Osmolality Impact

[0365] As described above, L-arginine HC1 was added to the 200 mg / mL efgartigimod formulation at 50 mM to prevent soluble-gel transition. However, the addition of L-arginine HC1 resulted in an increase in formulation osmolality (Table 6).

[0366] Different components that have an impact on the osmolality value are the protein itself and the excipients in the formulation, such as L-histidine / L-histidine HC1, L-arginine HC1, NaCl, sucrose, and L-methionine. The higher the concentration of constituents, the higher the osmolality value. To limit the osmolality increase in the efgartigimod concentrate for solution at 200 mg / mL following the addition of 50mM L-arginine HC1, it was investigated if the concentration of other excipients could be lowered without impacting product quality attributes.

[0367] A two-part study was conducted. In Part A, a formulation robustness study via Design of Experiments (DOE) was performed on the efgartigimod 180 mg / mL Efgartigimod PH20 SC Genl formulation to evaluate the impact of potential variations in the formulation on final drug product quality attributes. Since the concentration of efgartigimod in the Gen2 drug substance is set at 200 mg / mL, only excipient variation was examined. Variation in pH is not expected to impact osmolality but pH was added as a parameter to the DOE to investigate the pH limits of the 180 mg / mL Efgartigimod PH20 SC Genl formulation. The design consisted of 15 different formulations (Table 7). All formulations were tested at the initial timepoint, after agitation stress, and after long-term storage at +5°C ± 3°C, accelerated temperature conditions at +25°C ± 2°C, and stressed temperature condition at +40°C ± 2°C. The analysis included appearance, pH, protein concentration, subvisible particles, purity by GP-HPLC, icIEF, and CE-SDS (reduced / non-reduced) and PS concentration.

[0368] In Part B, the osmolality of the 180 mg / mL Efgartigimod PH20 SC Genl formulation was compared to the osmolality of the 200 mg / mL efgartigimod formulation, with following adaptations:• Surfactant change from 0.04% PS20 to 0.04% PS80 to improve the stability behavior of the 200 mg / mL efgartigimod formulation;• Addition of L-arginine HC1 to prevent soluble-gel transitions; and• Adaptation of NaCl concentration, based on the outcome of part A.

[0369] An overview of the formulations tested in part B is provided in Table 8.Table 7: Formulations Evaluated in the Formulation Robustness Study (Part A)Table 8: Formulations Evaluated in the Osmolality Screening (Part B)* Efgartigimod SC Genl

[0370] From the results of Part A, it could be concluded that decreasing the NaCl concentration had no significant impact on the level of subvisible particles, PS20 concentration, % aggregates (GP-HPLC), charged variants (icIEF) and % intact Fc by CE-SDS (non-reduced and reduced). The NaCl concentration showed minor variation in turbidity, with no impact on the product quality. The accelerated temperature condition and shaking stress study indicated no other significant differences (data not shown). In general, the data demonstrated that the NaCl concentration can be lowered without impacting the stability of the efgartigimod 200 mg / mL concentrate for solution.

[0371] The 180 mg / mL Efgartigimod SC Genl (Fl in Table 8) concentrate for solution had an osmolality of 322 mOsm / kg H2O, well within the acceptable range for injectable solutions. Several adaptations to the 200 mg / mL Efgartigimod Gen2 drug substance formulation were made compared to the 180 mg / mL Efgartigimod SC Genl drug substance formulation based on the different studies presented above: increasing the protein concentration, changing the surfactant from PS20 to PS80 to improve long-term stability, and adding 50 mM L-arginine HC1 to prevent soluble-gel transitions at +5°C ±3 °C. These adaptations caused an osmolality increase to 426 mOsm / kg H2O. With the resultsof Part A indicating that NaCl concentration can be lowered without impacting product quality attributes and long-term stability behavior, the NaCl concentration was lowered from 100 mM to 70 mM, causing the osmolality to decrease to 369 mOsm / kg H2O, close to the osmolality of the 180 mg / mL Efgartigimod SC Genl drug substance formulation.

[0372] The final selected Efgartigimod IV Gen2 is formulated as a concentrate for solution for intravenous infusion presented in single-dose vials containing 20.0 mg / mL efgartigimod; 1.4 mg / mL L-histidine and 2.2 mg / mL L-histidine hydrochloride monohydrate (20 mM L-histidine / L- histidine HC1); 4.1 mg / mL sodium chloride (70 mM sodium chloride); 10.5 mg / mL L-arginine hydrochloride (50 mM L-arginine hydrochloride); 1.5 mg / mL L-methionine (10 mM L-methionine); 20 mg / mL sucrose (60 mM sucrose); and 0.4 mg / mL polysorbate 80 (0.04% (w / v) polysorbate 80), at a pH of 6.0. The Efgartigimod IV Gen2 formulation does not contain any preservative. The formulation of Efgartigimod IV Gen2 as presented in the single-dose vials is colorless to slightly yellow; clear to slightly opalescent; and free of visible particulate matter in appearance. The drug product strength of the Efgartigimod IV Gen2 per vial is 400 mg of efgartigimod / 20 mL. Additional information on the Efgartigimod IV Gen2 formulation is available in Example 4.

[0373] The composition of Efgartigimod IV Gen2 is provided in Table 9, along with the composition of the approved Efgartigimod IV Genl formulation, for comparison. The composition of the Efgartigimod IV Gen2 and Efgartigimod IV Genl formulations per vial as well as the maximum amount in an infusion bag are also presented. The target fdl volume per vial is 20.6 mL, which includes 3% overfill to allow withdrawal of at least 20 mL of the drug product from the vial for injection into the infusion bag.Table 9: Composition of Efgartigimod Drug product for IV Administration - Efgartigimod IV Genl and IV Genlq.s.=quantum satisNA=not applicable1The target fill volume is 20.6 mL. This includes 3% overfill to allow withdrawal of 20 mL or more of the drug product from the vial.2Based on a maximum approved dose of 1200 mg efgartigimod (60 mL).

[0374] The Efgartigimod IV Gen2 formulation contains excipients that are not present in the Efgartigimod IV Genl formulation (L-histidine, L-histidine hydrochloride monohydrate, L- methionine, and sucrose), and contains excipients that are present at different concentrations (L- arginine hydrochloride, sodium chloride, and polysorbate 80) compared to the Efgartigimod IV Genl formulation.

[0375] Both Efgartigimod IV Gen2 and Efgartigimod IV Genl are formulated as a concentrate for solution for intravenous infusion presented in vials containing 20 mg / mL efgartigimod, which must be diluted into an infusion bag containing 0.9% Sodium Chloride Injection, USP prior to administration. The recommended dosage for both Efgartigimod IV Gen2 and Efgartigimod IV Genl is 10 mg / kg administered as an intravenous infusion via a 0.2 micron in-line filter over 1 hour. In patients weighing 120 kg or more, the recommended dose is 1200 mg efgartigimod per infusion. The maximum recommended dose for both Efgartigimod IV Gen2 and Efgartigimod IV Genl is 1200 mg efgartigimod (3 vials) in a volume of 125 mL per infusion.Accordingly, the pharmacokinetics, pharmacodynamics, or immunogenicity profile are expected to remain the same between IV Gen2 and IV Genl.

[0376] Comparison of Efgartigimod IV Gen2 and IV Genl Formulations

[0377] Initial stability of the Efgartigimod IV Gen2 formulation was monitored at the following temperatures over a period of 9 months: +5 ± 3°C; +25 ± 2°C at 60% ± 5% relative humidity; and +40°C ± 2°C at 75% ± 5% relative humidity. Stability data was assessed at 0 months, 1 month, 3 months, 6 months, and 9 months. The batches exposed to the long-term storage condition (+5°C) were demonstrated to be stable up to 9 months. Further testing is ongoing to assess stability at long-term storage conditions (+5°C) up to 60 months. Based on the data generated from the accelerated (+25°C) and stressed (+40°C) temperature conditions, the primary degradation pathways were identified as aggregation, fragmentation, and changes in the charged isoform profile.

[0378] Comprehensive analytical comparability studies between the Efgartigimod IV Gen2 and IV Genl formulations were performed. The results are summarized in Table 10.Table 10: Comparison Between Efgartigimod IV Genl and IV Genl Drug Product FormulationsNTU=nephelometric turbidity unit; icIEF=imaged capillary isoelectric focusing; ELISA=enzyme-linked immunosorbent assay; CESDS =capillary electrophoresis sodium dodecyl sulfate; GP=gel permeation; HPLC=high performance liquid chromatography; HlC=hydrophobic interaction chromatography; FMA=fluorescent micelle assay; EU=Endotoxin units1Less colored than or equal to Ph. Eur. Reference color standard Y5.2<18NTU corresponds to Opalescence of solution less than or equal to Ph. Eur. Reference Suspension III.3Identity is confirmed as efgartigimod if the following criteria are fulfilled: a The pl of the main peak in the sample solution electropherogram by icIEF aligns with the pl ± 0.2 of the main peak in the reference standard electropherogram. b The sample solution electropherogram by icIEF is visually comparable to the reference standard electropherogram. c The sample passes the acceptance criteria for potency by huIgGi competition ELISA.

[0379] Conclusion

[0380] An improved second-generation drug product concentrate for solution for intravenous administration (Efgartigimod IV Gen2) was developed which has the same active ingredient concentration (20mg / mL) and product strength (400mg / 20mL) as the current approved (Efgartigimod IV Genl) drug product concentrate for solution for intravenous administration. The change in the formulation allows for an enhanced manufacturing process. The formulation changes have been assessed to have no impact on safety and efficacy.

[0381] Comprehensive analytical comparability studies were performed and demonstrated analytical comparability between the Efgartigimod IV Gen2 and Efgartigimod IV Genl drug products.Example 2; Label with Prescribing Information for VYVGART-IV approved by the Food and Drug Administration

[0382] The text below is from the label with the prescribing information for VYVGART® (efgartigimod alfa-fcab) injection, for intravenous use, as approved by Food and Drug Administration (Initial U.S. Approval: 2021, revised Dec 2023).

