Methods for treating myositis using FCRN antagonists

Abstract

Provided herein are methods of treating myositis using an effective amount of a human neonatal Fc receptor (FcRn) antagonist, in particular efgartigimod. Also provided herein are FcRn antagonists (in particular efgartigimod) for use in the treatment of myositis and for use in the manufacture of a medicament for the treatment of myositis.

Description

404373-ARGX-T2418WO (221799)METHODS FOR TREATING MYOSITIS USING FCRN ANTAGONISTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Patent Application No. 63 / 722,419, filed November 19, 2024; the entire contents of which are hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to methods of treating myositis, including but not limited to immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), polymyositis (PM), and anti synthetase syndrome (ASyS) using efgartigimod and variations thereof.BACKGROUND

[0003] It is estimated that more than 2.5% of the human population is affected by autoantibody-driven autoimmune diseases, in which autoreactive antibodies are directly pathogenic. Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases that includes subtypes with varying pathologies primarily targeting muscle and / or skin and other organs. In many subsets, there is a potential role of myositis-specific autoantibodies, most of which are immunoglobulin G (IgG) in the disease pathogenesis.

[0004] Many patients with IIM have persistent impairment of muscle function, which leads to difficulties in daily life activities and a low health-related quality of life. The typical treatment for 11M is high-dose glucocorticoids combined with immunosuppressive drugs. The deleterious long-term effects of corticosteroids have been well established and include osteoporosis, cataracts, and weight gain. There are no therapies approved by the United States Food and Drug Administration (FDA) or the European regulatory authorities based on results of randomized controlled trials for IMNM and PM. Only 1 licensed treatment (10% intravenous immunoglobulin [IVIg]) is available for adults with DM that was approved based on results of randomized controlled clinical trials.

[0005] Accordingly, there is a need in the art for improved IIM treatment options thatBUSINESS.33769645 1 1404373-ARGX-T2418WO (221799)permit tapering or elimination of corticosteroid treatment.

[0006] Therapeutic antagonism of the neonatal Fc receptor (FcRn), a major histocompatibility complex class I-like molecule that is involved in the recycling of immunoglobulin G (IgG) and is thus responsible for the long half-life of IgG, has been explored as a strategy to treat IgG-mediated autoimmune diseases such as generalized myasthenia gravis (gMG), immune thrombocytopenia (ITP), and pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)). The remarkable clinical efficacy of FcRn antagonism appears to be directly linked to early removal of pathogenic IgG autoantibodies from circulation.

[0007] Given their ability to reduce IgG levels, FcRn antagonists may provide a safer, more effective treatment option for patients with IIM. The clinical trial data shown herein establish support for efgartigimod as an effective treatment for myositis.SUMMARY

[0008] The instant disclosure demonstrates that FcRn antagonists are highly effective in treating myositis. Accordingly, the instant disclosure is broadly directed to clinically effective methods for treating myositis with FcRn antagonists.

[0009] The instant disclosure provides a method of treating myositis in a subject in need thereof, the method comprising administering to the subject a clinically effective amount of a human neonatal Fc receptor (FcRn) antagonist and achieving a clinically established response. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or FcRn binding fragment thereof. In some embodiments, the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 as compared to a corresponding wild-type Fc region. In some embodiments the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 as compared to a corresponding wild-type Fc region.

[0010] In some embodiments, the variant IgG Fc region 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.

[0011] In some embodiments, the first Fc domain and / or the second Fc domain comprise 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 theBUSINESS.33769645 1 2404373-ARGX-T2418WO (221799)second Fc domain comprise 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.

[0012] 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.

[0013] 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) 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 both 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;BUSINESS.33769645 1 3404373-ARGX-T2418WO (221799)(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 both 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 are oxidized.

[0014] In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0015] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once weekly. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once weekly.

[0016] In some embodiments, the FcRn antagonist is co-formulated with hyaluronidase and administered subcutaneously. In some embodiments, the hyaluronidase is recombinant humanBUSINESS.33769645 1 4404373-ARGX-T2418WO (221799)hyaluronidase PH20 (rHuPH20). In some embodiments, the rHuPH20 is administered at about 11,000 U once per week.

[0017] In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered once weekly for 24 weeks.

[0018] In some embodiments, the method further comprises administering to the subject an effective amount of one or more of a corticosteroid, an immunosuppressant, or an antimalarial. In some embodiments, the corticosteroid is prednisone. In some embodiments, the corticosteroid is administered at a dose of <20 mg prednisone or dose equivalent per day. In some embodiments, the immunosuppressant is selected from the group consisting of: methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, and mizoribine. In some embodiments, the antimalarial is selected from the group consisting of: hydroxychloroquine, quinacrine, and chloroquine.

[0019] In some embodiments, the myositis is selected from the group consisting of immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), polymyositis (PM), and antisynthetase syndrome (ASyS).

[0020] In some embodiments, the subject is diagnosed with an idiopathic inflammatory myopathy (IIM). In some embodiments, the IIM is selected from the group consisting of IMNM, DM, PM, and ASyS. In some embodiments, the myositis is IMNM. In some embodiments, the myositis is DM. In some embodiments, the subject has an active DM skin rash. In some embodiments, the active DM skin rash is selected from the group consisting of Gottron’s papules, Gottron’s signs, and heliotrope rash. In some embodiments, the myositis is PM or ASyS.

[0021] In some embodiments, the subject has a detectable serum level of a myositis-associated antibody (MAA) or a myositis-specific antibody (MSA) before administration of the FcRn antagonist.

[0022] In some embodiments, the subject shows one or more clinically established responses following administration of the FcRn antagonist, wherein the clinically established responses are selected from the group consisting of:a) an increase in TIS compared to a baseline value;b) a TIS >20;c) a TIS >40;d) a TIS >60;BUSINESS.33769645 1 5404373-ARGX-T2418WO (221799)e) an increase in MMT8 compared to a baseline value;f) a decrease in PGA compared to a baseline value; andg) a decrease in MDGA compared to a baseline value.

[0023] In some embodiments, the clinically established responses are measured following administration of the FcRn antagonist once weekly for 24 weeks. In some embodiments, the clinically established responses are measured at 4 weeks, at 8 weeks, at 12 weeks, at 16 weeks, and / or at 24 weeks following initial administration of the FcRn antagonist.

[0024] In some embodiments, the subject has a TIS of >40 at 24 weeks following initial administration of the FcRn antagonist.

[0025] In some embodiments, the response in TIS >40 is 30% higher in efgartigimod-treated IMNM subjects compared to placebo-treated IMNM subjects. In some embodiments, the response in TIS >40 is 47% higher in efgartigimod-treated IMNM subjects compared to placebo-treated IMNM subjects.

[0026] The instant disclosure also provides an FcRn antagonist for use in the treatment of myositis, wherein the treatment is performed according to the methods described above and herein.

[0027] The instant disclosure also provides an FcRn antagonist for use in the manufacture of a medicament for the treatment of myositis, wherein the treatment is performed according to the methods described above and herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIGs. 1A-1D are graphs showing the mean (±SE) total improvement score (TIS) over time in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set. FIG.1A shows data from the total population;FIG. IB shows data from the IMNM subtype population; FIG. 1C shows data from the DM subtype population; and FIG. ID shows data from the PM subtype population.

[0029] FIGs. 2A-2C are Kaplan-Meier plots showing the time to first minimal improvement in TIS (TIS >20; FIG. 2A), time to first moderate improvement in TIS (TIS >40;FIG. 2B), and time to first major improvement in TIS (TIS >60; FIG.2C) in the ITT analysis set.

[0030] FIGs. 3A-3D are sets of graphs showing the percentage of total participants (FIG.3A), IMNN participants (FIG. 3B), DM participants (FIG. 3C), and PM participants (FIG. 3D)BUSINESS.33769645 1 6404373-ARGX-T2418WO (221799)with TIS response (minimum, moderate, and major) at week 24 analyzed using three different strategies (composite strategy, treatment policy, and while on treatment) in the ITT analysis set.

[0031] FIG. 4 is a graph showing the percentage of TIS in the total population at week 24 by core set measure.

[0032] FIG. 5 is a graph showing the mean (±SE) change from baseline over time in MMT8 in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0033] FIG. 6 is a graph showing the mean (±SE) change from baseline over time in PGA in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0034] FIG. 7 is a graph showing the mean (±SE) change from baseline over time in MDGA in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0035] FIG. 8 is a graph showing the mean (±SE) change from baseline over time in extramuscular global assessment in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0036] FIG. 9 is a graph showing the mean (±SE) change from baseline over time in HAQ-DI in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0037] FIG. 10A is a graph showing the absolute percentage mean (±SE) change from baseline over time in most abnormal enzymes in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set. FIG.10B is a graph showing mean (±SE) change from baseline over time in creatine kinase (CK) in efgartigimod PH20 SC-treated participants compared to placebo-treated participants measured using an intent-to-treat (ITT) analysis set.

[0038] FIG. 11 is a graph showing the percentage of TIS in the IMNM population, DM population, and PM population at week 24 by core set measure.

[0039] FIGs. 12A-12D are graphs showing patient and physician global assessments of disease activity. FIG. 12A shows the patient global impression change at the last assessment before or at ICE / week 24 and at week 24 in the ITT analysis set. FIG. 12B shows the clinical global impression change at the last assessment before or at ICE / week 24 and at week 24 in the ITT analysis set. FIG. 12C shows the patient global impression of severity at baseline, and at the BUSINESS.33769645 1 7404373-ARGX-T2418WO (221799)last assessment before or at ICE / week 24 and at week 24 in the ITT analysis set. FIG. 12D shows the clinical global impression of severity at baseline, and at the last assessment before or at ICE / week 24 and at week 24 in the ITT analysis set.

[0040] FIGs. 13A-13E are graphs showing data from DM-specific endpoints. FIG. 13A shows mean (±SE) change from baseline in CDASI activity in the subset of ITT in participants with the DM subtype. FIG. 13B shows mean (±SE) change from baseline in CDASI damage in the subset of ITT in participants with the DM subtype. FIG. 13C shows mean (±SE) change from baseline in average pruritus within the past 24 hours in the subset of ITT in participants with the DM subtype. FIG. 13D shows mean (±SE) change from baseline in worst pruritus within the past 24 hours in the subset of ITT in participants with the DM subtype. FIG. 13E shows mean (±SE) change from baseline in Skindex-16 total score in the subset of ITT in participants with the DM subtype.DETAILED DESCRIPTION

[0041] The present disclosure provides engineered FcRn antagonists and methods for their use in treating myositis, including immune-mediated necrotizing myopathy (1MNM), dermatomyositis (DM), polymyositis (PM), and anti synthetase syndrome (ASyS). Advantageously, the methods disclosed herein permit rapid treatment of disease, as well as the potential to taper and even discontinue corticosteroids after achieving clinical remission. The instant disclosure demonstrates that FcRn antagonists are highly effective in treating myositis. Treatment with FcRn antagonists significantly reduced myositis-specific autoantibodies and improved muscle strength within nine days in an animal model of immune-mediated necrotizing myopathy (IMNM), an idiopathic inflammatory myopathy.Definitions

[0042] 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.

[0043] 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).BUSINESS.33769645 1 8404373-ARGX-T2418WO (221799)

[0044] 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 (e.g., upper, middle, and / or lower hinge region) domain, 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 (e.g., upper, middle, and / or lower hinge region) region, a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not include the hinge region.

[0045] 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 domains. 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: 29).

[0046] 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 IgG heavy chain 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) mAbs 1(4): 332-338, and de Taeye et al. (2020) Front Immunol. 11:740, incorporated herein by reference in their entirety.

[0047] 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, BUSINESS.33769645 1 9404373-ARGX-T2418WO (221799)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.

[0048] As used herein the term “FcRn binding fragment” refers to a portion of an Fc region that is sufficient to confer FcRn binding.

[0049] 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, 63, 78-85 (1969) and Kabat et al, in “Sequences of Proteins of Immunological Interest,” U. S. Dept. Health and Human Services, 5th edition, 1991.

[0050] As used herein, the term “baseline” refers to a measurement (e.g., a frequency of B cells, IgG levels) in a patient, e g., in a patient’s blood or urine, prior to the first administration (e.g., intravenous, or subcutaneous administration) of a treatment (e.g., an FcRn antagonist).

[0051] As used herein, the term “autoantibody-mediated disease” refers to any disease or disorder in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0052] 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.

[0053] 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.

[0054] As used herein, the term “clinically 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 such as a clinically established response.

[0055] As used herein, the term “dose” or “dosing” refers to an amount of an agent administered to a subject in a single administration.BUSINESS.33769645 1 10404373-ARGX-T2418WO (221799)

[0056] 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.

[0057] As used herein, the term “prednisone equivalent dose” means a dose of prednisone or an equivalent dose of a systemic corticosteroid other than prednisone. Systemic corticosteroids are well-known and include compounds of various potencies and formulations. These are generally formulated as injectables or pills. Examples of commercially available systemic corticosteroids include, without limitation, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone.

[0058] As used herein, the term “remission” refers to a patient who has no new markers of an autoantibody-mediated disease and the baseline markers of the disease have completely resolved or healed.

[0059] As used herein, the term “relapse” or “flare” refers to a patient with an autoantibody-mediated disease who has an appearance of physical symptoms and / or an increase of a marker of the autoantibody-mediated disease after a period of remission of the autoantibody-mediated disease.

[0060] 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, or may 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.BUSINESS.33769645 1 11404373-ARGX-T2418WO (221799)

[0061] 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.

[0062] As used herein, the term “biosimilar” refers to a biological product that is highly similar to and has no clinically meaningful differences from a reference product. As used herein, the term “reference product” refers to a biological product that has been approved for clinical use. 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 BLA submitted under section 35 l(k) of the PHS Act (z.e., 351(k) BLA).

[0063] A biosimilar may have minor differences in clinically inactive components. A biosimilar may include minor modifications in amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance. A biosimilar is a type of approved product. A biosimilar can be shown to be highly similar 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 profiles, 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. In some embodiments, the biosimilar and the reference product do not BUSINESS.33769645 1 12404373-ARGX-T2418WO (221799)comprise the same amino acid sequence. In some embodiments, the biosimilar and the reference product comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid differences. In some embodiments, the amino acid differences are deletions, insertions, or substitutions.

[0064] 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 product 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 approved for 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.

[0065] 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 BUSINESS.33769645 1 13404373-ARGX-T2418WO (221799)action when administered at the same molar dose under similar conditions in an appropriately designed study.

[0066] 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, i.e., 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 authorization 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 authorization in the European Union (EU) on the basis of a complete dossier. The legal basis for authorization of biosimilars in Europe comes from the provisions of Article 10(4) of Directive 2001 / 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 authorized in the EU.

[0067] As used herein, the term “clinically established response” means a result obtained in a subject as a result of a clinical trial following administration of an effective amount of therapeutic agent to the subject wherein the subject demonstrates a response that meets or exceeds one or more of the clinical endpoints described herein.

[0068] As used herein, the term “subject” or “patient” or “participant” includes any human or non-human animal. In an embodiment, the subject or patient or participant is a human or nonhuman mammal. In an embodiment, the subject or patient or participant is a human.BUSINESS.33769645 1 14404373-ARGX-T2418WO (221799)

[0069] 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.Myositis

[0070] Myositis is a group of inflammatory disorders of the skeletal muscle also referred to as idiopathic inflammatory myopathies (IIM). This heterogeneous group of diseases includes many subtypes with varying pathologies. There is evidence that some IIM subtypes, specifically with immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), and certain subtypes of polymyositis (PM) such as anti synthetase syndrome (ASyS), are likely driven by IgG autoantibodies (including myositis-specific antibodies [MSAs] and myositis-associated antibodies [MAAs]).

[0071] General symptoms of chronic IIM include slow but progressive muscle weakness. Inflammation damages the muscle fibers, which causes weakness, and may affect the arteries and blood vessels that pass through muscle. Other symptoms include fatigue after walking or standing, frequent episodes of tripping or falling, and difficulty swallowing or breathing. Some individuals may have muscle pain or muscles that are tender to touch.

[0072] Immune-mediated necrotizing myopathies (IMNM) represent a rare and relatively newly recognized distinct group of inflammatory myopathies. IMNM can occur at any age but usually affect adults. Symptoms are similar to polymyositis and dermatomyositis, with weakness in both the upper and lower body, difficulty rising from low chairs, climbing stairs, or lifting objects. However, the onset of these symptoms can be more severe and sudden, reaching their peak over a period of days or weeks. Other symptoms include fatigue, weight loss, and muscle pain. IMNM are characterized by high creatine kinase levels, and necrosis of skeletal muscle fibers with deposition of C5b-9 membrane attack complex (MAC). Most IMNM patients have autoantibodies (aAbs) directed against signal recognition particle (SRP) or hydroxy-3-methylglutaryl-CoaA reductase (HMGCR). In addition to their role as biomarkers, the relationship observed between aAb titers and disease severity suggests that these aAbs could be pathogenic and therefore the central players in IMNM pathophysiology.

[0073] Polymyositis (PM) affects skeletal muscles and is rarely seen in children. Generally, onset occurs between age 30 and 60. Symptoms vary considerably from person toBUSINESS.33769645 1 15404373-ARGX-T2418WO (221799)person, which can make it difficult to diagnose. Untreated progressive muscle weakness may lead to difficulty swallowing, speaking, rising from a sitting position, climbing stairs, lifting objects, or reaching overhead. Some people with polymyositis may also develop arthritis, shortness of breath, heart arrhythmias (irregular heartbeats), or congestive heart failure (when the heart is no longer able to pump out enough oxygen-rich blood). Anti synthetase syndrome (ASyS) is a polymyositis subtype associated with anti-tRNA synthetase autoantibodies (such as anti-Jo-1, anti -PL-7, anti-PL-12, anti-EJ, and anti-OJ) and one or more of Raynaud’s phenomenon, arthritis, interstitial lung disease, fever that is not attributable to another cause, or evidence of myositis.

[0074] Dermatomyositis (DM) is characterized by a skin rash that precedes or accompanies progressive muscle weakness. The rash appears patchy and characteristically develops on the eyelids and on muscles used to extend or straighten joints (such as knuckles, elbows, knees, and toes). Rashes may also occur on the face, neck, shoulders, upper chest, back, and other locations and may be accompanied by swelling in the affected areas. One form the rashes take is called “heliotrope” (a purplish color) or lilac, but may also be red. It can occur around the eyes along with swelling, but also occurs on the upper chest or back what is called the “shawl” (around the neck) or “V-sign” above the breasts and may also occur on the face, upper arms, thighs, or hands. Another form the rash takes is called Gottron’s sign which are red or violet, sometimes scaly, slightly raised papules that erupt on any of the finger joints (the metacarpophalangeal joints or the interphalangeal joints) The rash sometimes occurs without obvious muscle involvement and often becomes more evident with sun exposure.

[0075] Adults with dermatomyositis may experience weight loss or a low-grade fever, have inflamed lungs, and be sensitive to light. Adult dermatomyositis, unlike polymyositis, may accompany tumors of the breast, lung, female genitalia, or bowel. Children and adults with dermatomyositis may develop calcium deposits under the skin or in the muscle (calcinosis). Raised, reddish bumps (Gottron’s papules) may appear on the knuckles. Calcinosis most often occurs one to three years after disease onset but may occur many years later.

[0076] Anti-TIFl antibody (human transcriptional intermediary factor) is the most common autoantibody found in children with juvenile dermatomyositis. It is also found in adults with dermatomyositis, and high levels of the antibody are associated with an increased risk of cancer-associated DM in adults. Other autoantibodies specific for DM include anti-NXP (nuclear matrix protein) antibodies, anti-SAE (anti-small ubiquitin like modifier activating enzymeBUSINESS.33769645 1 16404373-ARGX-T2418WO (221799)heterodimer) antibodies, and anti-IFN-induced melanoma differentiation-associated protein 5 (MDA5).

[0077] In some cases of polymyositis and dermatomyositis, distal muscles may be affected as the disease progresses. Polymyositis and dermatomyositis may be associated with collagen-vascular or autoimmune diseases such as lupus. Polymyositis may also be associated with infectious disorders such as HIV, which causes AIDS.

[0078] Anti-PM / Scl is associated with lung problems and an overlap of polymyositis and scleroderma. Anti-Ro / SSA antibodies (such as anti-Ro52 (SSA) and anti-Ro60 (SSA)) are the most prevalent MAA in myositis and frequently occurs together with anti-ARS antibodies or other MAAs (such as anti -Ku, anti-snRNP, and anti -La (SSB)).

[0079] Many patients with IIM have persistent impairment of muscle function, which leads to difficulties in daily life activities and a low health-related quality of life. The typical treatment for IIM is high-dose glucocorticoids combined with immunosuppressive drugs. The deleterious long-term effects of corticosteroids have been well established and include osteoporosis, cataracts, and weight gain. There are no therapies approved by the United States Food and Drug Administration (FDA) or the European regulatory authorities based on results of randomized controlled trials for 1MNM and PM. Only one licensed treatment (10% intravenous immunoglobulin [IVIg]) is available for adults with DM that was approved based on results of randomized controlled clinical trials.

[0080] The total improvement score (TIS) is endorsed by the American College of Rheumatology [ACR] and European League Against Rheumatism [EULAR] to monitor IIM symptoms. This score is the weighted sum of improvement in 6 core set measures (CSMs) for disease activity: physician global assessment of disease activity (MDGA), patient global assessment of disease activity (PGA), manual muscle testing-8 (MMT8), health assessment questionnaire disability index (HAQ-DI), muscle enzymes, and extramuscular disease activity (assessed by the Myositis Disease Activity Assessment Tool [MDAAT]).

[0081] The TIS comprises CSMs scored both by the patient and the physician, considering the muscle manifestations and the extramuscular disease activity and physical function. It also includes objective disease activity parameters, i.e., the activity of the muscle enzymes. The International Myositis Assessment and Clinical Studies Group (IMACS) recommends the minimal TIS as the primary endpoint in IIM therapeutic studies. The criteria may be used as a continuous outcome measure, using the TIS, or as a categorical outcome of improvement (minimal, moderate, BUSINESS.33769645 1 17404373-ARGX-T2418WO (221799)or major improvement). IMACS considers the threshold of minimal TIS to differentiate between treatment groups in clinical studies as clinically significant. To date, several phase 3 studies in patients with IIM have used the TIS as a primary endpoint (NCT02728752, NCT03981744, NCT04044690, and NCT04999020).

[0082] The absolute percentage change from baseline in each measure with varying weights is combined to obtain a TIS on a scale from 0 to 100. Higher scores indicate greater improvement. Improvements are defined by the following increases in TIS:

[0083] Minimal improvement — at least 20 points;

[0084] Moderate improvement — at least 40 points;

[0085] Major improvement — at least 60 points.

[0086] MDGA

[0087] The MDGA is a tool that measures the physician’s global evaluation of the participant’s overall disease activity, defined as potentially reversible pathology or physiology resulting from IIM. The physician rates disease activity on the MDGA using a 10-cm VAS. Overall disease activity is rated by drawing a vertical mark on a 10-cm VAS from the left end of the line (no evidence of disease activity), midpoint of the line (moderate disease activity), and the right end of the line (extremely active or severe disease activity).

[0088] PGA

[0089] The PGA is a tool that measures a patient’s global evaluation of their overall disease activity at the time of assessment using a 10-cm VAS. The patient rates their overall disease activity by drawing a vertical mark on a 10-cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (extremely active or severe disease activity).

[0090] MMT8

[0091] The MMT8 is a physician assessment of muscle strength in a set of 8 designated muscles tested bilaterally (proximal muscles [deltoids, biceps, gluteus maximus, gluteus medius, quadriceps] and distal muscles [wrist extensors and ankle dorsiflexors], potential score 0 to 140) and axially (neck flexors, potential score 0 to 10).

[0092] HA0-D1

[0093] The HAQ-DI assesses physical function and is recommended by IMACS as a CSM in therapeutic studies reporting on myositis disease activity. The patient assesses their usual abilities within the past week in 8 categories: dressing and grooming, arising, walking, reach, eating, hygiene, grip, and activities. Each category has 2 to 3 questions scored by the participant BUSINESS.33769645 1 18404373-ARGX-T2418WO (221799)using a 4-point scale from 0 (without any difficulty) to 3 (unable to do). Scores may be adjusted based on the patient’s responses to separate questions regarding their need for aids and devices or help from another person. A VAS may be included in the questionnaire. Respondents are asked to mark how much pain they have had because of their illness in the past week from 0 (no pain) to 100 (severe pain).

