Methods for treating chronic inflammatory demyelinating polyneuropathy

Abstract

The present invention relates to methods of treating chronic inflammatory demyelinating polyneuropathy (CIDP) using an antagonist of the human neonatal Fc receptor (FcRn), which, in certain embodiments, is idegamod.

Description

[0001] Cross-citation of related applications

[0002] This application claims the benefit and priority of UK Patent Application No. 2310890.5, filed July 16, 2023; U.S. Provisional Patent Application No. 63 / 617,702, filed January 4, 2024; and U.S. Provisional Patent Application No. 63 / 662,098, filed June 20, 2024, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] This invention relates to a method for treating chronic inflammatory demyelinating polyneuropathy (CIDP) using an antagonist of the human neonatal Fc receptor (FcRn), wherein the antagonist is, in some embodiments, egamod. Background Technology

[0004] CIDP is the most common chronic immune-mediated inflammatory polyneuropathy, with an estimated incidence of approximately 0.8–8.9 cases per 100,000 individuals (Lehmann et al., 2019). The incidence of CIDP increases with age, with a mean age of onset of 48 years. CIDP primarily affects men, with a male:female ratio of approximately 2:1 (Vallat et al., 2010).

[0005] CIDP is a symmetrical sensorimotor disorder characterized by cytoalbuminologic dissociation and infiltration of the interstitial and perivascular endothelial nerves by lymphocytes and macrophages. Clinically, CIDP most often presents with insidious onset, accompanied by a chronic progressive or relapsing course.

[0006] CIDP is a highly heterogeneous condition. Multiple variants of CIDP have been described, sharing common immune or inflammatory aspects and demyelinating electrophysiological and / or pathological features. There is no consensus on the optimal nomenclature for these conditions. CIDP variants include conditions with predominantly sensory symptoms, distal symmetrical conditions or distal acquired demyelinating symmetrical neuropathy (DADS), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and CIDP with associated central nervous system (CNS) demyelination or other systemic symptoms (Lehmann et al., 2019). Diagnosis is highly challenging due to the heterogeneity of indications for this disease, and misdiagnosis is common (Van den Bergh et al., 2021).

[0007] The underlying pathogenesis of CIDP is not fully understood. A long-standing theory is that cellular and humoral mechanisms work together to damage peripheral nerves. Neurological biopsies of CIDP patients have shown infiltration of inflammatory cells, including CD8+ cells. + T cells, CD4 + T cells and macrophages were also detected. Antibodies against myelin and nodal antigens were also detected; however, only limited direct evidence of pathogenic antibodies was found in the broad CIDP population. Heterogeneity in CIDP is thought to reflect the different immune mechanisms at play in patients with this condition (Mathey et al., 2015).

[0008] For patients with CIDP, the most common treatment is the current immunosuppressive or immunomodulatory intervention. Intravenous immunoglobulin (IVIg) is usually the first-line treatment for most patients. IVIg is a relatively nonspecific form of therapy, and its therapeutic effects are likely mediated through multiple mechanisms of action. In the treatment of CIDP, the therapeutic effects of IVIg are thought to be mediated through a combination of: (i) anti-idiotype antibody activity; (ii) FcRn saturation; (iii) anti-complement activity; (iv) upregulation of the inhibitory FcγRIIb receptor that inhibits macrophage activation; and (v) downregulation of co-stimulatory and adhesion molecules (Dalakas et al., 2022). The relative importance of these mechanisms is largely unknown. IVIg is usually administered to subjects at high maintenance doses every 2–6 weeks (Bunschoten et al., 2019). This dosing regimen suggests a more indirect mechanism of action of IVIg in the treatment of CIDP.

[0009] Other commonly used treatments include subcutaneous immunoglobulin (SCIg), corticosteroids, plasma exchange, plasma exchange, prednisone, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, and cyclophosphamide.

[0010] Despite available treatments, a large number of patients experience relapses or progressive disability-like disease progression. In the case of IVIg / SCIg, infusion requires hospitalization and long-term treatment, which is often expensive. Corticosteroids are generally more cost-effective, but are associated with adverse side effects (Kuwabara et al., 2006). Therefore, there is an unmet medical need for new and effective treatments for CIDP. Summary of the Invention

[0011] The clinical trial results presented in this article establish for the first time the efficacy of FcRn antagonists in the treatment of CIDP. As explained above, there is currently no consensus on the underlying pathology of CIDP. In fact, CIDP has long been considered a highly heterogeneous condition. Due to the multiple modes of action of relatively nonspecific immunosuppressive therapies (especially IVIg), treatment with such therapies is considered beneficial for CIDP by many experts in the field (Dalakas et al., 2022). The data reported in this article show that the FcRn antagonist egamod effectively improves symptoms in patients with CIDP and also prevents relapse after symptom improvement. These effects were observed in a broad population of CIDP patients with varying baseline characteristics. These results establish for the first time that blocking FcRn activity via the use of FcRn antagonists is an effective treatment for CIDP.

[0012] In a first aspect, the present invention provides a method for treating CIDP in a subject with this need, the method comprising administering an effective amount of an FcRn antagonist to the subject. This first aspect also covers the use of an FcRn antagonist in treating CIDP according to any of the methods described herein. This first aspect further covers the use of an FcRn antagonist in the manufacture of a medicament for treating CIDP, wherein the treatment is performed according to any of the methods described herein.

[0013] In some embodiments, the FcRn antagonist comprises two, three, or four FcRn binding regions.

[0014] In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn-binding fragment thereof. In some embodiments, the variant Fc region or the FcRn-binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 compared to the corresponding wild-type Fc region. Alternatively or additionally, the variant Fc region or the FcRn-binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

[0015] In some embodiments, the variant Fc region comprises or is composed of a first Fc domain and a second Fc domain forming a homodimer or heterodimer. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0016] In some embodiments, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, the first Fc domain and the second Fc domain comprise 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.

[0017] In some embodiments, the FcRn antagonist is iatrovid.

[0018] In some embodiments, the FcRn antagonist is an anti-FcRn antibody.

[0019] In some embodiments, the FcRn antagonist is administered to the subject at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered to the subject at a dose of 2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered to the subject at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered to the subject at a fixed dose of about 1000 mg.

[0020] In some embodiments, the FcRn antagonist is administered subcutaneously.

[0021] In some embodiments, the FcRn antagonist is administered to the subject once weekly. In some embodiments, the FcRn antagonist is administered to the subject once every two weeks. In some embodiments, the FcRn antagonist is administered to the subject once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0022] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1000 mg.

[0023] In some embodiments, the FcRn antagonist is administered during the induction phase followed by a maintenance phase, wherein the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg during the induction phase, and wherein the FcRn antagonist is administered subcutaneously every two weeks at a fixed dose of about 1000 mg during the maintenance phase.

[0024] In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of about 1000 mg once weekly, and subsequently subcutaneously at a fixed dose of about 1000 mg every two weeks based on clinical assessment. In some embodiments, subcutaneous administration at a fixed dose of about 1000 mg once weekly is resumed upon symptom exacerbation.

[0025] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once a week or every two weeks. 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 5 mg / kg, 10 mg / kg, or 25 mg / kg.

[0026] In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously.

[0027] In some embodiments, the FcRn antagonist is administered for 61 weeks or less, 52 weeks or less, or 48 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 12 weeks.

[0028] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly for at least 4 weeks. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject demonstrates signs of clinical improvement (ECI). In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject demonstrates ECI between two consecutive measurements. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject demonstrates ECI twice within two weeks. In some embodiments, ECI is a clinical improvement in one or more of the Rasch-constructed Inflammation Total Disability Scale (I-RODS), mean grip strength, or Inflammatory Neuropathy Etiology and Treatment (INCAT) score. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject demonstrates signs of clinically meaningful deterioration (ECMD). In some embodiments, ECMD is one or more of the following: an increase of ≥1 point in the adjusted INCAT (aINCAT) score, a decrease of ≥4 points in the I-RODS score (using percentile measures), or a decrease of ≥8 kPa in mean grip strength of one hand using a handheld grip dynamometer. In some embodiments, ECMD is an increase of ≥1 point in the aINCAT score, optionally an increase of ≥1 point in the aINCAT score between two consecutive measurements, or optionally an increase of ≥1 point in the aINCAT score twice within two weeks. In some embodiments, ECMD is an increase of ≥2 points in the aINCAT score.

[0029] In some embodiments, the subject has been diagnosed with CIDP according to the EFNS / PNS 2010 diagnostic criteria. In some embodiments, the subject has typical CIDP. In some embodiments, the subject has a CIDP variant, optionally selected from distal CIDP, multifocal CIDP, focal CIDP, motor CIDP, and sensory CIDP variants.

[0030] In some embodiments, the subject has progressive CIDP or recurrent CIDP.

[0031] In some embodiments, the subject had an aINCAT score of 2 or higher, optionally 3 or higher, optionally 4 or higher, optionally 5 or higher before administration of the FcRn antagonist.

[0032] In some embodiments, the subject had an I-RODS percentile score of 10 or higher, optionally 20 or higher, optionally 30 or higher, optionally 40 or higher, optionally 50 or higher before administration of the FcRn antagonist.

[0033] In some embodiments, the subject is newly diagnosed with CIDP. In some embodiments, the subject is untreated. In some embodiments, the subject has previously received treatment for CIDP, optionally with steroids, optionally with IVIg, or SCIg. In some embodiments, the subject has previously received treatment for CIDP, optionally with steroids, optionally with IVIg, or SCIg, but has not received treatment for CIDP within 6 months prior to starting FcRn antagonist treatment. In some embodiments, the subject has active disease despite treatment with corticosteroids or immunoglobulins.

[0034] In some embodiments, the subject is a CIDP patient characterized by the presence of autoantibodies, such as anti-NF155 antibody, anti-CNTN1 antibody, anti-Caspr1 antibody, anti-NF140 / 186 antibody, anti-GM-1 antibody and / or anti-LM-1 antibody.

[0035] In some embodiments, disease activity control, partial remission, or complete remission is achieved after administration of an FcRn antagonist. In some embodiments, disease activity control, partial remission, or complete remission is achieved within 12 weeks or less, optionally within 8 weeks or less, optionally within 6 weeks or less, optionally within 4 weeks or less, optionally within 3 weeks or less after initial administration of the FcRn antagonist. In some embodiments, the disease activity control, partial remission, or complete remission in the subject is maintained for at least 2 months or at least 6 months.

[0036] In some embodiments, continued administration of the FcRn antagonist prevents symptom exacerbation once disease activity is controlled, partially remitted, or completely remitted. The absence of symptom exacerbation can be measured using any of the following: INCAT score; Medical Research Council (MRC) total score; I-RODS; average grip strength test; or timed stand-up walk (TUG) test.

[0037] In some embodiments, the treatment prevents or delays recurrence. In some embodiments, the treatment to prevent or delay recurrence lasts for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks.

[0038] In some embodiments, the treatment prevents or delays relapse during the duration of treatment with an FcRn antagonist.

[0039] In some embodiments, the treatment prevents or delays relapse after discontinuation of FcRn antagonist treatment. In some embodiments, the treatment prevents or delays relapse for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks after discontinuation of treatment. In some embodiments, the treatment reduces the risk of relapse by at least 60%.

[0040] In some embodiments, subjects show symptom improvement after administration of the FcRn antagonist, as measured by an INCAT score, preferably by an aINCAT score. In some embodiments, subjects show a reduction of 1 or more points in their aINCAT score, optionally 2 or more points.

[0041] In some embodiments, subjects showed symptom improvement after administration of an FcRn antagonist, as measured using the MRC total score.

[0042] In some embodiments, subjects showed symptom improvement after administration of an FcRn antagonist, as measured using I-RODS. In some embodiments, subjects showed an increase of 4 or more points in their I-RODS percentile score.

[0043] In some embodiments, subjects showed symptom improvement after administration of an FcRn antagonist, as measured using a mean grip strength test. In some embodiments, subjects showed an increase in mean grip strength ≥8 kPa.

[0044] In some embodiments, subjects showed symptom improvement after administration of an FcRn antagonist, as measured using a TUG test.

[0045] In some embodiments, symptom improvement is achieved within 12 weeks or less, optionally within 8 weeks or less, optionally within 6 weeks or less, optionally within 4 weeks or less, optionally within 3 weeks or less after the first administration of the FcRn antagonist.

[0046] In some embodiments, subjects show decreased serum levels of total IgG, autoantibodies, cytokines / chemokines, or immune complexes after administration of an FcRn antagonist. In some embodiments, serum levels of total IgG, autoantibodies, cytokines / chemokines, or immune complexes are measured at 4, 12, 24, or 48 weeks after administration of an FcRn antagonist. In some embodiments, subjects show decreased serum levels of one or more autoantibodies selected from the group consisting of anti-GM1, anti-LM-1, anti-NF-155, anti-CNTN1, anti-Caspr-1 antibody, and anti-myelinated nerve antibody after administration of an FcRn antagonist.

[0047] In some embodiments, subjects did not show a decrease in serum albumin levels after administration of the FcRn antagonist. In some embodiments, subjects did not show an increase in serum cholesterol after administration of the FcRn antagonist.

[0048] In some embodiments, subjects exhibited ECI upon first administration of an FcRn antagonist. In some embodiments, subjects exhibited ECI between 31 and 51 days after first administration of an FcRn antagonist. In some embodiments, subjects exhibited ECI within 43 days after first administration of an FcRn antagonist.

[0049] In some embodiments, the method further includes administering an effective amount of one or more additional therapeutic agents, optionally corticosteroids, to the subject.

[0050] In some embodiments, the method is used to assist in the diagnosis of CIDP.

[0051] On the other hand, this article provides a method for treating CIDP in subjects within a patient population, comprising administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, wherein 66.5% of subjects in the patient population exhibited ECI following administration of egamod PH20 or a biosimilar thereof.

[0052] In some embodiments, the patient population achieves ECI within 31 to 51 days of first treatment with egamod PH20 or its biosimilar. In some embodiments, the patient population achieves ECI within 43 days of first treatment with egamod PH20 or its biosimilar.

[0053] In some embodiments, the patient population includes 322 subjects.

[0054] In some embodiments, anti-egamod α antibodies were detected in 6% of a patient population after administration of egamod PH20 for up to 12 weeks. In some embodiments, neutralizing anti-egamod α antibodies were detected in 0.3% of a patient population after administration of egamod PH20 for up to 12 weeks.

[0055] In some embodiments, subjects in the patient population remained relapse-free for significantly longer than subjects who did not receive eigamod PH20 or its biosimilar forms.

[0056] In some embodiments, subjects in the patient population experienced a longer time to clinical deterioration compared to subjects not receiving egamod PH20 or its biosimilar forms, where clinical deterioration is defined as an increase in aINCAT score of ≥1 point. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point between two consecutive measurements. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant.

[0057] In some embodiments, subjects in a patient population treated with egamod PH20 or its bioanalytes showed a 61% reduction in the risk of exacerbation in patients with CIDP.

[0058] On the other hand, this article provides a method for treating CIDP in subjects, comprising: administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, wherein the subject exhibits ECI following administration of egamod PH20 or a biosimilar thereof. In some embodiments, the subject achieves ECI within 31 to 51 days of first administration of egamod PH20 or a biosimilar thereof. In some embodiments, the subject achieves ECI within 43 days of first administration of egamod PH20 or a biosimilar thereof. In some embodiments, the subject remains relapse-free for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks following administration of egamod PH20 or a biosimilar thereof. In some embodiments, the subject exhibits a reduced risk of exhibiting ECMD. In some embodiments, ECMD is an increase of ≥1 point in the aINCAT score, optionally an increase of ≥1 point in the aINCAT score between two consecutive measurements, optionally an increase of ≥1 point in the aINCAT score twice within two weeks. In some embodiments, ECMD is an increase of ≥2 points in the aINCAT score.

[0059] On the other hand, this article provides a method of CIDP for treating subjects in a patient population, comprising administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, wherein, following administration of egamod PH20 or a biosimilar thereof, the mean percentage reduction in total IgG levels relative to baseline in the patient population ranges between 66.8% and 71.6%. In some embodiments, following administration of egamod PH20 or a biosimilar thereof four times weekly, the mean percentage reduction in total IgG levels relative to baseline in the patient population ranges between 66.8% and 71.6%. In some embodiments, the mean percentage reduction in total IgG levels relative to baseline is maintained from week 4 throughout the treatment period. In some embodiments, the patient population comprises 322 subjects.

[0060] On the other hand, this article provides a method for treating CIDP in subjects, comprising: administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, wherein the subject shows a reduction in serum total IgG levels between 66.8% and 71.6% after administration of egamod PH20 or a biosimilar thereof compared to baseline values ​​prior to administration of egamod PH20 or a biosimilar thereof. In some embodiments, the subject shows a reduction in serum total IgG levels between 66.8% and 71.6% after administration of egamod PH20 or a biosimilar thereof four times weekly. In some embodiments, the reduction in serum total IgG levels is maintained until the weekly administration of egamod PH20 or a biosimilar thereof is discontinued.

[0061] On the other hand, this article provides a method for treating subjects in a patient population with CIDP, comprising: administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, wherein subjects in the patient population experience a longer time to clinical deterioration that is statistically significant compared to subjects not receiving egamod PH20 or a biosimilar thereof, wherein clinical deterioration is defined as an increase of ≥1 point in the aINCAT score. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the patient population comprises 221 subjects.

[0062] On the other hand, this article provides a method for treating CIDP in subjects with this need, which involves administering a clinically proven safe and effective amount of egamod PH20 subcutaneously to the subject once a week.

[0063] In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is administered subcutaneously over approximately 30 to 90 seconds. In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is 1008 mg / 11,200 units.

[0064] In some embodiments, subjects showed signs of improvement after administration of iatrovid PH20. In some embodiments, subjects showed signs of improvement between two consecutive measurements. In some embodiments, signs of improvement were selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in average grip strength.

[0065] In some embodiments, subjects experienced a longer time to clinical deterioration after administration of eigamod PH20 compared to subjects who did not receive eigamod PH20. In some embodiments, the longer time to clinical deterioration was statistically significant. In some embodiments, clinical deterioration was defined as an increase of ≥1 point in the aINCAT score, optionally an increase of ≥1 point in the aINCAT score between two consecutive measurements, or optionally an increase of ≥1 point in the aINCAT score twice within two weeks. In some embodiments, clinical deterioration was defined as an increase of ≥2 points in the aINCAT score.

[0066] On the other hand, this article provides a method for treating CIDP in subjects within a patient population, comprising a weekly subcutaneous administration of a clinically proven safe and effective dose of egamod PH20.

[0067] In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is administered subcutaneously over approximately 30 to 90 seconds. In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is 1008 mg / 11,200 units.

[0068] In some embodiments, 69% of the patients in the patient population showed signs of improvement between two consecutive measurements after administration of iatrovid PH20. In some embodiments, signs of improvement were selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in average grip strength.

[0069] In some embodiments, subjects in the patient population experienced a longer time to clinical deterioration compared to subjects who did not receive egamod PH20 or its biosimilar forms, where clinical deterioration was defined as an increase in aINCAT score of ≥1 point. In some embodiments, clinical deterioration was defined as an increase in aINCAT score of ≥1 point between two consecutive measurements. In some embodiments, clinical deterioration was defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration was demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration was statistically significant. In some embodiments, the patient population comprised 221 subjects.

[0070] On the other hand, this article provides egamod PH20 for use in treating subjects with CIDP, wherein a clinically safe and clinically effective amount of egamod PH20 is administered subcutaneously to the subject once weekly or every other week. In some embodiments, a clinically safe and clinically effective amount of egamod PH20 is administered subcutaneously once weekly.

[0071] In some embodiments, a clinically proven safe and effective dose of egamod PH20 is initially administered subcutaneously once weekly, and subsequently subcutaneously every other week based on clinical assessment. In some embodiments, subcutaneous administration is resumed once weekly if symptoms worsen.

[0072] In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is administered subcutaneously over approximately 30 to 90 seconds.

[0073] In some embodiments, the clinically proven safe and effective amount of egamod PH20 comprises 1000 mg of egamod α.

[0074] In some embodiments, the subject still has an active disease despite treatment with corticosteroids or immunoglobulins.

[0075] In some embodiments, the subject received prior CIDP therapy before initiating egamod PH20 treatment, and wherein egamod PH20 was administered before the clinical effect of the prior CIDP therapy diminished. In some embodiments, the prior CIDP therapy was a corticosteroid or immunoglobulin.

[0076] In some embodiments, subjects showed a reduction in serum total IgG levels of 66.8% to 71.6% after administration of eigamod PH20 compared to baseline values ​​prior to administration. In some embodiments, subjects showed a reduction in serum total IgG levels of 66.8% to 71.6% after administration of eigamod PH20 four times weekly. In some embodiments, the reduction in serum total IgG levels was maintained until the weekly administration of eigamod PH20 was discontinued.

[0077] In some embodiments, when administered to a patient population of CIDP subjects, iatrovid PH20 induced an ECI response in 66.5% of the subjects in the patient population.

[0078] In some embodiments, subjects exhibited ECI following administration of igamaide PH20. In some embodiments, subjects exhibited ECI between 31 and 51 days after first administration of igamaide PH20. In some embodiments, subjects exhibited ECI within 43 days after first administration of igamaide PH20.

[0079] In some embodiments, subjects remained relapse-free for a significantly longer period after administration of eigamod PH20 compared to subjects who did not receive eigamod PH20.

[0080] In some embodiments, subjects showed a reduced risk of exhibiting signs of clinical deterioration after administration of eigamod PH20. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score twice within two weeks. In some embodiments, a sign of clinical deterioration is an increase of ≥2 points in the aINCAT score.

[0081] On the other hand, this article provides egamod PH20 for use in subjects within a CIDP treatment population, comprising subcutaneous administration of a clinically safe and clinically effective amount of egamod PH20 once weekly or every other week. In some embodiments, a clinically safe and clinically effective amount of egamod PH20 is administered subcutaneously once weekly. In some embodiments, a clinically safe and clinically effective amount of egamod PH20 is initially administered subcutaneously once weekly and subsequently subcutaneously every other week based on clinical assessment. In some embodiments, subcutaneous administration is resumed once weekly after symptom exacerbation.

[0082] In some embodiments, a clinically safe and clinically effective dose of egamod PH20 is administered subcutaneously over approximately 30 to 90 seconds.

[0083] In some embodiments, the clinically proven safe and effective amount of egamod PH20 comprises 1000 mg of egamod α.

[0084] In some embodiments, subjects in the patient population still have active disease despite treatment with corticosteroids or immunoglobulins.

[0085] In some embodiments, subjects in the patient population received prior CIDP therapy before initiating egamod PH20 treatment, and egamod PH20 was administered before the clinical effect of the prior CIDP therapy diminished. In some embodiments, the prior CIDP therapy was a corticosteroid or immunoglobulin.