[0383] HIGHLIGHTS OF PRESCRIBING INFORMATION

[0384] These highlights do not include all the information needed to use VYVGART safely and effectively. See full prescribing information for VYVGART.

[0385] VYVGART® (efgartigimod alfa-fcab) injection, for intravenous use Initial U.S. Approval: 2021

[0386] RECENT MAJOR CHANGES

[0387] Contraindications (4) 12 / 2023

[0388] Warnings and Precautions (5.2, 5.3) 12 / 2023

[0389] INDICATIONS AND USAGE

[0390] VYVGART is a neonatal Fc receptorblocker indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. (1)

[0391] DOSAGE AND ADMINISTRATION

[0392] Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART. (2.1)

[0393] The recommended dosage is 10 mg / kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1200 mg per infusion. (2.2)

[0394] Administer subsequent treatment cycles based on clinical evaluation; safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established. (2.2)

[0395] Must be diluted with 0.9% Sodium Chloride Injection, USP prior to administration.(2.3)

[0396] Administer as an intravenous infusion over one hour via a 0.2 micron in-line filter.(2.3)

[0397] CONTRAINDICATIONS

[0398] VYVGART is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART. (4)

[0399] WARNINGS AND PRECAUTIONS

[0400] Infections: Delay administration of VYVGART to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with VYVGART. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved. (5.1)

[0401] Hypersensitivity Reactions: Anaphylaxis, hypotension leading to syncope, angioedema, dyspnea, and rash have occurred. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. (4, 5.2)

[0402] Infusion-Related Reactions: If a severe infusion-related reaction occurs, discontinue the infusion and initiate appropriate therapy; consider risks and benefits of readministering. If a mild to moderate infusion-related reaction occurs, may re-challenge with close clinical observation, slower infusion rates, and pre-medications. (5.3)

[0403] ADVERSE REACTIONS

[0404] Most common adverse reactions (> 10%) in patients treated with gMG are respiratory tract infections, headache, and urinary tract infection. (6.1)

[0405] To report SUSPECTED ADVERSE REACTIONS, contact argenx at l-833-argx411 or FDA at 1-800-FDA-1088 or fda.gov / medwatch.

[0406] DRUG INTERACTIONS

[0407] Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing VYVGART and using alternative therapies. (7)

[0408] See 17 for PATIENT COUNSELING INFORMATION.

[0409] Revised: 12 / 2023

[0410] FULL PRESCRIBING INFORMATION: CONTENTS*

[0411] 1 INDICATIONS AND USAGE

[0412] 2 DOSAGE AND ADMINISTRATION

[0413] 2.1 Recommended Vaccination

[0414] 2.2 Recommended Dose and Dose Schedules

[0415] 2.3 Preparation and Administration Instructions

[0416] 3 DOSAGE FORMS AND STRENGTHS

[0417] 4 CONTRAINDICATIONS

[0418] 5 WARNINGS AND PRECAUTIONS

[0419] 5.1 Infections

[0420] 5.2 Hypersensitivity Reactions

[0421] 5.3 Infusion-Related Reactions

[0422] 6 ADVERSE REACTIONS

[0423] 6.1 Clinical Trials Experience

[0424] 6.2 Postmarketing experience

[0425] 6.3 Immunogenicity

[0426] 7 DRUG INTERACTIONS

[0427] 7.1 Effect of VYVGART on Other Drugs

[0428] 8 USE IN SPECIFIC POPULATIONS

[0429] 8.1 Pregnancy

[0430] 8.2 Lactation

[0431] 8.4 Pediatric Use

[0432] 8.5 Geriatric Use

[0433] 8.6 Renal Impairment

[0434] 11 DESCRIPTION

[0435] 12 CLINICAL PHARMACOLOGY

[0436] 12.1 Mechanism of Action

[0437] 12.2 Pharmacodynamics

[0438] 12.3 Pharmacokinetics

[0439] 13 NONCLINIC AL TOXICOLOGY

[0440] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0441] 14 CLINICAL STUDIES

[0442] 16 HOW SUPPLIED / STORAGE AND HANDLING

[0443] 17 PATIENT COUNSELING INFORMATION

[0444] * Sections or subsections omitted from the full prescribing information are not listed.

[0445] FULL PRESCRIBING INFORMATION

[0446] 1 INDICATIONS AND USAGE

[0447] VYVGART is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

[0448] 2 DOSAGE AND ADMINISTRATION

[0449] 2.1 Recommended Vaccination

[0450] Because VYVGART causes transient reduction in IgG levels, immunization with live- attenuated or live vaccines is not recommended during treatment with VYVGART. Evaluate the need to administer age-appropriate immunizations according to immunization guidelines before initiation of a new treatment cycle with VYVGART [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

[0451] 2.2 Recommended Dose and Dose Schedules

[0452] Dilute VYVGART prior to administration. Administer via intravenous infusion only [see Dosage and Administration (2.3) J.

[0453] The recommended dosage of VYVGART is 10 mg / kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose of VYVGART is 1200 mg (3 vials) per infusion.

[0454] Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.

[0455] If a scheduled infusion is missed, VYVGART may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.

[0456] 2.3 Preparation and Administration Instructions

[0457] Prior to administration, VYVGART single-dose vials require dilution in 0.9% Sodium Chloride Injection, USP, to make a total volume to be administered of 125 mL (see Preparation).

[0458] Check that the VYVGART solution is clear to slightly opalescent and colorless to slightly yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration, or other foreign particles are present.

[0459] Use aseptic technique when preparing the VYVGART diluted solution for intravenous infusion. Each vial is for single-dose only.

[0460] Discard any unused portion.

[0461] Preparation

[0462] • Calculate the dose (mg), total drug volume (mL) of VYVGART solution required, and the number of vials needed based on the recommended dose according to the patient’s body weight [see Dosage and Administration (2.2)]. Each vial contains a total of 400 mg of VYVGART at a concentration of 20 mg per mL.

[0463] • Gently withdraw the calculated dose of VYVGART from the vial(s) with a sterile syringe and needle. Discard any unused portion of the vials.

[0464] • Dilute the withdrawn VYVGART with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

[0465] • Gently invert the infusion bag containing the diluted VYVGART without shaking to ensure thorough mixing of the product and the diluent.

[0466] • The diluted solution can be administered using polyethylene (PE), polyvinyl chloride(PVC), ethylene vinyl acetate (EVA), or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0467] Storage Conditions of the Diluted Solution

[0468] VYVGART does not contain preservatives. Administer immediately after dilution and complete the infusion within 4 hours of dilution.

[0469] If immediate use is not possible, the diluted solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours. Do not freeze. Protect from light. Allow the diluted drug to reach room temperature before administration. Complete the infusion within 4 hours of removal from the refrigerator. Do not heat the diluted drug in any manner other than via ambient air.

[0470] Administration

[0471] • VYVGART should be administered via intravenous infusion by a healthcare professional.

[0472] • Visually inspect VYVGART diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, or if opaque or foreign particles are seen.

[0473] • Infuse the total 125 mb of diluted solution intravenously over one hour via a 0.2 micron in-line filter.

[0474] • After administration of VYVGART, flush the entire line with 0.9% Sodium ChlorideInjection, USP.

[0475] • Monitor patients during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs during administration, discontinue administration of VYVGART and institute appropriate supportive measures [see Warnings and Precautions (5.2)].

[0476] • Other medications should not be injected into infusion side ports or mixed withVYVGART.

[0477] 3 DOSAGE FORMS AND STRENGTHS

[0478] Injection: 400 mg / 20 mL (20 mg / mL) as a colorless to slightly yellow, clear to slightly opalescent solution, in a single-dose vial.

[0479] 4 CONTRAINDICATIONS

[0480] VYVGART is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART. Reactions have included anaphylaxis and hypotension leading to syncope [see Warnings and Precautions (5.2)].

[0482] 5.1 Infections

[0483] VYVGART may increase the risk of infection. The most common infections observed in Study 1 were urinary tract infection (10% of VYVGART -treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of VYVGART -treated patients compared to 29% of placebo-treated patients) [see Adverse Reactions (6.1) and Clinical Studies (14)]. A higher frequency of patients who received VYVGART compared to placebo were observed to have below normal levels for white blood cell counts (12% versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities were mild to moderate in severity. Delay VYVGART administration in patients with an active infection until the infection is resolved. During treatment with VYVGART, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved.

[0484] Immunization

[0485] Immunization with vaccines during VYVGART treatment has not been studied. The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Because VYVGART causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with VYVGART. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART.

[0486] 5.2 Hypersensitivity Reactions

[0487] In clinical trials, hypersensitivity reactions, including rash, angioedema, and dyspnea were observed in VYVGART -treated patients. Hypersensitivity reactions were mild or moderate, occurred within one hour to three weeks of administration, and did not lead to treatment discontinuation.

[0488] Anaphylaxis and hypotension leading to syncope have been reported in postmarketing experience with VYVGART. Anaphylaxis and hypotension occurred during or within an hour of administration and led to infusion discontinuation and in some cases to permanent treatment discontinuation.

[0489] Monitor patients during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs, the healthcareprofessional should institute appropriate measures if needed or the patient should seek medical attention. VYVGART is contraindicated in patients with a history of serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART [see Contraindications (4)].

[0490] 5.3 Infusion-Related Reactions

[0491] Infusion-related reactions have been reported with VYVGART in postmarketing experience. The most frequent symptoms and signs were hypertension, chills, shivering, and thoracic, abdominal, and back pain. Infusion-related reactions occurred during or within an hour of administration and led to infusion discontinuation. If a severe infusion-related reaction occurs during administration, discontinue VYVGART infusion and initiate appropriate therapy. Consider the risks and benefits of readministering VYVGART following a severe infusion-related reaction. If a mild to moderate infusion-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications.