[0094] Muscle Enzymes

[0095] Muscle-associated enzymes include creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransaminase (AST), lactate dehydrogenase (LDH), and aldolase. These enzymes are measured in patient blood samples using validated methods. Reduction in prevalence of at least one of these enzymes is indicative of improvement in myositis.

[0096] MDAAT

[0097] The MDAAT is a combined tool that includes the MYOACT, which is a series of physician’s assessments of disease activity of various organ systems modified from the Vasculitis Activity Index, and the MIT AX, which is modified from the British Isles Lupus Assessment Group approach to assess disease activity in lupus. Among the MYO ACT components of the MDAAT assessments, the extramuscular global assessment is a CSM of the TIS and is a tool used by the physician for an overall evaluation of disease activity in all the extramuscular organ systems. This assessment specifically excludes muscle disease activity. The physician uses a 10-cm VAS to rate the participant’s overall disease activity in all extramuscular systems within the past 4 weeks that are caused by active IIM disease. The MIT AX component of the MDAAT assesses disease activity of various organ systems by assessing 26 clinical features within the past 4 weeks that are caused by active disease, using a 5 point scale: 0=not present in the past 4 weeks; l=improving; 2=the same; 3=worse; 4=new.

[0098] CDASI

[0099] CDASI is a skin-specific outcome measure used to assess disease in patients with DM. Disease in 15 different anatomical locations is rated using 3 activity measures (erythema, scale, erosion / ulceration) and 2 damage measures (poikiloderma, calcinosis). The 3 activity measures on the 15 anatomical locations can add up to 90 points; Gottron’s papules on the hands, periungual, and alopecia can add up to 10 points. The 2 damage measures on the 15 anatomical locations can add up to 30 points with 2 additional points for Gottron’ s hands. CDASI also assesses the presence and severity of Gottron’s papules, periungual changes, and alopecia. The resultingBUSINESS.33769645 1 19404373-ARGX-T2418WO (221799)activity and damage scores range from 0 to 100 and 0 to 32, respectively. Higher scores indicate greater disease severity.FcRn Antagonists

[0100] FcRn antagonists that are useful in the 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.

[0101] 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.

[0102] 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.

[0103] Any Fc variant, or FcRn-binding fragment thereof, 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 an embodiment, 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 Fc region, or FcRn binding fragment thereof, which binds 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 a variant Fc region, or FcRn binding fragment thereof, which binds to FcRn with a higher affinity at both acidic and neutral pH.

[0104] 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 BUSINESS.33769645 1 20404373-ARGX-T2418WO (221799)immunoglobulin is human IgG. In some embodiments, the IgG is TgGl, 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.

[0105] In an embodiment, the variant Fc region, or FcRn binding fragment thereof consists of two Fc domains.

[0106] 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. In an embodiment, the first and / or second Fc domain comprise amino acids Y, T, E, K and Y at EU positions 252, 254, 256, 433, and 434, respectively. In an embodiment, the first and / or second Fc domain comprise Y, T, E, L, K and F at EU positions 252, 254, 428, 433, and 434, respectively. In an embodiment, the first and / or second Fc domain comprise amino acids Y, T, E, W, K, and Y at EU positions 252, 254, 256, 366, 433, and 434, respectively. In an embodiment, the first and / or second Fc domain comprise amino acids Y, T, E, S, A, V, K, and Y at EU positions 252, 254, 256, 366, 368, 407, 433, and 434, respectively. In an embodiment, the first and / or second Fc domain comprise amino acids Y, T, E, W, L, K, and F at EU positions 252, 254, 256, 366, 428, 433, and 434, respectively. In an embodiment, the first and / or second Fc domain comprise amino acids Y, T, E, S, A, V, L, K, and F at EU positions 252, 254, 256,366, 368, 407, 428, 433, and 434, respectively.

[0107] 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.Table 1Amino Acid Sequence SEQ ID NO:X1X2X3X4X5X6PPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHE 22 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SC SVMHEALKFHYTQKSLSLSPX7X8BUSINESS.33769645 1 21404373-ARGX-T2418WO (221799)wherein: Xi is D or absent; X2 is K or absent; X3 is T or absent; X4 is H or absent; X5is T or absent; Xe is C or absent; X7 is G or absent; Xs is K or absent.

[0108] 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.

[0109] 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 and 23-28 (see Table 2 below). In some embodiments, the dimer is a heterodimer or a homodimer.Table 2Amino Acid Sequence SEQ ID NO:CPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW 1 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALKFHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPE 2 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY P SDIAVEWE SNGQPENNYKTTPP VLD SDGSFFL YSKLT VDK SRWQQGNVF S CSVMHEALKFHYTQKSLSLSPGK DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPE 3 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALKFHYTQKSLSLSPG CPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW 4 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALKFHYTQKSLSLSPGKBUSINESS.33769645 1 22404373-ARGX-T2418WO (221799)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPE 5 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS C SVMHEALKFHYTQKSLSLSP KTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 6 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALKFHYTQKSLSLSPGK KTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 7 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALKFHYTQKSLSLSPG KTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 8 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALKFHYTQKSLSLSP THTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKF 9 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGF YPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALKFHYTQKSLSLSPGK THTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKF 10 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGF YP SDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALKFHYTQKSLSLSPG THTCPPCP APELLGGP S VFLFPPKPKDTL YITREPE VTC V V VD V SHEDPE VKF 11 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALKFHYTQKSLSLSP TCPPCP APELLGGP SVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 12 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGF YPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALKFHYTQKSLSLSPGK TCPPCP APELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 13 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGF YPSDIABUSINESS.33769645 1 23404373-ARGX-T2418WO (221799)VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALKFHYTQKSLSLSPG TCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 14 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQ VSLTCLVKGFYP SDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALKFHYTQKSLSLSP PPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWY 15 VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCL VKGF YP SDIA VE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALKFHYTQKSLSLSPGK PPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWY 16 VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCL VKGF YP SDIA VE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALKFHYTQKSLSLSPG PPCP APELLGGP S VFLFPPKPKDTL YITREPE VTC V V VD VSHEDPE VKFN W Y 17 VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCL VKGF YP SDIA VE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALKFHYTQKSLSLSP HTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 18 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGFYP SDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HE ALKFHYTQKSLSLSPGK HTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 19 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALP APIEKTISK AKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGFYP SDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALKFHYTQKSLSLSPG HTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFN 20 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALKFHYTQKSLSLSP CPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW 21 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALP APIEKTISKAKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGFYP SDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALKFHYTQKSLSLSPBUSINESS.33769645 1 24404373-ARGX-T2418WO (221799)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 23 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VLHEALKFHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 24 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHE ALK YHYTQK SL SLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 25 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS VMHEALKYHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 26 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALKYHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 27 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS VLHEALKFHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV 28 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVLHEALKFHYTQKSLSLSPG

[0110] 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.

[0111] In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, a 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 BUSINESS.33769645 1 25404373-ARGX-T2418WO (221799)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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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 NOs: 1, 2, 3, or 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: 1 and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NOs: 2, 3, or 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 BUSINESS.33769645 1 26404373-ARGX-T2418WO (221799)of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NOs: 1, 3, or 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 NOs: 1, 2, or 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 NOs: 1, 2, or 3.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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 G0F N-glycan, GIF N-glycan, G2F N-glycan, or GO N-glycan.BUSINESS.33769645 1 27404373-ARGX-T2418WO (221799)

[0122] In some embodiments, 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.

[0123] In some embodiments, the FcRn antagonist lacks an amino acid at EU position 447 of one or both Fc domains. In some embodiments, the FcRn antagonist comprises glycine and lysine at EU positions 446 and 447, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 446 and 447. In some embodiments, the FcRn antagonist comprises amidated proline atEU position 445. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 446 and 447 and comprise amidated proline at EU position 445.

[0124] 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 atEU 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.

[0125] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of multiple subpopulations of FcRn antagonist molecules. In 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.BUSINESS.33769645 1 28404373-ARGX-T2418WO (221799)

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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 is deaminated.

[0131] 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 BUSINESS.33769645 1 29404373-ARGX-T2418WO (221799)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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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 an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, BUSINESS.33769645 1 30404373-ARGX-T2418WO (221799)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 are oxidized.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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 BUSINESS.33769645 1 31404373-ARGX-T2418WO (221799)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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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 are oxidized.

[0148] 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 antagonist molecules comprises or consists of the first subpopulation combined with four of the second, third, BUSINESS.33769645 1 32404373-ARGX-T2418WO (221799)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.

[0149] 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.

[0150] 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.BUSINESS.33769645 1 33404373-ARGX-T2418WO (221799)

[0151] 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.

[0152] 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.

[0153] 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 1.1%-2.1% or 1.0%-1.9% of the population of FcRn antagonist molecules.

[0154] 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 BUSINESS.33769645 1 34404373-ARGX-T2418WO (221799)subpopulation makes up 5%, 4%, 3%, 2%, or 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 1%-5%, 2%-4%, or 2%-3% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 2.1%-3.2% or 2.0%-3.1% of the population of FcRn antagonist molecules.

[0155] 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.

[0156] In some embodiments, the sixth subpopulation makes up 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.

[0157] 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%, about 5.0%, 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 BUSINESS.33769645 1 35404373-ARGX-T2418WO (221799)embodiments, the seventh subpopulation makes up 0.5%-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.

[0158] 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.

[0159] 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.

[0160] 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 some embodiments, 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.

[0161] 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 BUSINESS.33769645 1 36404373-ARGX-T2418WO (221799)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%-1.5%, or 0.5%-1.5% of the population of FcRn antagonist molecules.

[0162] 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, filed 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.

[0163] In an embodiment, the FcRn antagonist is efgartigimod (CAS Registry No.1821402-21-4). The term “efgartigimod” as used herein is interchangeable with “efgartigimod alfa.” In some embodiments, efgartigimod is efgartigimod alfa-fcab.Pharmaceutical Compositions

[0164] In an aspect, the instant disclosure provides pharmaceutical compositions comprising an FcRn antagonist for use in methods of treating myositis.

[0165] In an embodiment, the FcRn antagonist is efgartigimod. 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. The increased affinity for FcRn of efgartigimod at both acidic and physiological pH results in a blockage of FcRn-mediated recycling of IgGs.

[0166] Efgartigimod is a prescription medicine registered as VYVGART®, which is approved in the United States, Europe, United Kingdom, China, Canada, Israel, and Switzerland for the treatment of adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (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 and in the United States BUSINESS.33769645 1 37404373-ARGX-T2418WO (221799)for the treatment of CIDP. Efgartigimod is under development for both the intravenous (IV) and subcutaneous (SC) administration route.

[0167] For SC administration, in certain embodiments, efgartigimod may be administered alone. Alternatively, for SC administration, in certain embodiments, efgartigimod may be administered co-formulated with hyaluronidase, for example, in particular, rHuPH20. The coformulated material will allow SC dosing of larger volumes.

[0168] In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising about 20 mM L-histidine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w / v) polysorbate 20, wherein the formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 180 mg / mL efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 20 mM L-histidine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20, wherein the formulation has a pH of 6.0. In some embodiments, the formulation comprises 180 mg / mL efgartigimod.

[0169] Efgartigimod PH20 SC is currently registered as VYVGART® HYTRULO, which was approved by the U. S. FDA in 2023 for the treatment of gMG in adult patients who are AChR antibody positive. VYVGART® HYTRULO contains 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg / 2,000 units per mL) in a single-dose vial. In certain embodiments, efgartigimod PH20 SC (also referred to as efgartigimod PH20) is used in the methods described herein.

[0170] In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising about 20 mM L-histidine, about 50 mM L-arginine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04 (w / v) polysorbate 80, wherein the formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 200 mg / mL efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 20 mM L-histidine, 50 mM L-arginine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04 (w / v) polysorbate 80, wherein the formulation has a pH of 6.0. In some embodiments, the formulation comprises 200 mg / mL efgartigimod.

[0171] In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 160-240 mg / mL, optionally 180-220 mg / mL, BUSINESS.33769645 1 38404373-ARGX-T2418WO (221799)optionally 190-210 mg / mL of efgartigimod, or optionally about 200 mg / mL of efgartigimod. In some embodiments, the aqueous pharmaceutical formulation comprises 200 mg / mL of efgartigimod. In some embodiments, the aqueous pharmaceutical formulation comprises 1,400-2,800, optionally 1,600-2,600, optionally 1,800-2,400 Units / mL of the hyaluronidase, or optionally about 2,000 Units / mL of the hyaluronidase. In some embodiments, the aqueous pharmaceutical formulation comprises 2,000 Units / mL of the hyaluronidase. In some embodiments, the aqueous pharmaceutical formulation comprises about 2,000 Units / mL of rHuPH20. In some embodiments, the aqueous pharmaceutical formulation comprises 2,000 Units / mL of rHuPH20.

[0172] In some embodiments, the aqueous pharmaceutical formulation comprises 4.2-6.2 mL, optionally 4.5-6.9 mL, optionally 4.7-6.2 mL, or optionally about 5.2 mL of liquid. In some embodiments, the aqueous pharmaceutical formulation has a volume of 5.2 mL of liquid. In some embodiments, the pre-fdled syringe comprises an extractable volume of the aqueous pharmaceutical formulation of 4-6 mL, optionally 4.3-6.7 mL, optionally 4.5-6.0 mL, or optionally about 5.0 mL of liquid. In some embodiments, the extractable volume of the aqueous pharmaceutical formulation is 5.0 mL of liquid. In some embodiments, the aqueous pharmaceutical formulation has an osmolality of 350-380 mOsm / kg H2O. In some embodiments, the aqueous pharmaceutical formulation has a viscosity of between 8 and 14 mPa s at room temperature.

[0173] In some embodiments, the aqueous pharmaceutical formulation comprises 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 about pH 6.0.

[0174] In some embodiments, the aqueous pharmaceutical formulation comprises about 50 mM L-arginine, about 20 mM L-histidine, about 10 mM L-methionine, about 0.04% polysorbate 80, about 70 mM sodium chloride, and about 60 mM sucrose.

[0175] In some embodiments, the aqueous pharmaceutical formulation comprises about 50 mM L-arginine hydrochloride, about 20 mM L-histidine and L-histidine hydrochloride monohydrate, about 10 mM L-methionine, about 0.04% polysorbate 80, about 70 mM sodium chloride, and about 60 mM sucrose.

[0176] In some embodiments, the aqueous pharmaceutical formulation comprises 10.5 mg / mL L-arginine hydrochloride, 1.4 mg / mL L-histidine, 2.2 mg / mL L-histidine hydrochlorideBUSINESS.33769645 1 39404373-ARGX-T2418WO (221799)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 pH 6.0.

[0177] In some embodiments, the aqueous pharmaceutical formulation comprises 50 mM L-arginine, 20 mM L-histidine, 10 mM L-methionine, 0.04% polysorbate 80, 70 mM sodium chloride, and 60 mM sucrose.

[0178] In some embodiments, the aqueous pharmaceutical formulation comprises 50 mM L-arginine hydrochloride, 20 mM L-histidine and L-histidine hydrochloride monohydrate, 10 mM L-methionine, 0.04% polysorbate 80, 70 mM sodium chloride, and 60 mM sucrose.

[0179] In some embodiments, the aqueous pharmaceutical formulation comprises about 200 mg / mL efgartigimod, about 2,000 U / mL rHuPH20, 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 about pH 6.0.

[0180] In some embodiments, the aqueous pharmaceutical formulation comprises about 200 mg / mL efgartigimod, about 2,000 U / mL rHuPH20, about 50 mM L-arginine, about 20 mM L-histidine, about 10 mM L-methionine, about 0.04% polysorbate 80, about 70 mM sodium chloride, and about 60 mM sucrose.

[0181] In some embodiments, the aqueous pharmaceutical formulation comprises about 200 mg / mL efgartigimod, about 2,000 U / mL rHuPH20, about 50 mM L-arginine hydrochloride, about 20 mM L-histidine and L-histidine hydrochloride monohydrate, about 10 mM L-methionine, about 0.04% polysorbate 80, about 70 mM sodium chloride, and about 60 mM sucrose.

[0182] In some embodiments, the aqueous pharmaceutical formulation comprises 200 mg / mL efgartigimod, 2,000 U / mL rHuPH20, 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 pH 6.0.

[0183] In some embodiments, the aqueous pharmaceutical formulation comprises 200 mg / mL efgartigimod, 2,000 U / mL rHuPH20, 50 mM L-arginine, 20 mM L-histidine, 10 mM L-methionine, 0.04% polysorbate 80, 70 mM sodium chloride, and 60 mM sucrose.

[0184] In some embodiments, the aqueous pharmaceutical formulation comprises 200 mg / mL efgartigimod, 2,000 U / mL rHuPH20, 50 mM L-arginine hydrochloride, 20 mM L-histidine and L-histidine hydrochloride monohydrate, 10 mM L-methionine, 0.04% polysorbate 80, 70 mM sodium chloride, and 60 mM sucrose.BUSINESS.33769645 1 40404373-ARGX-T2418WO (221799)

[0185] In some embodiments, the aqueous pharmaceutical formulation is contained within a pre-filled syringe for subcutaneous administration.

[0186] rHuPH20 is the active ingredient of Halozyme’s commercial product HYLENEX® recombinant (hyaluronidase human injection), referred to as HYLENEX®, which was approved by FDA for marketed use in the U. S. in December 2005. HYLENEX® is a tissue permeability modifier indicated as an adjuvant in SC fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in SC urography, for improving resorption of radiopaque agents.

[0187] rHuPH20 is a recombinant enzyme human hyaluronidase produced by genetically engineered Chinese hamster ovary (CHO) cells containing a deoxyribonucleic plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

[0188] The HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biologic drug products co-formulated with rHuPH20 DS. As such, in certain embodiments HZ202 rHuPH20 DS is used in the efgartigimod / rHuPH20 co-formulated product for SC administration (z.e., efgartigimod PH20 SC).

[0189] Provided in the co-formulations, combinations, uses and methods herein are soluble hyaluronidases. Soluble hyaluronidases include any that, upon expression, are secreted from a cell and exist in soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases, such as bovine PH20 and ovine PH20, human soluble PH20, and variants thereof. Generally soluble forms of PH20 are produced using protein expression systems that facilitate correct N-glycosylation to ensure the polypeptide retains activity, since glycosylation is important for the catalytic activity and stability of hyaluronidases. Such cells include, for example Chinese Hamster Ovary (CHO) cells (e.g., DG44 CHO cells).

[0190] In some embodiments, rHuPH20 refers to the composition produced upon expression in a cell, such as a CHO cell, of nucleic acid encoding residues 36-482 of SEQ ID NO: 30, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 30). rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 30) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence. As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of the polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 30, and some shorter polypeptides, in various abundance. Typically, rHuPH20 is produced in cells that facilitate BUSINESS.33769645 1 41404373-ARGX-T2418WO (221799)correct N-glycosylation to retain activity, such as CHO cells (e.g, DG44 CHO cells). In some embodiments, one of the most abundant species is the 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 30. In some embodiments, rHuPH20 refers to polypeptides that are soluble or secreted upon expression in a mammalian cell and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity with residues 36-482 of SEQ ID NO: 30. In some embodiments, the rHuPH20 is the 447 amino acid polypeptide of SEQ ID NO: 31.Table 7. Exemplary hyaluronidase sequencesSEQ ID NO: Amino Acid Sequence30 MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPF LWAWNAP SEFCLGKFDEPLDMSLF SFIGSPRINATGQGVTIF YVDRL GYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGM AVIDWEEWRPTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATE KAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHYKK PGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLY VRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYT FGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTL AAKMC SQVLCQEQGVCIRKNWNS SDYLHLNPDNFAIQLEKGGKFT VRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCIADG VCIDAFLKPPMETEEPQIFYNASPSTLSATMFIVSILFLIISSVASL31 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELV QQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWG YYLFPDCYNHHYKKPGYNGSCPNVEIKRNDDLSWLWNESTALYPS IYLNTQQ SP VA ATL YVRNRVRE AIR VSKIPD AK SPLP VF A YTRIVFT DQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLD NYMETILNPYIINVTLAAKMC SQVLCQEQGVCIRKNWNS SDYLHL NPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEK ADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFY

[0191] In some embodiments, the pharmaceutical formulation comprises about 1000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod.

[0192] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL efgartigimod. In some embodiments, the pharmaceutical formulation comprises 180 mg / mL efgartigimod.BUSINESS.33769645 1 42404373-ARGX-T2418WO (221799)

[0193] In some embodiments, the pharmaceutical formulation comprises about 200 mg / mL efgartigimod. In some embodiments, the pharmaceutical formulation comprises 200 mg / mL efgartigimod.

[0194] In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0195] The hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In an embodiment, the amount of hyaluronidase enzyme is from about 1000 U / mL to about 3000 U / mL. In an embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In an embodiment, the amount of hyaluronidase enzyme is 2000 U / mL.

[0196] In some embodiments, the rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U. In some embodiments, the rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U.

[0197] In some embodiments, the pharmaceutical formulation comprises at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase enzyme. In some aspects, the pharmaceutical formulation comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of an endoglycosidase hydrolase enzyme.

[0198] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises at least about 500 U / mL to at least about 5000 U / mL of an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 pM, at least about 2500 pM, at least about 3000 pM, BUSINESS.33769645 1 43404373-ARGX-T2418WO (221799)at least about 3500 pM, at least about 4000 pM, at least about 4500 U / mL, or at least about 5000 U / mL of an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises about 2000 U / mL of an endoglycosidase hydrolase enzyme.

[0199] In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at a hexosaminidic P (1-4) or (1-3) linkage. In some embodiments, the endoglycosidase hydrolase enzyme comprises a catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 30. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant, and any isoform thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0200] In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitution in an alpha-helix region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitution in linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase, wherein one or more N-terminal and / or C-terminal amino acids are deleted relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitution in an alpha-helix region, a linker region, or both an alpha- helix region and a linker region relative to wild-type rHuPH20; BUSINESS.33769645 1 44404373-ARGX-T2418WO (221799)ii. deletion of one or more N- terminal amino acid, one or more C-terminal amino acid, or one or more N-terminal amino acid and one or more C-terminal amino acid relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0201] " Hyaluronidase," as used herein, refers to an enzyme capable of catalyzing the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which is present in the subcutaneous space and contributes to the soluble gel-like component of the extracellular matrix of the skin and is restored by rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, which is a glycosylated 447-amino acid single chain polypeptide that depolymerizes hyaluronan in the subcutaneous space locally at the site of injection in the skin. Depolymerization of hyaluronan by hyaluronidase is accomplished by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronan results in a transient reduction in the viscosity of the gel-like phase of the extracellular matrix and increased hydraulic conductance that facilitates the dispersion and absorption of the coadministered therapeutic agent. Thus, a hyaluronidase, e.g., rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologies and drugs by acting as a permeation enhancer. In certain embodiments, the hyaluronidase comprises ENHANZE™.[00202J For IV administration, in certain embodiments, efgartigimod may be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, efgartigimod may be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7), with about 0.02% (w / v) polysorbate 80. In certain embodiments, efgartigimod may be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), with 0.02% (w / v) polysorbate 80. In certain embodiments, efgartigimod may be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7), with about 0.02% (w / v) polysorbate 80, via intravenous infusion in a total volume of about 250 mL over a period of about 2 hours. In certain embodiments, efgartigimod may be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), with 0.02% (w / v) polysorbate 80, via intravenous infusion in a total volume of 250 mL over a period of 2 hours. See, e.g., WO2019110823A1, which is incorporated by reference herein in its entirety.BUSINESS.33769645 1 45404373-ARGX-T2418WO (221799)

[0203] In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride with a pH of about 6.7, with about 0.02% (w / v) polysorbate 80, diluted for intravenous infusion to a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride with a pH of 6.7, with 0.02% (w / v) polysorbate 80, diluted for intravenous infusion to a total volume of 125 mL over a period of 1 hour.