[0086] In some embodiments, after administration of egamod PH20, the mean percentage reduction in total IgG levels relative to baseline in the patient population ranged between 66.8% and 71.6%. In some embodiments, after administration of egamod PH20 four times weekly, the mean percentage reduction in total IgG levels relative to baseline in the patient population ranged between 66.8% and 71.6%. In some embodiments, the mean percentage reduction in total IgG levels relative to baseline was maintained from week 4 throughout the treatment period.

[0087] In some embodiments, 66.5% of the patient population exhibited ECI following administration of egamod PH20. In some embodiments, ECI was achieved within 31 to 51 days of initial egamod PH20 administration. In some embodiments, ECI was achieved within 43 days of initial egamod PH20 administration.

[0088] In some embodiments, subjects in the patient population remained relapse-free for significantly longer than subjects who did not receive egamod PH20.

[0089] In some embodiments, subjects in a patient population treated with egamod PH20 showed a 61% reduction in the risk of deterioration.

[0090] In some embodiments, subjects in the patient population showed a reduced risk of exhibiting signs of clinical deterioration after administration of egamod PH20. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements. In some embodiments, a sign of clinical deterioration is an increase of ≥1 point in the aINCAT score twice within two weeks. In some embodiments, a sign of clinical deterioration is an increase of ≥2 points in the aINCAT score.

[0091] In some embodiments, the patient population includes 322 subjects.

[0092] In some embodiments, the subject in any of the methods or uses described herein is an adult.

[0093] On the other hand, this document provides a pharmaceutical product containing egamod and hyaluronidase, approved for the treatment of CIDP, wherein the pharmaceutical product is formulated for subcutaneous administration. In some embodiments, the pharmaceutical product is formulated for subcutaneous administration over approximately 30 to 90 seconds. In some embodiments, the pharmaceutical product is administered in a total volume of 5.6 mL.

[0094] In some embodiments, the pharmaceutical product is provided in a single-dose vial at a concentration of 180 mg egamod / 2000 units of hyaluronidase per mL. In some embodiments, the pharmaceutical product is provided in a single-dose vial with a total volume of 5.6 mL, the vial containing 180 mg / mL egamod, 2000 units / mL recombinant human hyaluronidase (rHuPH20), 1.4 mg / mL histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL methionine, 0.4 mg / mL polysorbate 20, 5.8 mg / mL sodium chloride, 20.5 mg / mL sucrose, and water for injection (USP) at pH 6.0.

[0095] In some embodiments, the pharmaceutical product listed is a reference product based on eigamod administered at a dose of 1000 mg. In some embodiments, the pharmaceutical product listed is a reference product based on eigamod administered at a dose of 1008 mg. In some embodiments, the pharmaceutical product listed is a reference product based on hyaluronidase administered at a dose of 11,200 units.

[0096] In some embodiments, the pharmaceutical products listed are reference products based on once-weekly or every other week administration. In some embodiments, the pharmaceutical products listed are reference products based on once-weekly administration. In some embodiments, the pharmaceutical products listed are reference products based on once-weekly administration, subsequently adjusted to every other week administration based on clinical assessment. In some embodiments, the pharmaceutical products listed are reference products based on resuming once-weekly administration in cases of worsening symptoms.

[0097] In some embodiments, the pharmaceutical product is approved for administration to adult patients. In some embodiments, the pharmaceutical product has an approved indication for treating CIDP in adult patients who have active disease despite treatment with corticosteroids or immunoglobulins.

[0098] In some embodiments, the pharmaceutical product is contraindicated in patients with severe hypersensitivity to the egamod α product, hyaluronidase, or any excipients of the pharmaceutical product.

[0099] In some embodiments, the pharmaceutical product induced improvement at two consecutive visits in 69% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly for up to 12 weeks. In some embodiments, improvement is defined as an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in mean grip strength.

[0100] In some embodiments, the drug product induced an ECI response in 66.5% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly. In some embodiments, the median time to initial confirmed ECI in the CIDP patient population was 43 days from the first administration of the drug product. In some embodiments, up to 40% of CIDP patients in the CIDP patient population had an ECI response four weeks after the first administration of the drug product. In some embodiments, 25% of CIDP patients in the CIDP patient population showed a clinically relevant improvement in at least one of the following within 9 days of the first administration of the drug product: aINCAT score, I-RODS, or average grip strength. In some embodiments, the CIDP patient population comprised 322 CIDP patients. In some embodiments, CIDP patients in the CIDP patient population receiving the drug product maintained a relapse-free period significantly longer than CIDP patients in the CIDP patient population receiving placebo. In some embodiments, CIDP patients in the CIDP patient population receiving the drug product showed a 61% reduction in the risk of exacerbation compared to CIDP patients in the CIDP patient population receiving placebo.

[0101] In some embodiments, CIDP patients in the CIDP patient population experienced a longer time to clinical deterioration compared to CIDP patients in the placebo-receiving CIDP patient population. In some embodiments, clinical deterioration is defined as an increase of ≥1 point in the aINCAT score. In some embodiments, clinical deterioration is defined as an increase of ≥1 point in the aINCAT score between two consecutive measurements. In some embodiments, clinical deterioration is defined as an increase of ≥2 points in the aINCAT score. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant.

[0102] In some embodiments, the pharmaceutical product induces a hypersensitivity reaction selected from the group consisting of allergic reactions and hypotension leading to syncope. In some embodiments, the allergic reaction and hypotension leading to syncope occur during or within 1 hour of administration of the pharmaceutical product.

[0103] In some embodiments, the pharmaceutical product induces an infusion-related reaction. In some embodiments, an infusion-related reaction includes one or more of the following: hypertension, chills, shivering, chest pain, abdominal pain, and back pain. In some embodiments, the infusion-related reaction occurs during or within one hour of administration of the pharmaceutical product. In some embodiments, when a mild to moderate infusion-related reaction occurs during administration of the pharmaceutical product, one or more subsequent doses of the pharmaceutical product are administered with close clinical observation, a slower infusion rate, and pre-medication.

[0104] In some embodiments, following treatment with the pharmaceutical product, the product induced anti-egamaide antibodies in 2% of subjects in a CIDP patient population. In some embodiments, following treatment with the pharmaceutical product, the product induced anti-egamaide antibodies in 6% of subjects in a CIDP patient population. In some embodiments, following treatment with the pharmaceutical product, the product induced neutralizing anti-egamaide antibodies in 0.3% of subjects in a CIDP patient population.

[0105] Biosimilar types of the drug products described above and in this article are also provided.

[0106] Biologics that are bioequivalent to the pharmaceutical products described above and in this article are also provided.

[0107] On the other hand, this document provides a kit comprising: any pharmaceutical product described above and herein, any biosimilar form described above and herein, or any biological product described above and herein, and a label including an indication for the treatment of CIDP in adult patients.

[0108] In some embodiments, the label includes a contraindication for patients with severe hypersensitivity to any excipient of the alpha product, hyaluronidase, or formulations thereof. In some embodiments, the label includes a warning for hypersensitivity reactions selected from anaphylactic reactions and hypotension leading to syncope. In some embodiments, the label states that the infusion should be discontinued if an anaphylactic reaction or hypotension leading to syncope occurs during or within 1 hour of product administration. In some embodiments, the label includes a warning for infusion-related reactions selected from hypertension, chills, shivering, chest pain, abdominal pain, and back pain. In some embodiments, the label states that appropriate therapy should be initiated if a severe infusion-related reaction occurs during product administration. In some embodiments, the label states that if a mild to moderate infusion-related reaction occurs during product administration, the patient may again be closely monitored clinically, given a slower infusion rate, and pre-medicated.

[0109] In some embodiments, the label includes data showing improvement at two consecutive visits in 69% of a CIDP patient population who received 1008 mg / 11,200 units of egamod PH20 once weekly for up to 12 weeks. In some embodiments, improvement is defined as an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in mean grip strength.

[0110] In some embodiments, the label includes data showing an ECI response in 66.5% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly. In some embodiments, the label includes data showing a median time to initial confirmed ECI of 43 days from the first administration of egamod PH20 in the CIDP patient population. In some embodiments, the label states the earliest time point at week 4 when ECI criteria may be met, with up to 40% of patients having ECI. In some embodiments, the label states that at least one of the three parameters (aINCAT, I-RODS, or grip strength) showed clinically relevant improvement in 25% of patients after 9 days. In some embodiments, the label includes data showing that CIDP patients receiving egamod PH20 maintained a significantly longer relapse-free period than CIDP patients receiving placebo. In some embodiments, the label includes data showing a 61% reduction in the risk of exacerbation in CIDP patients receiving egamod PH20 compared to CIDP patients receiving placebo. In some embodiments, the label includes data showing that CIDP patients receiving egamod PH20 experienced a longer time to clinical deterioration (i.e., an increase in aINCAT score of ≥1 point) compared to CIDP patients in a placebo-receiving cohort. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant.

[0111] In some embodiments, the label includes data indicating a 2% incidence of anti-egamod α antibodies in a cohort of 117 CIDP patients after treatment with the drug product. In some embodiments, the label includes data indicating a 6% incidence of anti-egamod α antibodies in a cohort of 317 CIDP patients after treatment with the drug product. In some embodiments, the label includes data indicating a 0.3% incidence of neutralizing anti-egamod α antibodies in a cohort of 317 CIDP patients after treatment with the drug product.

[0112] On the other hand, this article provides a method for treating a subject with CIDP who requires it, the method comprising administering to the subject any pharmaceutical product, any biosimilar form, or any biological product described above and herein. Attached Figure Description

[0113] Figure 1 This is a schematic diagram of a two-part phase 2 study investigating the efficacy, safety, tolerability, immunogenicity, pharmacokinetic (PK), and PD of subcutaneous (SC) administration of egamod PH20 SC (egamod co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) for SC injection) in patients aged 18 years and older with CIDP. d = day; OLE = open-label extension; placebo = placebo with rHuPH20; Q1W = once weekly; SC = subcutaneous; w = week.

[0114] Figure 2 This is the questionnaire used in I-RODS.

[0115] Figures 3A to 3B The results of Phase B of the study are presented, particularly the measurement of the primary endpoint: time to first deterioration of aINCAT score in both the placebo (lower line) and egamod (upper line) treatment groups. These results are presented for the trial’s primary population, the mITT analysis set. Figure 3A Kaplan-Meier plot of the results. Figure 3B : Calculation of the median time to first aINCAT score deterioration and the percentage of clinical deterioration observed at 24 and 48 weeks during the Phase B study.

[0116] Figures 4A to 4B The results of Phase B of the study are presented, particularly the measurement of the primary endpoint: time to first aINCAT score deterioration in both the placebo (lower line) and egamod (upper line) treatment groups. These results are presented for the protocol-compliant analysis set, i.e., all patients who fully adhered to the trial protocol during the study. Figure 4A Kaplan-Meier plot of the results. Figure 4B : Calculation of the median time to first aINCAT score deterioration and the percentage of clinical deterioration observed at 24 and 48 weeks during the Phase B study.

[0117] Figures 5A to 5F The results of Phase B of the study are shown, particularly the measurement of the primary endpoint: time to first aINCAT score deterioration in the placebo (lower line) and egamod (upper line) treatment groups. Patient groups were stratified according to prior treatment: (i) patients treated with corticosteroids ( Figure 5A and Figure 5B(ii) Patients treated with IVIg or SCIg ( Figure 5C and Figure 5D ); or untreated patients ( Figure 5E and Figure 5F ). Figure 5A , Figure 5C and Figure 5E Kaplan-Meier analysis of the results. Figure 5B , Figure 5D and Figure 5F : Calculation of the median time to the first deterioration of the aINCAT score.

[0118] Figures 6A to 6B Results from the Phase B study are presented, particularly measurements of secondary endpoints: time to CIDP progression in the placebo (lower line) and egamod (upper line) treatment groups. These results are presented for the trial’s primary population, i.e., the mITT analysis set. Time to CIDP progression was defined as the time from the first dose of the double-blind IMP (placebo or egamod) to a reduction in the initial I-RODS score, measured as a percentile measure, compared to Phase B baseline. > Four minutes. Figure 6A Cox proportional hazards model. Figure 6B Risk ratio. Detailed Implementation

[0119] This invention relates to methods for treating CIDP. Chronic inflammatory demyelinating polyneuropathy is also referred to in the literature as chronic inflammatory demyelinating polyradiculopathy (also abbreviated as CIDP). These methods involve administering an effective amount of an FcRn antagonist to a subject (e.g., a human subject). This invention also provides a human FcRn antagonist for use in treating CIDP. Further, the use of the FcRn antagonist in the manufacture of a medicament for treating CIDP is provided. All embodiments of the invention described herein are equally applicable to all aspects of the invention.

[0120] A. Definition

[0121] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the technical field of this invention.

[0122] As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene, as shown in RefSeqNM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

[0123] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to an FcRn and inhibits the binding of immunoglobulins to the FcRn (e.g., human FcRn). In one embodiment, an FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to an FcRn via its Fc region and inhibits the binding of immunoglobulins to the FcRn. In one embodiment, an FcRn antagonist is not a full-length IgG antibody. In one embodiment, an FcRn antagonist comprises an antigen-binding site that binds to a target antigen and a variant Fc region. In one embodiment, an FcRn antagonist is an Fc fragment that contains or is composed of an Fc region and lacks an antigen-binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or an antigen-binding fragment thereof that specifically binds to an FcRn via its antigen-binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to the FcRn.

[0124] As used herein, the term "antibody / antibodies" includes full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules containing antibody CDR, VH region, or VL region. Examples of antibodies include monoclonal antibodies, recombinant antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies containing two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intracellular antibodies, heteroconjugated antibodies, antibody-drug conjugates, single-domain antibodies (sdAbs), monovalent antibodies, single-chain antibodies or single-chain Fvs (scFvs), camel antibodies, affinity antibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. Antibodies can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b).

[0125] As used herein, the term "Fc domain" refers to a portion of a single immunoglobulin heavy chain that begins at a hinge region and terminates at the C-terminus of the antibody. Thus, 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 a portion of a single immunoglobulin heavy chain that comprises both the CH2 and CH3 domains of the antibody. In some embodiments, an 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, an Fc domain does not include a hinge region.

[0126] As used herein, the term "hinge region" refers to the portion of a heavy chain molecule that joins the CH1 and CH2 domains. In some embodiments, the hinge region is up to 70 amino acid residues long. In some embodiments, the hinge region contains approximately 11 to 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 long. In some embodiments, the hinge region is 15 amino acid residues long. In some embodiments, the hinge region is 62 amino acid residues long. The hinge region can be subdivided into three distinct domains: upper, middle, and lower hinge domains. The FcRn antagonists of this disclosure may include all or any portion of the hinge region. In some embodiments, the hinge region is derived from an IgG1 antibody. In some embodiments, the hinge region contains the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 31).

[0127] 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 (natural Fc region) or a variant Fc region. Natural Fc regions are homodimers. Fc regions can be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by the constant region of the IgA, IgD, IgE, or IgG heavy chain. In some embodiments, the Fc region is formed by the constant region of the IgG heavy chain. In some embodiments, the constant region of the IgG heavy chain is the constant region of the IgG1, IgG2, IgG3, or IgG4 heavy chain. In some embodiments, the Fc region is formed by the constant region of the IgG1 heavy chain. In some embodiments, the constant region of the IgG1 heavy chain comprises allotypes of G1m1(a), G1m2(x), G1m3(f), or G1m17(z), see, for example, Jefferis and Lefranc, 2009 and de Taeye et al., 2020.

[0128] As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations relative to the native Fc region. Alterations may include amino acid substitutions, additions and / or deletions, the linking of additional moieties, and / or changes to the native glycan. The term encompasses heterodimeric Fc regions where each of the constitutive Fc domains is distinct. The term also encompasses single-chain Fc regions where the constitutive Fc domains are linked together by linker sites.

[0129] As used herein, the term "FcRn binding fragment" refers to a portion of the Fc region sufficient to confer FcRn binding.

[0130] As used herein, the term “EU position” refers to the amino acid position of the Fc region in the EU numbering convention as described in Edelman, GM et al., Proc. Natl. Acad. USA, 1969; 63, 78-85 and Kabat et al., in “Sequences of Proteins of Immunological Interest”, US Dept. Health and Human Services, 5th edition, 1991.

[0131] As used herein, the term “baseline” refers to a measurement in the patient’s body (e.g., in the patient’s blood) prior to the first administration (e.g., intravenous or subcutaneous) of treatment (e.g., an FcRn antagonist).

[0132] As used herein, the terms “treat,” “treating,” and “treatment” refer to the therapeutic or preventative measures described herein. A method of “treatment” involves administering a peptide to a subject who has or is susceptible to a disease or condition, in order to prevent, cure, delay, relapse, reduce the severity of, or improve one or more symptoms of the disease or condition, or to extend the subject’s survival beyond what would be expected in the absence of such treatment.

[0133] As used in this article, the term "effective amount" in the context of administering a therapy to a subject refers to the amount of therapy required to achieve the desired preventive or therapeutic effect.

[0134] As used herein, the term “dosage” or “administration” refers to the amount of a drug administered to a subject in a single administration.

[0135] As used herein, the terms “fixed dose” or “flat dose” both refer to a dose that does not vary based on the characteristics of the subject (e.g., weight, for example, within a set range; sex; age, for example, within a set range; etc.).

[0136] As used in this article, the term “disease activity control” or “CDA” refers to a point where there is no further clinical deterioration and / or where ECI is present.

[0137] As used in this article, the term “relief” refers to complete or partial relief.

[0138] As used in this article, the terms “complete remission” or “CR” refer to the absence of symptoms as measured by standard diagnostic criteria for CIDP.

[0139] As used in this article, the terms "partial remission" or "PR" refer to a patient who has experienced ECI but has not experienced CR.

[0140] As used herein, the term “sign of clinical improvement” or “ECI” refers to symptom improvement as measured by any standard CIDP assessment method, including but not limited to (i) the INCAT Disability Scale; (ii) the MRC Scale (Vanhoutte et al., 2012); (iii) the I-RODS; (iv) the mean grip strength test; and (v) the TUG test. In a preferred embodiment, ECI refers to symptom improvement as measured using the INCAT Disability Scale, particularly a decrease in the INCAT score or aINCAT score. In some embodiments, ECI refers to clinical improvement in a parameter (I-RODS, grip strength) that worsened during the period between screening and stage A, or clinical improvement in INCAT.

[0141] As used herein, the term “relapse” refers to signs of clinical deterioration in a patient with CIDP following a period of remission (partial or complete remission). In other words, “relapse” refers to signs of clinical deterioration in a patient with CIDP following a period of remission (partial or complete remission).

[0142] As used herein, the term “worsening” or “clinically worsening” refers to any worsening of CIDP symptoms. The absence of CIDP symptom worsening can be measured using any of the following: INCAT score; MRC total score; I-RODS; mean grip strength test; or TUG test. As used herein, the terms “signs of clinical worsening,” “clinically significant signs of worsening,” and “ECMD” are used interchangeably. In some embodiments, ECMD is defined as an increase of ≥1 point in an aINCAT score, and / or a decrease of ≥4 points in I-RODS (using percentile measures), and / or a decrease of ≥8 kPa in mean grip strength of one hand using a handheld grip dynamometer. In some embodiments, ECMD is defined as two increases of 1 point in an aINCAT score within 7 days of each other. In some embodiments, ECMD is defined as a single increase of ≥2 points in an aINCAT score. In some embodiments, ECMD is defined as a decrease of 10% in I-RODS.

[0143] As used herein, the terms “subject” or “patient” or “participant” include any human or non-human animal. In one embodiment, the subject or patient or participant is a human or non-human mammal. In another embodiment, the subject or patient or participant is a human.

[0144] As used herein, when referring to measurable values, such as doses, the terms “about” or “approximately” cover a variation of ±5% of a given value or range, provided that it is appropriate to perform the methods disclosed herein.

[0145] As used herein, the term "biosimilar" refers to a biological product that is highly similar to a reference product and has no clinically significant differences from the reference product. As used herein, the term "reference product" refers to a biological product that has been approved for clinical use. In some embodiments, the reference product is approved in at least one of the United States, Europe, China, or Japan. Biosimilars may have minor differences in clinically inactive components. Biosimilars may include minor modifications in the amino acid sequence, such as N-terminal or C-terminal truncation, when compared to a reference product, which are not expected to alter the properties of the biosimilar.

[0146] As used herein, “no clinically significant difference” is determined in terms of safety, purity, and potency. For example, a biosimilar is compared and evaluated with a reference product to verify that the biosimilar has no clinically significant difference from the reference product in terms of safety, purity, and potency. In some embodiments, determining no clinically significant difference between a biosimilar and a reference product is based on data derived from: (a) analytical studies demonstrating a high degree of similarity between the biosimilar and the reference product, despite minor differences in clinically inactive components; (b) animal studies (including, for example, toxicity assessments); and / or (c) one or more clinical studies (including, for example, assessments of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate the safety, purity, and potency of both the reference product, which is licensed under one or more appropriate conditions of use, and the biosimilar seeking license. Biosimilars may be interchangeable products that can replace the reference product in a pharmacy without the need for a prescription from a healthcare professional. To meet the "interchangeability" criterion, the biosimilar is expected to produce the same clinical outcomes as the reference product in any given patient, and if the biosimilar is administered to an individual more than once, the risk of reduced safety or efficacy from alternating or switching between the biosimilar and the reference product is no greater than the risk of using the reference product without such alternation or switching. In some embodiments, the biosimilar utilizes the same mechanism of action as the reference product for the proposed conditions of use, to the extent known to the reference product. In some embodiments, one or more conditions of use specified, recommended, or suggested in the proposed biosimilar label have previously been approved for use with the reference product. In some embodiments, the route of administration, dosage form, and / or strength of the biosimilar are the same as those of the reference product, and the biosimilar is manufactured, processed, packaged, or stored in a compliant facility designed to ensure the continued safety, purity, and efficacy of the biosimilar.

[0147] As used herein, the terms “label,” “product label,” or “approved product label” refer to information provided to patients and / or healthcare providers that provides relevant information about an approved product. This information includes, but is not limited to, one or more of the following: a description of the approved product, clinical pharmacology, indications (for the approved product), contraindications (who should not take the approved product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use during pregnancy, use in breastfeeding women, use in children and elderly patients, how to obtain the approved product, patient safety information, or any combination thereof. In some embodiments, the label identifies Egamod and provides instructions for its use in patients.

[0148] As used herein, the term "clinically proven effective dose" refers to a regulatory decision based on clinical efficacy and other data. Efficacy can be measured based on changes in the course of the disease in response to the agent of this disclosure. For example, an FcRn antagonist of this disclosure (e.g., egamod) is administered to a patient at a dose and duration sufficient to induce (preferably maintain) improvement in at least one indicator reflecting the severity of the condition being treated. Various indicators reflecting the severity of a subject's ailment, disease, or symptom can be assessed to determine whether the dose and duration of treatment are adequate. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the condition. The degree of improvement is typically determined by a physician, who may make this determination based on signs, symptoms, blood samples, or other test results, and may also use questionnaires administered to the subject, such as quality of life questionnaires developed for a given disease. For example, an FcRn antagonist of this disclosure may be administered to achieve improvement in a subject's CIDP-related symptoms. Improvement can be indicated by improvement in the disease activity index, by improvement in clinical symptoms, or by any other measure of disease activity. Improvement in symptoms associated with CIDP can be measured using any of the standard CIDP assessment methods described herein, such as those used to define ECI. In some embodiments, clinical efficacy is defined as demonstrating ECI in a subject. In some embodiments, clinical efficacy is demonstrated by the length of time a subject remains relapse-free. In some embodiments, clinical efficacy is demonstrated by a reduction in the risk of clinical deterioration, such as ECMD.