[0492] 6. ADVERSE REACTIONS

[0493] The following clinically significant adverse reactions are described elsewhere in the labeling:

[0494] • Infections [see Warnings and Precautions (5.1)]

[0495] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

[0496] • Infusion-Related Reactions [see Warnings and Precautions (5.3)]

[0497] 6.1 Clinical Trials Experience

[0498] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

[0499] In clinical studies, the safety of VYVGART has been evaluated in 246 patients who received at least one dose of VYVGART, including 57 patients exposed to at least 7 treatment cycles and 8 patients exposed to at least 10 treatment cycles.

[0500] In a placebo-controlled study (Study 1) in patients with gMG, 84 patients received VYVGART 10 mg / kg [see Clinical Studies (14)]. Of these 84 patients, approximately 75% were female, 82% were White, 11% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean age at study entry was 46 years (range 19 to 78).

[0501] The minimum time between treatment cycles, specified by study protocol, was 50 days. On average, VYVGART-treated patients received 2 cycles in Study 1. The mean and median times to the second treatment cycle were 94 days and 72 days from the initial infusion of the first treatment cycle, respectively, for VYVGART-treated patients.

[0502] Adverse reactions reported in at least 5% of patients treated with VYVGART and more frequently than placebo are summarized in Table 11. The most common adverse reactions (reported in at least 10% of VYVGART-treated patients) were respiratory tract infection, headache, and urinary tract infection.Table 11: Adverse Reactions in > 5% of Patients Treated with VYVGART and More Frequently than in Placebo-Treated Patients in Study 1 (Safety Population)*Headache includes migraine and procedural headache. tParaesthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia.

[0503] 6.2 Postmarketing Experience

[0504] The following adverse reactions have been identified during postapproval use of VYVGART. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

[0505] Immune System Disorders: Hypersensitivity reactions including anaphylaxis and hypotension, and infusion-related reactions [see Warnings and Precautions (5.2, 5.3) J.

[0506] 6.3 Immunogenicity

[0507] As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of samplecollection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VYVGART in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

[0508] In up to 26 weeks of treatment in Study 1, 20% (17 / 83) of patients developed antibodies to VYVGART. Seven percent (6 / 83) of patients developed neutralizing antibodies.

[0509] Because few patients tested positive for anti-efgartigimod alfa-fcab antibodies and neutralizing antibodies, the available data are too limited to make definitive conclusions regarding immunogenicity and the effect on pharmacokinetics, safety, or efficacy of VYVGART.

[0510] 7 DRUG INTERACTIONS

[0511] 7.1 Effect of VYVGART on Other Drugs

[0512] Concomitant use of VYVGART with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivates containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing VYVGART and using alternative therapies.

[0513] 8 USE IN SPECIFIC POPULATIONS

[0514] 8.1 Pregnancy

[0515] Risk Summary

[0516] There are no available data on the use of VYVGART during pregnancy. There is no evidence of adverse developmental outcomes following the administration of VYVGART at up to 100 mg / kg / day in rats and rabbits (see Data).

[0517] The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

[0518] Clinical Considerations

[0519] Fetal / Neonatal Adverse Reactions

[0520] Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Therefore, efgartigimod alfa-fcab may be transmitted from the mother to the developing fetus.

[0521] As VYVGART is expected to reduce maternal IgG antibody levels, reduction in passive protection to the newborn is anticipated. Risk and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to VYVGART in utero [see Warnings and Precautions (5.1)].

[0522] Data

[0523] Animal Data

[0524] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0525] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0526] 8.2 Lactation

[0527] Risk Summary

[0528] There is no information regarding the presence of efgartigimod alfa-fcab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk.

[0529] The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VYVGART and any potential adverse effects on the breastfed infant from VYVGART or from the underlying maternal condition.

[0530] 8.4 Pediatric Use

[0531] Safety and effectiveness in pediatric patients have not been established.

[0532] 8.5 Geriatric Use

[0533] Clinical studies of VYVGART did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger adult patients.

[0534] 8.6 Renal Impairment

[0535] No dose adjustment of VYVGART is needed for patients with mild renal impairment. There are insufficient data to evaluate the impact of moderate renal impairment (eGFR 30-59 mL / min / 1.73 m2) and severe renal impairment (eGFR <30 mL / min / 1.73 m2) on pharmacokinetic parameters of efgartigimod alfa-fcab [see Clinical Pharmacology (12.3)].

[0536] 11 DESCRIPTION

[0537] Efgartigimod alfa-fcab is a human immunoglobulin G1 (IgGl) -derived Fc fragment (fragment, crystallized) of the za allotype. The efgartigimod alfa-fcab Fc fragment is a homodimer consisting of two identical peptide chains each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity for FcRn. The molecular weight of efgartigimod alfa-fcab is approximately 54 kDa.

[0538] VYVGART (efgartigimod alfa-fcab) injection is a sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow solution supplied in a single-dose vial for infusion after dilution.

[0539] Each 20 mL single-dose vial contains 400 mg of efgartigimod alfa-fcab at a concentration of 20 mg / mL. In addition, each mL of solution contains L-arginine hydrochloride (31.6 mg), polysorbate 80 (0.2 mg), sodium chloride (5.8 mg), sodium phosphate dibasic anhydrous (2.4 mg), sodium phosphate monobasic monohydrate (1.1 mg) and water for injection, USP, at a pH of 6.7.

[0540] 12 CLINICAL PHARMACOLOGY

[0541] 12.1 Mechanism of Action

[0542] Efgartigimod alfa-fcab is a human IgGl antibody fragment that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.

[0543] 12.2 Pharmacodynamics

[0544] In Study 1 [see Clinical Studies (14)], the pharmacological effect of efgartigimod alfa- fcab was assessed by measuring the decrease in serum IgG levels and AChR autoantibody levels. In patients testing positive for AChR antibodies and who were treated with VYVGART, there was a reduction in total IgG levels relative to baseline. Decrease in AChR autoantibody levels followed a similar pattern.

[0545] 12.3 Pharmacokinetics

[0546] Efgartigimod alfa-fcab exhibits linear pharmacokinetics, and following single doses of efgartigimod alfa-fcab, exposures increase proportionally up to 50 mg / kg (5 times the recommended dosage).

[0547] Distribution

[0548] The volume of distribution is 15 to 20L.

[0549] Metabolism and Elimination

[0550] Efgartigimod alfa-fcab is expected to be degraded by proteolytic enzymes into small peptides and amino acids.

[0551] The terminal half-life is 80 to 120 hours (3 to 5 days).

[0552] After a single intravenous dose of 10 mg / kg efgartigimod alfa-fcab in healthy subj ects, less than 0.1% of the administered dose was recovered in urine.

[0553] Specific Populations

[0554] Age, Sex, and Race

[0555] A population pharmacokinetics analysis assessing the effects of age, sex, and race did not suggest any clinically significant impact of these covariates on efgartigimod alfa-fcab exposures.

[0556] Patients with Renal Impairment

[0557] No dedicated pharmacokinetic study has been performed in patients with renal impairment.

[0558] A population PK analysis of data from the VYVGART clinical studies indicated that patients with mild renal impairment (eGFR 60-89 mL / min / 1.72m2) had 22% increase in exposure relative to the exposure in patients with normal renal function [see Use in Specific Populations (8.6)].

[0559] Patients with Hepatic Impairment

[0560] No dedicated pharmacokinetic study has been performed in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa- fcab.

[0561] Drug Interaction Studies

[0562] Clinical drug interactions studies have not been performed with efgartigimod alfa- fcab.

[0563] P450 Enzymes

[0564] Efgartigimod alfa-fcab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

[0565] Drug Interactions with Other Drugs or Biological Products

[0566] Efgartigimod alfa-fcab may decrease concentrations of compounds that bind to the human FcRn [see Drug Interactions (7.1)].

[0567] 13 NONCLINICAL TOXICOLOGY

[0568] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0569] Carcinogenesis and Mutagenesis

[0570] No studies have been conducted to assess the carcinogenic potential of efgartigimod alfa-fcab.

[0571] No studies have been conducted to assess the genotoxic potential of efgartigimod alfa- fcab.

[0572] Impairment of Fertility

[0573] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to male and female rats prior to and during mating and continuing in females through gestation day 7 resulted in no adverse effects on fertility. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0574] 14 CLINICAL STUDIES

[0575] The efficacy of VYVGART for the treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was established in a 26-week, multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT03669588).

[0576] Study 1 enrolled patients who met the following criteria at screening:

[0577] - Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV

[0578] - MG- Activities of Daily Living (MG-ADL) total score of > 5

[0579] - On stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone

[0580] IgG levels of at least 6 g / L

[0581] A total of 167 patients were enrolled in Study 1 and were randomized to receive either VYVGART lOmg / kg (1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83). Baseline characteristics were similar between treatment groups. Patients had a median age of 46 years at screening (range: 19 to 81 years) and a median time since diagnosis of 7 years. Seventy-one percent were female, and 84% were White. Median MG-ADL total score was 9, and median Quantitative Myasthenia Gravis (QMG) total score was 16. The majority of patients (n=65 for VYVGART; n=64 for placebo) were positive for AChR antibodies.

[0582] At baseline, over 80% of patients in each group received AChE inhibitors, over 70% in each treatment group received steroids, and approximately 60% in each treatment group received NSISTs, at stable doses.

[0583] Patients were treated with VYVGART at the recommended dosage regimen [see Dosage and Administration (2.2)].

[0584] The efficacy of VYVGART was measured using the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. In this study, an MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle.

[0585] The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders during the first treatment cycle between treatment groups in the AChR-Ab positive population. A statistically significant difference favoring VYVGART was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the VYVGART -treated group vs 29.7% in the placebo- treated group (p <0.0001)].

[0586] The efficacy of VYVGART was also measured using the Quantitative Myasthenia Gravis (QMG) total score which is a 13-item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. In this study, a QMG responder was defined as a patient who hada 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after last infusion of the cycle.