[0204] In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine, and about 0.0032% (w / v) polysorbate 80, with a pH of about 6.7. This formulation is administered via intravenous infusion in a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 4 mM sodium phosphate, 146 mM sodium chloride, 24 mM L-arginine, and 0.0032% (w / v) polysorbate 80, with a pH of 6.7. This formulation is administered via intravenous infusion in a total volume of 125 mL over a period of 1 hour.

[0205] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate solution at a concentration of about 20 mg / mL. In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate solution at a concentration of 20 mg / mL.

[0206] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a vial (e.g., a single-dose vial). In certain embodiments, a vial of efgartigimod contains about 400 mg of efgartigimod at a concentration of about 20 mg / mL. In certain embodiments, a vial of efgartigimod contains 400 mg of efgartigimod at a concentration of 20 mg / mL. In certain embodiments, each mL of solution in a vial of efgartigimod contains about 31.6 mg L-arginine hydrochloride, about 0.2 mg polysorbate 80, about 5.8 mg sodium chloride, about 2.4 mg sodium phosphate dibasic anhydrous, about 1.1 mg sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7. In certain embodiments, each mL of solution in a vial of efgartigimod 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.BUSINESS.33769645 1 46404373-ARGX-T2418WO (221799)

[0207] In certain embodiments, efgartigimod may be administered in a formulation comprising about 20 mg / mL efgartigimod, 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 certain embodiments, efgartigimod may be administered in a formulation comprising 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, and 20.5 mg / mL sucrose, at a pH of 6.0.

[0208] In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour once weekly for about 4 weeks. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once weekly for 4 weeks. In certain embodiments, for patients weighing 120 kg or more, efgartigimod is administered at a dose of about 1200 mg per IV infusion. In certain embodiments, for patients weighing 120 kg or more, efgartigimod is administered at a dose of 1200 mg per IV infusion.

[0209] In any of the above embodiments, the pharmaceutical formulation may be a unit dosage form.

[0210] 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.

[0211] 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 BUSINESS.33769645 1 47404373-ARGX-T2418WO (221799)comprised in a hermetically sealed container such as a vial, a sachet, a pre-filled syringe, a prefilled autoinjector, or a cartridge for a reusable syringe or applicator.

[0212] In an embodiment, the unit dosage per vial may contain 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml of an FcRn antagonist ranging from about 500 to about 2500 mg or from about 1000 mg to about 2000 mg. In an embodiment, these preparations can be adjusted to a desired concentration by adding a sterile diluent to each vial.

[0213] The formulations disclosed herein include bulk drug compositions useful in the manufacture of pharmaceutical compositions (e.g., compositions that are suitable for administration to a subject or patient) which can be used in the preparation of unit dosage forms. In an embodiment, a composition of the invention is a pharmaceutical composition. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an FcRn antagonist of the invention or other prophylactic or therapeutic agent), and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject. In some embodiments, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject as once weekly injections over approximately 30 to 90 seconds. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous use with a winged infusion set. In some embodiments, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject as once weekly injections over approximately 20 to 30 seconds. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous use with a pre-filled syringe.Methods

[0214] In an aspect, methods for treating myositis using an FcRn antagonist are provided. In certain embodiments, the myositis is one or more of the following: immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), juvenile dermatomyositis (JDM), polymyositis (PM), and anti synthetase syndrome (ASyS). In certain embodiments, the myositis is IMNM. In certain embodiments, the FcRn antagonist is efgartigimod. An important goal and feature of the methods disclosed herein is the reduction or even the elimination of the use of potentially toxic agents such as corticosteroids (e.g., prednisone) in the treatment of myositis. Another important goal and feature of the methods disclosed herein is rapid onset of diseaseBUSINESS.33769645 1 48404373-ARGX-T2418WO (221799)control. Yet another important goal and feature of the methods disclosed herein is achievement of long-lasting complete remission on minimal treatment, preferably without the use of potentially toxic agents such as corticosteroids (e.g., prednisone). Effective treatment of myositis using an FcRn antagonist may include at least one of the elements of the group consisting of: muscle strength improvement, muscle strength stabilization, QoL (Quality of Life) improvement, pulmonary function improvement, pulmonary function stabilization, safety and / or tolerability of the FcRn antagonist, steroid sparing effect and pain improvement.

[0215] In certain embodiments, the myositis may be characterized as severe or non-severe as classified by the physician’s global evaluation of disease activity (MDGA). In certain embodiments, the myositis may be characterized as severe myositis (e.g., MDGA score of > 5). In other embodiments, the myositis may be characterized as non-severe myositis (e.g., MDGA score of < 5).

[0216] In some embodiments, the myositis may by characterized by an MMT8 score of < 142 / 150. In some embodiments, the myositis may be characterized by one or more of the following: a MDGA score of > 2, a PGA score of > 2, an extramuscular global score of > 2, an HAQ-DI score of > 0.25, and muscle enzyme (such as CK, aldolase, lactate dehydrogenase (LDH), AST, or ALT) > 1.5 times the upper limit of normal.

[0217] In some embodiments, the myositis is IMNM and may be characterized as antisignal recognition particle (SRP) positive, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) positive, or both anti-SRP positive and anti-HMGCR positive.

[0218] In some embodiments, the myositis is PM (including ASyS) and may be characterized as positive for at least one anti-aminoacyl-tRNA synthetase (such as anti-Jo- 1, anti-PL-7, anti-PL-12, anti-EJ, and / or anti-OJ antibodies).

[0219] In some embodiments, the myositis is DM or JDM and may be characterized by active DM skin rash (such as Gottron’s papules, Gottron’s signs, and / or heliotrope rash).

[0220] 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 BUSINESS.33769645 1 49404373-ARGX-T2418WO (221799)to about 2000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0221] 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 efgartigimod, or a biosimilar version thereof.

[0222] 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, about 750 mg, about 1000 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.

[0223] 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, 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.

[0224] 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.BUSINESS.33769645 1 50404373-ARGX-T2418WO (221799)

[0225] 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.

[0226] 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 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.

[0227] 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.

[0228] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0229] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two 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 two weeks at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist BUSINESS.33769645 1 51404373-ARGX-T2418WO (221799)is administered intravenously once weekly or once every two 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 two 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 two 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.

[0230] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two 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.

[0231] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two 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, or 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0232] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two 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 two 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 two weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 20 mg / kg. In BUSINESS.33769645 1 52404373-ARGX-T2418WO (221799)some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two 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 two 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 two weeks at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 30 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0233] In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0234] In some embodiments, FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0235] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 BUSINESS.33769645 1 53404373-ARGX-T2418WO (221799)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 once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0236] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 20 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 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 once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0237] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0238] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0239] In some embodiments, the FcRn antagonist is first administered subcutaneously at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is first administered subcutaneously at a fixed dose of 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.BUSINESS.33769645 1 54404373-ARGX-T2418WO (221799)

[0240] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg to about 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1750 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0241] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg to 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg to 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1750 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0242] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once BUSINESS.33769645 1 55404373-ARGX-T2418WO (221799)weekly at a dose of about 25 mg / kg. Tn some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0243] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0244] 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 two weeks, once every three weeks, once every four weeks, once monthly, or once every six 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 two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0245] 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 two weeks, once every three weeks, once every four weeks, once monthly, or once every six 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 two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0246] In some embodiments, the FcRn antagonist is administered for 6, 12, 24, 39, or 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some BUSINESS.33769645 1 56404373-ARGX-T2418WO (221799)embodiments, the FcRn antagonist is administered for at least 6, 12, 24, 39, or 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

[0247] In an embodiment, the subject was previously treated with a corticosteroid and / or an immunosuppressive agent and / or an antimalarial. In an embodiment, the subject was previously treated with prednisone. In an embodiment, the corticosteroid is an oral corticosteroid. Examples of oral corticosteroids include, but are not limited to, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone. In an embodiment, the immunosuppressive agent is selected from methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, or mixoribine. In an embodiment, the antimalarial is selected from hydroxychloroquine, quinacrine, or chloroquine.

[0248] In an embodiment, the subject was previously treated with prednisone at a dose of 5 mg / day to 20 mg / day. In an embodiment, the subject was previously treated with prednisone at a dose of 7.5 mg / day to 15 mg / day. In an embodiment, the subject was previously treated with prednisone at a dose of 8 mg / day to 15 mg / day. In an embodiment, the subject was previously treated with prednisone at a dose of 10 mg / day to 15 mg / day.

[0249] In an embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid and / or an immunosuppressive agent and / or an antimalarial. In an embodiment, the corticosteroid is an oral corticosteroid. Examples of oral corticosteroids include, but are not limited to, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone. In an embodiment, the immunosuppressive agent is selected from methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, or mixoribine. In an embodiment, the antimalarial is selected from hydroxychloroquine, quinacrine, or chloroquine.

[0250] In an embodiment, the effective amount of the corticosteroid is administered at a dose of 2.5 mg / day to 20 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of 5 mg / day to 20 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of 7.5 mg / day to 20 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of 8 mg / day to 15 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of 10 mg / day to 15 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose BUSINESS.33769645 1 57404373-ARGX-T2418WO (221799)of about 20 mg per day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 10 mg per day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 7.5 mg per day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 5 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 2.5 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 5 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 3 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 2 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 1 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.5 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.4 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.3 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.25 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.2 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.1 mg / kg / day.

[0251] In an embodiment, the corticosteroid dosing regimen is tapered in the subject after treatment with the FcRn antagonist. In an embodiment, tapering the corticosteroid regimen is lowering the dose or lowering the dosing frequency of the corticosteroid. In an embodiment, the dose of corticosteroid is decreased after 16 weeks of treatment with the FcRn antagonist. In an embodiment, the dose of corticosteroid is decreased after 24 weeks of treatment with the FcRn antagonist. In an embodiment, the dose of corticosteroid is decreased after 16 weeks of treatment with the FcRn antagonist if the dose of corticosteroid is administered to the subject at more than 5 mg / day prior to the dose of corticosteroid being decreased. In an embodiment, the dose of corticosteroid is decreased after 24 weeks of treatment with the FcRn antagonist if the dose of corticosteroid is administered to the subject at more than 5 mg / day prior to the dose of corticosteroid being decreased. In an embodiment, the dose of corticosteroid is decreased after 16 weeks of treatment with the FcRn antagonist if the dose of corticosteroid is administered to the subject at more than 7.5 mg / day prior to the dose of corticosteroid being decreased. In an embodiment, the dose of corticosteroid is decreased after 24 weeks of treatment with the FcRn antagonist if the dose of corticosteroid is administered to the subject at more than 7.5 mg / day prior BUSINESS.33769645 1 58404373-ARGX-T2418WO (221799)to the dose of corticosteroid being decreased. In some embodiments, the dose of prednisone is decreased by 2.5 mg / day (or equivalent OCS) after 16 weeks of treatment with the FcRn antagonist. In some embodiments, the dose of prednisone is decreased by 2.5 mg / day (or equivalent OCS) after 24 weeks of treatment with the FcRn antagonist. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least two weeks before the dose is further decreased. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least three weeks before the dose is further decreased. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least four weeks before the dose is further decreased. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for four weeks before the dose is further decreased.

[0252] In an embodiment, the first corticosteroid tapering dose may be less than a 2.5-mg dose reduction. In an embodiment, for a baseline dose of 18 to 20 mg, the first decreased dose is 17.5 mg. In an embodiment, for a baseline dose of 16 to 17.5 mg, the first decreased dose is 15 mg. In an embodiment, for a baseline dose of 13 to 15 mg, the first decreased dose is 12.5 mg. In an embodiment, for a baseline dose of 11 to 12.5 mg, the first decreased dose is 10 mg. In some embodiments, for a baseline dose of 8 to 9 mg, the first decreased dose is 7.5 mg. In an embodiment, for a baseline dose of 6 to 7 mg, the first decreased dose is 5 mg. In some embodiments, the dose of corticosteroid is maintained for four weeks before the dose is further decreased. In some embodiments, the dose of corticosteroid is maintained for four weeks and then decreased by 2.5 mg. In some embodiments, each corticosteroid tapering dose is maintained for four weeks and then further decreased by 2.5 mg. In some embodiments, each corticosteroid tapering dose is maintained for four weeks and then further decreased by 2.5 mg until the dose of corticosteroid is < 5 mg prednisone / day or equivalent. In some embodiments, each corticosteroid tapering dose is maintained for four weeks and then further decreased by 2.5 mg until the dose of corticosteroid is zero (i.e., discontinuation of corticosteroid therapy).

[0253] In some embodiments, the corticosteroid is administered at < 20 mg prednisone / day or equivalent. In some embodiments, the corticosteroid dose is < 7.5 mg prednisone / day or equivalent. In some embodiments, the corticosteroid dose is < 5 mg prednisone / day or equivalent.

[0254] In some embodiments, the FcRn antagonist is administered in an induction phase and a maintenance phase. In certain embodiments, during the induction phase, the FcRn antagonist is administered once weekly or more frequently, e.g., twice a week or every other day. In certain embodiments, during the induction phase, the FcRn antagonist is administered less frequently than BUSINESS.33769645 1 59404373-ARGX-T2418WO (221799)once weekly, e.g., once every other week. In certain embodiments, (i) during the induction phase the FcRn antagonist is administered once weekly concurrently with corticosteroid and / or immunosuppressant and / or antimalarial; and (ii) during the maintenance phase the FcRn antagonist dose is decreased and / or the FcRn antagonist dosing interval is lengthened, e.g., to once every two weeks, with or without concurrent corticosteroid and / or immunosuppressant and / or antimalarial. In some embodiments, the corticosteroid dose is decreased and / or the corticosteroid dosing interval is lengthened during the maintenance phase. In some embodiments, (i) during the induction phase the FcRn antagonist is administered once weekly at a dose of 1000 mg; and (ii) during the maintenance phase the FcRn antagonist is administered once every two weeks at a dose of 1000 mg.

[0255] In an embodiment, the subject has a serum level of a pathogenic IgG autoantibody that is associated with myositis (e.g., a myositis-associated antibody (MAA) or a myositis-specific antibody (MSA)). In an embodiment, the pathogenic IgG autoantibody is an anti-HMGCR antibody, an anti-SRP antibody, or an anti-aminoacyl-tRNA synthetase antibody. In an embodiment, the level of a pathogenic IgG autoantibody is measured by ELISA or addressable laser bead immunoassay (ALBIA). In an embodiment, the serum level of a pathogenic IgG autoantibody is compared to baseline levels in the subject.

[0256] In an embodiment, the myositis is immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), juvenile dermatomyositis (FDM), polymyositis (PM), or anti synthetase syndrome (ASyS). In some embodiments, the myositis is IMNM.

[0257] In some embodiments, treatment of myositis is characterized by the reduction of autoantibodies. In some embodiments, the autoantibodies are anti-SRP autoantibodies. In some embodiments, the prevalence of anti-SRP autoantibodies is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% after administering one or more of the treatments described herein. In some embodiments, anti-SRP autoantibodies are undetectable in the subject after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clincially effective amount of efgartigimod. In some embodiments, the myositis is IMNM.

[0258] In some embodiments, the autoantibodies are anti-HMGCR autoantibodies. In some embodiments, the prevalence of anti-HMGCR autoantibodies is reduced by at least 10%, at BUSINESS.33769645 1 60404373-ARGX-T2418WO (221799)least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% after administering one or more of the treatments described herein. In some embodiments, anti-HMGCR autoantibodies are undetectable in the subject after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof. In some embodiments, the myositis is IMNM.

[0259] In some embodiments, treatment of myositis is characterized by total improvement score (TIS). In some embodiments, the TIS is at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, or at least 70 points after administering one or more of the treatments described herein. In some embodiments, minimal clinical improvement (TIS > 20) is observed within < 24 weeks, < 12 weeks, or < 6 weeks after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0260] In some embodiments, treatment of myositis is characterized by muscle strength improvement. In some embodiments, muscle strength improvement is measured by MMT8. In some embodiments, the MMT8 score is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0261] In some embodiments, treatment of myositis is characterized by decrease in patient’s global assessment of disease activity (PGA). In some embodiments, the PGA is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.BUSINESS.33769645 1 61404373-ARGX-T2418WO (221799)

[0262] In some embodiments, treatment of myositis is characterized by decrease in physician’s global assessment of disease activity (MDGA). In some embodiments, the MDGA is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0263] In some embodiments, treatment of myositis is characterized by improvement in extra-muscular global assessment of disease activity. In some embodiments, the extra-muscular global assessment of disease activity is improved by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0264] In some embodiments, treatment of myositis is characterized by improvement in pain and / or fatigue reported by a subject. In some embodiments, improvement in pain and / or fatigue in a subject is determined by subject-reported numerical score (NRS). In some embodiments, pain and / or fatigue is improved by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0265] In some embodiments, treatment of myositis is characterized by improvement in physical functioning. In some embodiments, improvement in physical functioning is determined by HAQ-DI. In some embodiments, physical functioning is improved by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount ofBUSINESS.33769645 1 62404373-ARGX-T2418WO (221799)an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0266] In some embodiments, treatment of myositis is characterized by reduction of muscle necrosis. In some embodiments, muscle necrosis is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0267] In some embodiments, treatment of myositis is characterized by regeneration of muscle fibers. In some embodiments, regeneration of muscle fibers is determined by the presence of centronucleated fibers, wherein an increase in centronucleated fibers indicates regeneration of muscle fibers. In some embodiments, regenerating muscle fibers are increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0268] In some embodiments, treatment of myositis, in particular dermatomyositis (DM), is characterized by decrease in CDASI. In some embodiments, the CDASI is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after administering one or more of the treatments described herein. In some embodiments, the treatment is administration of a clinically effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of a clinically effective amount of efgartigimod, or a biosimilar version thereof.

[0269] In an aspect, provided herein is a method for monitoring treatment of myositis in a subject following treatment with an FcRn antagonist, the method comprising: a) measuring a muscle enzyme, an autoantibody, or both in a blood sample taken from the subject; and b) comparing the muscle enzyme value, autoantibody value, or both to a reference value associated with the autoantibody-mediated disease in the subject, wherein the subject is in remission from the autoantibody-mediated disease if the a muscle enzyme, an autoantibody, or both in the sample is lower than or equal to the reference value.BUSINESS.33769645 1 63404373-ARGX-T2418WO (221799)

[0270] In an embodiment, the subject was previously treated with prednisone at a dose of < 5 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 3 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 2 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 1 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 0.5 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 0.4 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 0.3 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 0.2 mg / kg / day. In an embodiment, the subject was previously treated with prednisone at a dose of < 0.1 mg / kg / day.

[0271] In an embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid or an immunosuppressive agent. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 20 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 15 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 10 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 7.5 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 5 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 4 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 3 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 2 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 1 mg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.5 mg / day.

[0272] In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 5 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 3 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 2 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 1 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.75 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.5 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose BUSINESS.33769645 1 64404373-ARGX-T2418WO (221799)of about 0.4 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.3 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.25 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.2 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.1 mg / kg / day. In an embodiment, the effective amount of the corticosteroid is administered at a dose of about 0.05 mg / kg / day.

[0273] In an embodiment, the subject the corticosteroid dosing regimen is tapered based on the serum level of an MAA or an MSA in a subject with myositis. In an embodiment, tapering the corticosteroid regimen is lowering the dose or lowering the dosing frequency of the corticosteroid. In an embodiment, the tapered corticosteroid dose is < 5 mg prednisone / day or equivalent. In an embodiment, the tapered corticosteroid dose is <2 mg prednisone / kg / day or equivalent. In an embodiment, the tapered corticosteroid dose is less than or equal to about 1.5, 1.0, 0.75, 0.5, or 0.2 mg prednisone / kg / day or equivalent. In an embodiment, the tapered corticosteroid dose is <0.5 mg prednisone / kg / day or equivalent. In an embodiment, the tapered corticosteroid dose is <0.1 mg prednisone / kg / day or equivalent.

[0274] In an embodiment, the serum level of the MAA or the MSA is measured by ELISA or addressable laser bead immunoassay (ALBIA).

[0275] In an embodiment, the MSA is selected from the group consisting of anti-SRP, anti-HMGCR, anti-Mi-2, anti-TIFl, anti-SAE, anti-NXP, anti-MDA5, anti-Jo-1, anti, PL-7, anti-PL-12, anti -E J, and anti-0 J.

[0276] In an embodiment, the MAA is selected from the group consisting of anti-PM / Scl 75, anti-Ku, anti-snRNP, anti-Ro52 (SSA), anti-Ro / 60 (SSA), and anti-La (SSB).

[0277] In an embodiment, the subject is any human or non-human animal. In an embodiment, the subject is a human or non-human mammal. In an embodiment, the subject is a human.EXAMPLES

[0278] The following examples are offered by way of illustration, and not by way of limitation.BUSINESS.33769645 1 65404373-ARGX-T2418WO (221799)Example 1: Investigation of efficacy and safety of efgartigimod in patients with active idiopathic inflammatory myopathy (IIM)

[0279] Idiopathic inflammatory myopathy (IIM), also referred to as myositis, are inflammatory disorders of the skeletal muscle. This heterogeneous group of diseases includes many subtypes with varying pathologies. There is evidence that some IIM subtypes - specifically DM, IMNM, and certain other subtypes of PM (AsyS) - are likely driven by IgG autoantibodies (including myositis-specific antibodies [MSAs] and myositis-associated antibodies [MAAs]).

[0280] Many patients with IIM have persistent impairment of muscle function, which leads to difficulties in daily life activities and a low health-related quality of life. The typical treatment for IIM is high-dose glucocorticoids combined with immunosuppressive drugs. The deleterious long-term effects of corticosteroids have been well established and include osteoporosis, cataracts, and weight gain. There are no therapies approved by the United States Food and Drug Administration (FDA) or the European regulatory authorities based on results of randomized controlled trials for IMNM and PM. Only 1 licensed treatment (10% intravenous immunoglobulin [IVIg]) is available for adults with DM that was approved based on results of randomized controlled clinical trials.

[0281] Given efgartigimod ’s mechanism of action of reducing IgG levels, efgartigimod PH20 SC may benefit patients with these specific IIM subtypes.

[0282] ALKIVIA is a global Phase 2 / 3 randomized, double-blind, placebo-controlled trial of efgartigimod in patients with active IIM. The aim of the study is to investigate the efficacy, safety, tolerability, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of efgartigimod coformulated with recombinant human hyaluronidase PH20 (rHuPH20) administered subcutaneously (SC; referred to throughout as “efgartigimod PH20 SC”) in participants with immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), or polymyositis (PM; including PM with anti synthetase syndrome [ASyS]) concomitant to their background treatment for idiopathic inflammatory myopathies (IIM).

[0283] To allow for convenient SC injection of investigational medicinal product (IMP), participants will be administered efgartigimod PH20 SC, a solution of efgartigimod coformulated with rHuPH20, or a matching placebo with the same concentration of rHuPH20. rHuPH20 is currently being used in coformulations with approved therapeutic antibodies to facilitate SC injection of volumes >2 mL. Efgartigimod, as both an IV formulation (efgartigimod IV) and efgartigimod PH20 SC, has been investigated in nonclinical studies, clinical studies of healthy BUSINESS.33769645 1 66404373-ARGX-T2418WO (221799)volunteers, and clinical studies of patients with IgG-driven autoimmune diseases (generalized myasthenia gravis [gMG], primary immune thrombocytopenia [ITP], chronic inflammatory demyelinating polyneuropathy, and pemphigus).

[0284] In clinical studies that included PD assessments, efgartigimod IV and efgartigimod PH20 SC have effectively reduced IgG antibodies. Available clinical data support the clinical benefit of efgartigimod. Efficacy was proven in a pivotal phase 3 study in participants with gMG (ARGX-113-1704), and clear signs of efficacy were demonstrated in phase 2 studies in participants with primary ITP (ARGX-113-1603) or pemphigus (ARGX-113-1701).

[0285] The primary objective of ALKIVIA is to evaluate the clinical improvement of efgartigimod PH20 subcutaneous (SC) treatment compared with placebo, in addition to standard-of-care immunomodulatory therapy, for the treatment of IIM.A. Study designOverall design

[0286] This is a randomized, double-blinded, placebo-controlled, parallel group, multicenter, operationally seamless phase 2 / 3 study to evaluate the efficacy, safety, tolerability, PK, PD, and immunogenicity of efgartigimod PH20 SC in adult participants with active IIM. This study consists of 2 distinct stages (a phase 2 stage and a phase 3 stage) with separate cohorts of participants.