[0149] As used herein, the term "clinically proven safe," in relation to the dosage, dosing regimen, treatment, or method of administration of the FcRn antagonist of this disclosure (e.g., egamod), refers to a favorable risk:benefit ratio of adverse events (referred to as AEs or TEAEs) occurring with acceptable frequency and / or acceptable severity compared to standard care or another control care. As used herein, "adverse event," "treatment-related adverse event," and "adverse reaction" mean any harmful, adverse, unexpected, or undesirable sign or outcome associated with or caused by the administration of the pharmaceutical composition or therapeutic agent. These are adverse medical events occurring in subjects administering the pharmaceutical product. However, outliers or observations are not reported as adverse events unless the investigator considers them clinically significant. When the harm or undesirable outcome of an adverse event reaches such severity that a regulatory agency may consider the pharmaceutical composition or therapeutic agent unacceptable for the proposed use. Specifically, when “safety” is attributed to the use of an FcRn antagonist, if it is considered likely, probable, or highly probable to be due to the use of the FcRn antagonist, it means having an acceptable frequency and / or acceptable severity of adverse events associated with the administration of the FcRn antagonist.

[0150] As used herein, unless otherwise stated, the term "clinically proven" (used independently or to modify the terms "safe" and / or "effective") means that the efficacy of a drug has been demonstrated through clinical trials that have met the approval criteria of the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), or the China National Medical Products Administration (NMPA). For example, a clinical study can be a sufficiently large, randomized, double-blind study for the clinically proven efficacy of a drug.

[0151] B. FcRn antagonists

[0152] FcRn antagonists that can be used in the methods and uses provided herein may include any molecule that binds to and inhibits FcRn, including but not limited to any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region. In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions. In some embodiments, the FcRn antagonists disclosed herein comprise a combination of one or more Fc regions and one or more Fab regions.

[0153] Any Fc region can be modified to produce variant Fc regions used in the methods disclosed herein. Generally, the Fc region or its FcRn-binding fragment is derived from human immunoglobulins. However, it should be understood that the Fc region can be derived from immunoglobulins of any other mammalian species, including, for example, camel species, rodents (e.g., mice, rats, rabbits, guinea pigs), or non-human primate species (e.g., orangutans, macaques). Additionally, the Fc region or portions thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3, and IgG4.

[0154] In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in US 2011 / 0243966A1, which is incorporated herein by reference in its entirety. Various Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly available deposits.

[0155] The Fc region may be further truncated or internally deleted to produce its minimum FcRn binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any binding assay recognized in the art (e.g., ELISA).

[0156] To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the constitutive Fc region does not contain any non-disulfide-linked cysteine ​​residues. Therefore, in one embodiment, the Fc region does not contain free cysteine ​​residues.

[0157] The methods disclosed herein may use any Fc variant or its FcRn binding fragment that binds to FcRn with increased affinity and reduced pH-dependent specificity relative to the natural (i.e., wild-type) Fc region. In one embodiment, the variant Fc region comprises amino acid alterations, substitutions, insertions, and / or deletions that impart the desired characteristics.

[0158] In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn-binding fragment thereof, or is composed of such a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with a higher affinity at pH 5.5 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn-binding fragment thereof, or is composed of such a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with a higher affinity at pH 6.0 and / or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn-binding fragment thereof, or is composed of such a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with a higher affinity at both acidic and neutral pH levels.

[0159] 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 IgA, IgD, IgE, or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE, or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, IgG is IgG1, IgG2, IgG3, or IgG4. In some embodiments, human IgG is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region differs from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region contains allotypes of G1m1(a), G1m2(x), G1m3(f), or G1m17(z).

[0160] In one embodiment, the variant Fc region or its FcRn binding fragment consists of two Fc domains. In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0161] In one embodiment, the variant Fc region comprises or consists of the following: a first Fc domain and a second Fc domain forming a homodimer or heterodimer. In one embodiment, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In another embodiment, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0162] 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 in Table 1 below.

[0163] Table 1

[0164]

[0165] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of a variant Fc region comprising or consist of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 22.

[0166] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to or constitutes the same amino acid sequence as or constitutes a variant comprising a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of amino acid sequences independently selected from or constituted by the group consisting of: SEQ ID NO: 1-21 (see Table 2 below). In some embodiments, the dimer is a heterodimer or a homodimer.

[0167] Table 2

[0168]

[0169] In one embodiment, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, 3, and 4. In another embodiment, 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, 2, 3, and 4.

[0170] In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, the FcRn antagonist comprising a first Fc domain and a second Fc domain is the major FcRn antagonist molecule in the population of FcRn antagonist molecules, the first Fc domain and the second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3 and 4. In some embodiments, the major FcRn antagonist molecule constitutes at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the population of FcRn antagonist molecules.

[0171] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1.

[0172] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2.

[0173] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0174] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 4. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 4.

[0175] In one embodiment, the FcRn antagonist comprises a variant Fc region, wherein the variant Fc region contains two Fc domains, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

[0176] In some embodiments, the variant Fc region is a heterodimer, wherein the constitutive Fc domains are distinct from each other. Methods for generating Fc heterodimers are known in the art (see, for example, US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist comprises a variant Fc region comprising two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or is comprised of a variant Fc region comprising or is comprised of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is comprised of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or is comprised of the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3. In another embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0177] In one embodiment, the FcRn antagonist comprises a variant Fc region, wherein the variant Fc region comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4. In another embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO:1, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 4. In another embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 4. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 4, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0178] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0179] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0180] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0181] In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or is composed of the amino acid sequence of SEQ ID NO: 4.

[0182] In some embodiments, the FcRn antagonist comprises glycanization on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycanization at EU position 297 on one or both of the Fc domains. In some embodiments, the glycanization comprises N-glycans. In some embodiments, the N-glycans include G0F N-glycans, G1F N-glycans, G2F N-glycans, or G0 N-glycans.

[0183] In some embodiments, the FcRn antagonist comprises or consists of a group 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 Fc domain group of the FcRn antagonist comprises galactose. In some embodiments, the group comprises or consists of an FcRn antagonist, 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 Fc domain group of the FcRn antagonist comprises fucose.

[0184] In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both of the Fc domains. In some embodiments, the FcRn antagonist contains glycine and lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441. In some embodiments, the FcRn antagonist contains amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441 and contains amidated proline at EU position 439.

[0185] In some embodiments, the FcRn antagonist comprises aspartic acid, 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 position 221 and comprises lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221 and 222 and comprises threonine, histidine, threonine, and cysteine ​​at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221-224 and comprises threonine and cysteine ​​at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

[0186] In some embodiments, an FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of multiple subgroups 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 subgroups. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 subgroups.

[0187] In some embodiments, a first subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the amino acid sequence of SEQ ID NO: 3.

[0188] In some embodiments, the second subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 13, respectively.

[0189] In some embodiments, a third subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 10, respectively.

[0190] In some embodiments, a fourth subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the same amino acid sequence as the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked.

[0191] In some embodiments, the fifth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of an amino acid sequence that is 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 subgroup is deaminoked.

[0192] In some embodiments, the sixth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 2 and 3, respectively.

[0193] In some embodiments, the seventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of an amino acid sequence that is 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 subgroup is oxidized.

[0194] In some embodiments, the eighth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the amino acid sequence of SEQ ID NO: 2.

[0195] In some embodiments, the ninth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 7, respectively.

[0196] In some embodiments, the tenth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acid sequences to or composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subgroup is oxidized.

[0197] In some embodiments, the eleventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine residues or tryptophan residues in each FcRn antagonist molecule in the eleventh subgroup are oxidized.

[0198] In some embodiments, a first subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3.

[0199] In some embodiments, the second subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 13, respectively.

[0200] In some embodiments, the third subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 10, respectively.

[0201] In some embodiments, the fourth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked.

[0202] In some embodiments, the fifth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subgroup is deaminoked.

[0203] In some embodiments, the sixth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively.

[0204] In some embodiments, the seventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed 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 subgroup is oxidized.

[0205] In some embodiments, the eighth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 2.

[0206] In some embodiments, the ninth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 7, respectively.

[0207] In some embodiments, the tenth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subgroup is oxidized.

[0208] In some embodiments, the eleventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine residues or tryptophan residues in each FcRn antagonist molecule in the eleventh subgroup are oxidized.

[0209] In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and one of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and two of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and three of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and four of the following subgroups: a second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroup. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and five of the following subgroups: a second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroup. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and six of the following subgroups: a second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroup. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and seven of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and eight of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and nine of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises or consists of all of the first subgroup and the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups.

[0210] In some embodiments, a group comprises or consists of a first subgroup and a second subgroup. In some embodiments, a group comprises or consists of a first subgroup and a third subgroup. In some embodiments, a group comprises or consists of a first subgroup and a fourth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a fifth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a sixth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a seventh subgroup. In some embodiments, a group comprises or consists of a first subgroup and an eighth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a ninth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a tenth subgroup. In some embodiments, a group comprises or consists of a first subgroup and an eleventh subgroup. In some embodiments, the groups listed above further comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, or 9 additional subgroups. In some embodiments, these additional subgroups are one or more of the subgroups described above.

[0211] In some embodiments, the group comprises or consists of a first subgroup and a seventh subgroup, a ninth subgroup, or an eleventh subgroup.

[0212] In some embodiments, the first subgroup comprises 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 FcRn antagonist molecular population. In some embodiments, the first subgroup comprises 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 FcRn antagonist molecular population. In some embodiments, the first subgroup comprises 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the FcRn antagonist molecular population. In some embodiments, the first subgroup comprises 40%-90%, 50%-80%, or 55%-70% of the FcRn antagonist molecular population. In some embodiments, the first subgroup accounts for 56.9%-68.3% or 59.5%-67.9% of the FcRn antagonist molecular population.

[0213] In some embodiments, the second subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 0.8%-2.0% or 0.8%-2.1% of the FcRn antagonist molecular population.

[0214] In some embodiments, the third subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 1.1%-2.1% or 1.0%-1.9% of the FcRn antagonist molecular population.

[0215] In some embodiments, the fourth subgroup comprises less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises about 5%, about 4%, about 3%, about 2%, or about 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 5%, 4%, 3%, 2%, or 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 1%-5%, 2%-4%, or 2%-3% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 2.1%-3.2% or 2.0%-3.1% of the FcRn antagonist molecular population.

[0216] In some embodiments, the fifth subgroup comprises 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 FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 5%-12%, 6%-10%, or 7%-8% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 6.8%-9.4% or 6.9%-8.7% of the FcRn antagonist molecular population.

[0217] In some embodiments, the sixth subgroup comprises 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 FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises 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 FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises 7%-17%, 10%-15%, or 11%-12% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup accounts for 7.0%-14.0% or 10.0%-14.4% of the FcRn antagonist molecular population.

[0218] In some embodiments, the seventh subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the seventh subgroup constitutes approximately 6.0%, approximately 5.5%, approximately 5.0%, approximately 4.5%, approximately 4.0%, approximately 3.5%, approximately 3.0%, approximately 2.5%, approximately 2.0%, approximately 1.5%, approximately 1%, or approximately 0.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the seventh subgroup comprises 0.5%-5.5%, 1.0%-3.0%, or 1.5%-2.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup comprises 1.5%-5.5% or 1.4%-4.9% of the FcRn antagonist molecular population.

[0219] In some embodiments, the eighth subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the eighth subgroup constitutes approximately 7.5%, approximately 7.0%, approximately 6.5%, approximately 6.0%, approximately 5.5%, approximately 5.0%, approximately 4.5%, approximately 4.0%, approximately 3.5%, approximately 3.0%, or approximately 2.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the eighth subgroup comprises 2.5%-7.5%, 3.0%-5.0%, or 3.5%-4.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup comprises 2.9%-7.4% or 3.0%-6.3% of the FcRn antagonist molecular population.

[0220] In some embodiments, the ninth subgroup constitutes 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 FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 0.5%-3.5%, 1.5%-2.0%, or 1.0%-1.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 0.4%-3.2% or 0.5%-2.6% of the FcRn antagonist molecular population.

[0221] In some embodiments, the tenth subgroup comprises less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the FcRn antagonist molecular population.

[0222] In some embodiments, the eleventh subgroup constitutes less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the FcRn antagonist molecular population.

[0223] In some embodiments, the FcRn antagonist molecular group comprises one or more FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in U.S. Patent Application No. 63 / 383,599, filed November 14, 2022, the entire contents of which are incorporated herein by reference. In some embodiments, the FcRn antagonist is the FcRn antagonist family as described in U.S. Patent Application No. 63 / 383,599, filed November 14, 2022, the entire contents of which are incorporated herein by reference.

[0224] In one embodiment, the FcRn antagonist is igamatidec (CAS Registry No. 1821402-21-4). Igamod is described in further detail below. As used herein, the term "igamatidec" may be used interchangeably with "igamatidec α". In some embodiments, igamatidec is igamatidec α-fcab.

[0225] In one embodiment, the anti-FcRn antibody is rozanolizumab (UCB7665), nicarlimumab (M281), onolalimumab (ALXN1830 / SYNT001), or battolimumab (IMVT-1401 / RVT1401 / HBM9161).

[0226] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of immunoglobulins to FcRn is nicalimab, also known as M281. Nicalimab is a full-length "Fc dead" IgG1 monoclonal antibody. Nicalimab was administered intravenously in a phase 2 clinical trial for the treatment of myasthenia gravis (MG), warm antibody-type autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nicalimab comprises the light chain (SEQ ID NO: 23) and heavy chain (SEQ ID NO: 24) sequences shown in Table 3 below:

[0227] Table 3. Heavy and light chain sequences of nicarlimab

[0228]

[0229] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is rozanolipizumab, also known as UCB 7665. Rozanolipizumab is a full-length humanized IgG4 monoclonal antibody. Rozanolipizumab is administered subcutaneously in ongoing clinical trials for MG, immune thrombocytopenic purpura (ITP), and CIDP. Rozanolipizumab comprises the light chain (SEQ ID NO: 25) and heavy chain (SEQ ID NO: 26) sequences shown in Table 4 below:

[0230] Table 4. Heavy and light chain sequences of rozanoliptin.

[0231]

[0232] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is onolimab, also known as SYNT001. Onolimab is another full-length humanized IgG4 monoclonal antibody. Onolimab was administered intravenously in a phase 2 clinical trial for the treatment of WAIHA. Onolimab contains the light chain (SEQ ID NO: 27) and heavy chain (SEQ ID NO: 28) sequences shown in Table 5 below:

[0233] Table 5. Heavy and light chain sequences of orolimab

[0234]

[0235] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is battolimab, also known as IMVT1401 / RVT1401 / HBM9161. Battolimab is a full-length "Fc-ineffective" IgG1 monoclonal antibody. Battolimab is administered subcutaneously in an ongoing Phase 2 clinical trial for the treatment of MG and Graves' ophthalmopathy. Battolimab comprises the light chain (SEQ ID NO: 29) and heavy chain (SEQ ID NO: 30) sequences shown in Table 6 below:

[0236] Table 6. Heavy and light chain sequences of battolimab

[0237]

[0238] In some embodiments, the anti-FcRn antibody used according to the methods and uses described herein is any anti-FcRn antibody described in International Patent Application No. WO2015167293A1, the contents of which are incorporated herein in their entirety. In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is IMVT-1402 (Immunovant).

[0239] C. Pharmaceutical Composition

[0240] This disclosure provides pharmaceutical compositions comprising an FcRn antagonist for use in methods of treating CIDP. In some embodiments, these compositions comprise or consist of a variant Fc region or an FcRn-binding fragment thereof, which binds specifically to an FcRn, particularly a human FcRn, relative to a native Fc region with increased affinity and reduced pH dependence. In other embodiments, the FcRn antagonist composition is an antibody or an antigen-binding fragment thereof that specifically binds to an FcRn via its antigen-binding domain and inhibits the binding of the Fc region of an immunoglobulin to the FcRn. Generally, these FcRn antagonists inhibit the binding of Fc-containing agents (e.g., antibodies and immunoadhesins) to FcRn in vivo, resulting in an increased degradation rate of the Fc-containing agents and a decrease in serum levels of these agents.

[0241] In one embodiment, the FcRn antagonist is igamatidec or a bioanalyte thereof. igamatidec (ARGX-113) is a modified human immunoglobulin (Ig) γ (IgG) 1-derived Fc, a za allotype, that binds to human FcRn with nanomolar affinity. igamatidec encompasses the IgG1 Fc region (covering 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 levels, see Vaccaro C et al., Nat Biotechnol. 2005; 23(10):1283. See also U.S. Patent No. 10,316,073, the contents of which are incorporated herein by reference in their entirety. The increased affinity of igamatidec for FcRn at both acidic and physiological pH levels leads to the blockade of FcRn-mediated IgG recycling.

[0242] Artamod has a molecular weight of approximately 54 kDa, which is about one-third the molecular weight of full-length IgG (MW approximately 150 kDa). Therefore, 10 mg of artamod is approximately 185 nmol, meaning a dose of 10 mg artamod / kg body weight corresponds to approximately 185 nmol artamod / kg body weight, and a dose of 25 mg artamod / kg body weight corresponds to approximately 462.5 nmol artamod / kg body weight. In contrast, a dose of 10 mg full-length IgG antibody / kg body weight corresponds to approximately 67 nmol / kg body weight. Furthermore, a fixed dose of 1000 mg artamod corresponds to a fixed dose of approximately 18,500 nmol artamod, and a fixed dose of 2000 mg artamod corresponds to a fixed dose of approximately 37,000 nmol artamod.

[0243] Due to its increased affinity for FcRn at both acidic and neutral pH levels, egamod blocks the formation of the FcRn / IgG complex, leading to the degradation of endogenous IgG, including autoantibodies that cause IgG-mediated autoimmune diseases. This blockade of FcRn by egamod results in a rapid and significant reduction in autoantibody levels, which forms the basis of therapeutic strategies for autoimmune indications, in which IgG autoantibodies are expected to play a central role in the pathology of the disease.

[0244] Egamod is a prescription drug registered as VYVGART®, approved in the United States, Europe, the United Kingdom, China, Canada, and Israel for the treatment of adults with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) antibodies, and in Japan for the treatment of adults with gMG who have not responded adequately to steroid or non-steroidal immunosuppressive therapy (IST). Egamod is also approved in Japan for the treatment of chronic ITP. Egamod is being developed for both intravenous (IV) and subcutaneous (SC) administration routes for multiple indications.

[0245] For SC administration, in some embodiments, egamod may be administered alone. Alternatively, for SC administration, in some embodiments, egamod may be co-formulated with hyaluronidase, such as, in particular, rHuPH20 (recombinant human PH20). Co-formulated materials will allow for larger volumes of administration.

[0246] rHuPH20 is the active ingredient in Halozyme's commercial product HYLENEX® recombinant agent (human hyaluronidase injection), also known as HYLENEX®, which was approved by the FDA for use in the United States in December 2005. HYLENEX® is a tissue permeability modifier, indicated as an adjuvant in SC fluid administration to achieve hydration, thereby increasing the dispersion and absorption of other injectable drugs, and in SC urography to improve the reabsorption of radiopaque agents.

[0247] rHuPH20 is a recombinant enzyme, human hyaluronidase, produced by genetically engineered Chinese hamster ovary (CHO) cells containing a deoxyribonucleic acid plasmid encoding a soluble fragment of human hyaluronidase (hindhead protein 20 [PH20]).

[0248] HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biological products co-blended with rHuPH20 DS. Therefore, in some embodiments, HZ202 rHuPH20 DS is used in egamod / rHuPH20 co-blended products for SC administration (i.e., egamod PH20 SC).

[0249] Egamod 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 with AChR antibody positivity. In a single-dose vial, VYVGART® HYTRULO contains 1,008 mg of egamod α and 11,200 units of hyaluronidase per 5.6 mL vial (180 mg / 2,000 units per mL). In some embodiments, egamod PH20 SC (also known as egamod PH20) is used in the methods described herein.

[0250] The co-formulations, compositions, uses, and methods described herein pertain to soluble hyaluronidases. Soluble hyaluronidases encompass any enzyme that is secreted from cells and exists in a soluble form upon expression. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases such as bovine PH20 and sheep PH20, human soluble PH20, and their variants. Because glycosylation is important for the catalytic activity and stability of hyaluronidases, the soluble form of PH20 is typically produced using a protein expression system that promotes proper N-glycosylation to ensure the peptide remains active. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0251] In some embodiments, rHuPH20 refers to a composition produced when expressed in cells (such as CHO cells) encoding nucleic acids SEQ ID NO: 32 residues 36-482, typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO: 32). rHuPH20 is produced by expressing nucleic acid molecules, such as those encoding amino acids 1-482 (listed in SEQ ID NO: 32) in mammalian cells. Translational processing removes the 35-amino acid signal sequence. As produced in a culture medium, heterogeneity exists at the C-terminus, such that the product referred to as rHuPH20 comprises a mixture of species that may include any or more of peptides 36-480, 36-481, and 36-482 of SEQ ID NO: 32, as well as shorter peptides of varying abundance. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to maintain viability (such as CHO cells (e.g., DG44 CHO cells)). In some embodiments, one of the most abundant species is a 446-amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 32. In some embodiments, rHuPH20 refers to a polypeptide that is soluble or secreted when expressed in mammalian cells and has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity with residues 36-482 of SEQ ID NO: 32. In some embodiments, rHuPH20 is a 447-amino acid polypeptide of SEQ ID NO: 33.

[0252] Table 7. Exemplary hyaluronidase sequences

[0253]

[0254] Due to concerns about injection pain associated with excessively large volumes, SC injection volumes are typically limited to 2.5 mL. rHuPH20 has been shown to provide a solution to the volume limitations associated with rapid SC injections. rHuPH20 acts locally and temporarily to depolymerize hyaluronic acid (a gel-like substance found in the subcutaneous layer of the skin). This causes a reduction in resistance to fluid flow and may increase the dispersion and absorption of the injected drug and fluid, thus allowing for larger volumes to be injected with limited swelling or pain. rHuPH20 has been shown to allow for the rapid absorption of relatively large volumes (10 mL) when administered via SC (Shpilberg O et al., 2013). Very little injection site swelling was observed when administering 10 mL of IgG solution via SC with 2000 U / mL rHuPH20, while large injection site swelling was observed when 10 mL of IgG solution was injected without rHuPH20 (Shpilberg O et al., 2013).