[0587] The secondary endpoint was the comparison of the percentage of QMG responders during the first treatment cycle between both treatment groups in the AChR-Ab positive patients. A statistically significant difference favoring VYVGART was observed in the QMG responder rate during the first treatment cycle [63.1% in the VYVGART -treated group vs 14.1% in the placebo- treated group (p <0.0001)].

[0588] The results are presented in Table 12.Table 12: MG-ADL and QMG Responders During Cycle 1 in AChR-Ab Positive Patients (mITT Analysis Set)MG-ADL=Myasthenia Gravis Activities of Daily Living; QMG =Quantitative Myasthenia Gravis; mITT=modified intent-to-treat; n=number of patients for whom the observation was reported; CI = confidence interval;Logistic regression stratified for AChR-Ab status (if applicable), Japanese / Non-Japanese and standard of care, with baseline MG-ADL as covariate / QMG as covariates Two-sided exact p-value

[0589] 16 HOW SUPPL1ED / STORAGE AND HANDLING

[0590] VYVGART (efgartigimod alfa-fcab) injection is a preservative free, sterile, colorless to slightly yellow, clear to slightly opalescent solution supplied as 400 mg / 20 mL (20 mg / mL) in one single-dose vial per carton (NDC 73475-3041-5).

[0591] Store VYVGART vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. Do not shake.

[0592] Refer to Dosage and Administration (2.3) for information on stability and storage of the diluted solutions of VYVGART.

[0593] 17 PATIENT COUNSELING INFORMATION

[0594] Infections

[0595] Instruct patients to communicate any history of infections to the healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection. Advise patients to complete age-appropriate vaccines according to immunization guidelines prior to initiation of a new treatment cycle with VYVGART. Administration of live or live-attenuated vaccines is not recommended during treatment with VYVGART [see Warnings and Precautions (5.1)].

[0596] Hypersensitivity Reactions

[0597] Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with VYVGART. Inform patients about the signs and symptoms of these reactions, and advise patients to contact their healthcare provider immediately if these occur [see Warnings and Precautions (5.2)].

[0598] Infusion-Related Reactions

[0599] Advise patients of the potential risk of infusion-related reactions, which can include hypertension, chills, shivering, and chest, abdominal, and back pain [see Warnings and Precautions (5.3)].Example 3; Vaccination Updates to Label with Prescribing Information for VYVGART-IV

[0600] The text below is amended from the label included in Example 2, with amendments added regarding vaccination. Sections from the label that are identical to the label included in Example 2 have been omitted.

[0601] 2 DOSAGE AND ADMINISTRATION

[0602] 2.1 Recommended Vaccination

[0603] Evaluate the need to administer age-appropriate immunizations according to immunization guidelines before initiation of a new treatment cycle with VYVGART. Because VYVGART causes transient reduction in IgG levels, vaccination with live-attenuated or live vaccinesis not recommended during treatment with VYVGART. [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

[0604] 5 WARNINGS AND PRECAUTIONS

[0605] 5.1 Infections

[0606] VYVGART may increase the risk of infection. The most common infections observed in Study 1 were urinary tract infection (10% of VYVGART -treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of VYVGART -treated patients compared to 29% of placebo-treated patients) [see Adverse Reactions (6.1) and Clinical Studies (14)] . A higher frequency of patients who received VYVGART compared to placebo were observed to have below normal levels for white blood cell counts (12% versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities were mild to moderate in severity. Delay VYVGART administration in patients with an active infection until the infection is resolved. During treatment with VYVGART, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved.

[0607] Immunization

[0608] Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART.

[0609] The safety of immunization with live or live-attenuated vaccines and the response to immunization with these vaccines during treatment with VYVGART are unknown. Because VYVGART causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with VYVGART. Other vaccines may be administered as needed at any time during treatment with VYVGART.

[0610] 17 PATIENT COUNSELING INFORMATION

[0611] Infections

[0612] Instruct patients to communicate any history of infections to the healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection. Advise patients to complete age-appropriate vaccines according to immunization guidelines prior to initiation of anew treatment cycle with VYVGART. Vaccination with live or live-attenuated vaccines is not recommended during treatment with VYVGART [see Warnings and Precautions (5.1)].Example 4: Formulation Updates to Label with Prescribing Information for VYVGART-IV

[0613] The text below is amended from the label included in Example 2, with amendments added regarding additional formulations. Sections from the label that are identical to the label included in Example 2 have been omitted.

[0614] 11 DESCRIPTION

[0615] Efgartigimod alfa-fcab is a human immunoglobulin G1 (IgGl) -derived Fc fragment (fragment, crystallized) of the za allotype. The efgartigimod alfa-fcab Fc fragment is a homodimer consisting of two identical peptide chains each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity for FcRn. The molecular weight of efgartigimod alfa-fcab is approximately 54 kDa.

[0616] VYVGART (efgartigimod alfa-fcab) injection is a sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow solution supplied in a single-dose vial for infusion after dilution.

[0617] Each 20 mL single-dose vial contains 400 mg of efgartigimod alfa-fcab at a concentration of 20 mg / mL. In addition, each mL of solution contains:

[0618] - L-arginine hydrochloride (31.6 mg), polysorbate 80 (0.2 mg), sodium chloride (5.8 mg), sodium phosphate dibasic anhydrous (2.4 mg), sodium phosphate monobasic monohydrate (1.1 mg) and water for injection, USP, at a pH of 6.7 or,

[0619] -L-arginine hydrochloride (10.5 mg), L-histi dine (1.4 mg), L- histidine hydrochloride monohydrate (2.2 mg), L-methionine (1.5 mg), polysorbate 80 (0.4 mg), sodium chloride (4.1 mg), sucrose (20.5 mg), and water for injection, USP, at a pH of 6.0.Example 5: Label with Prescribing Information for VYVGART-IV approved by the Food and Drug Administration

[0620] The text below is from the label with the prescribing information for VYVGART® (efgartigimod alfa-fcab) injection, for intravenous use, as approved by Food and Drug Administration (Initial U.S. Approval: 2021, revised April 2025).

[0621] HIGHLIGHTS OF PRESCRIBING INFORMATION

[0622] These highlights do not include all the information needed to use VYVGART safely and effectively. See full prescribing information for VYVGART.

[0623] VYVGART® (efgartigimod alfa-fcab) injection, for intravenous use

[0624] Initial U.S. Approval: 2021

[0625] RECENT MAJOR CHANGES

[0626] Dosage and Administration (2.1) 8 / 2024

[0627] Contraindications (4) 12 / 2023

[0628] Warnings and Precautions (5.1) 8 / 2024

[0629] Warnings and Precautions (5.2, 5.3) 12 / 2023

[0630] INDICATIONS AND USAGE

[0631] VYVGART is a neonatal Fc receptor blocker indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. (1)

[0632] DOSAGE AND ADMINISTRATION

[0633] Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART. (2.1)

[0634] The recommended dosage is 10 mg / kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1200 mg per infusion. (2.2)

[0635] Administer subsequent treatment cycles based on clinical evaluation; safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established. (2.2)

[0636] Must be diluted with 0.9% Sodium Chloride Injection, USP prior to administration. (2.3)

[0637] Administer as an intravenous infusion over one hour via a 0.2 micron in-line filter. (2.3)

[0638] DOSAGE FORMS AND STRENGTHS

[0639] Injection: 400 mg in 20 mL (20 mg / mL) single-dose vial. (3)

[0640] CONTRAINDICATIONS

[0641] VYVGART is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART. (4)

[0642] WARNINGS AND PRECAUTIONS

[0643] Infections: Delay administration of VYVGART to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with VYVGART. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved. (5.1)

[0644] Hypersensitivity Reactions: Anaphylaxis, hypotension leading to syncope, angioedema, dyspnea, and rash have occurred. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. (4, 5.2)

[0645] Infusion-Related Reactions: If a severe infusion-related reaction occurs, discontinue the infusion and initiate appropriate therapy; consider risks and benefits of readministering. If a mild to moderate infusion-related reaction occurs, may rechallenge with close clinical observation, slower infusion rates, and pre-medications. (5.3)

[0646] ADVERSE REACTIONS

[0647] Most common adverse reactions (> 10%) in patients treated with gMG are respiratory tract infections, headache, and urinary tract infection. (6.1)

[0648] To report SUSPECTED ADVERSE REACTIONS, contact argenx at l-833-argx411 or FDA at 1-800-FDA-1088 or fda.gov / medwatch.

[0649] DRUG INTERACTIONS

[0650] Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing VYVGART and using alternative therapies. (7)

[0651] See 17 for PATIENT COUNSELING INFORMATION.

[0652] Revised: 4 / 2025

[0653] FULL PRESCRIBING INFORMATION: CONTENTS*

[0654] 1 INDICATIONS AND USAGE

[0655] 2 DOSAGE AND ADMINISTRATION

[0656] 2.1 Recommended Vaccination

[0657] 2.2 Recommended Dose and Dose Schedules

[0658] 2.3 Preparation and Administration Instructions

[0659] 3 DOSAGE FORMS AND STRENGTHS

[0660] 4 CONTRAINDICATIONS

[0661] 5 WARNINGS AND PRECAUTIONS

[0662] 5.1 Infections

[0663] 5.2 Hypersensitivity Reactions

[0664] 5.3 Infusion-Related Reactions

[0665] 6 ADVERSE REACTIONS

[0666] 6.1 Clinical Trials Experience

[0667] 6.2 Postmarketing experience

[0668] 6.3 Immunogenicity

[0669] 7 DRUG INTERACTIONS

[0670] 7. 1 Effect of VYVGART on Other Drugs

[0671] 8 USE IN SPECIFIC POPULATIONS

[0672] 8.1 Pregnancy

[0673] 8.2 Lactation

[0674] 8.4 Pediatric Use

[0675] 8.5 Geriatric Use

[0676] 8.6 Renal Impairment

[0677] 11 DESCRIPTION

[0678] 12 CLINIC AL PHARMACOLOGY

[0679] 12.1 Mechanism of Action

[0680] 12.2 Pharmacodynamics

[0681] 12.3 Pharmacokinetics

[0682] 13 NONCLINIC AL TOXICOLOGY

[0683] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0684] 14 CLINICAL STUDIES

[0685] 16 HOW SUPPLIED / STORAGE AND HANDLING

[0686] 17 PATIENT COUNSELING INFORMATION

[0687] * Sections or subsections omitted from the full prescribing information are not listed.