[0287] Participants with the IIM subtypes of IMNM, DM, and PM were included in the study. The PM subtype includes patients with ASyS as diagnosed under the Connors criteria (z.e., positive serologic testing for anti-tRNA synthetase antibody plus 1 or more of the following clinical features: Raynaud’s phenomenon, arthritis, interstitial lung disease, fever that is not attributable to another cause, or evidence of myositis). Participants were classified into IIM subtypes and met the disease activity parameters specified.

[0288] At screening, participants must be receiving a background IIM treatment of either oral corticosteroids (DCS), 1 antimalarial, or 1 protocol-specified immunosuppressant. Participants may receive a combination of either DCS and 1 antimalarial or OCS and 1 immunosuppressant. Background treatment for IIM has a required duration of treatment at a stable dose. The screening period is of no less than 4 weeks and up to 6 weeks, but an ad hoc extension may be permitted in certain circumstances.BUSINESS.33769645 1 67404373-ARGX-T2418WO (221799)

[0289] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. After the assessments are complete, laboratory results are reported, and, if applicable, eligibility is adjudicated, then the participant may be randomized. Certain specified screening assessments are submitted for medical monitor (MM) review before the investigator’s decision to randomize a participant. The sponsor will also review specified screening assessments for a subset of participants.

[0290] An independent data monitoring committee (IDMC) was appointed for this study. In addition, an independent committee comprising members with expertise in IIM was appointed to review historical biopsy data and adjudicate the eligibility of participants with a diagnosis of PM or IMNM who had a negative MSA test result (central laboratory) or PM-Sjbgren syndrome overlap (regardless of MSA result).

[0291] After screening, a 24-week (phase 2 stage) or 52-week (phase 3 stage) treatment period followed, during which participants were randomized to receive either efgartigimod PH20 SC 1000 mg or matching placebo (with the same concentration of rHuPH20) weekly in addition to their background treatment for IIM. Background treatment must follow protocol guidelines during the treatment period.

[0292] In both stages, during the treatment period, participants receive weekly SC fixed doses of IMP (either efgartigimod PH20 SC or matching placebo) except in the last week (week 24 [phase 2 stage] or week 52 [phase 3 stage]) in which participants will attend the final treatment period visit. At the end of the treatment period (i.e., week 24 [visit 7, phase 2 stage] or week 52 [visit 14, phase 3 stage]), eligible participants may enroll in the open-label extension (OLE) study ARGX- 113-2011, in which all participants are treated with efgartigimod PH20 SC. Otherwise, participants continue a 56-day safety follow-up period.

[0293] During the treatment period, IMP is administered at the investigative site at scheduled visits and may be performed at the site or at the participant’s home, either by a home nurse or by fully trained participants / caregivers.Phase 2 stage

[0294] Approximately 90 adult participants were enrolled and randomized in the phase 2 stage of the study, stratified by (1) IIM subtype (IMNM, DM, or PM) and (2) MDGA (severe [MDGA >5] or non-severe [MDGA <5]). Participants were randomized in a 1: 1 ratio within each stratum to receive either efgartigimod PH20 SC or matching placebo, concomitant to their background treatment for IIM. Randomization of approximately 30 participants of each IIMBUSINESS.33769645 1 68404373-ARGX-T2418WO (221799)subtype is targeted. The number of MSA-seronegative participants is capped at 30% of all participants.

[0295] Final data from the phase 2 stage is analyzed to assess proof of concept in each disease subtype and to support decisions for a predictive enrichment, to stop the study for futility if there is a lack of efficacy in all disease subtypes, and to confirm the design of the phase 3 stage. The unblinded phase 2 stage data is analyzed and used to recommend adaptation of the design of the phase 3 stage. Only the phase 2 stage data is unblinded; the sponsor and all clinical staff will remain blinded to all phase 3 stage data until the study is completed.Phase 3 stage

[0296] Recruitment for the phase 3 stage of the study commences after 90 participants have been randomized in the phase 2 stage. The two stages of this study will run in parallel during the time between commencing of recruitment for the phase 3 stage and the last participant visit in the phase 2 stage.

[0297] The design and sample size for the phase 3 stage is confirmed after analysis of the phase 2 stage data. It is planned that approximately 150 adult participants will be enrolled and randomized in the phase 3 stage, stratified by (1) IIM subtype (IMNM, DM, or PM) and (2) MDGA (severe [MDGA >5] or nonsevere [MDGA <5]). Participants are randomized in a 1: 1 ratio within each stratum to receive either efgartigimod PH20 SC or placebo, concomitant to their background treatment for IIM. The number of MSA-seronegative participants is capped at 30% of all participants.

[0298] For any participants in the phase 3 stage of the study with a deselected IIM subtype based on data from the phase 2 stage, the investigator and the participants are informed. Participants will permanently discontinue the study and complete the early discontinuation visit (EDV) and safety follow-up visit (SFV). However, if the participant is benefiting from IMP and the investigator determines that continuing treatment with the IMP is in the participant's best interest, they have the option to discontinue from this study, complete the EDV, and enroll in ARGX-113-2011.Rationale for primary endpoint

[0299] The primary endpoint of the study is the TIS (as assessed by the 2016 American College of Rheumatology [ACR] / European League Against Rheumatism [EULAR] criteria) in the placebo and efgartigimod groups. This score is the weighted sum of improvement in 6 core setBUSINESS.33769645 1 69404373-ARGX-T2418WO (221799)measures (CSMs) for disease activity: MDGA, PGA, MMT8, HAQ-DI, muscle enzymes, and extramuscular disease activity.

[0300] This composition of measures is designed to allow demonstration of efficacy in DM and PM (of which IMNM is a subset). To facilitate combined clinical studies, myositis experts used a common response criterion for adult DM / PM, acknowledging the limitation that the ACR / EULAR response criteria were developed using a PM diagnosis based on Bohan and Peter’s classification criteria, in which PM may include different syndromes, such as IMNM. These response criteria will still be applicable to these newer entities given that the data-driven and consensus-driven processes used herein were inclusive of those syndromes.

[0301] The response criteria have been endorsed by the ACR and EULAR. The TIS comprises CSMs scored both by the patient and the physician, considering the muscle manifestations and the extramuscular disease activity and physical function. It also includes objective disease activity parameters, i.e., the activity of the muscle enzymes. The International Myositis Assessment and Clinical Studies Group (IMACS) recommends the minimal TIS as the primary endpoint in IIM therapeutic studies. The criteria may be used as a continuous outcome measure, using the TIS, or as a categorical outcome of improvement (minimal, moderate, or major improvement). IMACS considers the threshold of minimal TIS to differentiate between treatment groups in clinical studies as clinically significant. IMACS has previously developed and partially validated International Consensus on Preliminary Definitions of Improvement in Adult and Juvenile Myositis, which combined CSMs of disease activity and defined a minimal degree of clinically meaningful change in each of the CSMs. These criteria were published and previously used as endpoints in myositis therapeutic studies. With the development of the TIS, these criteria / definitions of improvement are no longer recommended for use. To date, several phase 3 studies in patients with IIM have used the TIS as a primary endpoint (NCT02728752, NCT03981744, NCT04044690, and NCT04999020).

[0302] Response rates at the end of the treatment period and time to response in the TIS (secondary endpoints), together with changes in CSM of myositis activity (secondary endpoints), will provide supporting evidence for the primary endpoint.Rationale for inclusion criteria cuto ffs

[0303] The inclusion threshold cutoffs for MDGA, PGA, MMT8, and CDASI are based on previous clinical trials and input from key opinion leaders over the past 10 to 15 years.BUSINESS.33769645 1 70404373-ARGX-T2418WO (221799)

[0304] For MDGA and PGA, the minimum threshold of 2 / 10 or more is based on the “Rituximab in Myositis” study, which was the largest clinical study in myositis funded by the National Institutes of Health (NIH). These thresholds were based on discussions among the key opinion leaders and underwent a peer review process for the NIH grant. More importantly, these thresholds have been validated by multiple phase 2 and 3 clinical studies in participants with IIM, including the ProDERM study, the Acthar study, the Rituximab in Myositis study, and the tocilizumab clinical study (NCT02043548).

[0305] The MMT8 threshold of 142 / 150 is based on the ProDERM study and key opinion leader discussions. An MMT8 of <142 / 150 is identified as significant weakness that leads to difficulty in activities of daily living and affects quality of life. Moreover, a threshold of 142 gives approximate mean MMT8 of 125, which is severe weakness in patients with IIM.

[0306] For eligibility of participants with DM, the CDASI activity score threshold for the phase 2 stage has been set to >7, which is established as the mean for mild skin disease activity. The CDASI activity score threshold for the phase 3 stage has been set to >14, which is the cutoff for mild to moderate skin disease activity.

[0307] The 30% cap on MSA-seronegative participants is based on a review of real-world data and corresponds to estimates of MSA prevalence in patients with DM or PM.Rationale for treatment periods

[0308] The selected 24-week treatment period during the phase 2 stage follows the International Council for Harmonisation (ICH) El guideline for the safety evaluation of drugs intended for the long-term treatment (chronic or repeated intermittent use for longer than 6 months) of non-life threatening diseases. This guideline states that the number of patients treated for 6 months at dosage levels intended for clinical use should be adequate to characterize the pattern of adverse drug effects over time.

[0309] The selected 52-week treatment period during the phase 3 stage accounts for the different IIM subtypes that are slowly progressive and chronic with a waxing and waning disease course. After confirming treatment effect in the selected disease subtypes, this longer treatment period will more thoroughly assess the durability of treatment effect and permit full assessment of the primary and key secondary endpoints.BUSINESS.33769645 1 71404373-ARGX-T2418WO (221799)Justification for dose

[0310] The sponsor has selected a dose of 1000 mg efgartigimod with rHuPH20 to be administered as weekly SC injections over the full duration of the study as the appropriate dosage regimen for further clinical development.

[0311] Initially, the clinical development of efgartigimod was based on IV dosing. Results from phase 1 studies in healthy subjects, phase 2 and 3 studies in patients with gMG, a phase 2 study in patients with primary ITP, a phase 2 study in patients with pemphigus, and a PK / PD modeling analysis showed that efgartigimod IV 10 mg / kg administered once weekly achieved nearly maximal reduction in serum IgG levels. In interventional studies of patients with gMG or ITP, this dose regimen resulted in clinical efficacy outcomes and reduction in pathogenic autoantibody levels while also maintaining a favorable safety and tolerability profile.

[0312] The SC route of administration offers convenience for patients with IIM, their caregivers, and health care providers, because SC injections are easier to administer than IV injections. Additionally, the coformulation of efgartigimod with rHuPH20 permits SC dosing of higher volumes than typical SC injections, because rHuPH20 reduces resistance to fluid flow and increases dispersion and absorption of injected medicines and fluids, which allows for a larger volume to be injected with limited skin swelling or pain.

[0313] In this phase 2 / 3 study, participants are administered efgartigimod PH20 SC as a flat dose (rather than an adjusted dose based on body weight changes), because this is more convenient for study participants and site staff and may lower the risk of dosing errors. Results from a PK / PD modeling analysis indicate that efgartigimod PH20 SC 1000 mg once weekly would result in serum IgG levels equivalent to a once-weekly dose of efgartigimod IV 10 mg / kg. Results from a phase 1 study comparing the PK and PD properties of IV and SC administrations of efgartigimod in healthy subjects (ARGX-113-1907) confirmed that 4 once-weekly injections of efgartigimod PH20 SC 1000 mg was noninferior to 4 once-weekly infusions of efgartigimod IV 10 mg / kg in reducing serum IgG levels. Therefore, the sponsor has selected efgartigimod PH20 SC 1000 mg once weekly as the dose regimen for this study.

[0314] The dosage regimen of weekly dose administration throughout the study was selected to achieve and maintain the maximal PD effect: a steady-state reduction of IgGs, including pathogenic autoantibodies. This dose regimen is anticipated to maximize the chance of inducing a fast clinical improvement and to maintain this improvement during the 24-week study period. Based on the chronic dosage data from nonclinical studies and the completed and ongoing clinical BUSINESS.33769645 1 72404373-ARGX-T2418WO (221799)studies with efgartigimod PH20 SC, it is anticipated that this chronic dosage regimen in IIM will be well tolerated.B. Study population

[0315] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0316] Criteria that have been extensively updated have been assigned a new number.Inclusion criteria

[0317] Participants are eligible to be included in the study only if all of the following criteria apply at screening and baseline. Laboratory eligibility criteria are reviewed based on screening test results, except for the urine pregnancy test for WOCBP (inclusion criterion 13) wherein is verified again at baseline before the first dose of IMP:1. Aged at least 18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the informed consent;2. A definite or probable clinical diagnosis of IIM under the 2017 EULAR / ACR classification criteria;3. An inclusion criterion was removed in Protocol Amendment 2; refer to inclusion criterion 9.4. An inclusion criterion was removed in Protocol Amendment 2; refer to inclusion criterion 10.5. An inclusion criterion was removed in Protocol Amendment 2; refer to inclusion criterion 11.6. An inclusion criterion was removed in Protocol Amendment 2; refer to inclusion criterion 12.7. An inclusion criterion was removed in Protocol Amendment 2; refer to inclusion criterion 13.8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.9. One of the following medical histories:a. Clinical diagnosis of DM or juvenile DM (JDM), fulfilling the 2017 EULAR / ACR criteria for DM or JDM (age of disease onset <18 years of age). The diagnosis date for JDM should not be >5 years from the screening date.BUSINESS.33769645 1 73404373-ARGX-T2418WO (221799)b. Clinical diagnosis of PM (including ASyS), having either of the following:i. A prior muscle biopsy for IIMii. A positive test at the central laboratory for at least 1 anti-aminoacyl-tRNA synthetase MSA (-Jo-1, -PL-7, -PL-12, -EJ, -OJ)Participants with PM overlap with Sjogren’s syndrome and will be included only if the muscle biopsy does not demonstrate any of the following:P62 (+) inclusions, rimmed vacuoles, or increased number of ragged red fibers and cytochrome oxidase fibers for the patient’s age.Note: Participants with a clinical diagnosis of PM who have a negative MSA result and participants with a clinical diagnosis of PM- Sjogren’s overlap regardless of their MSA result will be included after adjudication by an independent committee selected for their expertise in IIM. Details of this process are described in the biopsy adjudication charter. c. Clinical diagnosis of IMNM, meeting the 2017 European Neuromuscular Center classification criteria, and having any of the following:i. Anti-signal recognition particle (SRP) positive (at the central laboratory) myopathyii. Anti-3 -hydroxy-3 -methylglutaryl coenzyme A reductase (HMGCR) positive (at the central laboratory) myopathyiii. A prior muscle biopsy with pathological features of IMNM Note: Participants with a clinical diagnosis of IMNM who have negative anti-SRP and anti- HMGCR results will be included after adjudication by an independent committee selected for their expertise in IIM. Details of this process are described in the biopsy adjudication charter.10. Active disease as defined by the presence of at least 1 of the following criteria:a. Abnormal levels of at least 1 of the following enzymes: CK (>4*upper limit of normal [ULN]), aldolase (>4 ULN), LDH (>4 L'LN), AST (>4*ULN), or ALT (>4*ULN), based on central laboratory resultsb. Electromyography demonstrating active disease performed <3 months before enrollmentc. Active DM skin rash (Gottron’s papules, Gottron’s signs, or heliotrope rash) or CDASI activity score >7 (phase 2 stage) or >14 (phase 3 stage) at screening and baseline d. Muscle biopsy indicative of active IIM before enrollment (in the past 3 months) BUSINESS.33769645 1 74404373-ARGX-T2418WO (221799)e. Magnetic resonance imaging indicative of active inflammation, performed <3 months before enrollment11. Muscle weakness as assessed by an MMT8 score of <142 / 150 and abnormalities in any 2 of the other 5 CSMs:a. MDGA >2b. PGA >2c. Extramuscular global assessment >2d. HAQ-DI>0.25e. Muscle enzyme >1.5*ULN12. Receiving a permitted background treatment for UM. Permitted background treatment includes: OCS; 1 antimalarial (hydroxychloroquine, quinacrine, or chloroquine); or 1 of the following immunosuppressants: methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, or mizoribine. Participants may receive a combination of either OCS and up to 1 antimalarial or OCS and up to 1 immunosuppressant.Permitted background treatment must meet the following dose duration(s):a. Immunosuppressants or antimalarials administered for >12 weeks before screening, and at a stable dose for >8 weeks before screening and then through baselinei. Participants who stopped treatment with an immunosuppressant or an antimalarial are eligible if their last dose was >8 weeks before screening (except for leflunomide).ii. Participants who stopped treatment with leflunomide are eligible if their last dose was >12 weeks before screening unless leflunomide washout treatment was used, in which case participants are eligible if the washout treatment was completed >4 weeks before screening.b. OCS administered for >8 weeks before screening and at a stable dose (<20 mg prednisone or dose equivalent) for >4 weeks before screening through baselinei. Participants who stopped treatment with OCS before enrollment are eligible if the last dose of the steroid was >4 weeks before screening.Note: If a participant is receiving both OCS and an additional agent, the dose durations described for both (a) and (b) must be met.BUSINESS.33769645 1 75404373-ARGX-T2418WO (221799)13. The participant agrees to use contraceptive measures consistent with local regulations and the following:WOCBP must have a negative serum pregnancy test at screening AND negative urine pregnancy test at baseline before receiving IMP.Exclusion criteria

[0318] Participants are excluded from the study if the following criteria apply:1. An exclusion criterion has been removed in Protocol Amendment 2; refer to exclusion criterion 23.2. An exclusion criterion has been removed in Protocol Amendment 2; refer to exclusion criterion 24.3. Any other known autoimmune disease that, in the investigator’s opinion, would interfere with an accurate assessment of clinical symptoms of IIM or put the patient at undue risk.4. A history of malignancy unless considered cured by adequate treatment, with no evidence of recurrence for >3 years before the first administration of IMP. Adequately treated participants with the following cancers can be included at any time:a. Basal cell or squamous cell skin cancer;b. Carcinoma in situ of the cervix;c. Carcinoma in situ of the breast;d. Incidental histological finding of prostate cancer (TNM stage Tla or Tib).Note: Because patients with IIM have an increased risk of an associated malignancy, it is recommended that participants in the study comply with and are current with local recommendations for cancer screening procedures (based on their age, gender, and autoantibodies).5. Severe muscle damage defined as a global muscle damage score of >5 on a 10-cm visual analog scale (VAS) scale on the Myositis Damage Index (MDI).6. Glucocorticoid-induced myopathy that the investigator considers the primary cause of muscle weakness or permanent weakness linked to a non-IIM cause.7 IDM diagnosed >5 years from screening or JDM with extensive calcinosis (defined as calcinosis involving the torso or 2 extremities) or severe calcinosis (indicated by a calcinosis associated with severe loss of function).BUSINESS.33769645 1 76404373-ARGX-T2418WO (221799)8. Uncontrolled interstitial lung disease or any other uncontrolled IIM manifestation that, in the opinion of the investigator, would be likely to require treatment with prohibited medication (e.g., cyclophosphamide) during the study.9. An exclusion criterion has been removed in Protocol Amendment 2; refer to exclusion criterion 25.10. An exclusion criterion has been removed in Protocol Amendment 2; refer to exclusion criterion 26.11. Known hypersensitivity reaction to IMP or 1 of its excipients.12. Received a live or live-attenuated vaccine less than 4 weeks before screening. The receipt of other types of vaccines at any time before screening is not considered exclusionary. It is recommended that participants are up to date with vaccinations before the first dose of IMP.13. An exclusion criterion has been removed in Protocol Amendment 2.14. Positive serum test at screening for active viral infection with any of the following conditions:a) Hepatitis B virus (HBV) indicative of an acute or chronic infection, unless associated with a negative HBV DNA test;b) Hepatitis C virus (HCV) based on HCV antibody assay, unless associated with a negative HCV RNA test;3) HIV based on test results associated with either: i) an AIDS-defining condition or a CD4 count of <200 cells / mm3ii) no adequate treatment with antiretroviral therapy.15. An exclusion criterion has been removed in Protocol Amendment 2; refer to exclusion criterion 27.16. Participant has previously participated in an efgartigimod clinical study and received at least 1 dose of IMP.17. Participant is concurrently participating in any other clinical study, including a noninterventional study.18. Participant has IgG <4 g / L at screening.19. An exclusion criterion has been removed; refer to exclusion criterion 28.20. Participant is pregnant or lactating or intends to become pregnant during the study.21. Participant has severe renal impairment (estimated glomerular fdtration rate <30 mL / min / 1.73 m2) at screening.BUSINESS.33769645 1 77404373-ARGX-T2418WO (221799)22. Participant is institutionalized by a court or other governmental order or is in a dependent relationship with the sponsor or investigator.23. Participant has a clinically significant active infection that is not sufficiently resolved before baseline in the investigator’s opinion.24. COVID-19 polymerase chain reaction (PCR)-positive test <72 hours before enrollment.a) COVID-19 testing will be done only if the participant is symptomatic or if required by local regulations. In these cases, a negative PCR test (central or local laboratory) is required <72 hours before enrollment and should occur regardless of a participant’s vaccination status.25. Other inflammatory and noninflammatory myopathies: inclusion body myositis (based on the biopsy or when the weakness affects the finger and / or the wrist flexors out of proportion to shoulder abductors), infectious myopathy, overlap myositis (connective tissue disease- associated myositis, except an overlap with Sjogren’s syndrome, which is allowed provided that the biopsy does not demonstrate any of the features listed in inclusion criterion 9, subsection b, metabolic myopathies, muscle dystrophies or a family history of muscle dystrophy, drug-induced or endocrine-induced myositis (except statin-induced 1MNM), and juvenile myositis (other than JDM).26. Recent major surgery (<3 months before screening) or intention to have surgery during the study, clinically significant diseases, or any other condition which, in the opinion of the investigator, could confound the results of the study or put the participant at undue risk.27. Any of the following prior therapy or procedures:a) Treatment during <1 week before screening with: - topical corticosteroids or topical immunomodulators (e.g., tacrolimus) for IIM-related rash; - inhaled corticosteroids or any inhaled medications with immunomodulatory properties for IIM-related interstitial lung disease (ILD).b) Treatment during <4 weeks before screening: local corticosteroid injections (intraarticular, bursa, and tendon sheath injections), Janus kinase (JAK) inhibitors (including tyrosine kinase 2 [TYK2] inhibitors), intramuscular or IV corticosteroids, PLEX, immunoadsorption, SC or intramuscular corticosteroid precursors (including adrenocorticotropic hormone [ACTH]), IVIg, SCIg, monoclonal antibody (refer to further restrictions for use of rituximab and other anti-CD20 antibodies in subsection e).c) A portion of this exclusion criterion has been removed.BUSINESS.33769645 1 78404373-ARGX-T2418WO (221799)d) Treatment during <12 weeks before screening with cyclophosphamide.e) Treatment during <24 weeks before screening with rituximab or other anti-CD20 antibody.f) Use of an investigational product during <12 weeks or 5 half-lives (whichever is longer) before screening.g) A portion of this exclusion criterion has been removed.h) Treatment with OC S dose >20 mg prednisone (or dose equivalent) during <4 weeks before screening.i) Treatment with >1 immunosuppressant, >1 antimalarial, or a combination of an immunosuppressant and an antimalarial during <8 weeks before screening. However, discontinuation of traditional Chinese medicines with immunosuppressive properties may be accomplished before baseline.Refer to Table S2 for a full list of permitted and prohibited concomitant therapies.C. IMP(s) and concomitant therapy

[0319] Investigational medicinal product (IMP) is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.IMP(s) administeredTable SI. IMP(s) administeredIntervention Efgartigimod PH20 SC PlaceboLabelIntervention Efgartigimod PH20 SC Placebo PH20 SCNameIntervention Efgartigimod PH20 SC will be Placebo PH20 SC will be provided as a Description provided as a sterile, clear to sterile, colorless, clear solution for opalescent, yellowish solution for SC injection in glass vials covered with a injection in glass vials covered with a blinding shell, with the same blinding shell. formulation as the efgartigimod PH20 SC solution for injection, but without the active ingredient (efgartigimod). Type Biologic Other: placeboDose Efgartigimod + 2000 U / mL rHuPH20 Matching placebo + 2000 U / mL Formulation solution for SC injection to be dosed at rHuPH20 solution for injectiona fixed dose of 1000 mg per injectionBUSINESS.33769645 1 79404373-ARGX-T2418WO (221799)Unit Dose 180 mg / mL efgartigimod (with Placebo (with 2000 U / mL rHuPH20) Strength(s) 2000 U / mL rHuPH20)Dosage Level(s) 1000 mg efgartigimod (and Placebo (and approximately 11 000 U approximately 11 000 U rHuPH20) rHuPH20) weeklyweeklyRoute of SC injection SC injectionAdministrationUse Experimental Placebo-comparatorIMP and AxMP IMP IMPSourcing Provided centrally by the sponsor Provided centrally by the sponsor Packaging and IMP will be provided in glass vials in IMP will be provided in glass vials in Labeling secondary packaging boxes. Each vial secondary packaging boxes. Each vial will be labeled and provided in will be labeled and provided in secondary packaging as required per secondary packaging as required per country requirements. Because there is country requirements. Because there is a a slight color difference between slight color difference between efgartigimod PH20 SC and placebo, efgartigimod PH20 SC and placebo, each vial will be masked with a each vial will be masked with a blinding blinding shell. shell.AxMP=auxiliary medicinal product: rHuPH20=recombinant human hyaluronidase PH20;S C=subcutaneous

[0320] At the end of the study, participants who reach week 24 (visit 7; phase 2 stage) or week 52 (visit 14; phase 3 stage), may be eligible to roll over to the extension study (ARGX-113-2011), where all participants receive open-label IMP (efgartigimod PH20 SC).