[0255] rHuPH20 has a temporary effect and is not absorbed systemically. It has been shown not to exert long-term local effects. The half-life of rHuPH20 in the skin is less than 30 minutes. Due to the rapid natural turnover of hyaluronic acid, hyaluronic acid levels in subcutaneous tissue return to normal within 24 to 48 hours.

[0256] rHuPH20 is approved in the United States and Europe for use in SC administration in combination with other active ingredients, namely RITUXAN HYCELA™ / MABTHERA™ SC [rituximab] and HERCEPTIN HYLECTA™ / HERCEPTIN™ SC [trastuzumab], for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), at an enzyme concentration of 2000 U / mL and an injectable volume ranging from 5 to 13.4 mL.

[0257] In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 1,000 mg to about 2,500 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 1,000 mg to about 2,000 mg.

[0258] In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 1000 mg to 2000 mg.

[0259] In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is iatrovid.

[0260] In some embodiments, the drug formulation comprises an amount of eigamod from about 800 mg to about 1200 mg. In some embodiments, the drug formulation comprises about 1000 mg of eigamod. In some embodiments, the drug formulation comprises 1000 mg of eigamod.

[0261] In some embodiments, the drug formulation comprises about 10 mg / mL to about 200 mg / mL egamod.

[0262] In some embodiments, the drug formulation comprises about 20 mg / mL egamod.

[0263] In some embodiments, the drug formulation comprises approximately 180 mg / mL egamod.

[0264] In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0265] Hyaluronidase may be present in any suitable amount in the pharmaceutical formulation. In one embodiment, the amount of hyaluronidase is from about 1000 U / mL to about 3000 U / mL. In one embodiment, the amount of hyaluronidase is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In one embodiment, the amount of hyaluronidase is 2000 U / mL.

[0266] In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U or about 22,000 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U or 22,000 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,200 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,200 U.

[0267] In some embodiments, the pharmaceutical formulation contains at least about 5 U to at least about 100,000 U of an endoglucosidase. In some respects, the drug formulation contains 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. U, at least about 90,000 U or at least about 100,000 U of endoglycoside hydrolase.

[0268] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of an endoglucosidase. In some embodiments, the pharmaceutical formulation comprises at least about 500 U / mL to at least about 5000 U / mL of an endoglucosidase. 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 µM, at least about 2500 µM, at least about 3000 µM, at least about 3500 µM, at least about 4000 µM, at least about 4500 U / mL, or at least about 5000 U / mL of an endoglucosidase. In some embodiments, the pharmaceutical formulation contains about 2000 U / mL of endoglycoside hydrolase.

[0269] In some embodiments, the endoglycoside hydrolase cleaves hyaluronic acid at the β (1–4) or (1–3) bond of the hexosamine glycoside. In some embodiments, the endoglycoside hydrolase comprises a catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycoside hydrolase 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 at least 100% sequence identity with amino acids 36-490 of SEQ ID NO: 32. In some embodiments, the endoglycoside hydrolase comprises hyaluronidase. In some embodiments, the endoglycoside hydrolase comprises hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants, and any isotypes thereof. In some embodiments, the endoglycoside hydrolase comprises rHuPH20 or a fragment thereof.

[0270] In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions in the α-helical region relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions in the junction region relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase 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 fragments thereof. In some embodiments, the endoglycosidase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitutions in the α-helix region, the linker region, or both the α-helix region and the linker region relative to wild-type rHuPH20; ii. the deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0271] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetylglucosamine and glucuronic acid, present in the subcutaneous space, contributing to the soluble gel-like component of the skin's extracellular matrix and recovering through rapid renewal (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, a glycosylated 447-amino acid single-chain polypeptide that locally depolymerizes hyaluronic acid in the subcutaneous space at the injection site on the skin. Depolymerization of hyaluronic acid by hyaluronidase is accomplished through the hydrolysis of the polysaccharide polymer. The depolymerization of hyaluronic acid results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and increases hydraulic conductivity, thereby facilitating the dispersion and absorption of adjuvant therapeutic agents. Therefore, hyaluronidase (e.g., rHuPH20) can improve the speed and convenience of subcutaneous delivery of injectable biologics and drugs by acting as a penetration enhancer. In some embodiments, the hyaluronidase comprises ENHANZE™.

[0272] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL of an FcRn antagonist, about 2,000 U / mL rHuPH20, 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 20, about 5.8 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, with a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0273] In some embodiments, the pharmaceutical formulation comprises 180 mg / mL of an FcRn antagonist, 2,000 U / mL rHuPH20, 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 20, 5.8 mg / mL sodium chloride, and 20.5 mg / mL sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0274] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL egamod, about 2,000 U / mL rHuPH20, 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 20, about 5.8 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, with a pH of about 6.0.

[0275] In some embodiments, the pharmaceutical formulation comprises 180 mg / mL egamod, 2,000 U / mL rHuPH20, 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 20, 5.8 mg / mL sodium chloride, and 20.5 mg / mL sucrose, with a pH of about 6.0.

[0276] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL of an FcRn antagonist, about 2,000 U / mL rHuPH20, about 20 mM L-histidine / L-histidine HCl, about 10 mM L-methionine, about 0.04% (w / v) polysorbate 20, about 100 mM sodium chloride, and about 60 mM sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0277] In some embodiments, the pharmaceutical formulation comprises 180 mg / mL of an FcRn antagonist, 2,000 U / mL rHuPH20, 20 mM L-histidine / L-histidine HCl, 10 mM L-methionine, 0.04% (w / v) polysorbate 20, 100 mM sodium chloride, and 60 mM sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0278] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL egamod, about 2,000 U / mL rHuPH20, about 20 mM L-histidine / L-histidine HCl, about 10 mM L-methionine, about 0.04% (w / v) polysorbate 20, about 100 mM sodium chloride and about 60 mM sucrose, with a pH of about 6.0.

[0279] In some embodiments, the pharmaceutical formulation comprises 180 mg / mL egamod, 2,000 U / mL rHuPH20, 20 mM L-histidine / L-histidine HCl, 10 mM L-methionine, 0.04% (w / v) polysorbate 20, 100 mM sodium chloride and 60 mM sucrose, with a pH of about 6.0.

[0280] In any of the above embodiments, the drug formulation may be a unit dosage form.

[0281] In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, freeze-dried powder, or anhydrous concentrate. In one embodiment, the dry formulation is contained in an airtight container, such as a vial, ampoule, or capsule.

[0282] In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a liquid formulation (e.g., an injectable or infusion solution). In one embodiment, the liquid formulation is contained in a hermetically sealed container, such as a vial, capsule, pre-filled syringe, pre-filled auto-injector, or cartridge for a reusable syringe or applicator. In one embodiment, the liquid formulation is contained in a single-dose vial.

[0283] In one embodiment, each 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 in the range of about 500 mg to about 2500 mg or about 1000 mg to about 2000 mg. In some embodiments, each vial contains 5.6 mL of 1008 mg of FcRn antagonist per unit dose. In some embodiments, each vial contains 5.6 mL of 1008 mg of FcRn antagonist per unit dose and 11,200 U of hyaluronidase per unit dose. In one embodiment, these formulations can be adjusted to the desired concentration by adding a sterile diluent to each vial.

[0284] In some embodiments, the unit dosage form is a single-dose vial containing at least 5.6 mL of a liquid formulation containing an FcRn antagonist at a concentration of 180 mg / mL. In some embodiments, the single-dose vial contains 5.6 mL of a liquid formulation containing 1,008 mg of the FcRn antagonist and 11,200 units of hyaluronidase (recombinant human). Each mL of the vial solution contains 180 mg of egamod α, 2,000 units of hyaluronidase (recombinant human), and histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), methionine (1.5 mg), polysorbate 20 (0.4 mg), sodium chloride (5.8 mg), sucrose (20.5 mg), and water for injection (USP) at pH 6.0. In some embodiments, the FcRn antagonist is egamod or a bioanalyte thereof.

[0285] The formulations disclosed herein include bulk pharmaceutical compositions that can be used to manufacture pharmaceutical compositions (e.g., compositions suitable for administration to a subject or patient) and can be used to prepare unit dosage forms. In one embodiment, the compositions of the present invention are pharmaceutical compositions. Such compositions comprise a preventive or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., the FcRn antagonist of the present invention or other prophylactic or therapeutic agents) and a pharmaceutically acceptable carrier. In one embodiment, these pharmaceutical compositions are formulated for intravenous administration to a subject. In one embodiment, these pharmaceutical compositions are formulated for subcutaneous administration to a subject. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous administration to a subject as a once-weekly injection over a period of about 30 to 90 seconds. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous use with a wing-shaped infusion device.

[0286] In some embodiments, the pharmaceutical compositions described herein are contraindicated in patients with severe hypersensitivity to FcRn antagonists (e.g., egamod), hyaluronidase, or any excipients in the composition. In some embodiments, hypersensitivity is an allergic reaction and / or hypotension leading to syncope.

[0287] D. Reagent kit

[0288] This disclosure provides a kit comprising an FcRn antagonist and a label. In some embodiments, the kit comprises a pharmaceutical composition comprising an FcRn antagonist and a label. Any FcRn antagonist or pharmaceutical composition thereof described herein may be included in the kit provided herein. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0289] In some embodiments, the pharmaceutical composition comprises about 180 mg / mL of an FcRn antagonist, about 2,000 U / mL rHuPH20, 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 20, about 5.8 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, with a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0290] In some embodiments, the pharmaceutical composition comprises 180 mg / mL of an FcRn antagonist, 2,000 U / mL rHuPH20, 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 20, 5.8 mg / mL sodium chloride, and 20.5 mg / mL sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0291] In some embodiments, the pharmaceutical composition comprises about 180 mg / mL egamod, about 2,000 U / mL rHuPH20, 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 20, about 5.8 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, with a pH of about 6.0.

[0292] In some embodiments, the pharmaceutical composition comprises 180 mg / mL egamod, 2,000 U / mL rHuPH20, 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 20, 5.8 mg / mL sodium chloride, and 20.5 mg / mL sucrose, with a pH of about 6.0.

[0293] In some embodiments, the pharmaceutical composition comprises about 180 mg / mL of an FcRn antagonist, about 2,000 U / mL rHuPH20, about 20 mM L-histidine / L-histidine HCl, about 10 mM L-methionine, about 0.04% (w / v) polysorbate 20, about 100 mM sodium chloride, and about 60 mM sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0294] In some embodiments, the pharmaceutical composition comprises 180 mg / mL of an FcRn antagonist, 2,000 U / mL rHuPH20, 20 mM L-histidine / L-histidine HCl, 10 mM L-methionine, 0.04% (w / v) polysorbate 20, 100 mM sodium chloride, and 60 mM sucrose, at a pH of about 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0295] In some embodiments, the pharmaceutical composition comprises about 180 mg / mL egamod, about 2,000 U / mL rHuPH20, about 20 mM L-histidine / L-histidine HCl, about 10 mM L-methionine, about 0.04% (w / v) polysorbate 20, about 100 mM sodium chloride and about 60 mM sucrose, with a pH of about 6.0.

[0296] In some embodiments, the pharmaceutical composition comprises 180 mg / mL egamod, 2,000 U / mL rHuPH20, 20 mM L-histidine / L-histidine HCl, 10 mM L-methionine, 0.04% (w / v) polysorbate 20, 100 mM sodium chloride and 60 mM sucrose, with a pH of about 6.0.

[0297] In some embodiments, the kit includes a single-dose vial containing an FcRn antagonist in liquid formulation and a label.

[0298] In some embodiments, a single-dose vial contains 5.6 mL of a liquid formulation comprising 1,008 mg of an FcRn antagonist, 11,200 units of rHuPH20, 7.8 mg of histidine, 12.3 mg of L-histidine hydrochloride monohydrate, 8.4 mg of methionine, 2.2 mg of polysorbate 20, 32.5 mg of sodium chloride, 114.8 mg of sucrose, and water for injection (USP) at pH 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0299] In some embodiments, a single-dose vial contains 5.6 mL of a liquid formulation comprising 1,008 mg of an FcRn antagonist and 11,200 units of rHuPH20, and each mL of the vial solution contains histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), methionine (1.5 mg), polysorbate 20 (0.4 mg), sodium chloride (5.8 mg), sucrose (20.5 mg), and water for injection (USP) at a pH of 6.0. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0300] In some embodiments, the label identifies egamod and provides instructions for its use in patients. In some embodiments, the label includes instructions for treating CIDP in adult patients. In some embodiments, the label includes data showing an ECI response in 66.5% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly. In some embodiments, the label includes data showing improvement at two consecutive visits in 69% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly for up to 12 weeks. In some embodiments, improvement is defined as an aINCAT improvement ≥1 point, an I-RODS improvement ≥4 points, or an improvement in mean grip strength ≥8 kPa. In some embodiments, the label includes data showing a median time to initial confirmed ECI in the CIDP patient population of 43 days from the first administration of egamod PH20. In some embodiments, the label states the earliest time point at week 4 that may meet the criteria for ECI, with up to 40% of patients having ECI. In some embodiments, the label states that at least one of the three parameters (aINCAT, I-RODS, or grip strength) showed clinically relevant improvement in 25% of patients after 9 days. In some embodiments, the label includes data showing that CIDP patients receiving the drug product experienced a longer time to clinical deterioration compared to CIDP patients receiving placebo, where clinical deterioration is defined as an increase in aINCAT score of ≥1 point. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point between two consecutive measurements. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant. In some embodiments, the label states that patients receiving egamod PH20 experienced a longer time to clinical deterioration (i.e., an increase in aINCAT score of ≥1 point) compared to patients receiving placebo, which is statistically significant, as demonstrated by a hazard ratio of 0.394 [95% CI (0.253; 0.614) p < 0.0001].

[0301] In some embodiments, the label includes data showing that CIDP patients in the CIDP patient population receiving eigamod PH20 maintained a significantly longer relapse-free period than CIDP patients in the CIDP patient population receiving placebo. In some embodiments, the label includes data showing that CIDP patients in the CIDP patient population receiving eigamod PH20 had a 61% lower risk of deterioration compared to CIDP patients in the CIDP patient population receiving placebo.

[0302] In some embodiments, the label includes data indicating a 2% incidence of anti-egamod α antibodies in a cohort of 117 CIDP patients after treatment with the drug product. In some embodiments, the label includes data indicating a 6% incidence of anti-egamod α antibodies in a cohort of 317 CIDP patients after treatment with the drug product. In some embodiments, the label includes data indicating a 0.3% incidence of neutralizing anti-egamod α antibodies in a cohort of 317 CIDP patients after treatment with the drug product.

[0303] In some embodiments, the label includes a contraindication for patients with severe hypersensitivity to any excipient of the egamod α product, hyaluronidase, or formulations thereof. In some embodiments, the label includes a warning for hypersensitivity reactions selected from anaphylactic reactions and hypotension leading to syncope. In some embodiments, the label states that the infusion should be discontinued if an anaphylactic reaction or hypotension leading to syncope occurs during or within 1 hour of product administration. In some embodiments, the label includes a warning for infusion-related reactions selected from hypertension, chills, shivering, chest pain, abdominal pain, and back pain. In some embodiments, the label states that appropriate therapy should be initiated if a severe infusion-related reaction occurs during product administration. In some embodiments, the label states that if a mild to moderate infusion-related reaction occurs during product administration, the patient may again be closely monitored clinically, given a slower infusion rate, and pre-medicated. In some embodiments, the label includes a combination of any of the features described above or elsewhere herein.

[0304] E. Treatment methods

[0305] Individuals awaiting treatment

[0306] This invention provides a method for treating CIDP. As explained elsewhere herein, CIDP is a heterogeneous disease encompassing conditions with predominantly sensory symptoms, distal symmetrical conditions or distal acquired demyelinating symmetrical neuropathy (DADS), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and CIDP with associated central nervous system (CNS) demyelination. Misdiagnosis of CIDP is relatively frequent.

[0307] In some embodiments, the subject to be treated according to the methods described herein has been diagnosed with CIDP using the official EFNS / PNS 2010 diagnostic criteria (Van den Bergh et al., 2010). In some embodiments, the subject has been diagnosed with definite, probable CIDP. In some embodiments, the subject has been diagnosed with probable CIDP.

[0308] The EFNS / PNS 2010 diagnostic criteria were revised in 2021 (see Van den Bergh et al., Eur J Neurol. 2021; 28: 3556-3583), and distinguished between “typical CIDP” and “CIDP variants”, as defined in Table 8 below. CIDP variants were previously classified as “atypical” forms of CIDP.

[0309] Table 8. Clinical criteria for typical CIDP and CIDP variants

[0310]

[0311] Subjects treated according to the methods described herein may have typical CIDP. Typical CIDP typically begins with sensory abnormalities and weakness in the distal extremities, as well as difficulty walking. Clinical examination reveals progressive symmetrical proximal and distal muscle weakness, sensory loss, and reduced or absent deep tendon reflexes.

[0312] Alternatively, subjects treated according to the methods described herein may have a CIDP variant selected from the group consisting of: distal CIDP; multifocal CIDP, focal CIDP, motor CIDP, and sensory CIDP. In some embodiments, subjects treated according to the methods described herein may have a CIDP variant selected from the group consisting of: distal CIDP; multifocal CIDP, focal CIDP, and motor CIDP. These CIDP variants are described in more detail below.

[0313] - Distal CIDP, also known as "distal acquired demyelinating symmetrical neuropathy" (DADS) or "distal symmetrical syndrome," is a variant of CIDP characterized by sensory loss and gait instability in the distal upper and lower extremities. Weakness may occur, and it is usually more severe in the lower extremities than in the upper extremities.

[0314] Multifocal CIDP, also known as "multifocal demyelinating neuropathy with persistent conduction block," "Louis-Sumner syndrome" (LSS), "multifocal acquired demyelinating sensory and motor neuropathy" (MADSAM), or multifocal inflammatory demyelinating neuropathy, is a variant of CIDP that typically affects the upper limbs first and may later involve the lower limbs. Cranial nerves are involved more frequently than in other forms of CIDP.

[0315] - Focal CIDP; This variant is rare and usually affects the brachial plexus or lumbosacral plexus, but can also affect individual peripheral nerves.

[0316] - Motor CIDP; This variant presents with relatively symmetrical proximal and distal weakness, but has normal sensation clinically and electrodiagnostively (unlike typical CIDP with sensory abnormalities).

[0317] - Sensory CIDP; this variant is typically characterized by gait ataxia, impaired vibration and position sense, and altered cutaneous sensation. Muscle weakness is absent.

[0318] CIDP can also be classified as "progressive" or "relapsing" at the time of diagnosis. In some embodiments, subjects treated according to the methods described herein have progressive CIDP. In some embodiments, subjects treated according to the methods described herein have relapsing CIDP.

[0319] In some cases, nodal and paranodal autoantibodies have been identified in patients with CIDP. These antibodies include anti-NF155 antibodies (Cortese et al., 2020), anti-CNTN1 antibodies (Querol et al., 2013), anti-Caspr1 antibodies (Pascual-Goñi et al., 2021), and anti-NF140 / 186 antibodies (Delmont et al., 2017).

[0320] In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-NF155 antibodies. In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-CNTN1 antibodies. In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-Caspr1 antibodies. In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-NF140 / 186 antibodies.

[0321] In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-GM1 antibodies. In some embodiments, the subjects treated according to the methods described herein are CIDP patients characterized by the presence of anti-LM1 antibodies.

[0322] Subjects with CIDP treated according to the methods described herein may have mild, moderate, or severe CIDP.

[0323] In some embodiments, the subjects treated according to the methods described herein are adult subjects. In some embodiments, the subjects treated according to the methods described herein are adult subjects aged between about 20 and 82 years. In some embodiments, the subjects treated according to the methods described herein are adult subjects aged between 20 and 82 years. The severity of the subject's CIDP disease can be assessed using any of the assessment methods described herein, including but not limited to: (i) the INCAT Disability Scale (Merkies et al., 2002); (ii) the MRC Scale (Vanhoutte et al., 2012); (iii) the I-RODS (van Nes et al., 2011); (iv) the average grip strength test (Vanhoutte et al., 2013); and (v) the TUG test.

[0324] In some embodiments, the severity of CIDP is assessed using the INCAT Disability Scale (an FDA-accepted scale for assessing the severity of motor disabilities). The INCAT scale is described elsewhere herein and is a 10-point scale covering function in the legs and arms. Arm disability scores range from 0 to 5, and leg disability scores also range from 0 to 5 (0 being normal and 5 being the most severe impairment). The total INCAT score is the sum of the arm and leg scores and ranges from 0 to 10. In some embodiments, CIDP symptoms are assessed using the aINCAT score. According to the aINCAT score, changes in arm function from 0 (normal) to 1 (mild symptoms) or from 1 to 0 are not recorded as worsening or improvement because these small changes are not considered clinically significant.

[0325] In some embodiments, the baseline INCAT score of the subject treated according to the methods described herein (i.e., prior to treatment with the FcRn antagonist) is 2 or higher, optionally 3 or higher, optionally 4 or higher, optionally 5 or higher, optionally 6 or higher, optionally 7 or higher, optionally 8 or higher, optionally 9 or higher, optionally 10. In some embodiments, the subject's baseline INCAT score is 2, 3, 4, or 5, wherein the disability is limited to the arm. In some embodiments, the subject's baseline INCAT score is 2, 3, 4, or 5, wherein the disability is limited to the leg. In some embodiments, the subject's baseline INCAT score is 2, 3, 4, or 5, wherein the disability affects both the arm and leg. In some embodiments, the subject's baseline INCAT score is 5, wherein the disability affects the arm, leg, or both. In some embodiments, the subject's baseline INCAT score is 3, wherein the disability affects the arm, leg, or both.

[0326] In some embodiments, the severity of CIDP is assessed using the I-RODS. As described elsewhere herein, the I-RODS is a 24-item scale, where each item represents a common daily activity, ranging from very difficult to perform (e.g., running or dancing) to very easy to perform (e.g., eating or reading). Higher scores indicate less disability. Raw I-RODS scores (range: 0 to 48) are typically converted to percentile metrics ranging from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations). In some embodiments, subjects treated according to the methods described herein have a baseline I-RODS percentile metric score of 10 or higher, optionally 20 or higher, optionally 30 or higher, optionally 40 or higher, optionally 50 or higher. In some embodiments, subjects treated according to the methods described herein have a baseline I-RODS percentile metric score of 37.

[0327] In some embodiments, the severity of CIDP is assessed using a mean grip strength test. Mean grip strength can be measured using a handheld Martin grip dynamometer or a Jamar hand grip dynamometer. In some embodiments, the baseline mean grip strength (measured using the dominant hand) of subjects treated according to the methods described herein is ≥20 kPa, optionally ≥30 kPa. In some embodiments, the baseline mean grip strength of subjects treated according to the methods described herein is 1-100 kPa, optionally 10-90 kPa, optionally 20-80 kPa, optionally 30-70 kPa, optionally 30-50 kPa.