[0688] FULL PRESCRIBING INFORMATION

[0689] 1 INDICATIONS AND USAGE

[0690] VYVGART is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

[0691] 2 DOSAGE AND ADMINISTRATION

[0692] 2.1 Recommended Vaccination

[0693] Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART. Because VYVGART causes transient reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with VYVGART [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

[0694] 2.2 Recommended Dose and Dose Schedules

[0695] Dilute VYVGART prior to administration. Administer via intravenous infusion only [see Dosage and Administration (2.3)].

[0696] The recommended dosage of VYVGART is 10 mg / kg administered as an intravenous infusion over one hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose of VYVGART is 1200 mg (3 vials) per infusion.

[0697] Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.

[0698] If a scheduled infusion is missed, VYVGART may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.

[0699] 2.3 Preparation and Administration Instructions

[0700] Prior to administration, VYVGART single-dose vials require dilution in 0.9% Sodium Chloride Injection, USP, to make a total volume to be administered of 125 mb (see Preparation) .

[0701] Check that the VYVGART solution is clear to slightly opalescent and colorless to slightly yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration, or other foreign particles are present.

[0702] Use aseptic technique when preparing the VYVGART diluted solution for intravenous infusion. Each vial is for single-dose only.

[0703] Discard any unused portion.

[0704] Preparation

[0705] Calculate the dose (mg), total drug volume (mL) of VYVGART solution required, and the number of vials needed based on the recommended dose according to the patient’s body weight [see Dosage and Administration (2.2)]. Each vial contains a total of 400 mg of VYVGART at a concentration of 20 mg per mL.

[0706] Gently withdraw the calculated dose of VYVGART from the vial(s) with a sterile syringe and needle. Discard any unused portion of the vials.

[0707] Dilute the withdrawn VYVGART with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

[0708] Gently invert the infusion bag containing the diluted VYVGART without shaking to ensure thorough mixing of the product and the diluent.

[0709] The diluted solution can be administered using polyethylene (PE), polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

[0710] Storage Conditions of the Diluted Solution

[0711] VYVGART does not contain preservatives. Administer immediately after dilution and complete the infusion within 4 hours of dilution.

[0712] If immediate use is not possible, the diluted solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours. Do not freeze. Protect from light. Allow the diluted drug to reach room temperature before administration. Complete the infusion within 4 hours of removal from the refrigerator. Do not heat the diluted drug in any manner other than via ambient air.

[0713] Administration

[0714] VYVGART should be administered via intravenous infusion by a healthcare professional.

[0715] Visually inspect VYVGART diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, or if opaque or foreign particles are seen.

[0716] Infuse the total 125 mL of diluted solution intravenously over one hour via a 0.2 micron in-line filter.

[0717] After administration of VYVGART, flush the entire line with 0.9% Sodium Chloride Injection, USP.

[0718] Monitor patients during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs during administration, discontinue administration of VYVGART and institute appropriate supportive measures [see Warnings and Precautions (5.2) J.

[0719] Other medications should not be injected into infusion side ports or mixed with VYVGART.

[0720] 3 DOSAGE FORMS AND STRENGTHS

[0721] Injection: 400 mg / 20 mL (20 mg / mL) as a colorless to slightly yellow, clear to slightly opalescent solution, in a single-dose vial.

[0722] 4 CONTRAINDICATIONS

[0723] VYVGART is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART. Reactions have included anaphylaxis and hypotension leading to syncope [see Warnings and Precautions (5.2) J .

[0724] 5 WARNINGS AND PRECAUTIONS

[0725] 5.1 Infections

[0726] VYVGART may increase the risk of infection. The most common infections observed in Study 1 were urinary tract infection (10% of VYVGART -treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of VYVGART -treated patients compared to 29% of placebo-treated patients) [see Adverse Reactions (6.1) and Clinical Studies (14)] . A higher frequency of patients who received VYVGART compared to placebo were observed to have below normal levels for white blood cell counts (12% versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities were mild to moderate in severity. Delay VYVGART administration in patients with an active infection until the infection is resolved. During treatment with VYVGART, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved.

[0727] Immunization

[0728] Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART. The safety of immunization with live vaccines and the immune response to vaccination during treatment with VYVGART are unknown. Because VYVGART causes a reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with VYVGART.

[0729] 5.2 Hypersensitivity Reactions

[0730] In clinical trials, hypersensitivity reactions, including rash, angioedema, and dyspnea were observed in VYVGART -treated patients. Hypersensitivity reactions were mild or moderate, occurred within one hour to three weeks of administration, and did not lead to treatment discontinuation.

[0731] Anaphylaxis and hypotension leading to syncope have been reported in postmarketing experience with VYVGART. Anaphylaxis and hypotension occurred during or within an hour of administration and led to infusion discontinuation and in some cases to permanent treatment discontinuation.

[0732] Monitor patients during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medicalI l lattention. VYVGART is contraindicated in patients with a history of serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART [see Contraindications (4)].

[0733] 5.3 Infusion-Related Reactions

[0734] Infusion-related reactions have been reported with VYVGART in postmarketing experience. The most frequent symptoms and signs were hypertension, chills, shivering, and thoracic, abdominal, and back pain. Infusion-related reactions occurred during or within an hour of administration and led to infusion discontinuation. If a severe infusion-related reaction occurs during administration, discontinue VYVGART infusion and initiate appropriate therapy. Consider the risks and benefits of readministering VYVGART following a severe infusion-related reaction. If a mild to moderate infusion-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications.

[0735] 6 ADVERSE REACTIONS

[0736] The following clinically significant adverse reactions are described elsewhere in the labeling:

[0737] Infections [see Warnings and Precautions (5.1) J

[0738] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ]

[0739] Infusion-Related Reactions [see Warnings and Precautions (5.3)]

[0740] 6.1 Clinical Trials Experience

[0741] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

[0742] In clinical studies, the safety of VYVGART has been evaluated in 246 patients who received at least one dose of VYVGART, including 57 patients exposed to at least 7 treatment cycles and 8 patients exposed to at least 10 treatment cycles.

[0743] In a placebo-controlled study (Study 1) in patients with gMG, 84 patients received VYVGART 10 mg / kg [see Clinical Studies (14)]. Of these 84 patients, approximately 75% were female, 82% were White, 11% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean age at study entry was 46 years (range 19 to 78).

[0744] The minimum time between treatment cycles, specified by study protocol, was 50 days. On average, VYVGART-treated patients received 2 cycles in Study 1. The mean and median times to the second treatment cycle were 94 days and 72 days from the initial infusion of the first treatment cycle, respectively, for VYVGART-treated patients.

[0745] Adverse reactions reported in at least 5% of patients treated with VYVGART and more frequently than placebo are summarized in Table 11. The most common adverse reactions (reported in at least 10% of VYVGART-treated patients) were respiratory tract infection, headache, and urinary tract infection.

[0746] 6.2 Postmarketing Experience

[0747] The following adverse reactions have been identified during postapproval use of VYVGART. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

[0748] Immune System Disorders: Hypersensitivity reactions including anaphylaxis and hypotension, and infusion-related reactions [see Warnings and Precautions (5.2, 5.3)].

[0749] 6.3 Immunogenicity

[0750] As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VYVGART in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

[0751] In up to 26 weeks of treatment in Study 1, 20% (17 / 83) of patients developed antibodies to VYVGART. Seven percent (6 / 83) of patients developed neutralizing antibodies.

[0752] Because few patients tested positive for anti-efgartigimod alfa-fcab antibodies and neutralizing antibodies, the available data are too limited to make definitive conclusions regarding immunogenicity and the effect on pharmacokinetics, safety, or efficacy of VYVGART.

[0754] 7.1 Effect of VYVGART on Other Drugs

[0755] Concomitant use of VYVGART with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivates containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing VYVGART and using alternative therapies.

[0756] 8 USE IN SPECIFIC POPULATIONS

[0757] 8.1 Pregnancy

[0758] Pregnancy Exposure Registry

[0759] There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VYVGART during pregnancy. Healthcare providers and patients may call 1-855-272- 6524 or go to Vyvgartpregnancy.com to enroll in or to obtain information about the registry.

[0760] Risk Summary

[0761] There are no available data on the use of VYVGART during pregnancy. There is no evidence of adverse developmental outcomes following the administration of VYVGART at up to 100 mg / kg / day in rats and rabbits (see Data).

[0762] The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

[0763] Clinical Considerations

[0764] Fetal Neonatal Adverse Reactions

[0765] Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Therefore, efgartigimod alfa-fcab may be transmitted from the mother to the developing fetus.

[0766] As VYVGART is expected to reduce maternal IgG antibody levels, reduction in passive protection to the newborn is anticipated. Risk and benefits should be considered prior to administering live vaccines to infants exposed to VYVGART in utero [see Warnings and Precautions (5.1)].

[0767] Data

[0768] Animal Data

[0769] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0770] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0771] 8.2 Lactation

[0772] Risk Summary

[0773] There is no information regarding the presence of efgartigimod alfa-fcab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk.

[0774] The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VYVGART and any potential adverse effects on the breastfed infant from VYVGART or from the underlying maternal condition.

[0775] 8.4 Pediatric Use

[0776] Safety and effectiveness in pediatric patients have not been established.

[0777] 8.5 Geriatric Use

[0778] Clinical studies of VYVGART did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger adult patients.