[0321] The following participants are ineligible for enrollment in the OLE study: Participants who permanently discontinued from IMP (regardless of whether the participant completed the study); Participants who discontinued from the study; Participants with an IIM subtype that is deselected based on data from the phase 2 stage, except for participants who are benefitting from IMP and, in the investigator’s judgment, continuing IMP is in the participant’s best interest.

[0322] Participants who complete the week 24 (phase 2 stage) or week 52 (phase 3 stage) visit while temporarily interrupted from IMP may enroll in the OLE study at the discretion of the investigator. These participants will enter the OLE study but will not be dosed with efgartigimod PH20 SC until they meet the relevant conditions specified by the protocol.

[0323] Any medication or vaccine (including over the counter or prescription medicines, recreational drugs, vitamins, and / or herbal supplements [including Chinese traditional medicine]) or other specific categories of interest that the participant is receiving at the time of screening orBUSINESS.33769645 1 80404373-ARGX-T2418WO (221799)receives during the study must be recorded and include the following information: 1) Reason for use; 2) Dates of administration including start and end dates; 3) Dosage information including dose and frequency.

[0324] The participant must be receiving background treatment for IIM and follow the requirements described. Allowed background treatments for IIM include any of the following: 1) Oral corticosteroid (OCS); 2) 1 antimalarial (hydroxychloroquine, quinacrine, or chloroquine); 3) 1 of the following immunosuppressants — methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, or mizoribine (Japan only).

[0325] Participants must be taking at least 1 of these specified background treatments and may receive a combination of either OCS and up to 1 antimalarial or OCS and up to 1 immunosuppressant. A combination of an antimalarial and an immunosuppressant is not permitted. Administration of >1 medication with immunosuppressive properties, including Chinese traditional medications, is prohibited.

[0326] An ongoing physical therapy or exercise program should follow the guidelines described.

[0327] Concurrent use of topical corticosteroid therapy or other topical treatments with immunomodulatory properties for HM-related rash are not permitted. Topical treatment for a non-IIM condition in the participant’s medical history or to treat a non-IIM-related AE is permitted.

[0328] Concurrent use of inhaled corticosteroids or any inhaled medications with immunomodulatory properties for IIM-related ILD is not permitted. Inhaled medications for non-IIM conditions in the participant’s medical history or to treat a non-IIM-related AE are permitted.

[0329] Antifibrotics (e.g., nintedanib and pirfenidone) are permitted, if initiated before screening. The dose must remain stable through the end of the treatment period but may be decreased for toxicity. The toxicity must be confirmed as a documented AE. The dose can be returned to the baseline level if the toxicity resolves and if clinically indicated.

[0330] Intramuscular or IV corticosteroids are permitted after baseline but the dose, duration and study period restrictions described herein apply. Moreover, participants who require intramuscular or IV corticosteroids during the screening period will be considered screen failures.

[0331] Local corticosteroid injections are permitted to treat non-IIM-related TEAEs (e.g., local tendon, joint, bursal inflammation). However, participants who require a local corticosteroid injection during the screening period will be considered screen failures.BUSINESS.33769645 1 81404373-ARGX-T2418WO (221799)

[0332] Statin use is permitted. Keeping the type and dose of statin consistent from screening to the end of the treatment period is advised. However, dose changes are permitted based on the investigator’s judgment.

[0333] Analgesics and nonsteroidal anti-inflammatory drugs are permitted as required, based on the investigator’s judgment.

[0334] Vaccines are permitted during the study except for live or live-attenuated vaccines. Vaccines must be documented as concomitant medications. Other types of vaccines are allowed at the discretion of the investigator during the study.

[0335] Table S2 summarizes concomitant medication rules. This includes use of medications for up to 24 weeks before the screening period.Background IIM treatment

[0336] If the participant’s background IIM treatment included immunosuppressants or antimalarials, they must have been administered for >12 weeks before screening, and at a stable dose for >8 weeks before screening and then through baseline.

[0337] Participants who stopped treatment with an immunosuppressant (except for leflunomide) or an antimalarial are eligible if their last dose was >8 weeks before screening.

[0338] Participants who stopped treatment with leflunomide are eligible if their last dose was >12 weeks before screening unless leflunomide washout treatment was used, in which case participants are eligible if the washout treatment was completed >4 weeks before screening.

[0339] Dose regimens must remain stable from baseline to end of the treatment period but may be decreased for toxicity or to optimize management of a TEAE, such as infection. The toxicity / event must be confirmed as a documented AE. The dose can be returned to the baseline level if the toxicity / event resolves and if clinically indicated.

[0340] If the participant’s background IIM treatment included OCS, they must have been administered for >8 weeks before screening and must be at a stable dose for >4 weeks before screening through baseline. Participants who stopped treatment with OCS before enrollment are eligible if the last dose was >4 weeks before screening.

[0341] All corticosteroid doses are expressed in equivalent prednisone daily dose.

[0342] Increasing the cumulative daily dose of systemically administered corticosteroids (oral, IM or IV) to more than the baseline dose is defined as a steroid burst. The preferred route of administration for corticosteroid bursts is oral. However, other routes of administration (IM or IV)BUSINESS.33769645 1 82404373-ARGX-T2418WO (221799)may be used if indicated, provided that the total corticosteroid dose does not exceed the limits described in this section.

[0343] The increased total daily dose must not exceed 20 mg more than the participant’s baseline dose. The following sections describe the conditions under which steroid bursts are permitted.

[0344] The following schedule is recommended if the steroid burst is performed because of IIM disease worsening: the maximum dose (< 20 mg more than the baseline dose) for 3 days, then decrease the dose by up to 5 mg every 2 to 3 days.

[0345] IIM worsening must by documented in the worsening report. A non-IIM-related TEAE must be documented as an AE.

[0346] Phase 2 Stage:

[0347] Before visit 5 (week 16): The dose must be kept stable, if possible, based on the participant’s condition. A steroid burst is allowed if a participant meets the IMACS disease worsening criteria described below (z.e., rescue treatment) or if needed for treatment of a non-IIM-related TEAE. The dose must be reduced to the participant’s baseline dose <14 days of the increase or no later than visit 5, whichever is sooner. Before visit 5, 1 steroid burst is allowed, regardless of the cause.

[0348] From visit 5 (week 16) until visit 7 (week 24): The dose must not be increased from visit 5 through visit 7. A dose increase is allowed only if there is an immediate risk to the participant’s safety as determined by the investigator.

[0349] Phase 3 Stage:

[0350] Before visit 5 (week 16): The dose must be kept stable, if possible, based on the participant’s condition. A steroid burst is allowed if the participant meets the IMACS disease worsening criteria described below or if needed for treatment of a non-IIM-related TEAE. The dose must be reduced to the participant’s baseline dose <14 days of the increase or no later than visit 5, whichever is sooner. Before visit 5, 1 steroid burst is allowed, regardless of the cause.

[0351] From visit 5 (week 16) up until visit 12 activities begin (week 44): 1 steroid burst is allowed from non-IIM-related TEAEs. The dose must be reduced to the participant’s baseline dose or pre-burst dose <14 days of the increase or no later than visit 12, whichever is sooner.

[0352] From visit 12 (week 44) up until visit 14 (week 52): The participant’s dose must not be increased from visit 12 through visit 14. A dose increase is allowed only if there is an immediate risk to the participant’s safety as determined by the investigator.BUSINESS.33769645 1 83404373-ARGX-T2418WO (221799)

[0353] OCS Tapering:

[0354] Phase 2 Stage:

[0355] Tapering of a participant’s OCS dose is not permitted unless it is required to reduce toxicity or optimize management of an TEAE. The steroid toxicity or TEAE must be documented as an AE. The dose can be returned to baseline level if the toxicity or AE is resolved and if clinically indicated.

[0356] Phase 3 Stage:

[0357] Before visit 5 (week 16): Tapering of a participant’s OCS dose is not permitted unless it is required to reduce toxicity or optimize management of an TEAE. The steroid toxicity or TEAE must be documented as an AE. The dose can be returned to baseline level if the toxicity or AE is resolved and if clinically indicated.

[0358] From visit 5 (week 16) up until visit 12 activities begin (week 44): OCS tapering must start at visit 5 and continue until visit 12 activities being in participants receiving >5 mg of corticosteroids unless any of the IMACS disease worsening criteria are met, or if the participant experiences any of the following: severe muscle weakness (MMT8<128 / 150), severe myositis disease activity as indicated by an MDGA score of >7.5 / 10, or severe extramuscular disease activity as indicated by an extramuscular global assessment score of >7.5 / 10. In such cases, tapering can be delayed until the participant no longer meets these criteria. It is recommended that tapering of the OCS dose be started at a study visit. However, if it is not feasible, then any such tapering may be started between visits, ideally <14 days from the preceding visit. Tapering will be based on the participant’s baseline dose and on prednisone equivalent doses if the participant is receiving other OCS. After the first decrease, participants will decrease their OCS by 2.5 mg approximately every 4 weeks. The first OCS tapering dose may be less than a 2.5 mg dose reduction, depending on the baseline dose. For a baseline dose of >17.5 and up to 20 mg, the first decreased dose will be to 17.5 mg. For abaseline dose of >15 and up to 17.5 mg, the first decreased dose will be to 15 mg. For a baseline dose of >12.5 and up to 15 mg, the first decreased dose will be to 12.5 mg. For a baseline dose of >10 and up to 12.5 mg, the first decreased dose will be to 10 mg. For a baseline dose of >7.5 and up to 10 mg, the first decreased dose will be to 7.5 mg. For a baseline dose of >5 and up to 7.5 mg, the first decreased dose will be to 5 mg. Tapering is not required for participants receiving < 5 mg of OCS. However, the dose may be tapered to below 5 mg to reduce safety or tolerability issues or if a decrease is otherwise clinically indicated.BUSINESS.33769645 1 84404373-ARGX-T2418WO (221799)

[0359] If, during the tapering, a participant has a clinically significant increase in IIM disease activity based on the investigator’s judgment, the taper may be reversed by > 1 step. It is recommended to reverse the taper by the minimum number of steps necessary. Reversing the taper up to the participant’s baseline OCS dose is not considered rescue treatment. If the taper is reversed, it may be restarted before week 44, at the discretion of the investigator.

[0360] From visit 12 (week 44) up until visit 14 activities begin (week 52): The participant’s OCS dose must not be decreased from visit 12 until visit 14 activities begin. Decreases in the OCS dose after visit 12 are only permitted to reduce toxicity or optimize the management of an AE. The steroid toxicity or AE must be documented as an AE. The dose can be reverted to the week 44 dose if the toxicity or AE resolves and if it is clinically indicated.Prohibited medications