[0328] In some embodiments, subjects treated according to the methods described herein have a newly diagnosed CIDP.

[0329] In some embodiments, subjects treated according to the methods described herein have CIDP diagnosed approximately 2 years prior to treatment with an FcRn antagonist. In some embodiments, subjects treated according to the methods described herein have CIDP diagnosed approximately 2.2 years prior to treatment with an FcRn antagonist. In some embodiments, subjects treated according to the methods described herein have CIDP diagnosed approximately 2 years prior to treatment with an FcRn antagonist. In some embodiments, subjects treated according to the methods described herein have CIDP diagnosed approximately 2.2 years prior to treatment with an FcRn antagonist.

[0330] In some embodiments, the subject has relapsed CIDP. In some embodiments, the subject has treatment-unstable and refractory CIDP, such as the CIDP Disease Activity Score (CDAS) characterized by 5B or 5C.

[0331] In some embodiments, the subjects treated according to the methods described herein are treatment-naïve patients. Subjects classified as “treatment-naïve” may have never previously received any treatment for CIDP. Subjects classified as “treatment-naïve” may also include subjects who have previously received treatment for CIDP but have not received any treatment for CIDP in the six months prior to treatment with an FcRn antagonist as described herein.

[0332] In some embodiments, the subject treated according to the methods described herein has previously received one or more CIDP treatments, including but not limited to corticosteroids, IVIg, SCIg, plasma exchange, or other immunosuppressive therapies. In some embodiments, the subject treated according to the methods described herein has previously been treated with IVIg. In some embodiments, the subject treated according to the methods described herein has previously been treated with corticosteroids. In some embodiments, the subject treated according to the methods described herein has active disease despite treatment with corticosteroids or immunoglobulins.

[0333] Dosage

[0334] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is iatrovid.

[0335] In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 300 mg to 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is iatrovid.

[0336] 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 iatrovid.

[0337] 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 iatrovid.

[0338] 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 iatrovid.

[0339] 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 iatrovid.

[0340] In some embodiments, the FcRn antagonist is administered at doses of approximately 0.2 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 12.5 mg / kg, approximately 15 mg / kg, approximately 17.5 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, approximately 100 mg / kg, approximately 110 mg / kg, approximately 12 ... Administered at doses of approximately 130 mg / kg, approximately 140 mg / kg, approximately 150 mg / kg, approximately 160 mg / kg, approximately 170 mg / kg, approximately 180 mg / kg, approximately 190 mg / kg, or approximately 200 mg / kg. In some embodiments, the FcRn antagonist is iatrovid.

[0341] In some embodiments, the FcRn antagonist is administered at 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, 95mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 Administered at doses of 1 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg. In some embodiments, the FcRn antagonist is iatrovid.

[0342] In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once a week. In some embodiments, the FcRn antagonist is administered subcutaneously once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0343] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, 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 a week, once every two weeks, once every three weeks, once every four weeks, once a month, 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 a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0344] 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 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 a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0345] 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 a week, once every two weeks, once every three weeks, once every four weeks, once a month, 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 iatrovid.

[0346] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg to about 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid-methyl.

[0347] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid-methyl.

[0348] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg. In some embodiments, egamod is administered subcutaneously once weekly at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once every two weeks at a fixed dose of about 1000 mg. In some embodiments, egamod is administered subcutaneously once every two weeks at a fixed dose of about 1000 mg.

[0349] In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is iatrovid.

[0350] In some embodiments, the first two administrations of the FcRn antagonist are administered subcutaneously at a fixed dose of about 2000 mg, followed by a fixed dose of about 1000 mg subcutaneously. In some embodiments, the first two administrations of the FcRn antagonist are administered subcutaneously at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the first two administrations of the FcRn antagonist are administered subcutaneously at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the first two administrations of the FcRn antagonist are administered subcutaneously at a fixed dose of 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is iatrovid.

[0351] 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 iatrovid.

[0352] 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 iatrovid.

[0353] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1008 mg. In some embodiments, the FcRn antagonist is iatrovid.

[0354] 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 weekly at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is iatrovid.

[0355] 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 iatrovid.

[0356] 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 iatrovid.

[0357] In some embodiments, the FcRn antagonist is administered intravenously once weekly or 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 every two weeks at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or 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 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 every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is iatrovid.

[0358] In some embodiments, the FcRn antagonist is administered at doses of approximately 0.2 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 12.5 mg / kg, approximately 15 mg / kg, approximately 17.5 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, approximately 100 mg / kg, approximately 110 mg / kg, approximately 12 ... The FcRn antagonist is administered intravenously once weekly or every two weeks at doses of approximately 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 iatrovid.

[0359] In some embodiments, the FcRn antagonist is administered at 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, 95mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 The FcRn antagonist is administered intravenously at doses of 1, 2, 3, 4, 5 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0360] In some embodiments, the FcRn antagonist is administered intravenously once weekly or 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 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 every two weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 15 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 20 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 30 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0361] In some embodiments, the FcRn antagonist is administered first intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is administered first intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered first intravenously and then 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 a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0362] In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose. In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose, at a fixed dose of 100 mg to 10,000 mg, once weekly, every two weeks, every three weeks, every four weeks, once monthly, or every six weeks. In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose, at a fixed dose of 1000 mg or 2000 mg, once weekly, every two weeks, every three weeks, every four weeks, once monthly, or every six weeks. In some embodiments, the FcRn antagonist is iatrovid.

[0363] In some embodiments, the FcRn antagonist is first administered by or under the supervision of a healthcare professional for at least five consecutive administrations. In some embodiments, subsequent administrations of a clinically proven safe and effective dose of egamod PH20 are given by a healthcare professional or by the patient or caregiver.

[0364] In some embodiments, the FcRn antagonist is administered for 61 weeks or less, 52 weeks or less, or 48 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 4 weeks. In some embodiments, the FcRn antagonist is administered for at least 12 weeks. In some embodiments, the FcRn antagonist is administered for at least 48 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 61 weeks.

[0365] In some embodiments, the FcRn antagonist is administered weekly until disease control or complete remission is achieved.

[0366] In some embodiments, the FcRn antagonist is administered during the induction phase, followed by a maintenance phase. In some embodiments, the FcRn antagonist is administered weekly during the induction phase, and during the maintenance phase, the dosing interval is extended to, for example, once every two weeks, once every three weeks, or once every four weeks. For embodiments where the induction phase involves administering the FcRn antagonist at a higher dose or frequency than during the maintenance phase, any specific dosing regimen described herein may be applied during both the induction and maintenance phases.

[0367] For example, in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously once weekly, and during the maintenance period, the FcRn antagonist is administered subcutaneously every two weeks. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg, and during the maintenance period, the FcRn antagonist is administered subcutaneously every two weeks at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is iatrovid. In some embodiments, the FcRn antagonist is administered spontaneously during the maintenance period.

[0368] The induction period can be at least 4 weeks, at least 8 weeks, or at least 12 weeks. The induction period can also be 61 weeks or less, 52 weeks or less, or 48 weeks or less. The induction period can be between 4 and 61 weeks, between 8 and 52 weeks, or between 12 and 48 weeks. In some embodiments, the induction period ends based on, for example, a clinical assessment by a healthcare provider. In some embodiments, the induction period ends when the subject exhibits ECI.

[0369] In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of about 1000 mg once weekly, and subsequently subcutaneously at a fixed dose of about 1000 mg every two weeks based on clinical assessment. In some embodiments, the clinical assessment is performed by a healthcare provider. In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of about 1000 mg once weekly, and subsequently subcutaneously at a fixed dose of about 1000 mg every two weeks when ECI is observed in the subject. In some embodiments, subcutaneous administration at a fixed dose of about 1000 mg once weekly is resumed after symptom exacerbation.

[0370] In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of 1000 mg once weekly, and subsequently at a fixed dose of 1000 mg every two weeks based on clinical assessment. In some embodiments, the clinical assessment is performed by a healthcare provider. In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of 1000 mg once weekly, and subsequently at a fixed dose of 1000 mg every two weeks if ECI is observed in the subject. In some embodiments, the weekly subcutaneous administration of a fixed dose of 1000 mg is resumed after symptom exacerbation.

[0371] In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of 1008 mg once weekly, and subsequently subcutaneously at a fixed dose of 1008 mg every two weeks based on clinical assessment. In some embodiments, the clinical assessment is performed by a healthcare provider. In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of 1008 mg once weekly, and subsequently subcutaneously at a fixed dose of 1008 mg every two weeks when ECI is observed in the subject. In some embodiments, subcutaneous administration at a fixed dose of 1008 mg once weekly is resumed after symptom exacerbation.

[0372] In some embodiments, treatment following any of the dosing regimens described herein is a period during which the subject does not receive any further FcRn antagonists. Subjects receiving an FcRn antagonist according to any of the dosing regimens described herein may achieve disease activity control (CDA), partial remission (PR), or complete remission (CR), making treatment withdrawal possible. Subjects may remain untreated during the period during which CDA, PR, or CR has been achieved, optionally for a period requiring further treatment if clinical exacerbation occurs. If further treatment according to any of the dosing regimens described herein fails to achieve CDA, PR, or CR, or if a relapse occurs, the subject may undergo a period of further treatment with an FcRn antagonist according to any of the dosing regimens described herein.

[0373] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly for at least 4 weeks. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject exhibits ECI. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject exhibits ECI between two consecutive measurements, optionally with an interval of about 1 week between the two consecutive measurements. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly until the subject exhibits ECI twice within two weeks. In some embodiments, ECI is a clinical improvement in one or more of I-RODS, mean grip strength, INCAT, or aINCAT score. In some embodiments, ECI is a clinical improvement in one or more of I-RODS, mean grip strength, or INCAT score.

[0374] In some embodiments, an FcRn antagonist is administered subcutaneously once weekly until the subject exhibits ECMD. In some embodiments, ECMD is one or more of the following: an increase of ≥1 point in an aINCAT score, a decrease of ≥4 points in I-RODS (using percentile measures), or a decrease of ≥8 kPa in average grip strength of one hand using a handheld grip dynamometer. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score between two consecutive measurements, optionally with an interval of approximately 1 week between the two consecutive measurements. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score over two weeks. In some embodiments, ECMD is an increase of ≥2 points in an aINCAT score.

[0375] In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly or every other week. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly for at least 4 weeks. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly until the subject exhibits ECI. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly until the subject exhibits ECI between two consecutive measurements, optionally with an interval of about 1 week between the two consecutive measurements. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously once weekly until the subject exhibits ECI twice within two weeks. In some embodiments, ECI is a clinical improvement in one or more of I-RODS, mean grip strength, INCAT, or aINCAT score.

[0376] In some embodiments, a clinically proven safe and effective dose of egamod PH20 is administered subcutaneously once weekly until the subject exhibits ECMD. In some embodiments, ECMD is one or more of the following: an increase of ≥1 point in aINCAT score, a decrease of ≥4 points in I-RODS (using percentile measures), or a decrease of ≥8 kPa in average grip strength of one hand using a handheld grip dynamometer. In some embodiments, ECMD is an increase of ≥1 point in aINCAT score. In some embodiments, ECMD is an increase of ≥1 point in aINCAT score between two consecutive measurements, optionally with an interval of approximately 1 week between the two consecutive measurements. In some embodiments, ECMD is an increase of ≥1 point in aINCAT score over two consecutive weeks. In some embodiments, ECMD is an increase of ≥2 points in aINCAT score.

[0377] In some embodiments, a clinically safe and effective dose of egamod PH20 is initially administered subcutaneously once weekly, and subsequently subcutaneously every two weeks based on clinical assessment. In some embodiments, the clinical assessment is performed by a healthcare provider. In some embodiments, a clinically safe and effective dose of egamod PH20 is initially administered subcutaneously once weekly, and subsequently subcutaneously every two weeks if ECI is observed in the subject. In some embodiments, a weekly subcutaneous dose of clinically safe and effective egamod PH20 is resumed after symptom exacerbation. In some embodiments, a clinically safe and effective dose of egamod PH20 is administered subcutaneously over approximately 30 to 90 seconds. In some embodiments, a clinically safe and effective dose of egamod PH20 is initially administered by or under the supervision of a healthcare professional for at least 5 consecutive administrations. In some embodiments, subsequent administrations of a clinically safe and effective dose of egamod PH20 are given by a healthcare professional or by the patient or caregiver.

[0378] In some embodiments, the clinically safe and clinically effective amount of egamod PH20 is 1008 mg / 11,200 units. In some embodiments, the clinically safe and clinically effective amount of egamod PH20 is 1000 mg / 11,200 units.

[0379] In some embodiments, the FcRn antagonist is rozanolizumab. In some embodiments, rozanolizumab is administered subcutaneously or intravenously. In some embodiments, rozanolizumab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0380] In some embodiments, rozanolizumab is administered at doses of approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg, approximately 12 mg / kg, and approximately 12 mg / kg.5 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, approximately 25 mg / kg, approximately 26 mg / kg, approximately 27 mg / kg, approximately 28 mg / kg, approximately 29 mg / kg, approximately 30 mg / kg, approximately 31 mg / kg, approximately 32 mg / kg, approximately 33 mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 ... mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, approximately 56 mg / kg, approximately 57 mg / kg, approximately 58 mg / kg, approximately 59 mg / kg, approximately 60 mg / kg, approximately 61 mg / kg, approximately 62 mg / kg, approximately 63 mg / kg, approximately 64 mg / kg, approximately 65 mg / kg, approximately 66 mg / kg, approximately 67 mg / kg, approximately 68 mg / kg, approximately 69 mg / kg, approximately 70 mg / kg, approximately 71 mg / kg, approximately 72 mg / kg, approximately 73 mg / kg, approximately 74 mg / kg, approximately 75 mg / kg, approximately 76 mg / kg, approximately 77 mg / kg, approximately 78 mg / kg, approximately 79 mg / kg, approximately 80 mg / kg, approximately 81 mg / kg Doses of approximately 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg may be administered once weekly, every two weeks, every three weeks, every four weeks, or monthly.

[0381] In some embodiments, the FcRn antagonist is nicarlimab. In some embodiments, nicarlimab is administered subcutaneously or intravenously. In some embodiments, nicarlimab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0382] In some embodiments, nicarlimab is administered at doses of approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg, approximately 12 mg / kg, or approximately 12 mg / kg.5 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, approximately 25 mg / kg, approximately 26 mg / kg, approximately 27 mg / kg, approximately 28 mg / kg, approximately 29 mg / kg, approximately 30 mg / kg, approximately 31 mg / kg, approximately 32 mg / kg, approximately 33 mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 ... mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, approximately 56 mg / kg, approximately 57 mg / kg, approximately 58 mg / kg, approximately 59 mg / kg, approximately 60 mg / kg, approximately 61 mg / kg, approximately 62 mg / kg, approximately 63 mg / kg, approximately 64 mg / kg, approximately 65 mg / kg, approximately 66 mg / kg, approximately 67 mg / kg, approximately 68 mg / kg, approximately 69 mg / kg, approximately 70 mg / kg, approximately 71 mg / kg, approximately 72 mg / kg, approximately 73 mg / kg, approximately 74 mg / kg, approximately 75 mg / kg, approximately 76 mg / kg, approximately 77 mg / kg, approximately 78 mg / kg, approximately 79 mg / kg, approximately 80 mg / kg, approximately 81 mg / kg Doses of approximately 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg may be administered once weekly, every two weeks, every three weeks, every four weeks, or monthly.

[0383] In some embodiments, the FcRn antagonist is orolinumab. In some embodiments, orolinumab is administered subcutaneously or intravenously. In some embodiments, orolinumab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0384] In some embodiments, onitroimab is administered at doses of approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg, approximately 12 mg / kg, or approximately 12 mg / kg.5 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, approximately 25 mg / kg, approximately 26 mg / kg, approximately 27 mg / kg, approximately 28 mg / kg, approximately 29 mg / kg, approximately 30 mg / kg, approximately 31 mg / kg, approximately 32 mg / kg, approximately 33 mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 ... mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, approximately 56 mg / kg, approximately 57 mg / kg, approximately 58 mg / kg, approximately 59 mg / kg, approximately 60 mg / kg, approximately 61 mg / kg, approximately 62 mg / kg, approximately 63 mg / kg, approximately 64 mg / kg, approximately 65 mg / kg, approximately 66 mg / kg, approximately 67 mg / kg, approximately 68 mg / kg, approximately 69 mg / kg, approximately 70 mg / kg, approximately 71 mg / kg, approximately 72 mg / kg, approximately 73 mg / kg, approximately 74 mg / kg, approximately 75 mg / kg, approximately 76 mg / kg, approximately 77 mg / kg, approximately 78 mg / kg, approximately 79 mg / kg, approximately 80 mg / kg, approximately 81 mg / kg Doses of approximately 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg may be administered once weekly, every two weeks, every three weeks, every four weeks, or monthly.

[0385] In some embodiments, onolinumab is administered intravenously at a dose of about 30 mg / kg once a week for three weeks, followed by intravenous administration at a dose of 10 mg / kg every other week.

[0386] In some embodiments, the FcRn antagonist is battolimab or IMVT-1402. In some embodiments, battolimab or IMVT-1402 is administered subcutaneously or intravenously. In some embodiments, battolimab or IMVT-1402 is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to 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.

[0387] In some embodiments, batolimumab or IMVT-1402 is administered at approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg, approximately 12 mg / kg, or approximately 12 mg / kg.5 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, approximately 25 mg / kg, approximately 26 mg / kg, approximately 27 mg / kg, approximately 28 mg / kg, approximately 29 mg / kg, approximately 30 mg / kg, approximately 31 mg / kg, approximately 32 mg / kg, approximately 33 mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 ... mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, approximately 56 mg / kg, approximately 57 mg / kg, approximately 58 mg / kg, approximately 59 mg / kg, approximately 60 mg / kg, approximately 61 mg / kg, approximately 62 mg / kg, approximately 63 mg / kg, approximately 64 mg / kg, approximately 65 mg / kg, approximately 66 mg / kg, approximately 67 mg / kg, approximately 68 mg / kg, approximately 69 mg / kg, approximately 70 mg / kg, approximately 71 mg / kg, approximately 72 mg / kg, approximately 73 mg / kg, approximately 74 mg / kg, approximately 75 mg / kg, approximately 76 mg / kg, approximately 77 mg / kg, approximately 78 mg / kg, approximately 79 mg / kg, approximately 80 mg / kg, approximately 81 mg / kg Doses of approximately 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg may be administered once weekly, every two weeks, every three weeks, every four weeks, or monthly.

[0388] Treatment results

[0389] Treatment of CIDP typically involves changes in disease status, particularly improvement. In some embodiments, administration of an FcRn antagonist to a subject with CIDP will result in disease activity control (CDA), partial remission (PR), or complete remission (CR) as defined herein. In some embodiments, complete remission is achieved. In some embodiments, CDA, PR, or CR is maintained in the subject for at least two months, at least three months, at least four months, at least five months, or at least six months.

[0390] In some embodiments, CDA, PR, or CR is achieved within 12 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, CDA, PR, or CR is achieved within 8 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, CDA, PR, or CR is achieved within 6 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, CDA, PR, or CR is achieved within 4 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, CDA, PR, or CR is achieved within 3 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, the FcRn antagonist is iatrovid.

[0391] In some embodiments, once CDA, PR, or CR is achieved, continuous administration of the FcRn antagonist is used to prevent symptom exacerbation. This prevention can be achieved throughout the duration of treatment (i.e., all the time the subject is receiving the FcRn antagonist). The absence of symptom exacerbation can be measured using any of the assessment methods described herein, including but not limited to: (i) the INCAT Disability Scale (Merkies et al., 2002); (ii) the MRC Scale (Vanhoutte et al., 2012); (iii) the I-RODS (van Nes et al., 2011); (iv) the average grip strength test (Vanhoutte et al., 2013); and (v) the TUG test.

[0392] In some embodiments, treatment with an FcRn antagonist achieves CDA, PR, and / or CR, and / or prevents or delays relapse, i.e., clinical worsening of symptoms. In some embodiments, disease relapse is prevented or delayed for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks.

[0393] In some embodiments, treatment following the achievement of PR or CR in CIDP is continued for at least 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, or 52 weeks.

[0394] In some embodiments, the duration of treatment to prevent or delay CIDP relapse is defined as the period during which the subject experiences no symptom worsening while receiving an FcRn antagonist.

[0395] In some embodiments, the treatment prevents or delays relapse after discontinuation of the treatment, i.e., the period of time following cessation of the subject's administration of the FcRn antagonist. In some embodiments, the treatment prevents or delays relapse for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks after discontinuation of the treatment. In some embodiments, the treatment prevents or delays relapse for at least 20 weeks after discontinuation of the treatment.

[0396] In some embodiments, treatment-naïve subjects are treated according to the methods described herein and achieve partial remission (PR) or complete remission. In these embodiments, subjects may experience a duration of continued treatment to prevent or delay relapse (when continuing FcRn antagonist treatment after achieving PR or CR). In these embodiments, treatment-naïve subjects may alternatively or additionally experience prevention or delay of relapse after discontinuation of treatment.

[0397] In some embodiments, the treatment reduces the risk of relapse by at least 60% compared to subjects not treated with an FcRn antagonist. In some embodiments, the treatment reduces the risk of relapse by at least 60% after discontinuation of the treatment compared to subjects not treated with an FcRn antagonist. In some embodiments, the treatment reduces the risk of relapse by approximately 61% compared to subjects not treated with an FcRn antagonist. In some embodiments, the treatment reduces the risk of relapse by approximately 61% after discontinuation of the treatment compared to subjects not treated with an FcRn antagonist. In some embodiments, the treatment reduces the risk of relapse by 61% after discontinuation of the treatment compared to subjects not treated with an FcRn antagonist. In some embodiments, the treatment reduces the risk of relapse by 61% after discontinuation of the treatment compared to subjects not treated with an FcRn antagonist.

[0398] In some embodiments, subjects treated according to the methods described herein show improvement in one or more CIDP symptoms after administration of an FcRn antagonist. Symptom improvement can be assessed using any of the assessment methods described herein, including but not limited to: (i) the INCAT Disability Scale (Merkies et al., 2002); (ii) the MRC Scale (Vanhoutte et al., 2012); (iii) the I-RODS (van Nes et al., 2011); (iv) the average grip strength test (Vanhoutte et al., 2013); and (v) the TUG test. In some embodiments, improvement in one or more CIDP symptoms is achieved within 12 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in one or more CIDP symptoms is achieved within 8 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in one or more CIDP symptoms is achieved within 6 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in one or more CIDP symptoms is achieved within 4 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in one or more CIDP symptoms is achieved within 3 weeks or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in one or more CIDP symptoms is achieved within 9 days or less of the first administration of an FcRn antagonist as described herein. In some embodiments, improvement in at least one of aINCAT score, I-RODS, or grip strength is achieved within 9 days of the first administration of an FcRn antagonist as described herein.