[0779] 8.6 Renal Impairment

[0780] No dose adjustment of VYVGART is needed for patients with mild renal impairment. There are insufficient data to evaluate the impact of moderate renal impairment (eGFR 30-59 mL / min / 1.73 m2) and severe renal impairment (eGFR <30 mL / min / 1.73 m2) on pharmacokinetic parameters of efgartigimod alfa-fcab [see Clinical Pharmacology (12.3)].

[0781] 11 DESCRIPTION

[0782] Efgartigimod alfa-fcab is a human immunoglobulin G1 (IgGl) -derived Fc fragment (fragment, crystallized) of the za allotype. The efgartigimod alfa-fcab Fc fragment is a homodimer consisting of two identical peptide chains each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity for FcRn. The molecular weight of efgartigimod alfa-fcab is approximately 54 kDa.

[0783] VYVGART (efgartigimod alfa-fcab) injection is a sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow solution supplied in a single-dose vial for infusion after dilution.

[0784] Each 20 mL single-dose vial contains 400 mg of efgartigimod alfa-fcab at a concentration of 20 mg / mL. In addition, each mL of solution contains L-arginine hydrochloride (10.5 mg), L-histidine (1.4 mg), L- histidine hydrochloride monohydrate (2.2 mg), L-methionine (1.5 mg), polysorbate 80 (0.4 mg), sodium chloride (4.1 mg), sucrose (20.5 mg), and water for injection, USP, at a pH of 6.0.

[0785] 12 CLINICAL PHARMACOLOGY

[0786] 12.1 Mechanism of Action

[0787] Efgartigimod alfa-fcab is a human IgGl antibody fragment that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.

[0788] 12.2 Pharmacodynamics

[0789] In Study 1 [see Clinical Studies (14)], the pharmacological effect of efgartigimod alfa- fcab was assessed by measuring the decrease in serum IgG levels and AChR autoantibody levels. In patients testing positive for AChR antibodies and who were treated with VYVGART, there was a reduction in total IgG levels relative to baseline. Decrease in AChR autoantibody levels followed a similar pattern.

[0790] 12.3 Pharmacokinetics

[0791] Efgartigimod alfa-fcab exhibits linear pharmacokinetics, and following single doses of efgartigimod alfa-fcab, exposures increase proportionally up to 50 mg / kg (5 times the recommended dosage).

[0792] Distribution

[0793] The volume of distribution is 15 to 20L.

[0794] Metabolism and Elimination

[0795] Efgartigimod alfa-fcab is expected to be degraded by proteolytic enzymes into small peptides and amino acids.

[0796] The terminal half-life is 80 to 120 hours (3 to 5 days).

[0797] After a single intravenous dose of 10 mg / kg efgartigimod alfa-fcab in healthy subjects, less than 0.1% of the administered dose was recovered in urine.

[0798] Specific Populations

[0799] Age, Sex, and Race

[0800] A population pharmacokinetics analysis assessing the effects of age, sex, and race did not suggest any clinically significant impact of these covariates on efgartigimod alfa-fcab exposures.

[0801] Patients with Renal Impairment

[0802] No dedicated pharmacokinetic study has been performed in patients with renal impairment.

[0803] A population PK analysis of data from the VYVGART clinical studies indicated that patients with mild renal impairment (eGFR 60-89 mL / min / 1.72m2) had 22% increase in exposure relative to the exposure in patients with normal renal function [see Use in Specific Populations (8.6)].

[0804] Patients with Hepatic Impairment

[0805] No dedicated pharmacokinetic study has been performed in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa- fcab.

[0806] Drug Interaction Studies

[0807] Clinical drug interactions studies have not been performed with efgartigimod alfa- fcab.

[0808] P450 Enzymes

[0809] Efgartigimod alfa-fcab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

[0810] Drug Interactions with Other Drugs or Biological Products

[0811] Efgartigimod alfa-fcab may decrease concentrations of compounds that bind to the human FcRn [see Drug Interactions (7.1)].

[0812] 13 NONCLINICAL

[0813] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0814] Carcinogenesis and Mutagenesis

[0815] No studies have been conducted to assess the carcinogenic potential of efgartigimod alfa-fcab.

[0816] No studies have been conducted to assess the genotoxic potential of efgartigimod alfa- fcab.

[0817] Impairment of Fertility

[0818] Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg / kg / day) to male and female rats prior to and during mating and continuing in females through gestation day 7 resulted in no adverse effects on fertility. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10 mg / kg, on a body weight (mg / kg) basis.

[0819] 14 CLINICAL STUDIES

[0820] The efficacy of VYVGART for the treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was established in a 26-week, multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT03669588).

[0821] Study 1 enrolled patients who met the following criteria at screening:

[0822] - Myasthenia Gravis Foundation of America (MGFA) clinical classification class II toIV

[0823] - MG- Activities of Daily Living (MG-ADL) total score of > 5

[0824] - On stable dose of MG therapy prior to screening, that included acetylcholinesterase(AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone

[0825] - IgG levels of at least 6 g / L

[0826] A total of 167 patients were enrolled in Study 1 and were randomized to receive either VYVGART lOmg / kg (1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83). Baseline characteristics were similar between treatment groups. Patients had a median age of 46 years at screening (range: 19 to 81 years) and a median time since diagnosis of 7 years. Seventy-one percent were female, and 84% were White. Median MG-ADL total score was 9, and median QuantitativeMyasthenia Gravis (QMG) total score was 16. The majority of patients (n=65 for VYVGART; n=64 for placebo) were positive for AChR antibodies.

[0827] At baseline, over 80% of patients in each group received AChE inhibitors, over 70% in each treatment group received steroids, and approximately 60% in each treatment group received NSISTs, at stable doses.

[0828] Patients were treated with VYVGART at the recommended dosage regimen [see Dosage and Administration (2.2)].

[0829] The efficacy of VYVGART was measured using the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. In this study, an MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle.

[0830] The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders during the first treatment cycle between treatment groups in the AChR-Ab positive population. A statistically significant difference favoring VYVGART was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the VYVGART -treated group vs 29.7% in the placebo-treated group (p <0.0001)].

[0831] The efficacy of VYVGART was also measured using the Quantitative Myasthenia Gravis (QMG) total score which is a 13-item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. In this study, a QMG responder was defined as a patient who had a 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week after last infusion of the cycle.

[0832] The secondary endpoint was the comparison of the percentage of QMG responders during the first treatment cycle between both treatment groups in the AChR-Ab positive patients. A statistically significant difference favoring VYVGART was observed in the QMG responder rateduring the first treatment cycle [63.1% in the VYVGART-treated group vs 14.1% in the placebo- treated group (p <0.0001)].

[0833] The results are presented in Table 12.

[0834] 16 HOW SUPPLIED / STORAGE AND HANDLING

[0835] VYVGART (efgartigimod alfa-fcab) injection is a preservative free, sterile, colorless to slightly yellow, clear to slightly opalescent solution supplied as 400 mg / 20 mL (20 mg / mL) in one single-dose vial per carton (NDC 73475-3041-5).

[0836] Store VYVGART vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. Do not shake.

[0837] Refer to Dosage and Administration (2.3) for information on stability and storage of the diluted solutions of VYVGART.

[0838] 17 PATIENT COUNSELING INFORMATION

[0839] Infections

[0840] Instruct patients to communicate any history of infections to the healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection. Advise patients to complete age-appropriate vaccines according to immunization guidelines prior to initiation of a new treatment cycle with VYVGART. Administration of live vaccines is not recommended during treatment with VYVGART [see Warnings and Precautions (5.1)].

[0841] Hypersensitivity Reactions

[0842] Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with VYVGART. Inform patients about the signs and symptoms of these reactions, and advise patients to contact their healthcare provider immediately if these occur [see Warnings and Precautions (5.2)].

[0843] Infusion-Related Reactions

[0844] Advise patients of the potential risk of infusion-related reactions, which can include hypertension, chills, shivering, and chest, abdominal, and back pain see Warnings and Precautions (5.3)].

[0845] Pregnancy Registry

[0846] There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VYVGART during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use In Specific Populations (8.1)].

[0847] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS1. A pharmaceutical composition comprising about 20 mg / mL of a neonatal Fc receptor (FcRn) antagonist, about 10.5 mg / mL L-arginine hydrochloride, about 1.4 mg / mL L-histidine, about 2.2 mg / mL L- histidine hydrochloride monohydrate, about 1.5 mg / mL L-methionine, about 0.4 mg / mL polysorbate 80, about 4.1 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, at a pH of about 6.0, wherein the FcRn antagonist comprises or consists of a variant IgG Fc region, or FcRn- binding fragment thereof, wherein the variant IgG Fc region, or FcRn-binding fragment thereof, comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or a heterodimer, and wherein the first Fc domain and the second Fc domain each comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

2. The pharmaceutical composition of claim 1, wherein the first Fc domain and / or the second Fc domain comprise or consist of an amino acid sequence independently selected from the group consisting of SEQ ID NO : 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.

3. The pharmaceutical composition of claim 1 or 2, wherein the first Fc domain and the second Fc domain comprise or consist of an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.

4. The pharmaceutical composition of any one of claims 1-3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 1.

5. The pharmaceutical composition of any one of claims 1-3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 2.

6. The pharmaceutical composition of any one of claims 1-3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3.

7. The pharmaceutical composition of any one of claims 1-3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 4.

8. The pharmaceutical composition of claim 1, wherein the FcRn antagonist is a population of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the population consists of a dimer of a first Fc domain and a second Fc domain, and wherein the population comprises:(a) a first subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the first subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3; and(b) at least one of:(i) a second subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the second subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 13, respectively;(ii) a third subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the third subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 10, respectively;(iii) a fourth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the fourth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated;(iv) a fifth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the fifth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated;(v) a sixth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the sixth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively;(vi) a seventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the seventh subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized;(vii) an eighth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eighth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 2;(viii) a ninth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the ninth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 7, respectively;(ix) a tenth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the tenth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized; and(x) an eleventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eleventh subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue and a tryptophan residue, in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

9. The pharmaceutical composition of claim 1, wherein the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

10. A pharmaceutical composition comprising 20 mg / mL of an FcRn antagonist, 10.5 mg / mL L- arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0, wherein the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

11. The pharmaceutical composition of any one of claims 1-10, wherein the pharmaceutical composition is sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow.