[0361] The use of cyclophosphamide, monoclonal antibodies, JAK inhibitors (including TYK2 inhibitors), immunoglobulin therapy, PLEX, immunoadsorption, corticosteroid precursors (including ACTH), any other experimental / study IMP are not permitted from their respective washout periods before enrollment through visit 7 for the phase 2 stage, visit 14 for the phase 3 stage, or the IMP discontinuation visit for participants who permanently discontinue IMP. Live or live-attenuated vaccine are not permitted from their respective washout period before enrollment through the safety follow-up period (56 days after the last dose of IMP). Participants who use any of these prohibited therapies will be permanently discontinued from IMP. If the participant’s condition mandates treatment with any prohibited medications based on the judgment of the investigator, IMP must be permanently discontinued before prohibited medication is administered.BUSINESS.33769645 1 85404373-ARGX-T2418WO (221799)Table S2. Summary of Prior and Concomitant Medication UseRules for prior and concomitant useMedications and therapies Before screening During screening During the treatment period Topical corticosteroids orany topical s withimmunomodulatoryproperties (e.g., tacrolimus)for UM-related rashProhibited during <1 weekInhaled corticosteroids or Prohibited Prohibitedbefore screening.any inhaled medicationswith immunomodulatoryproperties for IIM-relatedILDDose maintenance is recommended from screening to the end of Other topical treatments forthe treatment period.DM (e.g., symptomatic), otherNo restrictionsinhaled medication for IIM-ILDModifications based on the investigator’s judgment are (e.g., bronchodilators)permissible.Stable dose.Antifibrotics (e.g., nintedanib,No restrictions Dose decrease is permitted for toxicity.pirfenidone)Initiation of a new antifibrotic is prohibitedBUSINESS.33769645.1 86404373-ARGX-T2418WO (221799)Topicals for non-IIM- related medical history ornon-IIM-related AE- Inhaled medications forNo restrictionsnon-IIM-related medicalhistory or non-IIM-relatedAE JAK inhibitors (including TYKinhibitors), PLEX,immunoadsorption, SC, orintramuscular corticosteroidprecursors (includingProhibited during <4 weeks Prohibited; leading to adrenocorticotropic hormone Prohibitedbefore screening permanent IMP d / c [ACTH]), IVIg, SCIg,monoclonal antibodies (refer tofurther restrictions forrituximab and other anti-CD20antibodies in this table)Permitted for non-IIM-related TEAEs.Prohibited during <4 weeksLocal corticosteroid injections Prohibitedbefore screeningProhibited for IIM manifestations.Permitted under the conditions described in section C. The total dose of systemicIM or IV corticosteroid Prohibited during <4 weeks corticosteroids (OCS, IM, IV)Prohibitedinjections before screening must not exceed 20 mg / day (prednisone equivalent) above the baseline dose (i.e., during asteroid burst)BUSINESS.33769645.1 87404373-ARGX-T2418WO (221799)Prohibited during <12 weeks Prohibited; leading to Cyclophosphamide Prohibitedbefore screening permanent IMP d / c Rituximab or other anti-CD20 Prohibited during <24 weeks Prohibited; leading to Prohibitedantibody before screening permanent IMP d / c Prohibited during <12 weeks Prohibited; leading to Other IMPs Prohibitedbefore screening permanent IMP d / c Stability Period:Dose tapering rules are - Initiated >8 weeks before described in section C.screeningOCS Stabile dose (<20 mg / d of Dose changes are prohibited Dose increases (steroid bursts) prednisone or dose are permitted under the equivalent) maintained for conditions described in section >4 weeks before screening CStability period:Initiated >12 weeks beforescreeningStable dose required Stable dose for >8 weeksbefore screeningDose decrease is permitted for If leflunomide was stoppedtoxicity or a TEAE before screening, the lastImmunosuppressants, dose must have been >12Dose changes are prohibited Dose increases above baseline antimalarials weeks before screening, orlevels are prohibited a leflunomide washouttreatment must have beenInitiation of a new completed >4 weeks beforeimmunosuppressant or screeningantimalarial is prohibited Prohibited for <8 weeksbefore screening: >1immunosuppressant, >1antimalarial, or aBUSINESS.33769645.1 88404373-ARGX-T2418WO (221799)combination ofimmunosuppressant andantimalarialMay continue at stable dose Maintain stable dose orTraditional Chinese medicines discontinue before baselineInitiation of new traditional with immunosuppressive No limitationsChinese medicines with properties Combination with an IS or AMimmunosuppressive properties is prohibitedis prohibitedIf used for IIM, dose maintenance is recommended from screening to the end of the treatment periodAnalgesics, NSAIDs No limitationsModifications based on the investigator’s judgment are permissibleMaintaining the type and dosage of statin treatment is recommended, from screening to the end of the treatment periodStatinsModifications based on the investigator’s judgment are permissibleProhibited through the safety Live vaccines or live-attenuated Prohibited during <4 weeksProhibited follow-up period; leading to vaccines before screeningpermanent IMP d / cNon-live vaccines No limitationsBUSINESS.33769645.1 89404373-ARGX-T2418WO (221799)D. Study assessments and proceduresTable S3. Schedule of activities (Phase 2 stage)IMP d / c Safety Study visit SCR Vl / BL Opt-in V2 V3 V4 V5 V6 V7aUNSbvisit0EDVdfollow-upeStudy week -6 to -4 0 NA 4 8 12 16 20 24 NA NA NA NA Next <7d(+3d) 56 d (±3 d) Study day -42 to 3 29 57 85 113 141 169 scheduled after final after final (±day) -28f1 (±1) (±2) (±2) (±2) (±2) (±2) (±2) NA visit dose dose Informed consent XEligibility criteria X XDemographic characteristics8XMedical and surgical history XAdjudication committee review of (X)hhistorical muscle biopsy slides12-leadECG1X X X (X) X X X Height X X XWeight X X (X) X XPhysical exammation (full) X X (X)Physical exammation (abbreviated)1X X X X X X (X) X X X Vital signs1X X X X X X X X (X) X X X MDI X X (X)Randomization XDispense administration log and Xpatient diaryBUSINESS.33769645.1 90404373-ARGX-T2418WO (221799) IMP d / c Safety Study visit SCR Vl / BL Opt-in V2 V3 V4 V5 V6 V7aUNSbvisit0EDVdfollow-upeStudy week -6 to -4 0 NA 4 8 12 16 20 24 NA NA NA NA Next <7 d (+3 d) 56 d (±3 d) Study day -42 to 3 29 57 85 113 141 169 scheduled after final after final (±day) -28f1 (±D (±2) (±2) (±2) (±2) (±2) (±2) NA visit dose dose TIS CSMsMMT8J’kX1X X X X X X X (X) X XHAQ-DP X X X X X X X X (X) X XMDGAj kX X X X X X X X (X) X XPGAJX X X X X X X X (X) X X MDAATJ’k,mX X X X X X X X (X) X XBlood sample for muscle X X X X X X X X (X) X Xenzymes1-nClinical efficacy parametersm30 STS X X X (X) X X Abbreviated HHD X X X X X X X (X) X XCGI-SbkX X X X X X X (X) X XCGI-CkX X X X X X (X) X XFI-3kX X X (X) X XCDASIk 0X X X X (X) X XActigraphy measurespRecorded 7 days after BL and 7 days before V7Patient-reported outcomes and quality of life assessmentsPGI-S1X X X X X X X (X) X XPGI-C X X X X X X (X) X XSF-36v2 X X X X X X X (X) X XEQ-5D-5L X X X X X X X(X) X XBUSINESS.33769645.1 91404373-ARGX-T2418WO (221799) IMP d / c Safety Study visit SCR Vl / BL Opt-in V2 V3 V4 V5 V6 V7aUNSbvisit0EDVdfollow-upeStudy week -6 to -4 0 NA 4 8 12 16 20 24 NA NA NA NA Next <7 d (+3 d) 56 d (±3 d) Study day -42 to 3 29 57 85 113 141 169 scheduled after final after final (±day) -28f1 (±D (±2) (±2) (±2) (±2) (±2) (±2) NA visit dose dose PROMIS Pain Interference X X X X X X X (X) X XPROMIS Fatigue X X X X X X X (X) X XPROMIS Physical Function X X X X X X X (X) X XPainNRS> X X X X X X X (X) X XFatigue NRS’ X X X X X X X (X) X XPruritus NRS° X X X X X X X (X) X XSkindex-16° X X X X X X X (X) X XClinical laboratory assessmentsBlood sample for clinical X X X X X X X X (X) X X X laboratory tests’11HBV, HCV, and HIV tests X (X)COVID-19 test’ (X) (X) (X)Serum pregnancy test1X (X)Urine pregnancy test1,1X (X) (xy X Urinalysis1X X X X (X) X X X Other blood samples"MSA determination X (X)MSA / MAA titers1X X X X X X X X (X) X X X PD (total IgG)1XsXsX X X X X X (X) X X X Inmiunophenotyping of PBMC X X X X X(X)BUSINESS.33769645.1404373-ARGX-T2418WO (221799)IMP d / c Safety Study visit SCR Vl / BL Opt-in V2 V3 V4 V5 V6 V7aUNSbvisit0EDVdfollow-upeStudy week -6 to -4 0 NA 4 8 12 16 20 24 NA NA NA NA Next <7 d (+3 d) 56 d (±3 d) Study day -42 to 3 29 57 85 113 141 169 scheduled after final after final (±day) -28f1 (±D (±2) (±2) (±2) (*Z) (±2) (±2) NA visit dose dose IFN score measurement1X X X (X) X XIFN concentrations X X X (X) X XSerological markers of X X X (X) X Xcomplement activationImmunogenicity1XsXsX X X X X X (X) X X X PK1XsXuX X X X X X (X) X X X MSA exploratory research X(optional)Future biomarker research X(optional)IMP administration trainingv(X) (X) (X) (X) (X) (X)Review administration log and X X X X X X (X) X Xpatient diaryIMP administration"' X X X X X XConcomitant therapies1Continuous monitoring from signing the ICF to last study-related activityAEsi’xContinuous monitoring from signing the ICF to last study-related activityAE=adverse event; BL=baseline visit; CDASI=Cutaneous Dennatomyositis Disease Area and Severity Index; CGI-C=Clinical Global Impression of Change; CGI-S=Clinical Global Impression of Severity; CSM=core set measure; d=day(s); d / c=discontinuation; DM=dermatomyositis; ECG=electrocardiogram; EDV=early discontinuation visit; FI-3=Functional Index-3; HAQ-DI=Health Assessment Questionnaire Disability Index; HBV= hepatitis B virus; HCV= hepatitis C virus; HHD=handheld dynamometry; ICF=informed consent form; IFN=interferon; IgG=immunoglobulin G; IIM=idiopathic inflammatory myopathy;IMP=investigational medicinal product; m30 STS=Modified 30-Second Sit-to-Stand Test; MAA=myositis-associated antibodies; MDAAT=Myositis Disease Activity’ Assessment Tool; MDGA=physician global assessment of disease activity’; MDI=Myositis Damage Index; MMT8=manual muscle testing-8;MSA=myositis-specific antibody; NA=not applicable; NRS=numeric rating scale; OLE=open-label extension; PBMC=peripheral blood mononuclear cell;PCR=polymerase chain reaction; PD=pharmacodynamics; PGA=Patient Global Assessment of Disease Activity; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; PK=pharmacokinetics; PROMIS=Patient-Reported Outcomes Measurement Information System; SCR=screening;BUSINESS.33769645.1 93404373-ARGX-T2418WO (221799)SFV=safety follow-up visit; SF-36v2=36-Item Short Form Survey version 2; TEAE=treatment-emergent adverse event; TIS=total improvement score;UNS=unscheduled visit; V=visit; WOCBP=women (female participants) of childbearing potentialNote; IMP must be administered at the site or by a home nurse for a minimum of 3 consecutive administrations before (self-)administration of IMP by the participant or caregiver is allowed at home. Participants or caregivers must also have completed 3 (self-)administration trainings at the site and be considered capable by the site of performing the (self-)administration.aThe treatment period ends at visit 7. At this mandatory on-site visit, eligible participants may enroll in the OLE study ARGX-113-2011. This will be this study's final visit for participants rolling over to ARGX- 113-2011. If the participant does not emoll in tire OLE study, they will not receive IMP and will complete the SFV.bUnscheduled visit activities marked “(X)” are optional or only required under specific circumstances. Investigators are free to decide which assessments will be performed at each unscheduled visit. Refer to associated footnotes for more details. It is advised that the 6 CSMs of the TIS be assessed during an unscheduled visit before changing the participant’s corticosteroid dose to treat disease worsening. The investigator can decide which of the remaining assessments will be performed at each unscheduled visit.cParticipants who permanently discontinue IMP will attend the IMP discontinuation visit and then attend every other visit of their regularly scheduled visits (once every 8 weeks), without receiving IMP. The IMP discontinuation visit will be performed at the next scheduled visit after permanent IMP discontinuation. If a participant discontinues at a scheduled visit, that visit will become the IMP discontinuation visit.dThe EDV visit is performed when participants discontinue the study.eThe SFV applies to all participants unless a participant has been temporarily interrupted from IMP and >56 days have elapsed since their final dose or enrollment in ARGX- 113 -2011. If IMP is permanently discontinued >56 days from week 24 and the participant agrees to continue with on-site prescheduled visits (refer to footnote i), the SFV assessments will be performed at their scheduled visit closest to 56 days after their final dose.fAd hoc extensions of the screening period may be permitted in certain circumstances (e.g., when screening laboratory results are pending or if the participant is unable to visit the site for the scheduled baseline [week 0] visit). Screening period extensions will only occur on a case-by-case basis with the sponsor’s approval.8Demographic characteristics comprise age, birth year, sex, race, and ethnicity (per local regulations). Race and ethnicity data will be source verified only if permitted by local laws.hThese activities will only be performed if specific eligibility criteria apply.1Participants permanently discontinuing IMP will undergo the following assessments only at their IMP discontinuation visit and the SFV at the scheduled visit closest to 56 days (± 3 days) after the final dose: 12-lead ECG. urinalysis. MSA / MAA titers, PD, immunogenicity’, and PK assessments. WOCBP will also undergo a urine pregnancy test at the SFV.JAfter tire IMP discontinuation visit, participants will attend every other visit (once every 8 weeks) and undergo the following assessments at these visits; abbreviated physical examination, vital signs, MMT8, HAQ-DI. MDGA. PGA. the extramuscular global assessment of the MDAAT, muscle enzymes, CGI-S, PGLS, Pain NRS, Fatigue NRS, blood sampling for clinical laboratory’ tests, concomitant therapy monitoring, and AE monitoring. Participants performing phone visits will only undergo monitoring for concomitant medication and AEs. All participants who permanently discontinue IMP and remain in the study will perform an on-site visit at week 24.kA participant’s disease activity assessments must be performed by the same individual throughout the study, unless it is not feasible to do so. All disease activity assessments except the m30 STS, HHD and the FI-3 must be performed by a physician; the m30 STS and FI3 must be performed by a trained rater and HHD must be performed by a certified assessor.1At screening, the following muscles should be assessed for weakness (in addition to those tested in the MMT8): wrist flexors, finger flexors (flexor digitorum profundus, flexor pollicis longus), and finger extensors. All 15 MMT8 muscle groups must be assessed at screening to determine eligibility. If any of the MMT8 muscle groups are not assessable, the participant will not be considered eligible.mFollowing IMP discontinuation, only the extramuscular global assessment of tire MDAAT needs to be performed.BUSINESS.33769645.1 94404373-ARGX-T2418WO (221799)nBlood samples must be taken predose on dosing days, preferably <2 hours before administering IMP. It is recommended that blood samples are collected before the MMT8 and other muscle assessments.° Assessment will be performed on only participants with DM. Both the CDASI activity and damage scores will be calculated. However, only the activity score will be considered forthe participant’s eligibility, per inclusion criterion 10, subsection c.pActigraphy measures include step counts, cadence, vector magnitude, and time spent in different levels of daily activities (mild to moderate to strenuous activity' and sedentaiy activity).qParticipants will be tested for SARS-CoV-2 if they are symptomatic or if local regulations requires testing; if applicable, a negative PCR test (central or local laboratoiy) is required <72 hours before enrollment and should occur regardless of a participant’s vaccination status. Week 24 (V7) COVID-19 testing applies only to participants who will enroll in ARGX-113-2011 and only if the participant is symptomatic or applicable law requires testing.rSerum and urine pregnancy tests apply only to women of childbearing potential. Where required by local regulations, more frequent urine pregnancy tests will be performed while the participant is receiving IMP. In any case, when the EDV would be the participant’s last site visit, a urine pregnancy test must be performed.sBlood samples may also be used to cross-validate the PK. PD. and immunogenicity assays in the IIM matrix (serum and plasma).1Refer to genetics assessment described herein.uThis optional PK blood sampling should preferably occur at the site, but if needed, the sample may be taken at the participant’s home by a qualified person.vTraining sessions for the participant or their caregiver can occur at any time during the study.wIMP will be administered weekly. At scheduled visits, the administration will be performed by site staff after all visit activities have been completed. The last administration of the double-blinded treatment period is at week 23 (study day 162 ±2 days).xAny AEs that are ongoing at die Ume when a participant enrolls in ARGX- 113 -2011 will be followed up within die OLE study.Table S4. Schedule of activities (Phase 3 stage)VI / IMP d / cStudy visit SCR BL V2 V3 V4 V5 V6 V7 V8 V9 V10 Vll V12 V13 V14aUNSbvisit0EDVdSFV Study week -6 to -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 NA NA NA NA <7 d 56 d (+3 d) (±3 d) From - Next after after Study day 42 to 29 57 85 113 141 169 197 225 253 281 309 337 365 schedule Anal final (±day) — 28f1 (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) NA d visit dose dose Informed consent XEligibility criteria X XDemographic Xcharacteristics8BUSINESS.33769645.1 95404373-ARGX-T2418WO (221799) VI / IMP d / cStudy visit SCR BL V2 V3 V4 V5 V6 V7 V8 V9 V10 Vll V12 V13 V14aUNSbvisit0EDVdSFV Study week -6 to -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 NA NA NA NA <7 d 56 d (+3 d) (±3 d) From - Next after after Study day 42 to 29 57 85 113 141 169 197 225 253 281 309 337 365 schedule final final (±day) — 28f1 (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) NA d visit dose dose Medical and surgical Xhi stor,’Adjudication committee (X)hreview of historicalmuscle biopsy slides12-lead ECG1X X X X X X (X) X X X Height X X X X Weight X X X X (X) X X Physical examination X X (X)(Ml)Physical examination X X X X X X X X X X X X X (X) X X X (abbreviated)1Vital signs1X X X X X X X X X X X X X X X (X) X X X MDI X X (X)Randomization XDispense administration Xlog and patient diaryTIS CSMsMMT8J,kX1X X X X X X X X X X X X X X (X) X X HAQ-DP X X X X X X X X X X X X X X X (X) X X MDGA’kX X X X X X X X X X X X X X X (X) X X PGAi X X X X X X X X X X X X X X X (X) X XBUSINESS.33769645.1 96404373-ARGX-T2418WO (221799) VI / IMP d / cStudy visit SCR BL V2 V3 V4 V5 V6 V7 V8 V9 V10 Vll V12 V13 V14aUNSbvisit0EDVdSFV1Study week -6 to -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 NA NA NA NA <7 d 56 d (+3 d) (±3 d) From - Next after after Study day 42 to 29 57 85 113 141 169 197 225 253 281 309 337 365 schedule final final (±day) — 28f1 (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) NA d visit dose dose MDAATi-k-mX X X X X X X X X X X X X X X (X) X X Blood sample for X X X X X X X X X X X X X X X (X) X X muscle enzymes'’11Clinical efficacy parametersm30 STS X X X X X X (X) X X Abbreviated HHD X X X X X X X X X X X X X X (X) X XCGI-Sl,kX X X X X X X X X X X X X X (X) X XCGI-CkX X X X X X X X X X X X X (X) X XFI-3kX X X X X X (X) X X CDASIk,° X X X X X X X (X) X X CDMA-IGA X X X X X X X (X) X X Actigraphy measures'1Recorded 7 days after BL, 7 days before week 24, and 7 days before week 52 (X)C-GTI X X X X X Patient-reported outcomes and quality of life assessmentsPGI-S> X X X X X X X X X X X X X X (X) X XPGI-C X X X X X X X X X X X X X (X) X XSF-36v2 X X X X X X X X X X X X X X (X) X XEQ-5D-5L X X X X X X X X X X X X X X (X) X X PROMIS Pain X X X X X X X X X X X X X X (X) X XInterferenceBUSINESS.33769645.1 97404373-ARGX-T2418WO (221799) VI / IMP d / cStudy visit SCR BL V2 V3 V4 V5 V6 V7 V8 V9 V10 Vll V12 V13 V14aUNSbvisit0EDVdSFV0Study week -6 to -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 NA NA NA NA <7 d 56 d (+3 d) (±3 d) From - Next after after Study day 42 to 29 57 85 113 141 169 197 225 253 281 309 337 365 schedule final final (±day) — 28f1 (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) NA d visit dose dose PROMIS Fatigue X X X X X X X X X X X X X X (X) X X PROMIS Physical X X X X X X X X X X X X X X (X) X X FunctionPain NRS> X X X X X X X X X X X X X X (X) X X Fatigue NRS1X X X X X X X X X X X X X X (X) X X Pruritus NRS0X X X X X X X X X X X X X X (X) X X Skindex-160X X X X X X X X X X X X X X (X) X X Clinical laboratory assessmentsBlood sample for X X X X X X X X X X X X X X X (X) X X X clinical laboratorytests'’"HBV, HCV, and HIV X (X)testsCOVID-19 test1' (X) (X) (X)Serum pregnancy testrX (X)Urine pregnancy test1 1X (X) (xy X Urinalysis1X X X X X X X (X) X X X Other blood samples"MSA determination X (X)MSA / MAA titers1X X X X X X X X X X X X X X X (X) X X X PD (total IgG)1XsXsX X X X X X X X X X (X) X X XBUSINESS.33769645.1 98404373-ARGX-T2418WO (221799)VI / IMP d / cStudy visit SCR BL V2 V3 V4 V5 V6 V7 V8 V9 V10 Vll V12 V13 V14aUNSbvisit0EDVdSFV Study week -6 to -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 NA NA NA NA <7 d 56 d (+3 d) (±3 d) From - Next after after Study day 42 to 29 57 85 113 141 169 197 225 253 281 309 337 365 schedule final final (±day) — 28f1 (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) (±2) NA d visit dose dose Immunophenotyping X X X X (X) X Xof PBMCIFN score X X X X (X) X X measurement1IFN concentrations X X X X (X) X XSerological markers X X X X (X) X Xof complementactivationImmunogenicity1XsXsX X X X X X X X X X (X) X X X PK1XsX X X X X X X X X X (X) X X X MSA exploratory Xresearch (optional)Future biomarkers Xresearch (optional)IMP administration (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X)training11Review administration X X X X X X X X X X X X (X) X Xlog and patient diaryIMP administration'' X X X X X X X X X X X X XConcomitant therapies1Continuous monitoringAdverse events1" Continuous monitoringAE=adverse event; C-GTI=composite glucocorticoid toxicity index; CDASI=Cutaneous Dermatomyositis Disease Area and Severity Index; CDMA-IGA=Cutaneous Dermatomyositis Activity Investigator’s Global Assessment; CGI-C=Clinical Global Impression of Change; CGI-S=Clinical Global Impression of Severity; CSM=core set measure; d=day(s); d / c=discontinuation; DM=dermatomyositis; ECG=electrocardiogram; EDV=early discontinuation visit; FI-3=FunctionalBUSINESS.33769645.1 99404373-ARGX-T2418WO (221799)Index-3; HAQ-DI=Health Assessment Questionnaire Disability Index; HBV=hepatitis B virus; HCV=hepatitis C virus; HHD=handheld dynamometry;IFN=interferon; IgG=immunoglobulin G; IIM=idiopathic inflammatory myositis; IMP=investigational medicinal product; m30 STS=Modified 30-Second Sit-to-Stand Test; MAA=myositis-associated antibodies; MDAAT=Myositis Disease Activity Assessment Tool; MDGA=pliysician global assessment of disease activity; MDI=Myositis Damage Index; MMT8=manual muscle testing-8; MSA=myositis-specific antibody; NA=not applicable; NRS=numeric rating scale; OLE=open-label extension; PD=pharmacodynamics; PGA=Patient Global Assessment of Disease Activity7; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; PK=phannacokinetics; PROMIS=Patient-Reported Outcomes Measurement Information System; SCR=screening;SFV=safety follow-up visit; SF-36v2=36-Item Short Form Survey version 2; TEAE=treatment-emergent adverse event; TIS=total improvement score;UNS=unscheduled visit; V=visit; WOCBP=women (female participants) of childbearing potential.Note: IMP must be administered at the site or by a home nurse for a minimum of 3 consecutive administrations before (self-)administration of IMP by the participant or caregiver is allowed at home. Participants or caregivers must also have completed 3 (self-)administration trainings at the site and be considered capable by the site of performing the (self-)administration.aThe treatment period ends at visit 14. At this mandatory on-site visit, eligible participants may emoll in the OLE study ARGX- 113-2011. This visit will be this study ’ s final visit for participants rolling over to ARGX- 113 -2011. If the participant does not emoll in the OLE study, they will not receive IMP and will complete the SFV.bUnscheduled visit activities marked “(X)" are optional or only required under specific circumstances. Investigators are free to decide which assessments will be performed at each unscheduled visit. It is advised that the 6 CSMs of the TIS be assessed during an unscheduled visit before changing the participant’s corticosteroid dose to treat disease worsening. The investigator can decide which of the remaining assessments will be performed at each unscheduled visit.cParticipants who permanently discontinue IMP will attend the IMP discontinuation visit and then attend every odier visit of their regularly scheduled visits, (once every 8 weeks) without receiving IMP. The IMP discontinuation visit will be performed at the next scheduled visit after permanent IMP discontinuation. If a participant discontinues at a scheduled visit, that visit will become the IMP discontinuation visit.dThe EDV visit is performed when participants discontinue the study.eThe SFV applies to all participants unless a participant has been temporarily interrupted from IMP and >56 days have elapsed since their final dose or enrollment in ARGX- 113-2011. If IMP is permanently discontinued >56 days from week 52 and the participant agrees to continue with on-site prescheduled visits (refer to footnote j). the SFV assessments will be performed at their scheduled visit closest to 56 days after their final dose.fAd hoc extensions of the screening period may be permitted in certain circumstances (e.g., when screening laboratory7results are pending or if the participant is unable to visit the site for the scheduled baseline [week 0] visit). Screening period extensions will only occur on a case-by-case basis widi dre sponsor's approval.8Demographic characteristics comprise age, birth year, sex. race, and ethnicity (per local regulations). Race and ethnicity data will be source verified only if permitted by local laws.hThese activities will only be performed if specific eligibility criteria apply.1Participants permanently discontinuing IMP will undergo the following assessments only at their IMP discontinuation visit and the SFV at the scheduled visit closest to 56 days (±3 days) after the final dose: die 12-lead ECG, urinalysis, the MSA / MAA titers, PD, immunogenicity7, and PK assessments. WOCBP will also undergo a urine pregnancy test at die SFV.JAfter the IMP discontinuation visit, participants will attend every other visit (once every 8 weeks) and undergo the following assessments at these visits: abbreviated physical examination, vital signs, MMT8, HAQ-DI, MDGA, PGA, die extramuscular global assessment of die MDAAT, muscle enzymes. CGI-S, PGI-S. Pain NRS, Fatigue NRS, blood sampling for clinical laboratory tests, concomitant therapy monitoring, and AE monitoring. Participants performing phone visits will only undergo monitoring for concomitant medication and AEs. All participants who permanently discontinue IMP and remain in the study will perform an on-site visit at week 52 and the SFV.BUSINESS.33769645.1 100404373-ARGX-T2418WO (221799)kA participant’s disease activity assessments must be performed by the same individual throughout the study, unless it is not feasible to do so. All disease activity assessments except the m30 STS, HHD and the FI-3 must be performed by a physician; the m30 STS and FI3 must be performed by a trained rater and HHD must be performed by a certified assessor.1At screening, the following muscles should be assessed for weakness (in addition to those tested in the MMT8): wrist flexors, finger flexors (flexor digitorum profundus, flexor pollicis longus), and finger extensors. All 15 MMT8 muscle groups must be assessed at screening to determine eligibility. If any of the MMT8 muscle groups are not assessable, the participant will not be considered eligible.mFollowing IMP discontinuation, only the extramuscular global assessment of the MDAAT needs to be performed.nBlood samples must be taken predose on dosing days, preferably within 2 hours before administering IMP. It is recommended that blood samples are collected before the MMT8 and other muscle assessments.0Assessment will be performed on only participants with DM. Both the CDASI activity and damage scores will be calculated. However, only the activity score will be considered for the participant’s eligibility, per inclusion criterion 10, subsection c.pActigraphy measures include step counts, cadence, vector magnitude, and time spent in different levels of daily activities (mild to moderate to strenuous activity and sedentary' activity ).4Participants will be tested for SARS-CoV-2 if they are symptomatic or if local regulations requires testing; if applicable, a negative PCR test (central or local laboratory) is required <72 hours before enrollment and should occur regardless of a participant’s vaccination status. Week 52 (V14) COVID-19 testing applies only to participants who will enroll in ARGX-113-2011 and only if the participant is symptomatic or applicable law requires testing.rSerum and urine pregnancy tests apply only to women of childbearing potential. Where required by local regulations, more frequent urine pregnancy tests will be performed while the participant is receiving IMP. In any case, when the EDV would be the participant’s last visit, a urine pregnancy test must be performed.sBlood samples may also be used to cross-validate the PK, PD, and immunogenicity assays in the IIM matrix (serum and plasma).1Refer to genetics assessment described herein.uTraining sessions for the participant or their caregiver can occur at any time during the study.vIMP will be administered weekly. At scheduled investigative site visits, the administration will be performed by site staff after all visit activities have been completed. The last administration of the double-blinded treatment period is at week 51 (study day 358 ±2 days)." Any AEs that are ongoing at the time when a participant enrolls in ARGX-113-2011 will be followed up within the OLE study.BUSINESS.33769645.1 101404373-ARGX-T2418WO (221799)TISandCSMs

[0362] The TIS assesses minimal, moderate, and major clinical response, and is assessed using the ACR / EULAR criteria.

[0363] The ACR / EULAR criteria calculates TIS using the 6 CSMs: MDGA, PGA, MMT8, HAQ-DI, muscle enzymes, and extramuscular global assessment (assessed by the Myositis Disease Activity Assessment Tool [MDAAT]).

[0364] The absolute percentage change from baseline in each measure with varying weights is combined to obtain a TIS on a scale from 0 to 100. Higher scores indicate greater improvement. Improvements are defined by the following increases in TIS: Minimal improvement — at least 20 points; Moderate improvement — at least 40 points; Major improvement — at least 60 points.MDGA

[0365] The MDGA is a tool that measures the physician’s global evaluation of the participant’s overall disease activity, defined as potentially reversible pathology or physiology resulting from IIM. The physician rates disease activity on the MDGA using a 10-cm VAS.

[0366] Overall disease activity is rated by drawing a vertical mark on a 10-cm VAS from the left end of the line (no evidence of disease activity), midpoint of the line (moderate disease activity), and the right end of the line (extremely active or severe disease activity).

[0367] Data will not be collected for the MDGA Likert scale in this study.PGA

[0368] The PGA is a tool that measures a patient’s global evaluation of their overall disease activity at the time of assessment using a 10-cm VAS.

[0369] The participant rates their overall disease activity by drawing a vertical mark on a 10-cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (extremely active or severe disease activity).MMT8

[0370] The MMT8 is a physician assessment of muscle strength in a set of 8 designated muscles tested bilaterally (proximal muscles [deltoids, biceps, gluteus maximus, gluteus medius, and quadriceps] and distal muscles [wrist extensors and ankle dorsiflexors], potential score 0 to 140) and axially (neck flexors, potential score 0 to 10). The MMT8 is scored according to the Kendall scale. The highest total potential MMT8 score is 150. All 15 MMT8 muscles groups must BUSINESS.33769645 1 102404373-ARGX-T2418WO (221799)be assessed at screening to determine eligibility. If any of the MMT8 muscle groups are not assessable at screening, the participant will not be considered eligible. The following muscles should be assessed for weakness at screening (in addition to those tested in the MMT8): wrist flexors, finger flexors (flexor digitorum profundus, flexor pollicis longus), and finger extensors.HAQ-DI

[0371] The HAQ-DI assesses physical function and is recommended by IMACS as a CSM in therapeutic studies reporting on myositis disease activity.

[0372] The participant assesses their usual abilities within the past week in 8 categories: dressing and grooming, arising, walking, reach, eating, hygiene, grip, and activities. Each category has 2 to 3 questions scored by the participant using a 4-point scale from 0 (without any difficulty) to 3 (unable to do). Scores may be adjusted based on the participant’s responses to separate questions regarding their need for aids and devices or help from another person.Muscle enzymes

[0373] Muscle-associated enzymes include CK, the transaminases (ALT, AST), LDH, and aldolase. These enzymes will be measured using validated methods from blood sampled as indicated in Tables S3 and S4. The actual date and time of the blood sample collection will be collected and included in the central laboratory data transfer.MPA AT

[0374] The MDAAT is a combined tool that includes the MYOACT, which is a series of physician’s assessments of disease activity of various organ systems modified from the Vasculitis Activity Index, and the MIT AX, which is modified from the British Isles Lupus Assessment Group approach to assess disease activity in lupus.

[0375] Among the MYOACT components of the MDAAT assessments, the extramuscular global assessment is a CSM of the TIS and is a tool used by the physician for an overall evaluation of disease activity in all the extramuscular organ systems. This assessment specifically excludesBUSINESS.33769645 1 103404373-ARGX-T2418WO (221799)muscle disease activity. The physician uses a 10-cm VAS to rate the participant’s overall disease activity in all extramuscular systems within the past 4 weeks that are caused by active IIM disease.

[0376] MDAAT assessments relating to pulmonary imaging and pulmonary function tests will only be considered if tests have been conducted as part of the participant’s medical care and tests results are available.

[0377] The MITAX component of the MDAAT assesses disease activity of various organ systems by assessing 26 clinical features within the past 4 weeks that are caused by active disease, using a 5 point scale: 0=not present in the past 4 weeks; I -improving; 2=the same; 3=worse; 4=new.PGIS and PGI-C

[0378] The PGI-S and PGI-C are simple, valid, participant-rated, single-item global measures of their condition.

[0379] The PGT-S asks participants to rate the severity of their disease symptoms over the past 7 days on a 4-point Likert scale, where scores range from “no symptoms” to “severe.”

[0380] The PGI-C asks participants to rate how much their overall status has changed from the start of the study on a 7-point Likert scale, where scores range from “much better” to “much worse.”CGIS and CGI-C

[0381] The CGI-S and CGI-C are simple, valid, physician-rated, single-item global measures of the participant’s disease.

[0382] The CGI-S asks the physician to rate the severity of the participant’s disease on a 4-point Likert scale, where scores range from “no activity” to “severe.”

[0383] The CGLC asks the physician to rate how much the participant’s overall disease has changed from the start of the study on a 7-point Likert scale, where scores range from “much better” to “much worse.”FIS

[0384] The FL3 is a validated method for assessing functional disability ( / .<?., muscle endurance and stamina) in patients with DM or PM. Participants will attempt to perform 3 differentBUSINESS.33769645 1 104404373-ARGX-T2418WO (221799)muscle group tasks: head lift (neck flexion), shoulder flexion, and hip flexion. Hip and shoulder flexion will be performed only on the dominant side.

[0385] The movement pace for each task will be standardized using a metronome (40 beats / min). Participants will attempt to perform up to 60 hip and shoulder flexion repetitions <3 minutes and up to 30 head flexion repetitions <1.5 minutes. After performing each task, participants will rate their perceived muscle exertion on the Borg CR-10 scale from 0 (no exertion) to 10 (maximal exertion).PROMIS assessments

[0386] PROMIS is a publicly available system of highly reliable, precise measures of patient-reported health status for physical, mental, and social well-being. PROMIS instruments measure concepts including pain, fatigue, and physical function.