[0399] In some embodiments, subjects treated according to the methods described herein showed symptom improvement, as measured using the INCAT Disability Scale, compared to baseline (i.e., before treatment). In some embodiments, subjects showed a decrease (i.e., an increase) of 1 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 1 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 2 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 3 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 4 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 5 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 6 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 7 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 8 or more in their INCAT score. In some embodiments, subjects showed a decrease (i.e., an increase) of 9 or more in their INCAT score.

[0400] In some embodiments, subjects showed a decrease in aINCAT score, such that the aINCAT score was 5 or lower, 4 or lower, 3 or lower, 2 or lower, or 1 or lower after administration of the FcRn antagonist. Subjects may show improvement in upper limb performance, lower limb performance, or both, as measured using an aINCAT score.

[0401] In some embodiments, subjects treated according to the methods described herein showed improvement in symptoms, as measured using the MRC scale. As described elsewhere herein, the MRC scale is a 5-point scale (0-5), where 0 indicates complete paralysis and 5 indicates normal strength. The scale is applied bilaterally to six muscle groups of the upper and lower extremities (1. arm abductors, 2. elbow flexors, 3. wrist extensors, 4. hip flexors, 5. knee extensors, and 6. foot dorsiflexors) to obtain a total score ranging from 0 to 60. In some embodiments, subjects showed an increase (i.e., improvement) of 2 or more, 3 or more, 5 or more, 10 or more, 20 or more, 30 or more, or 40 or more in their MRC score. Subjects may show improvement in upper extremity performance, lower extremity performance, or both, as measured using the MRC scale.

[0402] In some embodiments, subjects treated according to the methods described herein showed improvement in symptoms, as measured using the I-RODS. As described elsewhere herein, the I-RODS is a 24-item scale, where each item represents a common daily activity, ranging from very difficult to perform (e.g., running or dancing) to very easy to perform (e.g., eating or reading). Higher scores indicate less disability. The raw I-RODS scores (range: 0 to 48) are typically converted to percentile metric scores, ranging from 0 (most severe activity and social participation limitation) to 100 (no activity and social participation limitation). In some embodiments, subjects showed an increase (i.e., improvement) of 4 or more, 8 or more, 12 or more, or 20 or more in their I-RODS percentile metric score.

[0403] In some embodiments, subjects treated according to the methods described herein showed improvement in symptoms, as measured using a mean grip strength test. Mean grip strength can be measured using a handheld Martin grip strength meter. In some embodiments, subjects showed an increase in mean grip strength ≥8 kPa after administration of an FcRn antagonist. > 16 kPa > 24 kPa. Average grip strength is typically measured by testing the subject's dominant hand.

[0404] In some embodiments, subjects treated according to the methods described herein showed symptom improvement, as measured using the TUG test. The TUG test is a simple test for assessing a person's activity level and requires both static and dynamic balance. In the TUG test, the time spent getting up from a chair, walking 3 meters, turning around, walking back to the chair, and sitting down is measured. In some embodiments, subjects showed improvement in the TUG test by reducing the time spent completing 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more of the test.

[0405] In some embodiments, subjects showed improvements in quality of life (QoL), as measured by any QoL scale / test described herein. In some embodiments, QoL was assessed by one or more of the following: the EuroQoL 5-dimensional 5-point scale (EQ-5D-5L); the Brief Pain Inventory-SF (BPI-SF); the Treatment Satisfaction Questionnaire-9 (TSQM-9); the Rasch Change in Fatigue Severity Scale (RT-FSS); the Hospital Anxiety and Depression Scale (HADS); and the Patient Global Impression Change (PGIC).

[0406] In some embodiments, subjects show a decrease in serum levels of one or more of the following following administration of an FcRn antagonist: (i) total IgG levels; (ii) autoantibody levels; (iii) cytokine levels; (iv) chemokine levels; and (v) immune complexes. The decrease can be measured using any suitable technique known to those skilled in the art.

[0407] In some embodiments, subjects show a decrease in serum levels of one or more autoantibodies after administration of an FcRn antagonist. Such autoantibodies may be selected from the group consisting of: anti-GM1 antibody; anti-LM-1 antibody; anti-NF-155 antibody; anti-CNTN1 antibody; anti-Caspr-1 antibody; and anti-myelinated nerve antibody.

[0408] FcRn also binds to and recirculates serum albumin, a regulator of serum cholesterol levels. Some FcRn antagonists (particularly certain anti-FcRn antibodies) have been found to decrease serum albumin levels and thus increase serum cholesterol levels in human subjects, both of which are undesirable.

[0409] In some embodiments, subjects treated according to the methods described herein do not experience a decrease in serum albumin levels after administration of an FcRn antagonist. In some embodiments, a decrease in serum albumin levels of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to baseline albumin levels. In one embodiment, a decrease in serum albumin levels of less than about 10% is observed compared to baseline albumin levels. In some embodiments, subjects treated according to the methods described herein do not experience an increase in serum cholesterol levels after administration of an FcRn antagonist. In some embodiments, an increase in serum cholesterol levels of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to baseline cholesterol levels. In one embodiment, an increase in serum cholesterol levels of less than about 10% is observed compared to baseline serum cholesterol levels. Serum cholesterol can be measured in the form of total cholesterol, high-density lipoprotein (HDL) cholesterol, and / or the total cholesterol:HDL ratio. Advantageously, igamatidec does not decrease serum albumin levels. Therefore, in some embodiments, the FcRn antagonist is igamatidec.

[0410] In some embodiments, subjects treated according to the methods described herein do not experience significant proteinuria, i.e., significant or abnormal levels of protein in the urine. Proteinuria can be quantified by the albumin / creatinine ratio (ACR) or the protein / creatinine ratio (PCR). In some embodiments, subjects treated according to the methods described herein have an ACR of 15 mg / mmol or less, preferably 3 mg / mmol or less.

[0411] In some embodiments, subjects treated according to the methods described herein, particularly those receiving FcRn antagonists via subcutaneous administration, experience minimal injection site reactions. An injection site reaction (ISR) is a well-defined phenomenon following the administration of a pharmaceutical agent (e.g., a biologic) and includes swelling, erythema, itching, and pain around the injection site.

[0412] In some embodiments, treatment according to the methods described herein exhibits a safety profile that excludes the need for continuous monitoring of standard patient parameters, particularly those routinely monitored during treatment of CIDP patients. In some embodiments, treatment according to the methods described herein exhibits a safety profile that excludes the need for continuous or periodic monitoring of serum albumin levels, serum cholesterol levels, and / or proteinuria. In some embodiments, treatment according to the methods described herein exhibits a safety profile that excludes the need for prior patient medication.

[0413] In some embodiments, a method is provided for treating CIDP in subjects within a patient population. In some embodiments, the method includes administering an FcRn antagonist as described herein to subjects within a patient population. In some embodiments, the method includes administering an FcRn antagonist as described herein, co-formulated with hyaluronidase, to subjects within a patient population. In some embodiments, the method includes administering egamod PH20 or a biosimilar thereof to a patient population. In some embodiments, the method includes administering 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof to a patient population. In some embodiments, the method includes subcutaneous administration of an FcRn antagonist (e.g., egamod) once weekly.

[0414] In some embodiments, 66.5% of the subjects in the patient population exhibited ECI. In some embodiments, 66.5% of the subjects in the patient population exhibited ECI after administration of an FcRn antagonist. In some embodiments, 66.5% of the subjects in the patient population exhibited ECI. In some embodiments, 66.5% of the subjects in the patient population exhibited ECI after administration of an FcRn antagonist. In some embodiments, ECI was achieved in the patient population within 31 to 51 days after the first administration of the FcRn antagonist. In some embodiments, ECI was achieved in the patient population within 43 days. In some embodiments, ECI was achieved in the patient population within 43 days after the first administration of the FcRn antagonist. In some embodiments, the patient population included 322 subjects. In some embodiments, the FcRn antagonist was iatrovid PH20 or a biosimilar thereof.

[0415] In some embodiments, after administration of the FcRn antagonist, 69% of the subjects in the patient population showed signs of improvement between two consecutive measurements. In some embodiments, signs of improvement were selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in mean grip strength. In some embodiments, the patient population included 322 subjects. In some embodiments, the FcRn antagonist was iatrovid PH20 or a biosimilar thereof.

[0416] In some embodiments, anti-egamod α antibodies were detected in 6% of subjects in the patient population after administration of an FcRn antagonist. In some embodiments, anti-egamod α antibodies were detected in 6% of subjects in the patient population after administration of an FcRn antagonist for up to 12 weeks. In some embodiments, neutralizing anti-egamod α antibodies were detected in 0.3% of subjects in the patient population after administration of an FcRn antagonist. In some embodiments, neutralizing anti-egamod α antibodies were detected in 0.3% of subjects in the patient population after administration of an FcRn antagonist for up to 12 weeks. In some embodiments, anti-egamod α antibodies were detected in 2% of subjects in the patient population after administration of an FcRn antagonist. In some embodiments, anti-egamod α antibodies were detected in 2% of subjects in the patient population after administration of an FcRn antagonist for up to 48 weeks. In some embodiments, the FcRn antagonist is egamod PH20 or a biosimilar thereof.

[0417] In some embodiments, subjects in the patient population remained relapse-free for a longer period (e.g., significantly longer) than subjects who did not receive egamod PH20 or its biosimilars. In some embodiments, subjects in the patient population remained CIDP symptom-free for a longer period (e.g., significantly longer) than subjects who did not receive egamod PH20 or its biosimilars.

[0418] In some embodiments, subjects in the patient population experienced a longer time to clinical deterioration compared to subjects who did not receive egamod PH20 or its biosimilar forms. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point between two consecutive measurements. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant.

[0419] In some embodiments, subjects treated with egamod PH20 or its biosimilars showed a 61% reduction in the risk of deterioration. In some embodiments, subjects treated with egamod PH20 or its biosimilars showed a 61% reduction in the risk of deterioration in patients with CIDP. In some embodiments, subjects treated with egamod PH20 or its biosimilars showed a 61% reduction in the risk of deterioration compared to subjects not treated with egamod PH20 (e.g., subjects treated with placebo).

[0420] In some embodiments, following administration of eigamod PH20 or its biosimilar form, the mean percentage reduction in total IgG levels (e.g., serum IgG levels) relative to baseline in the patient population ranged between approximately 66.8% and approximately 71.6%. In some embodiments, the mean percentage reduction in total IgG levels (e.g., serum IgG levels) relative to baseline in the patient population ranged between 66.8% and 71.6%. In some embodiments, the mean percentage reduction in total IgG levels (e.g., serum IgG levels) relative to baseline was maintained from week 4 throughout the treatment period.

[0421] In some embodiments, subjects showed a reduction in serum total IgG levels between about 66.8% and about 71.6% after administration of eigamod PH20 or a biosimilar thereof. In some embodiments, subjects showed a reduction in serum total IgG levels between about 66.8% and about 71.6% after administration of eigamod PH20 or a biosimilar thereof four times weekly. In some embodiments, subjects showed a reduction in serum total IgG levels between 66.8% and 71.6% after administration of eigamod PH20 or a biosimilar thereof four times weekly. In some embodiments, the reduction in serum total IgG levels was maintained until the weekly administration of eigamod PH20 or a biosimilar thereof was discontinued.

[0422] In some embodiments, the patient population prior to treatment with egamod PH20 includes untreated CIDP patients, CIDP patients receiving immunoglobulins, and CIDP patients receiving corticosteroids.

[0423] In some embodiments, the patient population includes patients with treatment-unstable and refractory CIDP (CIDP Disease Activity Score (CDAS) 5B and 5C) prior to treatment with egamod PH20, and patients with stable CIDP on existing treatments (CDAS 3 and 4) prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with mild to severe disability prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with an INCAT score of 2–9 prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with an IRODS of 11–61 prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with a mean grip strength of 1–120 kPa prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with a mean INCAT score of 5 prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with a mean IRODS of 37 prior to treatment with egamod PH20. In some embodiments, the patient population includes CIDP patients with an average grip strength of 39 kPa prior to treatment with egamod PH20.

[0424] Additional treatments

[0425] The methods described herein may include the additional step of administering an effective amount of one or more additional therapeutic agents to the subject.

[0426] In some embodiments, the method further includes administering an effective amount of one or more immunosuppressants. Examples include, but are not limited to, methotrexate, mycophenolate mofetil (MMF), azathioprine, cyclophosphamide, doxycycline, and dapsone.

[0427] In some embodiments, the method further includes administering an effective amount of one or more corticosteroids to the subject. In some embodiments, 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 some embodiments, the oral corticosteroid is dexamethasone. In some embodiments, the oral corticosteroid is methylprednisolone, prednisone, or prednisolone.

[0428] In one embodiment, an effective amount of corticosteroid is administered at a dose of 2.5 mg / day to 20 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of 5 mg / day to 20 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of 7.5 mg / day to 20 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of 8 mg / day to 15 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of 10 mg / day to 15 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 20 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 10 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 7.5 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 5 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 2.5 mg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 1 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.75 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.5 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.4 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.3 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.25 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.2 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.15 mg / kg / day. In one embodiment, an effective amount of corticosteroid is administered at a dose of about 0.1 mg / kg / day.

[0429] Subjects treated with corticosteroids may gradually reduce their corticosteroid dosage before, during, or after treatment with an FcRn antagonist. Gradual reduction of corticosteroid dosage may refer to lowering the dose of corticosteroids or reducing the frequency of administration.

[0430] In one embodiment, the dose of corticosteroids is reduced after CDA or remission (partial or complete). In some embodiments, the dose of corticosteroids is reduced after CDA has been maintained for at least two weeks.

[0431] In some embodiments, the corticosteroid dosing regimen is reduced by following a gradual reduction schedule. Examples of gradual reduction schedules that can be used to reduce the dose of corticosteroids are provided herein. Those skilled in the art will understand that the gradual reduction schedule can vary and can be adjusted based on several subject-specific factors, such as the initial corticosteroid dose, changes in CIDP symptoms, the subject's overall health condition, etc.

[0432] In some embodiments, the daily dose of an oral corticosteroid (OCS), such as prednisone, is reduced from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of the OCS (e.g., prednisone) is maintained for at least two weeks before further dose reduction. In some embodiments, the daily dose of the OCS (e.g., prednisone) is maintained at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks, optionally provided that CIDP symptoms do not worsen.

[0433] In some embodiments, the daily dose of OCS (e.g., prednisone) is reduced from 0.75 mg / kg / day to 0.5 mg / kg / day, from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of OCS (e.g., prednisone) is maintained for at least two weeks before further dose reduction. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.5 mg / kg / day for at least 2 weeks, then at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.5 mg / kg / day for at least 2 weeks, then at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks, optionally provided that CIDP symptoms do not worsen.

[0434] In some embodiments, the daily dose of OCS (e.g., prednisone) is reduced from 1 mg / kg / day to 0.75 mg / kg / day, from 0.75 mg / kg / day to 0.5 mg / kg / day, from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of OCS (e.g., prednisone) is maintained for at least two weeks prior to further dose reduction. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.75 mg / kg / day for at least 2 weeks, then at 0.5 mg / kg / day for at least 2 weeks, then at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.75 mg / kg / day for at least 2 weeks, then at 0.5 mg / kg / day for at least 2 weeks, then at 0.3 mg / kg / day for at least 2 weeks, then at 0.2 mg / kg / day for at least 2 weeks, then at 0.15 mg / kg / day for at least 2 weeks, and then at 0.1 mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks, optionally provided that CIDP symptoms do not worsen.

[0435] After maintaining a dose of 0.1 mg / kg / day for at least 2 weeks, the daily dose of OCS (e.g., prednisone) may optionally be further reduced by 2.5 mg every two weeks for one or more two-week periods. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.1 mg / kg / day for at least 8 weeks, then further reduced by 2.5 mg every two weeks for one or more two-week periods. In some embodiments, the daily dose of OCS (e.g., prednisone) is reduced by 2.5 mg every two weeks for one or more two-week periods until the daily dose of OCS (e.g., prednisone) is zero (i.e., discontinuation of corticosteroid therapy). In some embodiments, each daily dose is maintained for two weeks, optionally provided that CIDP symptoms do not worsen.

[0436] Alternatively, after maintaining a dose of 0.1 mg / kg / day for at least 2 weeks, the daily dose of OCS (e.g., prednisone) may optionally be further reduced by 1 mg weekly for one or more one-week periods. In some embodiments, the daily dose of OCS (e.g., prednisone) is maintained at 0.1 mg / kg / day for at least 8 weeks, then further reduced by 1 mg weekly for one or more one-week periods. In some embodiments, the daily dose of OCS (e.g., prednisone) is reduced by 1 mg weekly for one or more one-week periods until the daily dose of OCS (e.g., prednisone) is zero (i.e., discontinuation of corticosteroid therapy). In some embodiments, each daily dose is maintained for one week, optionally provided that CIDP symptoms do not worsen.

[0437] diagnosis

[0438] In some embodiments, the methods described herein can be used to assist in the diagnosis of CIDP. As described elsewhere herein, CIDP is a highly heterogeneous condition and its diagnosis is challenging; misdiagnosis is common. The results presented herein demonstrate the efficacy of egamod in the treatment of CIDP, establishing CIDP as an autoimmune disease responsive to treatment with an FcRn antagonist. The methods described herein can be used to assist in the diagnosis of CIDP based on the following: a patient suspected of having CIDP (e.g., according to standard diagnostic criteria) and treated according to any of the embodiments described herein can be confirmed as having CIDP if they exhibit a positive response to treatment. A positive response to treatment can be measured as control of disease activity, partial remission, or complete remission. A positive response to treatment can be measured as symptom improvement or stabilization as measured using any of the assessment methods described herein. In some embodiments, the methods described herein (where the FcRn antagonist is egamod) are used to assist in the diagnosis of CIDP.

[0439] F. Pharmaceutical Products

[0440] This disclosure provides a pharmaceutical product containing egamod and hyaluronidase, both approved for the treatment of CIDP. A method of treating CIDP is also provided, comprising administering the pharmaceutical product containing egamod and hyaluronidase. The use of the pharmaceutical product containing egamod and hyaluronidase for the treatment of CIDP is also provided.

[0441] In some embodiments, the pharmaceutical product is formulated for optional subcutaneous administration over approximately 30 to 90 seconds. In some embodiments, the pharmaceutical product is administered in a total volume of approximately 5.6 mL. In some embodiments, the pharmaceutical product is administered in a total volume of 5.6 mL. In some embodiments, the pharmaceutical product is provided in a single-dose vial for subcutaneous administration via a wing-type infusion device.

[0442] In some embodiments, the pharmaceutical product is provided in a single-dose vial at a concentration of 180 mg egamod / 2000 units of hyaluronidase per mL. In some embodiments, the pharmaceutical product is provided in a single-dose vial containing about 180 mg / mL egamod, about 2000 units / mL recombinant human hyaluronidase (rHuPH20), 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 20, about 5.8 mg / mL sodium chloride, and about 20.5 mg / mL sucrose, at a pH of about 6.0.

[0443] In some embodiments, the pharmaceutical product is provided in a single-dose vial containing 180 mg / mL egamod, 2,000 U / mL rHuPH20, 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 20, 5.8 mg / mL sodium chloride, and 20.5 mg / mL sucrose, at a pH of about 6.0.

[0444] In some embodiments, the pharmaceutical product is provided in a single-dose vial containing a 5.6 mL liquid formulation comprising 1,008 mg egamod, 11,200 units rHuPH20, 7.8 mg histidine, 12.3 mg L-histidine hydrochloride monohydrate, 8.4 mg methionine, 2.2 mg polysorbate 20, 32.5 mg sodium chloride, 114.8 mg sucrose, and water for injection (USP) at pH 6.0.

[0445] In some embodiments, the pharmaceutical product is provided in a single-dose vial containing 5.6 mL of a liquid formulation comprising 1,008 mg of egamod and 11,200 units of rHuPH20, and each mL of the vial solution contains histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), methionine (1.5 mg), polysorbate 20 (0.4 mg), sodium chloride (5.8 mg), sucrose (20.5 mg), and water for injection (USP) at a pH of 6.0.

[0446] In some embodiments, the pharmaceutical product is provided in a single-dose vial with a total volume of 5.6 mL, the vial containing 180 mg / mL egamod, 2,000 units / mL recombinant human hyaluronidase (rHuPH20), 1.4 mg / mL histidine, 2.2 mg / mL L-histidine hydrochloride monohydrate, 1.5 mg / mL methionine, 0.4 mg / mL polysorbate 20, 5.8 mg / mL sodium chloride, 20.5 mg / mL sucrose, and water for injection (USP) at pH 6.0.

[0447] In some embodiments, the pharmaceutical product is a reference product.

[0448] In some embodiments, the pharmaceutical product listed is a reference product based on elastatin administered at a dose of 1000 mg. In some embodiments, the pharmaceutical product listed is a reference product based on elastatin administered at a dose of 1008 mg. In some embodiments, the pharmaceutical product listed is a reference product based on hyaluronidase administered at a dose of 11,200 units. In some embodiments, the pharmaceutical product listed is a reference product based on once-weekly or every other week. In some embodiments, the pharmaceutical product listed is a reference product based on once-weekly administration. In some embodiments, the pharmaceutical product listed is a reference product based on once-weekly administration, subsequently adjusted to every other week based on clinical assessment. In some embodiments, the pharmaceutical product listed is a reference product based on resuming once-weekly administration in cases of worsening symptoms.

[0449] In some embodiments, the pharmaceutical product is a reference product listed based on the first 5 injections, which must be administered by or under the supervision of a medical professional, and subsequent treatments should be administered by a medical professional or may be administered at home by a patient or caregiver after appropriate training in subcutaneous injection techniques.

[0450] In some embodiments, the pharmaceutical product is approved for administration to adult patients. In some embodiments, the pharmaceutical product has an approved indication for treating CIDP in adult patients who have active disease despite treatment with corticosteroids or immunoglobulins.

[0451] In some embodiments, the drug product induced an ECI response in 66.5% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly. In some embodiments, the median time to initial confirmed ECI in the CIDP patient population was 43 days from the first administration of the drug product. In some embodiments, up to 40% of CIDP patients in the CIDP patient population had an ECI response four weeks after the first administration of the drug product. In some embodiments, 25% of CIDP patients in the CIDP patient population showed a clinically relevant improvement in at least one of the following within 9 days of the first administration of the drug product: aINCAT score, I-RODS, or mean grip strength. In some embodiments, the CIDP patient population consisted of 322 CIDP patients. In some embodiments, patients in the CIDP patient population receiving the drug product maintained a relapse-free period significantly longer than patients in the CIDP patient population receiving placebo. In some embodiments, patients in the CIDP patient population receiving the drug product showed a 61% reduction in the risk of exacerbation compared to patients in the CIDP patient population receiving placebo. In some embodiments, 69% of CIDP patients in the cohort receiving the drug product showed signs of improvement between two consecutive measurements following administration of the FcRn antagonist. In some embodiments, signs of improvement were selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in mean grip strength. In some embodiments, CIDP patients in the cohort receiving the drug product experienced a longer time to clinical deterioration compared to CIDP patients in the cohort receiving placebo. In some embodiments, clinical deterioration was defined as an increase of ≥1 point in the aINCAT score. In some embodiments, clinical deterioration was defined as an increase of ≥1 point in the aINCAT score between two consecutive measurements. In some embodiments, clinical deterioration was defined as an increase of ≥2 points in the aINCAT score. In some embodiments, the longer time to clinical deterioration was demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration was statistically significant.