12. The pharmaceutical composition of any one of claims 1-11, wherein the pharmaceutical composition is for intravenous administration.

13. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition is contraindicated in patients with serious hypersensitivity to efgartigimod products or to any composition excipients.

14. The pharmaceutical composition of claim 13, wherein the hypersensitivity is anaphylaxis and / or hypotension leading to syncope.

15. A single-dose vial comprising the pharmaceutical composition of any one of claims 1-14.

16. The single-dose vial of claim 15, wherein the single-dose vial contains 20 mL of the pharmaceutical composition.

17. The single-dose vial of claim 15 or 16, wherein the single-dose vial contains 400 mg of the FcRn antagonist.

18. A method of reducing serum IgG levels in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 1-14 or an effective amount of the pharmaceutical composition contained within the singledose vial of any one of claims 15-17.

19. The method according to claim 18, wherein the subject has an autoimmune disease.

20. The method according to claim 19, wherein the autoimmune disease is myasthenia gravis (MG).21 . The method according to claim 20, wherein the MG is generalized MG (gMG).

22. The method according to claim 21, wherein the subject is anti -acetylcholine receptor (AChR) antibody positive.

23. The method according to claim 21, wherein the subject is anti-AChR antibody negative.

24. The method according to any one of claims 21-23, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

25. The method according to any one of claims 18-24, wherein the subject is a human.

26. The method according to any one of claims 18-25, wherein the subject is an adult human.

27. The method according to any one of claims 18-26, wherein the pharmaceutical composition is administered to the subject at a dose of 10 mg / mL of the FcRn antagonist.

28. The method according to any one of claims 18-27, wherein the pharmaceutical composition is administered to the subject once weekly or once biweekly.

29. The method according to any one of claims 18-28, wherein the pharmaceutical composition is diluted prior to use.

30. The method according to claim 29, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

31. The method according to any one of claims 18-30, wherein the pharmaceutical composition is contained within the single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using polyethylene (PE), polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

32. A method of treating MG in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 1-14 or an effective amount of the pharmaceutical composition contained within the single-dose vial of any one of claims 15-17.

33. The method according to claim 32, wherein the MG is generalized MG (gMG) or ocular MG (oMG).

34. The method according to claim 32 or 33, wherein the subject is anti-AChR antibody positive.

35. The method according to claim 32 or 33, wherein the subject is anti-AChR antibody negative.

36. The method according to any one of claims 32-35, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

37. The method according to any one of claims 32-36, wherein the subject is a human.

38. The method according to any one of claims 32-37, wherein the subject is an adult human.

39. The method according to any one of claims 32-38, wherein the pharmaceutical composition is administered to the subject at a dose of 10 mg / mL of the FcRn antagonist.

40. The method according to any one of claims 32-39, wherein the pharmaceutical composition is administered to the subject once weekly or once biweekly.

41. The method according to any one of claims 32-40, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

42. The method according to any one of claims 32-41, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or moresubsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

43. The method according to claim 42, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

44. The method according to claim 42 or 43, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

45. The method according to any one of claims 42-44, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

46. The method according to any one of claims 42-45, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

47. The method according to any one of claims 32-46, wherein the pharmaceutical composition is diluted prior to use.

48. The method according to claim 47, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

49. The method according to any one of claims 32-48, wherein the pharmaceutical composition is contained within the single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

50. A method of treating gMG in a subject in need thereof, the method comprising:(a) administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion;(b) monitoring the subject for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope; and(c) initiating an appropriate measure to mitigate the hypersensitivity reaction when detected.

51. The method according to claim 50, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

52. The method according to claim 50, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

53. The method according to any one of claims 50-52, wherein the pharmaceutical composition is diluted prior to use.

54. The method according to claim 53, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

55. The method according to any one of claims 50-54, wherein the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

56. The method according to any one of claims 50-55, wherein the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour.

57. The method according to any one of claims 50-56, wherein the pharmaceutical composition is administered to the subject once weekly.

58. The method according to any one of claims 50-57, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

59. The method according to any one of claims 50-58, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

60. The method according to claim 59, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

61. The method according to claims 59 or 60, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

62. The method according to any one of claims 59-61, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

63. The method according to any one of claims 59-62, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

64. The method according to any one of claims 50-63, wherein the anaphylaxis and / or hypotension occurs during administration or within 1 hour of administration of the pharmaceutical composition to the subject.

65. The method according to any one of claims 50-64, wherein the subject is monitored during administration of the pharmaceutical composition to the subject and for 1 hour thereafter.

66. The method according to any one of claims 50-65, wherein the appropriate measure comprises discontinuation of the intravenous infusion.

67. The method according to any one of claims 50-66, wherein the appropriate measure comprises permanent discontinuation of treatment with the pharmaceutical composition.

68. The method according to any one of claims 50-67, wherein the appropriate measure comprises seeking medical attention.

69. The method according to any one of claims 50-68, wherein the subject is anti-AChR antibody positive.

70. The method according to any one of claims 50-69, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

71. The method according to any one of claims 50-70, wherein the subject is a human.

72. The method according to any one of claims 50-71, wherein the subject is an adult human.

73. A method of treating gMG in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion, wherein the subject has been informed of the signs and symptoms of a hypersensitivity reaction and advised to contact their healthcare provider immediately should they occur, wherein the hypersensitivity reaction is selected from the group consisting of anaphylaxis and hypotension leading to syncope.

74. The method according to claim 73, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

75. The method according to claim 73, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

76. The method according to any one of claims 73-75, wherein the pharmaceutical composition is diluted prior to use.

77. The method according to claim 76, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

78. The method according to any one of claims 73-77, wherein the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

79. The method according to any one of claims 73-78, wherein the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour.

80. The method according to any one of claims 73-79, wherein the pharmaceutical composition is administered to the subject once weekly.

81. The method according to any one of claims 73-80, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

82. The method according to any one of claims 73-81, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

83. The method according to claim 82, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

84. The method according to claim 82 or 83, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

85. The method according to any one of claims 82-84, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

86. The method according to any one of claims 82-85, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

87. The method according to any one of claims 73-86, wherein the subject is anti-AChR antibody positive.

88. The method according to any one of claims 73-87, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

89. The method according to any one of claims 73-88, wherein the subject is a human.

90. The method according to any one of claims 73-89, wherein the subject is an adult human.

91. A method of treating gMG in a subject in need thereof, the method comprising:(a) administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion;(b) monitoring the subject for an infusion-related reaction; and(c) discontinuing the infusion when an infusion-related reaction is detected.

92. The method according to claim 91, further comprising:(d) rechallenging the subject with the pharmaceutical composition when the infusion- related reaction is mild-to-moderate, wherein the rechallenging comprises one or more of the following: close clinical observation, slower infusion rate, and pre-medication.

93. The method according to claim 92, wherein the rechallenging comprises close clinical observation, slower infusion rate, and pre-medication.

94. The method according to any one of claims 91-93, further comprising initiating appropriate therapy when the infusion-related reaction is severe.

95. The method according to any one of claims 91-94, wherein the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

96. The method according to any one of claims 91-95, wherein the subject is anti-AChR antibody positive.

97. The method according to any one of claims 91-96, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

98. The method according to any one of claims 91-97, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

99. The method according to any one of claims 91-98, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

100. The method according to any one of claims 91-99, wherein the pharmaceutical composition is diluted prior to use.101 . The method according to claim 100, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

102. The method according to any one of claims 91-101, wherein the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

103. The method according to any one of claims 91-102, wherein the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour.

104. The method according to any one of claims 91-103, wherein the pharmaceutical composition is administered to the subject once weekly.

105. The method according to any one of claims 91-104, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

106. The method according to any one of claims 91-105, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or moresubsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

107. The method according to claim 106, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

108. The method according to claims 106 or 107, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

109. The method according to any one of claims 106-108, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

110. The method according to any one of claims 106-109, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

111. The method according to any one of claims 91-110, wherein the subj ect is anti-AChR antibody positive.

112. The method according to any one of claims 91-111, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

113. The method according to any one of claims 91-112, wherein the infusion-related reaction occurs during administration or within 1 hour of administration of the pharmaceutical composition to the subject.

114. The method according to any one of claims 91-113, wherein the subject is monitored during administration of the pharmaceutical composition to the subject and for 1 hour thereafter.

115. The method according to any one of claims 91-114, wherein the subject is a human.

116. The method according to any one of claims 91-115, wherein the subject is an adult human.

117. A method of treating gMG in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion, wherein the subject has been advised of the potential risk of an infusion-related reaction.

118. The method according to claim 117, wherein the infusion-related reaction is selected from hypertension, chills, shivering, chest pain, abdominal pain, and back pain.

119. The method according to claim 117 or 118, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

120. The method according to claim 117 or 118, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

121. The method according to any one of claims 117-120, wherein the pharmaceutical composition is diluted prior to use.

122. The method according to claim 121, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

123. The method according to any one of claims 117-122, wherein the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

124. The method according to any one of claims 117-123, wherein the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour.

125. The method according to any one of claims 117-124, wherein the pharmaceutical composition is administered to the subject once weekly.

126. The method according to any one of claims 117-125, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

127. The method according to any one of claims 117-126, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

128. The method according to claim 127, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

129. The method according to claims 127 or 128, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

130. The method according to any one of claims 127-129, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

131. The method according to any one of claims 127-130, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

132. The method according to any one of claims 117-131, wherein the subject is anti-AChR antibody positive.

133. The method according to any one of claims 117-132, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

134. The method according to any one of claims 117-133, wherein the subject is a human.

135. The method according to any one of claims 117-134, wherein the subject is an adult human.

136. A method of treating gMG in a subject in need thereof, the method comprising:(a) administering a pharmaceutical composition comprising efgartigimod, or a biosimilar version thereof, to the subject at a dose of 10 mg / kg via intravenous infusion; and(b) administering to the subject a vaccine as needed at any time during treatment with the pharmaceutical composition, wherein the vaccine is not a live vaccine.