[0387] PROMIS Fatigue (Short Form 7a) instrument assesses the impact and experience of fatigue over the past 7 days. This validated 7-question scale has 5 response options, with scores ranging from 1 to 5. Scores are converted to a T-score, and higher scores indicate higher levels of fatigue. A decrease in score (negative change from baseline) indicates improvement in fatigue.

[0388] The PROMIS Pain Interference (Short Form 6a) instrument measures the selfreported consequences of pain across aspects of life, including social, cognitive, emotional, physical, and recreational activities over the past 7 days. This validated 6-question scale has 5 response options, with scores ranging from 1 to 5. Scores are converted to a T-scores, and higher scores indicate greater pain interference. A decrease in score (negative change from baseline) indicates improvement in pain interference.

[0389] The PROMIS Physical Function (Short Form 8b) instrument measures selfreported capability rather than actual performance of physical activities. A single physical function capability score is obtained from a short form. This validated 8-question scale has 5 response options, with scores ranging from 1 to 5. Scores are converted to T-scores, and higher scoresBUSINESS.33769645 1 105404373-ARGX-T2418WO (221799)indicate better self-reported capability in physical function. An increase in score (positive change from baseline) indicates improvement in self-reported physical function.Pain NRS

[0390] Participants will record a score (0 to 10) for worst pain experienced within the past 7 daysFatigue NRS

[0391] Participants will record a score (0 to 10) for worst physical fatigue experienced within the past 7 days.SF-36v2

[0392] The SF-36v2 is a 36-item scale constructed to survey health-related quality of life on 8 domains: 1) Limitations in physical activities caused by health problems; 2) Limitations in social activities caused by physical or emotional problems; 3) Limitations in usual role activities caused by physical health problems; 4) Bodily pain; 5) General mental health (psychological distress and well-being); 6) Limitations in usual role activities caused by emotional problems; 7) Vitality (energy and fatigue); 8) General health perceptions.EO-5D-5L

[0393] The EQ-5D-5L questionnaire is a standardized test recognized by many health authorities as a generic measure of health status for clinical and economic appraisal.

[0394] The descriptive system comprises 5 dimensions: 1) Mobility; 2) Self-care; 3) Usual activities; 4) Pain / discomfort; 5) Anxiety / depression.

[0395] Each dimension has 5 levels: 1) No problem; 2) Slight problem; 3) Moderate problem; 4) Severe problem; 5) Extreme problem.

[0396] The participant will be asked to indicate his / her health state by ticking the (or placing a cross in) the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1 -digit number expressing the level selected for that dimension. The digits for 5 dimensions are combined in a 5-digit number describing the respondent’s health state. A unique health state is defined by combining 1 level from each of the 5 dimensions. A total of 3125 possible health states could be defined in this way. Each state is referred to in terms of a 5-digit code. For example, state 11111 would indicate no problems in any of the 5 dimensions, and state 12345BUSINESS.33769645 1 106404373-ARGX-T2418WO (221799)would indicate no problem with mobility, slight problems with washing or dressing, moderate problems with doing usual activities, severe pain or discomfort, and extreme anxiety or depression.

[0397] A VAS is included in the EQ-5D-5L. Participants will mark their health status from 0 (the worst health you can imagine) to 100 (the best health you can imagine) on the day the interview is conducted.IMACS Disease Worsening Criteria

[0398] IMACS disease worsening is defined as when any of the following conditions occur (compared with baseline): 1) MDGA worsening by >2 cm on the VAS and MMT8 worsening by >20%; 2) Global extramuscular activity worsening by >2 cm on the 10-cm MDAAT VAS; 3) Any 3 of 6 IMACS CSMs worsening by >30%. A disease worsening report will be available for investigators’ review.m30 STS test

[0399] The m30 STS test measures proximal muscle weakness. Participants will be seated in a standard chair with armrests and instructed to stand up and then sit down again for 30 seconds. Participants may use their hands and arms to help stand if needed. The number of sit-to-stand repetitions will be recorded.Monitor actigraphy

[0400] Participants will be instructed to wear an actigraph (a physical activity monitor) at the times specified in the SoA. The actigraph will record step counts, cadence, vector magnitude, and time spent in different levels of daily activities (mild, moderate, to strenuous activity, and sedentary activity).Abbreviated handheld dynamometry (HHD)

[0401] Handheld dynamometry measures the peak isometric force generated from a muscle group and is used to quantify muscle strength in patients with IIM. Muscle strength will be assessed by handheld dynamometry in the deltoid and iliopsoas bilaterally using a provided dynamometer and according to methods designated in the study manual.CDASI (Participants with DM only)

[0402] CDASI is a skin-specific outcome measure used to assess disease in patients with DM. Disease in 15 different anatomical locations is rated using 3 activity measures (erythema, scale, erosion / ulceration) and 2 damage measures (poikiloderma, calcinosis). CDASI also assesses the presence and severity of Gottron’s papules, periungual changes, and alopecia. The resultingBUSINESS.33769645 1 107404373-ARGX-T2418WO (221799)activity and damage scores range from 0 to 100 and 0 to 32, respectively. Higher scores indicate greater disease severity.Pruritis NRS (Participants with DM only)

[0403] Pruritic symptoms of DM will be indicated by the participant on the Pruritis NRS, recording an average and a worst score (0 to 10) for itch experienced within the past 24 hours.Skindex-16 (Participants with DM only)

[0404] The Skindex-16 is a single-page survey that assesses how the symptoms, emotions, and functioning from the cutaneous symptoms of DM affect the participant’s quality of life. Using a Likert scale of 0 (never) to 6 (always), the participant rates how often of each skin disease effect has been over the preceding week. Skindex-16 provides a single score for each domain (symptoms, emotions, and functioning) and an average score.CDMA-IGA (Participants with DM only. Phase 3 only)

[0405] The CDMA-IGA is a 5-point scale created at the University of Pennsylvania to measure the severity of DM rash as determined by a combination of 2 characteristics (erythema, scale), and secondary changes based on descriptions of each characteristic. This DM-specific assessment is an adaptation of the Psoriasis Investigator’s Global Assessment scale.MDI

[0406] The MDI is a tool used for physician assessment of the extent and severity of disease damage in 11 organ systems. Only the muscle damage VAS will be used in this study, where the severity of damage is measured by a physician’s overall rating of disease damage to the muscular system, using a 10-cm VAS.Muscle biopsy

[0407] Participants who require a muscle biopsy diagnostic for inclusion in the study will have their historical muscle biopsy slides submitted for biopsy adjudication committee review. Full details of this process are described in the biopsy adjudication charter.

[0408] If a participant who requires a muscle biopsy diagnostic does not have historical biopsy data available, the participant will not be considered eligible for enrollment. If a biopsy is performed after a screening failure that is within the course of the participant’s routine medical care, then that biopsy may be used if the participant is rescreened.C-GTI (Phase 3 Stage Only)

[0409] The C-GTI serves as a primary instrument to capture toxicities likely caused by glucocorticoid exposure and enables monitoring of long-term tolerability of glucocorticoids during BUSINESS.33769645 1 108404373-ARGX-T2418WO (221799)prolonged use. The C-GTI has 9 functional domains: body mass index, glucose control, BP, lipid metabolism, bone mineral density, muscle strength, skin toxicity, neuropsychiatric effects, and infection. Each domain includes several weighted items that correspond to varying degrees of glucocorticoid toxicity. The bone mineral density and muscle strength domain will not be assessed in this study.

[0410] Two analytical scores are generated from the weighted C-GTI items: the CWS and the AIS. The CWS is designed to assess cumulative glucocorticoid toxicity, and the AIS can be used to assess whether a new therapy is effective in reducing glucocorticoid toxicity over time. Together, the CWS and AIS provide complementary information about the ability of an investigational agent to reduce overall glucocorticoid toxicity.E. Pharmacokinetics

[0411] Blood samples for PK analysis will be collected for measurement of serum concentrations of efgartigimod, as specified in Tables S3 and S4. Sampling must be taken predose, preferably <2 hours before IMP is administered. During unscheduled visits, blood samples for PK will be collected only if IMP is administered.

[0412] Serum efgartigimod concentrations will be determined using a validated assay.

[0413] In the phase 2 stage of the study only, an optional additional PK sample will be taken at day 3 (±1 day; opt-in visit) at selected investigative sites until these additional PK samples are obtained from at least 32 participants. This blood sampling should preferably take place at the site, but if needed, the sample may be taken at the participant’s home by a qualified person.

[0414] Intervention concentration information that may unblind the study will not be reported to investigative sites or blinded personnel.F. Pharmacodynamics

[0415] Blood samples will be collected for the determination of total IgG serum levels, as described in Tables S3 and S4. Total IgG will be determined using a validated assay.

[0416] At screening, total IgG serum levels will be measured to assess eligibility.

[0417] For baseline and all post-baseline PD assessment time points, sample collection will be performed pre-dose.

[0418] Total IgG concentrations will be quantified at a central laboratory, and results will not be reported to investigative sites or other study personnel to maintain study blind.BUSINESS.33769645 1 109404373-ARGX-T2418WO (221799)

[0419] PD blood samples collected at the screening visit may be used for methodology validation and / or future research purposes. Such use of these samples is permitted only after obtaining consent from the participant.G. Genetics

[0420] Assessment will include measuring the IFN signature, which is a normalized score calculated from a set of transcripts that are systemically induced by IFNs (IFN score). This assessment is mandatory, unless it is classified as genetic testing by local regulations. In that case, this assessment is optional and will only be assessed if the participant consents.H. Biomarkers

[0421] Blood samples will be collected and serum will be aliquoted for the measurement of biomarkers, according to Tables S3 and S4. Full details of measurements and methods are described in a laboratory manual provided separately to sites.MSAs and MAAs

[0422] Blood samples will be collected and serum will be aliquoted for the measurement of MSAs and MAAs. Samples will be collected according to the schedule described in Tables S3 and S4. For MSAs and MAAs, separate samples will be collected as follows:

[0423] A screening sample for presence of specified MSAs used for eligibility and classification of the participant’s IIM subtype.

[0424] Measurement of MSA / MAA titers. The MSA / MAA panel may include but is not limited to the following: MSA: anti-SRP, -HMGCR, -Mi-2, -TIF1, -SAE, -NXP, -MDA5, -Jo-1, -PL-7, -PL-12, -EJ, -OJ, PM / Scl-75, and Ku; MAA: snRNP, -Ro52 (SSA), -Ro / 60 (SSA), -La (SSB).

[0425] An optional baseline sample for research in MSA assay testing and methodology. These samples may be used for further MSA assay testing and research in IIM population only. Therefore, where local regulations and IRB / IECs allow, a blood sample may be collected for future exploratory research.Other Exploratory Biomarkers

[0426] Samples will be collected for the following measurements, as specified in Tables S3 and S4:BUSINESS.33769645 1 110404373-ARGX-T2418WO (221799)

[0427] Immunophenotyping of PBMC, including but not limited to the assessment of the proportion of CD 19+ B cells within the CD45+ population, and may include assessment of myositis-antigen specificity.

[0428] Assessment of IFN concentrations, including but not limited to IFN-alpha and IFN-beta protein levels.

[0429] Assessment of IFN score (regulation of IFN-regulated gene expression), including but not limited to the mRNA quantification of the following 6 interferon-stimulated genes (ISGs): interferon alpha inducible protein 27 (IFI27), interferon induced protein 44 (IFI44L), interferon induced protein with tetratricopeptide repeats 1 (IFIT1), ISG15 ubiquitin like modifier (ISG15), radical S-adenosyl methionine domain containing 2 (RSAD2), and sialic acid binding Ig like lectin 1 (SIGLEC1). Also, housekeeping genes will be assessed, including but not limited to: actin beta (ACTB), hypoxanthine phosphoribosyltransferase (HPRT1), and RNA polymerase II subunit A (POLR2A).

[0430] Assessment of the IFN score aims to understand which biological processes or pathways drive the disease and how efgartigimod PH20 SC could interfere with these pathways. IFN pathways play a key role in driving myositis. They activate and inactivate specific genes (DNA) that are transcribed into a specific set of RNA, which is known as “the IFN signature.” This IFN signature induces systemic manifestations such as interstitial lung disease, muscle inflammation, and skin rashes, and has been detected in the blood of patients with myositis. It is hypothesized that efgartigimod can interfere with IFN pathways, and hence suppresses the interferon signature.

[0431] Measuring the IFN signature using an IFN score is important because it can be determined whether the participant shows a characteristic that is an indicator of the processes underlying the disease. Moreover, this may help researchers to better understand how the treatment affects the disease.

[0432] Testing of this sample is mandatory, unless it is classified as a genetic test by local regulations. If it is considered genetic testing, this assessment is optional.

[0433] Serological markers of complement activation, including but not limited to C3, C4, and / or split products thereof (C3b / c and C4b / c).I. Immunogenicity assessmentsBUSINESS.33769645 1 111404373-ARGX-T2418WO (221799)

[0434] Blood samples will be collected to assess the serum levels of ADA to efgartigimod and plasma levels of antibodies to rHuPH20 from all participants described in Tables S3 and S4. Samples must be taken predose, preferably <2hours before IMP is administered. Full details of measurements and methods are described in a laboratory manual provided separately to sites. The immunogenicity sample taken at screening will be used for validation purposes only.

[0435] All samples will be analyzed in a 3-tiered approach using validated immunogenicity method. First, all samples will be evaluated in a screening assay (tier 1) and scored positive or negative. Second, screened positive samples will be evaluated in a confirmatory assay (tier 2) to assess the specificity of the immunogenicity response. The samples will be scored confirmed positive or confirmed negative. Samples confirmed positive in tier 2 will be further analyzed in a titration assay to characterize the magnitude of the antibody response and a neutralizing antibody assay to assess the antibodies for neutralizing activity (tier 3).J. Objectives and endpointsTable S5. Objectives and endpointsObjectives EndpointsPrimaryTo evaluate the clinical improvement • Total improvement score (TIS)of efgartigimod PH20 SC treatmentcompared with placebo, in addition tostandard-of-care immunomodulatorytherapyKey secondaryTo evaluate additional measures of • Time to reach TIS >20 (first “minimal clinicalthe efficacy of efgartigimod PH20 SC improvement”)in achieving clinical response• Percentage of participants with TIS >20• Time to reach TIS >40 (first “moderate clinical improvement”)• Percentage of participants with TIS >40To evaluate the effect of efgartigimodPH20 SC on muscle strength• Change in manual muscle testing-8 (MMT8) scoreTo evaluate the effect of efgartigimod • Change in Patient Global Assessment of Disease Activity PH20 SC on patient and physician (PGA)global assessments of disease activity• Change in Physician Global Assessment of Disease Activity (MDGA)BUSINESS.33769645 1 112404373-ARGX-T2418WO (221799)Objectives EndpointsTo evaluate the steroid-sparing effect • Proportion of participants achieving target oral prednisone of efgartigimod PH20 SC (phase 3stage onlv) dose of <5 mg / day (or equivalent)Other secondaryTo evaluate the steroid-sparing effect • Change in steroid dose from baseline to last visit of efgartigimod PH20 SC (phase 3stage only) • Proportion of participants who achieve at least minimal improvement (>20) in TIS and adhere to an oral prednisone dose of <5 mg / day (or equivalent) at week 52• Proportion of participants who achieve at least moderate improvement (>40) in TIS and adhere to an oral prednisone dose of <5 mg / day (or equivalent) at week 52To evaluate the effect of efgartigimod • Change in Health Assessment Questionnaire Disability PH20 SC on physical function Index (HAQ-DI)parametersTo evaluate the effect of efgartigimod • Change in the extramuscular global assessment PH20 SC on extramuscular diseaseactivityTo evaluate the effect of efgartigimod • Change in abbreviated handheld dynamometry (HHD) PH20 SC on additional measures ofmuscle strengthTo evaluate the effect of efgartigimod • Change in Patient Global Impression of Severity (PGI-S) PH20 SC on additional measures ofpatient and physician global • Patient Global Impression of Change (PGI-C) assessments of disease activity • Change in Clinical Global Impression of Severity (CGI-S)• Clinical Global Impression of Change (CGI-C)To evaluate the effect of efgartigimod • Change in the Myositis Functional Index (FI-3) PH20 SC on muscle enduranceTo evaluate the effect of efgartigimod • Change in Patient-Reported Outcomes Information System PH20 SC on pain (PROMIS) Pain Interference 6a vl.0• Change in pain numeric rating scale (NRS) assessing worst pain in the past 7 daysTo evaluate the effect of efgartigimod • Change in PROMIS Fatigue 7a v 1.0PH20 SC on fatigue• Change in Fatigue NRS assessing worst physical fatigue in the past 7 daysTo evaluate tire effect of efgartigimod • Change in PROMIS Physical Function 8b v2.0PH20 SC on additional physicalfunctioning measures • Change in the Physical Functioning subscale and Physical Component Summary scores of the 36-Item Short Form Survey version 2 (SF-36v2)BUSINESS.33769645 1 113404373-ARGX-T2418WO (221799)Objectives EndpointsTo assess the health impact of • Composite Glucocorticoid Toxicity Index (C-GTI) glucocorticoid use and the steroid- comprising the Aggregate Improvement Score (AIS) and the sparing effect of efgartigimod PH20SC (phase 3 stage only) Cumulative Worsening Score (CWS)To evaluate the effect of efgartigimod • Change in EQ-5D-5L utilitiesPH20 on health-related quality of life• Change in EQ-5D-5L VASTo evaluate the effect of efgartigimod • Change in the most abnormal enzyme in each participant: PH20 SC on muscle enzymes creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransaminase (AST), aldolase, or lactate dehydrogenase (LDH)To evaluate the effect of efgartigimod • Proportion of participants who meet IMACS worsening PH20 SC in preventing disease criteriadeterioration• Time to worseningTo assess tire PK of efgartigimod • Efgartigimod serum concentrations over timePH20 SCTo assess the PD effect on total IgG • Percent change from baseline in total IgG levels in serum levels of efgartigimod PH20 SC over timeTo assess tire immunogenicity of • Incidence and prevalence of antidrug antibodies (ADA) efgartigimod and rHuPH20 against efgartigimod in serum over time• Incidence and prevalence of antibodies against rHuPH20 in plasma over timeTo assess tire safety and tolerability of • Incidence and severity of treatment-emergent AEs (TEAEs), efgartigimod PH20 SC AESIs, and serious AEs (SAEs) presented by system organ class (SOC) and preferred term (PT)• Changes and abnormalities in vital signs, electrocardiogram (ECG), and laboratory parametersExploratoryTo evaluate the efficacy of • Time to reach TIS >60 (first ‘“major clinical improvement") efgartigimod PH20 SC in achievingmajor clinical response • Percentage of participants with TIS >60To evaluate efgartigimod PH20 SC • Percentage of participants withdrawing from IMP because of midstudy treatment failure lack of clinical responseTo evaluate tire effect of efgartigimod • Change in Myositis Intention-to-Treat Activity Index PH20 SC on additional extramuscular (MITAX) total and individual scores (constitutional, disease activity parameterscutaneous, skeletal, gastrointestinal, pulmonary, muscle and cardiac disease activity)BUSINESS.33769645 1 114404373-ARGX-T2418WO (221799)Objectives Endpoints• Change in Myositis Disease Activity Assessment Visual Analog Scales (MYOACT) total and individual scores (constitutional, cutaneous, skeletal, gastrointestinal, pulmonary and cardiac disease activity)To evaluate the effect of efgartigimod • Change in Modified 30-Second Sit-to-Stand Test (m30 STS) PH20 SC on proximal muscleweaknessTo evaluate the effect on physical • Change in the mean daily activity levels over time using step activity using monitor actigraphy counts, cadence, vector magnitude, and time spent in different levels of daily activities (mild to moderate to strenuous activity and sedentary activity variables; average scores across 7 consecutive days)To assess the efficacy of efgartigimod • TIS in each IIM subtype separately (IMNM, DM, PM) PH20 SC in each IIM subtypeseparately (IMNM, DM, PM) • Time to first minimal, moderate, and major improvement on the TIS in each IIM subtype separately (IMNM, DM, PM) • Percentage of participants with at least “minimal clinical improvement,’’ percentage of participants with at least “moderate clinical improvement,” percentage of participants with “major clinical improvement” in TIS in each IIM subtype separately (IMNM, DM, PM)• Change in MMT8, FI-3 and CK in participants with IMNM • Change in MMT8, FI-3 and CK in participants with PM • Change in MMT8, most abnormal enzyme, FI-3, Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Pruritis NRS, and Skindex-16 in participants with DM• Change in Cutaneous Dennatomyositis Activity Investigator’s Global Assessment (CDMA-IGA, phase 3 stage only)• Proportion of DM participants who improve by at least 1 category on the CDMA-IGA (phase 3 stage only)To assess additional changes in • Change in the remaining 7 subscales and the Mental functional status (beyond physical Component Summary Score of the SF-36v2 functioning)To evaluate the effect of efgartigimod • Change in MSA and MAA levelsPH20 SC on myositis antibodiesTo evaluate the effect of efgartigimod • Changes in lymphocyte dynamics including but not limited PH20 SC on the immunological to the proportion of CD 19+ B cells within the CD45+ profilespopulationBUSINESS.33769645 1 115404373-ARGX-T2418WO (221799)Objectives Endpoints• Changes in serum cytokine profiles (including but not limited to interferon [IFN] type I signature)• Changes in serum markers of complement activation including but not limited to C3, C4, and / or split products thereofTo assess additional measures of the • Duration of clinical response (maximal duration of efficacy of efgartigimod PH20 SC inachieving clinical response consecutive visits with TIS >20)• Duration of moderate clinical response (maximal duration of consecutive visits with US >40)Example 2: Phase 2 Results from ALKIVIA study

[0436] Data from the phase 2 portion of ALKIVIA study described in Example 1 is presented below. Two populations were analyzed. The intent-to-treat (ITT) analysis set includes all randomized participants and is used for efficacy analyses. In the ITT set, participants are included in the analyses according to the treatment to which they were randomized (and their confirmed subtype). The safety analysis set (SAF) includes all enrolled participants who have received at least one dose or part of a dose of IMP and is used for safety analyses. In the SAF set, participants are analyzed according to the treatment they received (and their confirmed subtype).