[0452] In some embodiments, the pharmaceutical product induces a hypersensitivity reaction selected from the group consisting of allergic reactions and hypotension leading to syncope. In some embodiments, the allergic reaction and hypotension leading to syncope occur during or within 1 hour of administration of the pharmaceutical product. In some embodiments, the pharmaceutical product is contraindicated in patients with severe hypersensitivity to the eigenin α product, hyaluronidase, or any excipients in the pharmaceutical product.

[0453] In some embodiments, the pharmaceutical product induces an infusion-related reaction. In some embodiments, an infusion-related reaction is one or more of the following: hypertension, chills, shivering, chest pain, abdominal pain, and back pain. In some embodiments, when a mild to moderate infusion-related reaction occurs during administration of the pharmaceutical product, one or more subsequent doses of the pharmaceutical product are administered with close clinical observation, a slower infusion rate, and pre-medication.

[0454] In some embodiments, the label of the pharmaceutical product includes a contraindication for patients with severe hypersensitivity to any excipient of the eigamod alpha product, hyaluronidase, or formulations thereof. In some embodiments, the label of the pharmaceutical product includes a warning for hypersensitivity reactions selected from anaphylactic reactions and hypotension leading to syncope. In some embodiments, the label of the pharmaceutical product includes a warning for infusion-related reactions selected from hypertension, chills, shivering, chest pain, abdominal pain, and back pain. In some embodiments, the label of the pharmaceutical product states that appropriate therapy should be initiated when a severe infusion-related reaction occurs during product administration. In some embodiments, the label of the pharmaceutical product states that when a mild to moderate infusion-related reaction occurs during product administration, the patient may again be closely monitored clinically, given a slower infusion rate, and pre-medicated.

[0455] In some embodiments, following treatment with the pharmaceutical product, the product induced anti-egamaide antibodies in 2% of subjects in a CIDP patient population. In some embodiments, following treatment with the pharmaceutical product, the product induced anti-egamaide antibodies in 6% of subjects in a CIDP patient population. In some embodiments, following treatment with the pharmaceutical product, the product induced neutralizing anti-egamaide antibodies in 0.3% of subjects in a CIDP patient population.

[0456] In some embodiments, the drug product label includes data showing an ECI response in 66.5% of a CIDP patient population receiving 1008 mg / 11,200 units of egamod PH20 once weekly. In some embodiments, the drug product label includes data showing a median time to initial confirmed ECI of 43 days from the first administration of the drug product in the CIDP patient population. In some embodiments, the drug product label includes data showing an ECI response in up to 40% of CIDP patients in the CIDP patient population four weeks after the first administration of the drug product. In some embodiments, the drug product label includes data showing a clinically relevant improvement in at least one of the following in 25% of the CIDP patients in the CIDP patient population within 9 days of the first administration of the drug product: aINCAT score, I-RODS, or average grip strength. In some embodiments, the CIDP patient population consists of 322 CIDP patients. In some embodiments, the drug product label includes data showing that patients in the CIDP patient population receiving the drug product maintained a significantly longer relapse-free period than patients in the CIDP patient population receiving placebo. In some embodiments, the label of the pharmaceutical product includes data demonstrating a 61% reduction in the risk of deterioration among patients in the CIDP patient population receiving the pharmaceutical product compared to patients in the CIDP patient population receiving placebo. In some embodiments, the label includes data demonstrating improvement at two consecutive visits in 69% of the CIDP patient population receiving 1008 mg / 11,200 units of the pharmaceutical product once weekly for up to 12 weeks. In some embodiments, improvement is defined as an aINCAT improvement of ≥1 point, an I-RODS improvement of ≥4 points, or an improvement in mean grip strength of ≥8 kPa. In some embodiments, the label includes data demonstrating a longer time to clinical deterioration among CIDP patients receiving the pharmaceutical product compared to CIDP patients receiving placebo. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥1 point between two consecutive measurements. In some embodiments, clinical deterioration is defined as an increase in aINCAT score of ≥2 points. In some embodiments, the longer time to clinical deterioration is demonstrated by a hazard ratio of 0.394. In some embodiments, the longer time to clinical deterioration is statistically significant. In some embodiments, the label states that patients receiving the pharmaceutical product experienced a longer time to clinical deterioration (i.e., an increase of ≥1 point in aINCAT score) compared to patients receiving placebo, which is statistically significant, as demonstrated by a hazard ratio of 0.394 [95% CI (0.253; 0.614) p < 0.0001]. In some embodiments, the label of the pharmaceutical product includes a combination of any features described above or elsewhere herein.

[0457] In some embodiments, the CIDP patient population prior to treatment with egamod PH20 includes untreated patients, patients receiving immunoglobulins, and patients receiving corticosteroids.

[0458] In some embodiments, the CIDP patient population includes patients with treatment-unstable and refractory CIDP (CIDP Disease Activity Score (CDAS) 5B and 5C) prior to treatment with egamod PH20, and patients with stable CIDP on existing treatment (CDAS 3 and 4) prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by mild to severe disability prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by an INCAT score of 2–9 prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by an IRODS score of 11–61 prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by a mean grip strength of 1–120 kPa prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by a mean INCAT score of 5 prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by a mean IRODS of 37 prior to treatment with egamod PH20. In some embodiments, the CIDP patient population is characterized by a mean grip strength of 39 kPa prior to treatment with egamod PH20.

[0459] Biosimilars and bioequivalents of the pharmaceutical products described herein are also covered in this disclosure.

[0460] Methods of treating CIDP are also provided, including administering to a subject a pharmaceutical product containing egamod and hyaluronidase, a biosimilar of a pharmaceutical product containing egamod and hyaluronidase, or a bioequivalent of a pharmaceutical product containing egamod and hyaluronidase. The use of a pharmaceutical product containing egamod and hyaluronidase, a biosimilar of a pharmaceutical product containing egamod and hyaluronidase, or a bioequivalent of a pharmaceutical product containing egamod and hyaluronidase for treating CIDP in a subject is also provided.

[0461] In some embodiments, the drug product, biosimilar, or bioequivalent is administered to the subject once weekly or every other week. In some embodiments, the drug product, biosimilar, or bioequivalent is administered subcutaneously once weekly. In some embodiments, the drug product, biosimilar, or bioequivalent is administered subcutaneously once weekly for at least 4 weeks. In some embodiments, the drug product, biosimilar, or bioequivalent is administered subcutaneously once weekly until the subject exhibits ECI. In some embodiments, the drug product, biosimilar, or bioequivalent is administered weekly until the subject exhibits ECI between two consecutive measurements, optionally with an interval of about 1 week between the two consecutive measurements. In some embodiments, the drug product, biosimilar, or bioequivalent is administered subcutaneously once weekly until the subject exhibits ECI twice within two weeks. In some embodiments, ECI is a clinical improvement in one or more of I-RODS, mean grip strength, INCAT, or aINCAT score. In some embodiments, ECI is a clinical improvement in one or more of I-RODS, mean grip strength, or INCAT score.

[0462] In some embodiments, the pharmaceutical product, biosimilar, or bioequivalent is administered subcutaneously once weekly until the subject exhibits ECMD. In some embodiments, ECMD is one or more of the following: an increase of ≥1 point in an aINCAT score, a decrease of ≥4 points in I-RODS (using percentile measures), or a decrease of ≥8 kPa in average grip strength of one hand using a handheld grip dynamometer. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score between two consecutive measurements, optionally with an interval of approximately 1 week between the two consecutive measurements. In some embodiments, ECMD is an increase of ≥1 point in an aINCAT score over two weeks. In some embodiments, ECMD is an increase of ≥2 points in an aINCAT score.

[0463] In some embodiments, the pharmaceutical product, biosimilar, or bioequivalent is initially administered subcutaneously once weekly, and subsequently subcutaneously every two weeks based on clinical evaluation. In some embodiments, the clinical evaluation is performed by a healthcare provider. In some embodiments, the pharmaceutical product, biosimilar, or bioequivalent is initially administered subcutaneously once weekly, and subsequently subcutaneously every two weeks if ECI is observed in the subject. In some embodiments, weekly subcutaneous administration of the pharmaceutical product, biosimilar, or bioequivalent is resumed after symptom worsening. In some embodiments, the pharmaceutical product, biosimilar, or bioequivalent is administered subcutaneously over approximately 30 to 90 seconds.

[0464] In some embodiments, the pharmaceutical product, biosimilar, or bioequivalent is initially administered by or under the supervision of a medical professional for at least five consecutive administrations. In some embodiments, subsequent administrations of the pharmaceutical product, biosimilar, or bioequivalent are given by a medical professional or by a patient or caregiver.

[0465] In some embodiments, the subject still has an active disease despite treatment with corticosteroids or immunoglobulins.

[0466] In some embodiments, the methods or uses described herein further include monitoring a subject for hypersensitivity reactions selected from a group consisting of allergic reactions and hypotension leading to syncope; and initiating appropriate measures to mitigate the hypersensitivity reactions when detected.

[0467] In some embodiments, the methods or uses described herein further include monitoring infusion-related reactions in subjects and initiating appropriate measures upon detection of severe infusion-related reactions. In some embodiments, infusion-related reactions include one or more of the following: high blood pressure, chills, shivering, chest pain, abdominal pain, and back pain.

[0468] In some embodiments, the subject is a person, such as, for example, an adult.

[0469] Example

[0470] The invention will be further understood with reference to the following non-limiting examples.

[0471] Example 1: Study on the efficacy, safety, and tolerability of egamod PH20 SC in adult patients with CIDP. Phase 2 trial

[0472] 1.1 Summary of the Solution

[0473] 1.1.1 Principles of Clinical Trials

[0474] There is an unmet medical need for an effective treatment for CIDP that offers a favorable safety and tolerability profile and is easier to administer compared to currently available treatments. A weekly subcutaneous (SC) treatment option consisting of Aigamod PH20 SC administered within minutes could provide significant clinical benefit to patients with CIDP.

[0475] In the ADHERE clinical trial described herein (protocol number: ARGX-113-1802), egamod PH20 SC was administered at a dose of 1000 mg to patients with CIDP. This dose was well tolerated in the previous Phase 1 trial ARGX-113-1901 in healthy adult subjects and reduced immunoglobulin G (IgG) levels to those associated with the clinical benefit in previous trials in patients with autoimmune diseases (i.e., patients with generalized myasthenia gravis [gMG] and patients with primary immune thrombocytopenic purpura [ITP]).

[0476] 1.1.2 Clinical Trial Methods

[0477] The ADHERE clinical trial is a phase 2, prospective, multicenter trial designed to investigate the efficacy, safety, tolerability, immunogenicity, pharmacokinetic (PK), and disease progression (PD) of 'Agamod PH20 SC' administered to patients aged 18 years and older with CIDP. The trial was conducted in two phases: an open-label phase A and a randomized, double-blind, placebo-controlled phase B. A complete schematic diagram is shown below. Figure 1 As shown.

[0478] During the screening period of up to 28 days, the diagnosis of CIDP is confirmed by the CIDP Confirmation Committee (CCC), and overall eligibility is confirmed by the Medical Monitor. Eligible patients who received treatment for CIDP at screening discontinued the treatment and entered an adjustment period lasting up to 12 weeks until ECMD was confirmed (i.e. observed during the trial visit), at which point eligible patients entered Phase A baseline (D1A).

[0479] If there is evidence during the screening period that the total aINCAT disability score (further referred to as the “aINCAT score”) in the 3 months prior to screening has worsened compared to the previous aINCAT score in the 6 months prior to screening, then eligible patients who have not received treatment or have discontinued corticosteroid and / or intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg) treatment for at least 6 months prior to screening (these patients are considered equivalent to untreated patients) will directly enter Phase A.

[0480] Patients meeting the Phase A criteria received weekly SC administration of the open-label investigational medicine product (IMP) of egamod PH20 SC for up to 12 weeks (with an optional additional week for confirmatory ECI if needed), for a minimum of 4 administrations. Patients' ECI was monitored during Phase A.

[0481] Patients who met the ECI criteria (confirmed ECI status) at two consecutive visits were transferred to a randomized, placebo-controlled Phase B trial. Patients without confirmed ECI did not meet the criteria for Phase B and terminated the trial after a safety follow-up 28 days after their last IMP administration.

[0482] After the first 30 patients reached the end of Phase A, an interim analysis was conducted to assess the proportion of patients with confirmed ECI, using a precise (Clopper-Pearson) 90% one-sided low confidence interval (CI) to decide whether to continue the trial. During the interim analysis, the trial continued without any interruption, neither for trial enrollment nor for visits or treatment of patients participating in any trial phase.

[0483] Patients confirmed to have ECI in Phase A were enrolled in a double-blind, randomized exit phase B trial and randomly assigned at a 1:1 ratio at Phase B baseline (D1B) to receive weekly IMP consisting of egamod PH20 SC or placebo. Randomization to exit phase B lasted up to 48 weeks.

[0484] All patients randomly assigned to the double-blind, randomized exit phase B trial received weekly IMP administration but returned to the clinic at 4-week intervals. Randomized IMP administration was only administered after completion of all indicated assessments. Patients were discharged from the center if the investigator deemed no safety concerns. Between phase B trial visits, patients could choose to visit the trial center weekly for administration or receive IMP injections through home care services. The most appropriate solution was provided after consensus was reached with the investigator, field staff, and patient. IMP administration was always performed within a time window of ± 2 days relative to the pre-planned administration date.

[0485] Patients who completed week 48 and were deemed by the investigator to have benefited from the trial treatment at week 48, or patients whose aINCAT score worsened by 1 point or ≥2 points compared to Phase B baseline (for the latter, no confirmation is required), were permitted to transfer to the open-label extension (OLE) trial when they received IMP. Patients who completed week 48 but did not transfer to the OLE trial, as well as patients who discontinued early, were followed up for safety 28 days after their last IMP administration, discontinued the trial, and were deemed by the investigator to be appropriately treated.

[0486] The trial was terminated when 88 (88) events were observed in the primary endpoint analysis for Phase B. Patients in Phases A and B underwent early discontinuation visits, and those receiving IMP had the opportunity to continue egamod PH20SC treatment in the OLE trial. Additionally, patients in the break-in period at event 88 could opt to transfer to the OLE trial after undergoing an early discontinuation visit. Patients who did not transfer to the OLE trial were followed up 28 days after their last IMP dose.

[0487] Starting from Phase A, patients received IMP self-administration training as expected in the OLE trial (rather than the ARGX-113-1802 trial).

[0488] 1.1.3 Objectives

[0489] 1.1.3.1 Phase A (Open Label, Egamod PH20 SC; 4-12 weeks [optional + 1 extra week])

[0490] Main objectives

[0491] • Assess the activity of egamod PH20 SC (egamod co-regulated with recombinant human hyaluronidase PH20 [rHuPH20]) based on the percentage of patients classified as treatment responders.

[0492] Secondary objectives

[0493] • Assess the time to clinical improvement.

[0494] • The therapeutic effect of iatrovid PH20 SC is determined by clinical functional assessment based on motor function and muscle strength.

[0495] • Evaluate the short-term safety and tolerability of icomod PH20 SC.

[0496] • Evaluate the pharmacokinetics (PK) of edamod PH20 SC.

[0497] • Evaluate the pharmacodynamic (PD) effects of edemamod PH20 SC.

[0498] • Assess the immunogenicity of egamod and rHuPH20.

[0499] • Assess the EuroQol 5-dimensional and 5-level health-related quality of life questionnaire (EQ-5D-5L).

[0500] Exploratory goals

[0501] • Assess additional patient-reported outcomes (PROs) (including additional patient-reported quality of life and treatment satisfaction).

[0502] • Biomarkers for assessing CIDP disease activity.

[0503] • Assess the association between biomarkers and clinical outcomes.

[0504] • Explore composite endpoint validation analysis.

[0505] 1.1.3.2 Phase B (double-blind, randomized exit, edamame PH20 SC or placebo; up to 48 weeks)

[0506] Main objectives

[0507] • The efficacy of egamod PH20 SC compared to placebo was determined based on the time required for the first clinical sign of deterioration to occur.

[0508] Secondary objectives

[0509] • The efficacy of iatrovid PH20 SC compared to placebo was determined based on clinical functional assessments of disease disability, motor function, and muscle strength.

[0510] • Evaluate the safety and tolerability of icomod PH20 SC.

[0511] • Evaluate the PK of Aigamod PH20 SC.

[0512] • Evaluate the PD effect of icotinamide PH20 SC.

[0513] • Assess the immunogenicity of egamod and rHuPH20.

[0514] • Evaluate EQ-5D-5L.

[0515] Exploratory goals

[0516] • Assess additional PROs (including additional patient reports of quality of life and treatment satisfaction).

[0517] • Biomarkers for assessing CIDP disease activity.

[0518] • Assess the association between biomarkers and clinical outcomes.

[0519] • Explore composite endpoint validation analysis.

[0520] 1.1.4 Maximum duration of patient participation in the trial

[0521] Following a screening period of up to 28 days and an adjustment period of up to 12 weeks, the total duration of IMP administration is up to 61 weeks and includes two treatment phases:

[0522] Phase A is an open-label treatment of eigamod PH20 SC for up to 12 weeks (with an optional additional week); and

[0523] Phase B is a 48-week double-blind treatment of IMP (Agamod PH20 SC or placebo).

[0524] Patients who were not transferred to the extension trial or who discontinued IMP early were followed up for 28 days after the last dose of IMP.

[0525] The longest total trial duration is 80 weeks, with the IMP trial lasting a maximum of 61 weeks.

[0526] • Screening period: Up to 28 days

[0527] • Adjustment period: up to 12 weeks (not required for untreated patients)

[0528] • Phase A: 4-12 weeks (with an optional additional week)

[0529] • Phase B: Up to 48 weeks

[0530] • Follow-up period: 28 days after the last dose of IMP for patients not included in the OLE trial ARGX-113-1902.

[0531] 1.1.5 End Point

[0532] 1.1.5.1 Analyzing the Group

[0533] Safety cohorts: The Phase A safety cohort (SAF-A) includes all patients who received at least one dose of IMP in Phase A. The Phase B safety cohort (SAF-B) includes all patients who received at least one dose of IMP in Phase B.

[0534] Modified Intention-to-Treat (mITT) cohort: The mITT cohort includes all randomly assigned patients who received at least one dose of IMP in Phase B.

[0535] According to the protocol (PP) group: The PP group includes all Phase B patients in the mITT group who have not reported major protocol deviations.

[0536] 1.1.5.2 Phase A

[0537] Primary endpoint :

[0538] • Percentage of patients with confirmed ECI.

[0539] Secondary endpoint:

[0540] • Signs of clinical activity:

[0541] - The time until the initial confirmation of ECI.

[0542] - Changes in the Phase A baseline (D1A) over time:

[0543] o aINCAT rating

[0544] o MRC Overall Score

[0545] o 24-item I-RODS Disability Score

[0546] o TUG rating

[0547] o Average grip strength as assessed by a Martin grip strength meter.

[0548] • Security:

[0549] - Incidence of treatment-related adverse events (TEAEs) and serious adverse events (SAEs) adjusted by system organ class (SOC) and preferred term (PT);

[0550] - The incidence of clinically significant laboratory abnormalities.

[0551] •PK Overview:

[0552] - Serum concentrations of pre-administered icotinamide over time during Phase A.

[0553] •PD Overview:

[0554] - Changes in serum IgG levels (total IgG) over time during phase A.

[0555] • Immunogenicity:

[0556] - Percentage and titer of patients with binding antibodies (BAb) against egamod and / or rHuPH20 during Phase A.

[0557] - Neutralizing antibodies (NAb) against egamod and NAb titers against rHuPH20 were present during phase A.

[0558] •PRO:

[0559] - The change of D1A of base EQ-5D-5L over time during phase A.

[0560] Exploratory endpoint:

[0561] Additional patient-reported results

[0562] • During Phase A, the Phase A baseline (D1A) changes over time:

[0563] - Short Form of the Body Pain Inventory (BPI-SF)

[0564] - (9 items) Drug Treatment Satisfaction Questionnaire (TSQM-9)

[0565] -Rasch Transform Fatigue Severity Scale (RT-FSS)

[0566] Hospital Anxiety and Depression Scale (HADS)

[0567] - Changes in Patient Overall Impression (PGIC)

[0568] Biomarker analysis

[0569] • During phase A of autoantibody levels, the changes in phase A baseline (D1A) over time may include, but are not limited to, levels of anti-GM1, anti-LM-1, anti-NF-155, anti-CNTN1, anti-Caspr-1 antibodies, and anti-myelinated nerve antibodies.

[0570] 1.1.5.3 Phase B

[0571] Primary endpoint :

[0572] • The time until the first aINCAT deterioration occurs, compared to the B-stage baseline.

[0573] Note: The time to the first aINCAT deterioration is defined as the time from the first dose of double-blind IMP to the first aINCAT score increase of 1 point compared to stage B baseline, if the deterioration is confirmed during follow-up visits 3 to 7 days after the first aINCAT score increase of 1 point. For patients with an aINCAT score increase of 2 or more points compared to stage B baseline, confirmation is not required.

[0574] Secondary endpoint :

[0575] •Clinical efficacy:

[0576] - The time until CIDP disease progression occurs.

[0577] Note: The time to CIDP disease progression is defined as the time from the first dose of double-blind IMP to a reduction of ≥4 points in the first I-RODS score (measured as percentile) compared to the stage B baseline.

[0578] - The percentage of patients whose functional level improved compared to the baseline in Stage B, as measured by increasing the 24-item I-RODS score up to week 48.

[0579] - Changes in the B-stage baseline over time:

[0580] o aINCAT rating

[0581] o MRC Overall Score

[0582] o 24-item I-RODS Disability Score

[0583] o TUG rating

[0584] o Average grip strength as assessed by a Martin grip strength meter.

[0585] - During Phase B, the time for 24 Project I-RODS was reduced by 10%.

[0586] • Security:

[0587] - During phase B, the incidence of TEAE and SAE via SOC and PT.

[0588] - The incidence of clinically significant laboratory abnormalities during Phase B.

[0589] •PK Overview:

[0590] - Serum concentrations of pre-administered icotinamide over time during Phase B.

[0591] •PD Overview:

[0592] - Changes in serum IgG levels (total IgG) over time during phase B.

[0593] • Immunogenicity:

[0594] - Percentage and titer of patients with BAb targeting egamod and / or rHuPH20 during Phase B.

[0595] - During phase B, there were NAb titers against egamod and rHuPH20.

[0596] •PRO:

[0597] - During Phase B, the change of the Phase B baseline of EQ-5D-5L over time.