137. The method according to claim 136, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 31.6 mg / mL L-arginine hydrochloride, 0.2 mg / mL polysorbate 80, 5.8 mg / mL sodium chloride, 2.4 mg / mL sodium phosphate dibasic anhydrous, 1.1 mg / mL sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

138. The method according to claim 136, wherein the pharmaceutical composition comprises 20 mg / mL efgartigimod, or a biosimilar version thereof, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

139. The method according to any one of claims 136-138, wherein the pharmaceutical composition is diluted prior to use.

140. The method according to claim 139, wherein the pharmaceutical composition is diluted with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion.

141. The method according to any one of claims 136-140, wherein the pharmaceutical composition is contained within a single-dose vial, and wherein the pharmaceutical composition is diluted prior to use by:(a) calculating the dose (mg), total drug volume (mL) of the pharmaceutical composition required, and the number of vials needed based on the recommended dose according to the subject’s body weight;(b) withdrawing the calculated dose of the pharmaceutical composition from the vial(s) with a sterile syringe and needle;(c) diluting the withdrawn pharmaceutical composition with 0.9% Sodium Chloride Injection, USP to make a total volume of 125 mL for intravenous infusion;(d) inverting the infusion bag containing the diluted composition without shaking to ensure thorough mixing of the product and the diluent; and(e) administering the diluted composition to the subject using PE, PVC, EVA, or ethylene / polypropylene copolymer bags (polyolefins bags), and with PE, PVC, EVA, or polyurethane / polypropylene infusion lines.

142. The method according to any one of claims 136-141, wherein the pharmaceutical composition is administered to the subject via intravenous infusion over 1 hour.

143. The method according to any one of claims 136-142, wherein the pharmaceutical composition is administered to the subject once weekly.

144. The method according to any one of claims 136-143, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

145. The method according to any one of claims 136-144, wherein the pharmaceutical composition is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the pharmaceutical composition within 1 month.

146. The method according to claim 145, wherein the first treatment cycle comprises weekly administration of the pharmaceutical composition for 4 weeks.

147. The method according to claims 145 or 146, wherein the one or more subsequent treatment cycles each comprise weekly administration of the pharmaceutical composition for 4 weeks.

148. The method according to any one of claims 145-147, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

149. The method according to any one of claims 145-148, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

150. The method according to any one of claims 145-149, wherein the vaccine is a COVID-19 vaccine, an influenza vaccine, a pneumococcal vaccine, a shingles vaccine, a human papillomavirus (HPV) vaccine, or a respiratory syncytial virus (RSV) vaccine.

151. The method according to claim 150, wherein the COVID- 19 vaccine is selected from tozinameran, elasomeran, NVX-CoV2373, Ad26.COV2.S, AZD1222, CoronaVac, BBV152, AD5-152. The method according to claim 150, wherein the influenza vaccine is selected from Audenz, Fluad Quadrivalent, Fluad, Afluria Quadrivalent, Afluria Quadrivalent Southern Hemisphere, Flucelvax Quadrivalent, Flulaval Quadrivalent, Afluria, Afluria Southern Hemisphere, FluLaval, FluMist, Fluarix, Fluvirin, Agriflu, Fluzone, Fluzone High-Dose, Fluzone Intradermal, Flucelvax, Flublok, Flublok Quadrivalent, FluMist Quadrivalent, Fluarix Quadrivalent, and Fluzone Quadrivalent.

153. The method according to claim 150, wherein the pneumococcal vaccine is selected from Pneumovax 23, Prevnar 13, VAXNEUVANCE™, and Prevnar 20.

154. The method according to claim 150, wherein the shingles vaccine is SHINGRIX.

155. The method according to claim 150, wherein the HPV vaccine is selected from GARDASIL® 9, GARDASIL®, and CERVARIX®.

156. The method according to claim 150, wherein the RSV vaccine is selected from AREXVY® and ABRYSVO™.

157. The method according to any one of claims 145-156, wherein the subject is anti-AChR antibody positive.

158. The method according to any one of claims 145-157, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

159. The method according to any one of claims 145-158, wherein the subject is a human.

160. The method according to any one of claims 145-159, wherein the subject is an adult human.

161. An approved product comprising efgartigimod for treatment of gMG.

162. The approved product of claim 161, wherein the product is approved for treatment of gMG in adult patients who are anti-AChR antibody positive.

163. The approved product of claim 161 or 162, wherein the product is approved for treatment of gMG in adult patients who do not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

164. The approved product of any one of claims 161-163, wherein the product is provided in a single-dose vial containing 20 mg / mL efgartigimod, 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL L-methionine, 0.4 mg / mL polysorbate 80, 4.1 mg / mL sodium chloride, 20.5 mg sucrose, and water for injection, USP, at a pH of 6.0.

165. The approved product of any one of claims 161-164, wherein the product is for administration via intravenous infusion.

166. The approved product of any one of claims 161-165, wherein the product is administered via intravenous infusion over 1 hour.

167. The approved product of any of claims 161-166, wherein the product induces an MG-ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

168. The approved product of any of claims 161-167, wherein the product induces a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope.

169. The approved product of claim 168, wherein the anaphylaxis or hypotension leading to syncope occurs during or within 1 hour of administration of the product.

170. The approved product of any one of claims 161-169, wherein the product is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof.

171. The approved product of any one of claims 161-170, wherein the product induces an infusion- related reaction.

172. The approved product of claim 171, wherein the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

173. The approved product of any one of claims 161-172, wherein one or more subsequent doses of the product are administered with close clinical observation, slower infusion rates, and premedications when a mild-to-moderate infusion-related reaction occurs during administration of the product.

174. The approved product of any one of claims 161-173, wherein the product is co-administered with a vaccine, wherein the vaccine is not a live vaccine.

175. A biosimilar of the approved product of any one of claims 161-174.

176. A biological product that is bioequivalent to the approved product of any one of claims 161- 174.

177. A kit compri sin :(a) the pharmaceutical composition of any one of claims 1-14, the single-dose vial of any one of claims 15-17, the approved product of any one of claims 161-174, the biosimilar of claim 175, or the biological product of claim 176, and(b) a label.

178. The kit of claim 177, wherein the label includes a contraindication in patients with serious hypersensitivity to efgartigimod alfa products or to any excipients in formulations thereof.

179. The kit of claim 177 or 178, wherein the label includes a warning for hypersensitivity reactions selected from anaphylaxis and hypotension leading to syncope.

180. The kit of any one of claims 177-179, wherein the label states infusion discontinuation when anaphylaxis or hypotension leading to syncope occur during or within 1 hour of administration of the product.

181. The kit of any one of claims 177-180, wherein the label includes a warning for infusion-related reactions selected from hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

182. The kit of any one of claims 177-181, wherein the label states to discontinue infusion and initiate appropriate therapy when a severe infusion-related reaction occurs during administration of the product.

183. The kit of any one of claims 177-182, wherein the label states that patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medications when a mild- to-moderate infusion-related reaction occurs during administration of the product.

184. The kit of any one of claims 177-183, wherein the label includes data demonstrating an MG- ADL response rate of 67.7% and a QMG response rate of 63.1% in a population of gMG patients who received 10 mg / kg efgartigimod, compared to a MG-ADL response rate of 29.7% and a QMG response rate of 14.1% in a population of gMG patients who received placebo.

185. A method of treating gMG in a subject in need thereof, the method comprising administering the approved product of any one of claims 161-174, the biosimilar of claim 175, or the biological product of claim 176 to the subject.

186. The method according to claim 185, wherein the approved product, biosimilar, or biological product is administered to the subject once weekly.

187. The method according to claim 185 or 186, wherein the approved product, biosimilar, or biological product is administered to the subject once weekly for 4 weeks.

188. The method according to any one of claims 185-187, wherein the approved product, biosimilar, or biological product is administered to the subject using a phased dosing schedule comprising a first treatment cycle and one or more subsequent treatment cycles, wherein the first treatment cycle and the one or more subsequent treatment cycles each independently comprise administration of 1-5 doses of the approved product, biosimilar, or biological product within 1 month.

189. The method according to claim 188, wherein the first treatment cycle comprises weekly administration of the approved product, biosimilar, or biological product for 4 weeks.

190. The method according to claim 188 or 189, wherein the one or more subsequent treatment cycles each comprise weekly administration of the approved product, biosimilar, or biological product for 4 weeks.

191. The method according to any one of claims 188-190, wherein each of the one or more subsequent treatment cycles is administered to the subject based on clinical evaluation.

192. The method according to any one of claims 188-191, wherein each of the one or more subsequent treatment cycles is administered to the subject > 50 days from the start of the previous treatment cycle.

193. The method according to any one of claims 185-192, wherein the subject is anti-AChR antibody positive.

194. The method according to any one of claims 185-193, wherein the subject does not have sufficient response to steroids or non-steroidal immunosuppressive therapies.

195. The method according to any one of claims 185-194, further comprising monitoring the subject for a hypersensitivity reaction selected from the group consisting of anaphylaxis and hypotension leading to syncope; and initiating an appropriate measure to mitigate the hypersensitivity reaction when detected.

196. The method according to any one of claims 185-195, further comprising monitoring the subject for an infusion-related reaction; and discontinuing the infusion when an infusion-related reaction is detected.

197. The method according to claim 196, wherein the infusion-related reaction comprises one or more of the following: hypertension, chills, shivering, thoracic pain, abdominal pain, and back pain.

198. The method according to any one of claims 185-197, further comprising administering to the subject a vaccine as needed at any time during treatment with the approved product, biosimilar, or biological product, wherein the vaccine is not a live vaccine.

199. The method according to any one of claims 185-198, wherein the subject is a human.

200. The method according to any one of claims 185-199, wherein the subject is an adult human.

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