[0437] There were no apparent differences in demographics, baseline disease characteristics, background IIM therapy at baseline and treatment discontinuation observed between the two treatment groups. Higher study discontinuation in the efgartigimod (7(14.9%)) vs. placebo (3(7.1%)) was driven by the DM subtype (see Table S7 below). Within subtypes, no apparent difference were seen between treatment groups apart from some difference within the DM subtype due to low number of participants in that group. Total participant disposition is shown in Table S6 and disposition by IIM subtype is shown in Table S7. The two deaths were due to car accident and septic shock.Table S6. Study Withdrawal and Treatment Discontinuation (Safety Analysis Set)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) n (%) n (%) n (%) Treated 47 42 89 Treatment completed 38 (80.9) 34 (81.0) 72 (80.9)BUSINESS.33769645 1 116404373-ARGX-T2418WO (221799)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) n (%) n (%) n (%) Treatment discontinued 9 (19.1) 8 (19.0) 17 (19.1) Primary reason for treatment discontinuationAdverse event 3 (6.4) 4 (9.5) 7 (7.9) Physician decision 0 1 (2.4) 1 (1.1) Protocol violation 1 (2.1) 0 1 (1.1) Protocol-specified withdrawal criterion 3 (6.4) 0 3 (3.4) metWithdrawal by participant 0 3 (7.1) 3 (3.4) Withdrawal of consent 2 (4.3) 0 2 (2.2) Study withdrawal 7 (14.9) 3 (7.1) 10 (11.2) Primary reason for study withdrawalDeath 2 (4.3) 0 2 (2.2) Lost to follow-up 0 1 (2.4) 1 (1.1) Physician decision 2 (4.3) 0 2 (2.2) Protocol-specified withdrawal criterion 1 (2.1) 0 1 (1.1) metWithdrawal by participant 0 2 (4.8) 2 (2.2) Withdrawal of consent 2 (4.3) 0 2 (2.2) Rolled over to ARGX-113-2011 35 (74.5) 34 (81.0) 69 (77.5) Entered follow-up period 5 (10.6) 3 (7.1) 8 (9.0)Efgartigimod PH20 SC=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; N=number of participants in the analysis set; n=number of participants in a category; SC=subcutaneous(ly)BUSINESS.33769645 1 117404373-ARGX-T2418WO (221799)Table S7. Study Withdrawal and Treatment Discontinuation by TIM Subtype (Safety Analysis Set)IMNM DM PM EFG PBO EFG PBO EFG PBO(N=27) (N=27) (N=14) (N=12) (N=6) (N=3) n (%) n (%) n (%) n (%) n (%) n (%) Treated 27 27 14 12 6 3 Treatment completed 22 (81.5) 21 (77.8) 11 (78.6) 10 (83.3) 5 (83.3) 3 (100) Treatment discontinued 5 (18.5) 6 (22.2) 3 (21.4) 2 (16.7) 1 (16.7) 0 Primary reason for treatment discontinuationAdverse event 1 (3.7) 3 (11.1) 2 (14.3) 1 (8.3) 0 0 Physician decision 0 1 (3.7) 0 0 0 0 Protocol violation 1 (3.7) 0 0 0 0 0 Protocol-specified 2 (7.4) 0 0 0 1 (16.7) 0 withdrawal criterionmetWithdrawal by0 2 (7.4) 0 1 (8.3) 0 0 participantWithdrawal of consent 1 (3.7) 0 1 (7.1) 0 0 0 Study withdrawal 3 (11.1) 3 (11.1) 3 (21.4) 0 1 (16.7) 0 Primary reason for study withdrawalDeath 1 (3.7) 0 1 (7.1) 0 0 0 Lost to follow-up 0 1 (3.7) 0 0 0 0 Physician decision 0 0 1 (7.1) 0 1 (16.7) 0 Protocol-specified 1 (3.7) 0 0 0 0 0 withdrawal criterionmetWithdrawal by0 2 (7.4) 0 0 0 0 participantWithdrawal of consent 1 (3.7) 0 1 (7.1) 0 0 0 Rolled over to argx-113- 21 (77.8) 21 (77.8) 9 (64.3) 10 (83.3) 5 (83.3) 3 (100) 2011Entered follow-up period 3 (11.1) 2 (7.4) 2 (14.3) 1 (8.3) 0 0DM=dermatomyositis; EFG=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; IMNM=immune-mediated necrotizing myopathy; N=number of participants in the analysis set; n=number of participants in a category; PBO=placebo; PM=polymyositis; SC=subcutaneous(ly)BUSINESS.33769645 1 118404373-ARGX-T2418WO (221799)

[0438] Participant demographics of the total population is shown in Table S8. Demographics by IIM subtype are shown in Table S9.Table S8. Demographic Data (Safety Analysis Set)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) Age, yearsn 47 42 89Mean (SD) 58.2 (13.86) 54.7 (12.66) 56.6 (13.34) Median (min, max) 60.0 (26, 81) 53.5 (29, 82) 57.0 (26, 82) Age category, years18 to <65 30 (63.8) 33 (78.6) 63 (70.8) 65 to <75 13 (27.7) 6 (14.3) 19 (21.3) >75 4 (8.5) 3 (7.1) 7 (7.9)Sex at birth, n (%)Female 35 (74.5) 33 (78.6) 68 (76.4) Male 12 (25.5) 9 (21.4) 21 (23.6) Weight, kgn 47 42 89Mean (SD) 75.15 (20.339) 75.39 (17.333) 75.27 (18.874) Median (min, max) 72.20 (35.0, 71.50 (42.3, 72.10 (35.0,140.0) 124.0) 140.0) BMI, kg / m2n 46 41 87Mean (SD) 27.28 (6.303) 27.33 (6.119) 27.31 (6.181) Median (min, max) 25.55 (17.9, 26.64 (18.8, 25.71 (17.9,43.8) 47.8) 47.8)BMI category, kg / m2Underweight (<18.5 kg / m2) 1 (2.2) 0 1 (1.1) Normal weight (18.5 to <25 kg / m2) 21 (45.7) 18 (43.9) 39 (44.8) Overweight (25 to <30 kg / m2) 14 (30.4) 12 (29.3) 26 (29.9) Obese (>=30 kg / m2) 10 (21.7) 11 (26.8) 21 (24.1)BUSINESS.33769645 1 119404373-ARGX-T2418WO (221799)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) Race, n (%)American Indian or Alaska Native 0 1 (2.5) 1 (1.2) Asian 9 (20.0) 5 (12.5) 14 (16.5) Black or African American 3 (6.7) 3 (7.5) 6 (7.1) White 32 (71.1) 29 (72.5) 61 (71.8) Other 1 (2.2) 1 (2.5) 2 (2.4) Not Reported 0 1 (2.5) 1 (1.2) Ethnicity, n (%)Hispanic or Latino 5 (11.1) 6 (15.0) 11 (12.9) Not Hispanic or Latino 39 (86.7) 34 (85.0) 73 (85.9) Not Reported 1 (2.2) 0 1 (1.2) Geographical region, n (%)Asia 11 (23.4) 5 (11.9) 16 (18.0) Europe (EU / EEA / EFTA / UK) 20 (42.6) 23 (54.8) 43 (48.3) North America (US and Canada) 16 (34.0) 11 (26.2) 27 (30.3) Rest of World 0 3 (7.1) 3 (3.4)BMI=body mass index; efgartigimod PH20 SC=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; max=maximum; min=minimum; N=number of participants in the analysis set; n=number of participants in a category; SC=subcutaneous(ly)Note: The denominator for the percentage calculation was the total number of participants per arm in the safety analysis set.BUSINESS.33769645 1 120404373-ARGX-T2418WO (221799)Table S9. Demographic Data by TTM Subtype (ITT Analysis Set)IMNM DM PM EFG PBO EFG PBO EFG PBO(N=27) (N=27) (N=14) (N=12) (N=6) (N=3) Age, yearsn 27 27 14 12 6 3 Mean (SD) 58.8 55.8 59.2 53.8 53.0 49.0 (14.50) (14.00) (12.32) (11.00) (15.53) (1.00) Median (min, max) 60.0 54.0 62.0 56.5 47.5 49.0 (26, 79) (29, 82) (34, 75) (33, 73) (36, 81) (48, 50) Age category, years18 to <65 16 (59.3) 19 (70.4) 9 (64.3) 11 (91.7) 5 (83.3) 3 (100) 65 to <75 9 (33.3) 5 (18.5) 4 (28.6) 1 (8.3) 0 0 >75 2 (7.4) 3 (11.1) 1 (7.1) 0 1 (16.7) 0 Sex at birth, n (%)Female 20 (74.1) 20 (74.1) 9 (64.3) 11 (91.7) 6 (100) 2 (66.7) Male 7 (25.9) 7 (25.9) 5 (35.7) 1 (8.3) 0 1 (33.3) Weight, kgn 27 27 14 12 6 3 Mean (SD) 77.13 73.32 73.55 78.72 69.98 80.70(23.834) (16.717) (14.339) (19.442) (16.027) (16.747) Median (min, max) 72.60 70.90 72.73 73.50 65.15 72.10(35.0, (42.3, (50.0, (54.0, (55.2, (70.0, 140.0) 117.4) 102.8) 124.0) 99.2) 100.0) BMI, kg / m211 27 27 14 11 5 3 Mean (SD) 27.77 26.59 26.41 28.60 27.08 29.38(6.820) (5.647) (4.662) (7.862) (8.346) (1.588) Median (min, max) 25.66 25.71 25.65 25.01 24.61 28.65(17.9, (18.8, (20.4, (21.6, (19.3, (28.3, 43.8) 37.1) 39.4) 47.8) 40.2) 31.2)BUSINESS.33769645 1 121404373-ARGX-T2418WO (221799)IMNM DM PM EFG PBO EFG PBO EFG PBO(N=27) (N=27) (N=14) (N=12) (N=6) (N=3) BMI category, kg / m2Underweight (<18.5 kg / m2) 1 (3.7) 0 0 0 0 0 Normal weight 11 (40.7) 13 (48.1) 7 (50.0) 5 (45.5) 3 (60.0) 0 (18.5 to <25 kg / m2)Overweight 7 (25.9) 7 (25.9) 6 (42.9) 3 (27.3) 1 (20.0) 2 (66.7) (25 to <30 kg / m2)Obese (>=30 kg / m2) 8 (29.6) 7 (25.9) 1 (7.1) 3 (27.3) 1 (20.0) 1 (33.3) Race, n (%)American Indian or Alaska 0 1 (4.0) 0 0 0 0 NativeAsian 5 (20.0) 5 (20.0) 3 (21.4) 0 1 (16.7) 0 Black or African American 3 (12.0) 3 (12.0) 0 0 0 0 White 17 (68.0) 16 (64.0) 10 (71.4) 11 (91.7) 5 (83.3) 2 (66.7) Other 0 0 1 (7.1) 0 0 1 (33.3) Not Reported 0 0 0 1 (8.3) 0 0 Ethnicity, n (%)Hispanic or Latino 3 (12.0) 2 (8.0) 1 (7.1) 2 (16.7) 1 (16.7) 2 (66.7) Not Hispanic or Latino 22 (88.0) 23 (92.0) 12 (85.7) 10 (83.3) 5 (83.3) 1 (33.3) Not Reported 0 0 1 (7.1) 0 0 0 Geographical region, n (%)Asia 4 (14.8) 3 (11.1) 6 (42.9) 2 (16.7) 1 (16.7) 0 Europe (EU / EEA / EFTA / UK) 11 (40.7) 14 (51.9) 4 (28.6) 8 (66.7) 5 (83.3) 1 (33.3) North America (US and 12 (44.4) 9 (33.3) 4 (28.6) 1 (8.3) 0 1 (33.3) Canada)Rest of World 0 1 (3.7) 0 1 (8.3) 0 1 (33.3)BMI=body mass index; DM=dermatomyositis; EFG=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; IIM=idiopathic inflammatory myopathies; IMNM=immune-mediated necrotizing myopathy; max=maximum; min=minimum; N=number of participants in the analysis set; n=number of participants in a category; PBO=placebo; PM=polymyositis; SC=subcutaneous(ly)Note: The denominator for the percentage calculation was tire total number of participants per arm in the safety analysis set.

[0439] Baseline disease characteristics in the total population is shown in Table S10. Baseline disease characteristics by IIM subtype are shown in Table SI 1.BUSINESS.33769645 1 122404373-ARGX-T2418WO (221799)Table S10. Baseline Disease Characteristics (ITT Analysis Set)Efgartigimod PH20 SC Placebo Total (N=47) (N=42) (N=89) Time since diagnosis (years)n 47 42 89Mean (SD) 5.34 (4.254) 5.53 (4.618) 5.43 (4.405) Median (min, max) 4.35 (0.4, 17.0) 4.26 (0.4, 18.4) 4.35 (0.4, 18.4) IIM subtype (confirmed source), n (%)IMNM 27 (57.4) 27 (64.3) 54 (60.7) DM 14 (29.8) 12 (28.6) 26 (29.2) PM 6 (12.8) 3 (7.1) 9 (10.1) MDGA category (CRF source), n (%)Nonsevere [MDGA <5] 17 (36.2) 15 (35.7) 32 (36.0) Severe [MDGA >5] 30 (63.8) 27 (64.3) 57 (64.0) Antisynthetase syndrome, n (%)n 47 42 89Yes 8 (17.0) 5 (11.9) 13 (14.6) No 39 (83.0) 37 (88.1) 76 (85.4) Positive MSA determination, n (%)n 47 42 89Yes 40 (85.1) 36 (85.7) 76 (85.4) No 7 (14.9) 6 (14.3) 13 (14.6) Positive MSA or MAA determination, n (%)n 47 42 89Yes 42 (89.4) 36 (85.7) 78 (87.6) No 5 (10.6) 6 (14.3) 11 (12.4)CRF=case report form; DM=dermatomyositis; efgartigimod PH20 SC=efgartigimod for SC administration coformulatcd with recombinant human hyaluronidase PH20; IIM=idiopathic inflammatory' myopathy;IMNM=immune-mediated necrotizing myopathy; MAA=myositis-associated antibodies; max=maximum; MDGA=Physician Global Assessment of Disease Activity; min=minimum; MSA=myositis-specific antibodies; N=number of participants in the analysis set; n=number of participants in a category'; PBO=placebo;PM=polymyositis; SC=subcutaneous(ly)Note: The denominator for the percentage calculation was the total number of participants per arm in the safety analysis set.BUSINESS.33769645 1 123404373-ARGX-T2418WO (221799)Table SI 1. Baseline Disease Characteristics by ITM Subtype (ITT Analysis Set)IMNM DM PM EFG PBO EFG PBO EFG PBO(N=27) (N=27) (N=14) (N=12) (N=6) (N=3) Time since diagnosis (years)n 27 27 14 12 6 3 Mean (SD) 4.08 5.09 6.34 6.06 8.63 7.42(3.366) (4.035) (4.636) (5.362) (5.230) (7.599) Median (min, max) 2.44 4.10 6.48 4.68 8.42 3.58(0.7, 11.8) (0.4, 15.3) (0.4, 15.5) (1.0, 18.4) (1.9, 17.0) (2.5, 16.2) MDGA category (CRF source), n (%)Nonsevere [MDGA 9 (33.3) 9 (33.3) 5 (35.7) 4 (33.3) 3 (50.0) 2 (66.7) <5]Severe [MDGA >5] 18 (66.7) 18 (66.7) 9 (64.3) 8 (66.7) 3 (50.0) 1 (33.3) Antisynthetase syndrome, n (%)n 27 27 14 12 6 3 Yes 1 (3.7) 1 (3.7) 3 (21.4) 2 (16.7) 4 (66.7) 2 (66.7) No 26 (96.3) 26 (96.3) 11 (78.6) 10 (83.3) 2 (33.3) 1 (33.3) Positive MSA determination, n (%)n 27 27 14 12 6 3 Yes 26 (96.3) 27 (100) 10 (71.4) 7 (58.3) 4 (66.7) 2 (66.7) No 1 (3.7) 0 4 (28.6) 5 (41.7) 2 (33.3) 1 (33.3) Positive MSA or MAA determination, n (%)n 27 27 14 12 6 3 Yes 26 (96.3) 27 (100) 11 (78.6) 7 (58.3) 5 (83.3) 2 (66.7) No 1 (3.7) 0 3 (21.4) 5 (41.7) 1 (16.7) 1 (33.3)CRF=case report form; DM=dermatomyositis; EFG=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; IIM=idiopathic inflammatory myopathy; IMNM=immune-mediated necrotizing myopathy; max=maximum; MDGA=Physician Global Assessment of Disease Activity; min=minimum; MSA=myositis-specific antibodies; N=number of participants in the analysis set; n=number of participants in a category; PBO=placebo; PM=polymyositis; SC=subcutaneous(ly)Note: The denominator for the percentage calculation was the total number of participants per arm in the safety analysis set.

[0440] Concurrent IIM therapy at baseline is shown in Table S12. Participant exposure to IMP is shown in Table S 13.Table S12. Concurrent IIM Therapy at Baseline (Safety Analysis Set)BUSINESS.33769645 1 124404373-ARGX-T2418WO (221799)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) Non-corticosteroid IIM medication at 36 (76.6) 32 (76.2) 68 (76.4) baselineImmunosuppressants 31 (66.0) 31 (73.8) 62 (69.7) Antimalarials 5 (10.6) 1 (2.4) 6 (6.7) Systemic corticosteroid administration at 38 (80.9) 35 (83.3) 73 (82.0) baselineTotal prednisone equivalent daily dose (mg) ongoing at baselineMean (SD) 11.57 (6.62) 11.10 (5.94) 11.34 (6.26) Median 10.00 10.00 10.00 Q1, Q3 5.00, 20.00 5.00, 15.00 5.00. 20.00 Min, max 2.5, 20.0 2.5, 20.0 2.5, 20.0 Both non-corticostcroid and corticosteroid 27 (57.4) 25 (59.5) 52 (58.4) IIM medications administered at baselineEfgartigimod PH20 SC=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; N=numberof participants in the analysis set; n=number of participants in a category; SC=subcutaneous(ly)Table S13. IMP Administration (Safety Analysis Set)EfgartigimodPH20 SC Placebo Total (N=47) (N=42) (N=89) Number of administrations, n (%)1 to 10 1 (2.1) 5 (11.9) 6 (6.7)11 to 15 3 (6.4) 2 (4.8) 5 (5.6)16 to 20 2 (4.3) 5 (11.9) 7 (7.9)21 to 23 12 (25.5) 8 (19.0) 20 (22.5) 24 29 (61.7) 22 (52.4) 51 (57.3)Source: Table 14.1.19Efgartigimod PH20 SC=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; IMP=investigational medicinal product; N=number of participants in the analysis set; n=number of participants in a category'; SC=subcutaneous(ly)

[0441] Efficacy

[0442] As shown in detail below, all primary and key secondary endpoints described in Example 1 reached statistical significance except for TIS >20 at week 24 due to a high placeboBUSINESS.33769645 1 125404373-ARGX-T2418WO (221799)response. Consistency across all six core set measures shows a clear improvement due to efgartigimod treatment.

[0443] In the IMNM subtype (n=54), a statistically significant treatment effect in mean TIS score was shown. A statistically significant treatment effect was not found in the DM (n=26) and PM (n=9) patients due to limited data, but trends suggest a response to efgartigimod treatment in both subtypes.

[0444] For the primary endpoint, FIG. 1A shows the mean TIS score over time in the total participant population. FIGs. IB, 1C, and ID show the mean TIS score over time in the IMNM, DM, and PM subtypes, respectively. Tables S14-S17 provide various analyses of the TIS score at week 24.BUSINESS.33769645 1 126404373-ARGX-T2418WO (221799)Table S14. TIS at Week 24 (Composite Strategy) - Stratified ANCOVA (ITT Analysis Set)Efgartigimod PH20 SC versus Placebo Efgartigimod PH20 LS-means differenceSC Placebo (95% CI) P-value Descriptive statisticsn 47 42Mean (SD) 41.60 (25.889) 30.30 (23.427)Median (min, max) 47.50 (0.0, 77.5) 30.00 (0.0, 80.0)LS-means (SE) 45.21 (4.201) 32.60 (4.491) 12.60 (2.11 to 23.09) 0.0191ANCOVA=analysis of covariance; efgartigimod PH20 SC=efgartigimod for SC administration coformulated with recombinant human hyaluronidase PH20; ICE=intercurrent event; lIM=idiopathic inflammatory myopathy;ITT=intent-to-treat; LS=least square; max=maximum; MDAAT=Myositis Disease Activity Assessment Tool; MDGA=Physician Global Assessment of Disease Activity; min=minimum; MMT8=Manual Muscle Testing-8; SC=subcutaneous(ly); TIS=Total Improvement ScoreNotes: The week 24 value (composite strategy) was derived using the last value before or at week 24. If an ICE occurred before week 24, the week 24 value was imputed with 0. TIS at week 24 (composite strategy) was evaluated as the response variable using an ANCOVA. The arms and stratification factors (IIM subtype and baseline MDGA score) were factors, and the baseline MMT8 and the extramuscular global assessment of tire MDAAT scores were the covariates used to calculate an unadjusted 2-sided p-value.Table S15. TIS at Week 24 (Treatment Policy) - Stratified ANCOVA (ITT Analysis Set) Efgartigimod PH20 SC versus Placebo Efgartigimod PH20 LS-means differenceSC Placebo (95% CI) P-value Descriptive statisticsn 47 42Mean (SD) 49.57 (19.042) 35.18 (20.773)Medi...

Claims

404373-ARGX-T2418WO (221799)Claims1. A method of treating myositis in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist, 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 and achieving a clinically established response.

2. The method of claim 1, wherein the first Fc domain and / or the second Fc domain comprise 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 method of claim 1 or 2, wherein the first Fc domain and the second Fc domain comprise 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 method 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 method 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 method 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 method 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.BUSINESS.33769645 1 136404373-ARGX-T2418WO (221799)8. The method 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 both 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 both the first and the second Fc domains of the FcRn antagonist molecules in theBUSINESS.33769645 1 137404373-ARGX-T2418WO (221799)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 are oxidized.

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

10. The method of any one of claims 1-9, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once weekly.

11. The method of any one of claims 1-10, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once weekly.BUSINESS.33769645 1 138404373-ARGX-T2418WO (221799)12. The method of any one of claims 1-11, wherein the FcRn antagonist is co-formulated with hyaluronidase and administered subcutaneously.

13. The method of claim 12, wherein the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

14. The method of claim 13, wherein the rHuPH20 is administered at about 11,000 U once per week.

15. The method of any one of claims 1-14, wherein the FcRn antagonist is administered for 52 weeks or less.

16. The method of any one of claims 1-15, wherein the FcRn antagonist is administered for 24 weeks or less.

17. The method of any one of claims 1-16, wherein the FcRn antagonist is administered once weekly for 24 weeks.

18. The method of any one of claims 1-17, further comprising administering to the subject an effective amount of one or more of a corticosteroid, an immunosuppressant, or an antimalarial.

19. The method of claim 18, wherein the corticosteroid is prednisone.

20. The method of claim 18 or 19, wherein the corticosteroid is administered at a dose of <20 mg prednisone or dose equivalent per day.

21. The method of any one of claims 18-20, wherein the immunosuppressant is selected from the group consisting of: methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, cyclosporine, leflunomide, and mizoribine.BUSINESS.33769645 1 139404373-ARGX-T2418WO (221799)22. The method of any one of claims 18-21, wherein the antimalarial is selected from the group consisting of: hydroxychloroquine, quinacrine, and chloroquine.

23. The method of any one of claims 1-22, wherein the myositis is selected from the group consisting of immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), polymyositis (PM), and anti synthetase syndrome (ASyS).

24. The method of any one of claims 1-23, wherein the subject is diagnosed with an idiopathic inflammatory myopathy (IIM).

25. The method of claim 24, wherein the IIM is selected from the group consisting of IMNM, DM, PM, and ASyS.

26. The method of any one of claims 1-25, wherein the myositis is IMNM.

27. The method of any one of claims 1-25, wherein the myositis is DM.

28. The method of any one of claims 1-25, wherein the subject has an active DM skin rash.

29. The method of claim 28, wherein the active DM skin rash is selected from the group consisting of Gottron’s papules, Gottron’s signs, and heliotrope rash.

30. The method of any one of claims 1-25, wherein the myositis is PM or ASyS.

31. The method of any one of claims 1-30, wherein the subject has a detectable serum level of a myositis-associated antibody (MAA) or a myositis-specific antibody (MSA) before administration of the FcRn antagonist.

32. The method of any one of claims 1-31, wherein the subject shows one or more clinically established responses following administration of the FcRn antagonist, wherein the clinically established responses are selected from the group consisting of:BUSINESS.33769645 1 140404373-ARGX-T2418WO (221799)a) an increase in TIS compared to a baseline value;b) a TIS >20;c) a TIS >40;d) a TIS >60;e) an increase in MMT8 compared to a baseline value;f) a decrease in PGA compared to a baseline value; andg) a decrease in MDGA compared to a baseline value.

33. The method of claim 32, wherein the clinically established responses are measured following administration of the FcRn antagonist once weekly for 24 weeks.

34. The method of claim 32, wherein the clinically established responses are measured at 4 weeks, at 8 weeks, at 12 weeks, at 16 weeks, and / or at 24 weeks following initial administration of the FcRn antagonist.

35. The method of any one of claims 1-34, wherein the subject has a TIS of >40 at 24 weeks following initial administration of the FcRn antagonist.

36. The method of any one of claims 1-35, wherein the response in TIS >40 is 30% higher in efgartigimod-treated IMNM subjects compared to placebo-treated IMNM subjects.

37. The method of any one of claims 1-35, wherein the response in TIS >40 is 47% higher in efgartigimod-treated IMNM subjects compared to placebo-treated IMNM subjects.

38. An FcRn antagonist for use in the treatment of myositis, wherein the treatment is performed according to the method of any one of the previous claims.

39. An FcRn antagonist for use in the manufacture of a medicament for the treatment of myositis, wherein the treatment is performed according to the method of any one of the previous claims.BUSINESS.33769645 1 141

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