[0598] Exploratory endpoint:

[0599] Additional patient-reported results

[0600] • During Phase B, the Phase B baseline changes over time:

[0601] - Short Form of the Body Pain Inventory (BPI-SF)

[0602] - (9 items) Drug Treatment Satisfaction Questionnaire (TSQM-9)

[0603] -Rasch Transform Fatigue Severity Scale (RT-FSS)

[0604] Hospital Anxiety and Depression Scale (HADS)

[0605] - Changes in Patient Overall Impression (PGIC)

[0606] Biomarker analysis

[0607] • During phase B of autoantibody levels, the changes in the phase B baseline over time may include, but are not limited to, anti-GM1, anti-LM-1, anti-NF-155, anti-CNTN1, anti-Caspr-1 antibody levels and anti-myelinated nerve antibodies.

[0608] 1.2 Experimental Design

[0609] 1.2.1 Overall Design

[0610] The ADHERE trial is a phase 2, prospective, multicenter trial investigating the efficacy, safety, tolerability, pharmacokinetics (PK), and disease progression (PD) of egamod PH20 SC in patients aged 18 years and older with CIDP. The trial was conducted in two phases: an open-label phase A and a randomized phase B.

[0611] Following a screening period for all patients and an adjustment period for eligible patients (excluding treatment-naïve patients), all patients entered open-label Phase A baseline (D1A) and received weekly trial treatment (egamod PH20SC) for up to 12 weeks (with an optional additional week). During this period, upon confirmation of ECI at two consecutive visits, patients were transferred to the randomized, placebo-controlled Phase B, and randomly assigned 1:1 at Phase B baseline (D1B) to either egamod PH20SC or placebo. Randomization to Phase B lasted up to 48 weeks.

[0612] The experiment includes the following time periods:

[0613] • Screening period: up to 28 days;

[0614] • Adjustment period: up to 12 weeks (not for untreated patients);

[0615] • Phase A: Open-label treatment of eigamod PH20 SC for up to 12 weeks (with an optional additional week) (weekly trial visits);

[0616] • Phase B: A double-blind, randomized withdrawal trial of egamod PH20 SC or placebo for up to 48 weeks (trial visits every 4 weeks); and

[0617] • Follow-up: If the patient does not wish to switch to the open-label extension (OLE) trial ARGX-113-1902, follow-up will be conducted 28 days after the last dose of IMP.

[0618] The total trial duration for each patient is up to 80 weeks, with IMP lasting up to 61 weeks. A trial diagram is provided in... Figure 1 middle.

[0619] 1.2.1.1 Screening period

[0620] During the screening period of up to 28 days, the investigator's diagnosis of CIDP was reviewed by the CIDP Confirmation Committee (CCC), and overall eligibility was confirmed by the medical monitor. To be admitted to this study, participants must be diagnosed with CIDP, as confirmed by the CCC and the medical monitor.

[0621] The CCC comprises neurologists with at least 10 years of experience diagnosing CIDP and a record of at least 100 CIDP diagnoses. The CCC ensures that the CIDP trial cohort included in this trial meets the formal EFNS / PNS 2010 diagnostic criteria (Van den Bergh et al., 2010). These are used to define a possible or definitive progressive or recurrent form of CIDP, where sensory symptoms and limited motor function, or only limited motor function, are required for trial eligibility.

[0622] 1.2.1.2 Break-in period

[0623] Following the screening period and based on the previously permitted CIDP treatment type, eligible patients begin an adjustment period. This adjustment period can last up to 12 weeks. It includes the following, depending on the patient's prior or current treatment at the time of screening:

[0624] 1. If there is evidence of a worsening aINCAT score within 3 months prior to screening compared to the previous aINCAT score within 6 months prior to screening, patients who have not received treatment for CIDP are allowed to skip the adjustment period;

[0625] (Patients who have not received pulsed monthly or daily corticosteroid, IVIg, or SCIg treatment for at least 6 months prior to screening are considered equivalent to untreated patients).

[0626] 2. Patients treated with IVIg or SCIg during the screening period should discontinue IVIg or SCIg treatment at the start of the break-in period (i.e., RI-V1);

[0627] 3. Patients treated with pulsatile corticosteroids (IV or oral) or daily oral corticosteroids ≤10 mg during the screening period should discontinue corticosteroid treatment at the start of the break-in period (i.e., RI-V1).

[0628] Patients will be monitored by collecting data on grip strength, I-RODS score, MRC total score, aINCAT score, and TUG test. Regular visits to the trial center are planned every 4 weeks.

[0629] Patients receive appropriate training and instructions to assess their disability status weekly using I-RODS and grip strength. Patients' I-RODS scores and mean grip strength are captured, calculated, and transmitted to the electronic case report form (eCRF). If any of the following signs of deterioration are observed in the patient, a trial visit is scheduled within 5 business days for evaluation by a physician:

[0630] • I-RODS deterioration ≥ 4 points (using percentile measures), and / or

[0631] • The average grip strength of one hand deteriorated by ≥8 kPa when using a handheld grip strength meter.

[0632] At the trial center, the evaluating physician assessed whether deterioration could be confirmed by meeting the ECMD criteria.

[0633] Any patient exhibiting ECMD at the trial center immediately proceeds to Phase A. Patients who do not provide signs of ECMD by the end of the adjustment period are recorded as having failed the adjustment.

[0634] 1.2.1.3 Phase A

[0635] All patients with ECMD were initiated in Phase A, with the first administration of open-label IMP at Phase A baseline (D1A). After completion of all pre-treatment baseline assessments, patients received weekly SCs of IMP consisting of edemamod PH20 SC for up to 12 weeks (with an optional additional week), with a minimum of 4 SC injections of IMP.

[0636] The procedures performed during D1A and other trial visits are provided in the Activity Schedule (SoA) in Table 9. Each patient remains in Phase A and returns to the trial center weekly as described in the SoA until the evaluating investigator identifies an ECI relative to D1A at two consecutive visits.

[0637] An interim analysis was performed after the first 30 patients in Phase A reached the end of Phase A (EOSA). During the interim analysis, the trial continued without any interruption, neither for trial enrollment nor for visits or treatment of patients participating in any trial phase.

[0638] Patients who did not show ECI at two consecutive visits during Phase A were classified as non-responders. Non-responders ended the trial and participated in follow-up 28 days after the last IMP administration, and were considered to have received appropriate treatment by the investigator.

[0639] All patients with confirmed ECI were randomized to one of two treatment groups (SC with egamod PH20 SC or placebo) and began Phase B. Randomization was performed on the same day as the confirmed ECI. Patients who only showed ECI at the last visit of Phase A (i.e., 1 week after A-V12) were allowed an additional one-week extension of Phase A and one additional consecutive visit. If ECI was first observed at this visit, a consecutive visit was performed 1 week later. The rationale for this possible one-week extension of Phase A was to confirm ECI after 1 week of consecutive visits (and if ECI was confirmed, patients in Phase B were randomized). In cases where ECI was not confirmed after the additional week of Phase A, an EOSA visit was performed, and the patient ended the trial (followed by a follow-up visit 28 days after the last IMP administration).

[0640] During Phase A, IMP was administered at the trial center after obtaining blood samples for laboratory safety, PK, PD, immunogenicity and / or biomarker analysis, and after all assessments required to determine ECI. All patients received training on self-administration of IMP during Phase A (expected in the OLE trial).

[0641]

[0642] 1.2.1.4 Phase B

[0643] Eligibility for Phase B randomization at Phase B baseline (D1B) was determined using screening, during the adjustment period (RI-V1 to RI-V4 visits), and prior to the first treatment in Phase A (D1A; A-V1 visit), as well as assessment of treatment response during Phase A.

[0644] ECI patients during Phase A were randomly assigned in a 1:1 ratio at Phase B baseline (D1B) to receive either weekly escitaloid PH20 SC or placebo SC.

[0645] All patients randomly assigned to a double-blind, randomized exit phase B clinic received weekly IMP but returned to the clinic at 4-week intervals. At each of these visits, the specific procedures specified in the Activity Schedule (SoA) as outlined in Table 10 were performed.

[0646] After all planned procedures for the visit were carried out according to SoA, and when the researchers deemed there were no safety concerns, the patient left the trial center.

[0647] The trial was stopped when 88 events were observed in the primary endpoint analysis of Phase B. At this point, patients in Phases A and B underwent early discontinuation visits, and patients receiving IMP had the opportunity to continue egamod PH20 SC treatment in the OLE trial (in which case, the early discontinuation visits of the ARGX-113-1802 trial could overlap with the enrollment visits). Patients who did not enroll in the OLE trial were followed up 28 (±3) days after their last IMP dose.

[0648] Patients may continue egamod PH20 SC treatment in the OLE trial (ARGX-113-1902) if any of the following three conditions are met:

[0649] 1. The patient experienced clinical deterioration (i.e., aINCAT score deterioration) during stage B.

[0650] 2. The patient completed the 48-week visit of Phase B without any clinical deterioration.

[0651] 3. Record the 88th event during phase B, and the patient received IMP during phase A or phase B.

[0652] The event is a deterioration of the aINCAT score in any patient treated during Phase B.

[0653] Additionally, in the 88th event, patients in the adjustment period could choose to switch to the OLE trial after early cessation of visits.

[0654] During Phase B, patients received further IMP self-administration training (expected in the OLE trial, not the ARGX-113-1802 trial), as specified in the SoA in Table 10. Patients with clinical deterioration or who completed their 48-week visit also had the opportunity to enter the safety follow-up period and complete the trial without transitioning to the OLE trial.

[0655] 1.2.1.5 Follow-up

[0656] Follow-up visits are conducted 28 days after the last dose of IMP (in cases where the patient prematurely discontinues IMP or the trial), or in cases where the patient does not meet the ECI criteria [non-responder] in Phase A, or if the patient has not been transferred to the OLE trial ARGX-113-1902 28 days after the last dose in Phase B.

[0657]

[0658] 1.2.2 Scientific Principles of Experimental Design

[0659] The ADHERE trial design used some key elements from the PATH trial (van Schaik et al., 2018). All patients showing signs of disease activity during the adjustment period were eligible to enter the treatment phase (Phase A).

[0660] The break-in period serves two purposes:

[0661] • Select patients with clinical signs of disease activity (enhanced design);

[0662] • Ensure that the half-life of the previous drug (if applicable) has passed and that the clinical effect will not compromise the efficacy analysis of the trial.

[0663] The pre-randomization observation period (Phase A) can be any length between 4 and 13 weeks. The post-discontinuation observation period in this trial (i.e., for patients in the placebo group during Phase B) has a maximum duration of 48 weeks. Careful attention should be paid to procedures used for monitoring patients and assessing trial endpoints to ensure rapid identification of patients who have not received the designated treatment.

[0664] The advantage of this experimental design is that individuals receiving the intervention continue only if they respond, while those receiving a placebo only do so if their symptoms recur. Another advantage of this design is its ability to study long-term efficacy or safety (withdrawal effect).

[0665] The trial design allows for the collection of information about the onset of the therapeutic effect, whether the effect persists after drug discontinuation, and whether there is a relapse (in the placebo group). Furthermore, the trial also generates data on placebo responses in populations interested in further clinical development.

[0666] In Phase B, any difference between the group receiving continuous treatment and the group randomly assigned to placebo reflects the effect of active treatment.

[0667] All eligible patients were enrolled in the trial through an open-label period (Phase A), during which they were all receiving active therapy. This selection was deemed necessary to provide minimal levels of egamod PH20 SC treatment to all patients with active disease, even those randomized to the placebo group after this period (Phase B). Phase A had a variable duration of at least 4 weeks and up to 12 weeks (with an optional additional week) during which patients received weekly SC treatment until clinical improvement was achieved and maintained at 2 concurrent visits. This variable duration was chosen to maximize IgG reduction, which would maximize the duration of the effect. Based on clinical practice with other therapies (3 months), the maximum number of injections was set at 12 (or 13, with an optional additional week).

[0668] When the placebo group was introduced, all patients were expected to receive initial open-label treatment with egamod PH20 SC (Phase A). This allows patients to receive active treatment before potential randomization to placebo (during Phase B), making this design more acceptable in the context of highly effective standards of treatment for a currently debilitating disease. Additionally, Phase A randomization to the placebo group was subsequently conducted to establish how long the treatment effect lasts before clinical signs of disease activity reappear. In this way, the trial allows for evaluation via biomarker analysis if a personalized treatment schedule is an option for clinical practice.

[0669] Patients whose clinical deterioration was measured by an increase in their aINCAT score at any time during Phase B had the opportunity to be transferred to a separate OLE trial by weekly administration of egamod PH20 SC. The original double-blind treatment allocation was maintained throughout the trial, even at the time of withdrawal.

[0670] The possibility of transitioning to the OLE trial makes the trial attractive to patients who have benefited from open-label treatment during Phase A and understand that they will again receive effective open-label treatment (in the OLE trial), despite the option to be randomized to placebo and the possibility of deterioration in the randomized Phase B of the trial.

[0671] All efficacy, safety, and quality-of-life assessments used in this trial were standard, widely used (including in the CIDP trial), and considered reliable, accurate, and relevant.

[0672] Biomarker analysis is exploratory, and biomarkers were selected to assess the therapeutic effects of egamod PH20 SC on the pathophysiology of CIDP, and to evaluate the correlation between biomarkers and clinical outcomes. The evaluation of these biomarkers may lead to the development of personalized treatment regimens using egamod PH20 SC, and has prognostic values ​​for the likelihood of clinical deterioration or predictive values ​​for the likelihood of establishing a treatment response. However, these are not currently described as acceptable alternative biomarkers. Therefore, this evaluation is exploratory in nature. Total human IgG levels are only a measure of how long IgG levels decrease after egamod PH20 SC treatment is discontinued. This serves as a relevant reference biomarker for these patients, who were randomized to the placebo group after the induction period.

[0673] 1.2.3 Dosage Principle

[0674] For both Phase A and Phase B, a dose of 1000 mg of egamod PH20 SC was selected. Based on a population PK / PD model, the predicted effect of this dose of egamod PH20 SC (administered weekly) on IgG levels was comparable to that of 10 mg / kg egamod administered weekly via IV infusion. Egamod 10 mg / kg IV dose:

[0675] 1. Produced transient clinical efficacy in a phase 2 trial in ITP patients and long-term clinical efficacy after four weekly infusions in a phase 2 trial in MG patients.

[0676] 2. Showing a PD effect that leads to near saturation:

[0677] Dosing more than weekly or more frequently than weekly is not expected to produce an improved PD effect (i.e., further reduction of autoantibodies) and / or clinical effect, and may be associated with a lower optimal risk / benefit ratio. Lower doses are expected to produce a lower PD effect and may therefore lead to less consistent and / or incomplete clinical responses, which are undesirable due to the severe and chronic nature of CIDP. Therefore, weekly dosing is advantageous until the patient is in a stable clinical condition.

[0678] 3. A favorable safety profile was demonstrated in the phase 2 trial in patients with MG and ITP.

[0679] In addition, based on favorable phase 3 trial results in patients with MG, egamod IV at a dose of 10 mg / kg has been approved in the United States (US) and the European Union (AChR-Ab seropositive patients in both regions) and Japan (patients who have had an inadequate response to steroid or non-steroidal immunosuppressive therapy).

[0680] A study of healthy participants demonstrated that the profile of a decrease in total IgG levels over time after four weekly injections of 1000 mg echinomod PH20 SC was comparable to that observed after four weekly infusions of 10 mg / kg echinomod IV.

[0681] Hylenex's rHuPH20 has been approved in the United States. Co-formulations of rHuPH20 with other active ingredients have been approved in the US and EU (e.g., HERCEPTIN HYLECTA / Herceptin SC, RITUXAN HYCELA / MabThera SC, HYQVIA / HyQvia), with rHuPH20 concentrations of 2000 U / mL and SC injection volumes ranging from 5 to 13.4 mL.

[0682] 1.2.4 The principle of random assignment and blindness

[0683] Phase A was an open-label treatment involving administration of egamod PH20 SC. In Phase B, patients were randomized in a 1:1 ratio to either double-blind SC egamod PH20 SC or placebo. Patients were stratified based on their prior CIDP medication and a reduction in aINCAT score during Phase A as follows:

[0684] 1: Previous CIDP drugs:

[0685] • Untreated;

[0686] • Pulsed corticosteroid therapy or oral corticosteroids equivalent to prednisolone / prednisolone ≤10 mg / day;

[0687] • IVIg or SCIg treatment.

[0688] 2: aINCAT score:

[0689] • The aINCAT score remained unchanged during Phase A;

[0690] • The aINCAT score decreased by ≥1 point during Phase A.

[0691] Except for the non-blinding for safety reasons, Phase B treatment allocation was double-blind throughout the randomization-withdrawal period, even if a patient withdrew from the trial or enrolled in the OLE trial ARGX-113-1902. The treatments received by each patient were not disclosed to the investigators, research center staff, patients, trial commissioners, or commissioning research organizations (CROs) designated by the trial commissioners.

[0692] 1.2.5 Transition to Open Label Extension (OLE) Trial

[0693] The researchers suggested that patients receiving IMP at week 48, or those experiencing clinical deterioration (i.e., worsening aINCAT score) during phase B of treatment, could be selected to switch to a long-term single-arm OLE trial, during which they would receive weekly SC egamod PH20 SC. The dosage and frequency used in OLE would be the same as those used by patients enrolled in phase A of the trial.

[0694] Patients who received IMP in Phase A or Phase B, or who were in the adjustment period at the 88th event recorded in the trial, had their visits terminated early and were eligible to switch to the OLE trial because the ARGX-113-1802 trial was discontinued at this time. An event was a worsening of the aINCAT score in any patient treated during Phase B.

[0695] 1.3 Experimental Group

[0696] Each patient has signed an informed consent form (ICF) prior to any trial-related assessment. Before giving informed consent, patients are instructed not to participate in any other clinical trials involving medical interventions or data collection prior to the completion of the current trial.

[0697] If a patient meets all inclusion criteria and does not meet any exclusion criteria, and their CIDP diagnosis eligibility is confirmed by the CCC and the medical monitor, the patient is classified as eligible.

[0698] 1.3.1 Inclusion Criteria

[0699] Patients are eligible for enrollment in the trial only if they meet all of the following criteria:

[0700] 1. Able to understand the trial requirements, provide written informed consent (including consent for the use and disclosure of research-related health information), and willing and able to comply with the trial protocol procedures (including required trial visits).

[0701] 2. Male or female patients who are 18 years of age or older at the time of signing the informed consent form.

[0702] 3. Diagnosed with possible or confirmed progressive or recurrent CIDP according to the criteria of the European Society of Neurology / Peripheral Neurology (EFNS / PNS, 2010).

[0703] 4. At the time of screening, the CIDP Disease Activity Status (CDAS) score was ≥2 (Gorson et al., 2019).

[0704] 5. An INCAT score ≥2 at the initial adjustment visit (RI-V1; for patients entering the adjustment period) or at baseline in Phase A (A-V1; for untreated patients with evidence of worsening total aINCAT disability score within 3 months prior to screening). Patients with an INCAT score of 2 at enrollment must have that score obtained solely from the leg disability score; for patients with an INCAT score ≥3 at enrollment, there are no specific requirements for the arm or leg score.

[0705] 6. Meet any of the following treatment criteria:

[0706] • Currently (i.e., within the past 6 months) using a corticosteroid, an oral corticosteroid equivalent to prednisolone / prednisolone ≤10 mg / day, and / or IVIg or SCIg, and the patient is willing to discontinue this treatment at the first break-in visit (RI-V1); or

[0707] • No prior treatment (no prior medical history); or

[0708] • Discontinue corticosteroid and / or IVIg or SCIg treatment at least 6 months prior to screening.

[0709] Note: Patients who have not been treated with corticosteroids, IVIg, or SCIg monthly or daily for at least 6 months prior to screening are considered equivalent to untreated patients.

[0710] 7. Women of childbearing age who have a negative pregnancy test and a negative urine pregnancy test up to stage A baseline (D1A) at the time of screening.

[0711] From the date of signing the ICF until the date of the last IMP dose, women of childbearing age must use an acceptable method of contraception.

[0712] 1.3.2 Exclusion Criteria

[0713] A patient will be excluded from the trial if any of the following criteria apply:

[0714] 1. Purely sensory atypical CIDP (EFNS / PNS definition).

[0715] 2. Other causes of multiple kidney disease, including the following:

[0716] Multifocal motor neuropathy

[0717] - Monoclonal gammopathy with antibodies of undetermined significance against myelin-associated glycoprotein immunoglobulin M (IgM)

[0718] - Hereditary demyelinating neuropathy

[0719] - Polyneuropathy, organ enlargement, endocrine disorders, monoclonal protein and skin change syndrome

[0720] - Lumbosacral nerve root plexus neuropathy

[0721] - Most likely caused by diabetic polyneuropathy

[0722] - Most likely caused by a systemic disease, polyneuropathy

[0723] - Drug- or toxin-induced polyneuropathy.

[0724] 3. Any other disease that can better explain the patient's signs and symptoms.

[0725] 4. Any history of bone marrow disease or signs of central demyelination.

[0726] 5. Current or past history of alcoholism, drug abuse or substance abuse (within the 12 months prior to screening).

[0727] 6. Severe mental illness (such as major depressive disorder, psychosis, bipolar disorder), history of suicidal tendencies or current suicidal ideation, and the researcher believes that it may pose an undue risk to the patient or may affect adherence to the trial protocol.

[0728] 7. Patients with clinically significant active or chronic uncontrolled bacterial, viral, or fungal infections at screening time, including patients who tested positive for the following active viral infections at screening time:

[0729] • Active hepatitis B virus (HBV): Serological test results indicate active (acute or chronic) infection;

[0730] • Active hepatitis C virus (HCV): HCV-Ab serological positive;

[0731] • Serological positivity for human immunodeficiency virus (HIV) associated with symptoms defined as acquired immunodeficiency syndrome (AIDS) or a cluster 4 (CD4) count ≤200 cells / mm3.

[0732] 8. Total IgG level <6 g / L at screening.

[0733] 9. a. Treat with the following:

[0734] • Within 3 months prior to screening (or 5 half-lives of the drug, whichever is longer): plasma exchange or immunoadsorption, any accompanying Fc-containing therapeutic agent or other biological product, or any other investigational product.

[0735] • Within 6 months prior to screening: rituximab, alemtuzumab, any other monoclonal antibody, cyclophosphamide, interferon, tumor death factor-α inhibitors, fingolimod, methotrexate, azathioprine, mycophenolate mofetil, any other immunomodulatory or immunosuppressive drugs, and oral daily corticosteroids >10 mg / day.

[0736] This may include patients using IVIg, SCIg, pulsatile corticosteroids, and oral daily corticosteroids ≤10 mg / day.

[0737] • Patients who (intend) to use prohibited drugs and therapies during the trial.

[0738] 10. a. Women who are pregnant or breastfeeding during the trial, and women who intend to become pregnant.

[0739] 11. Patients with any other known autoimmune disease that researchers believe would interfere with the accurate assessment of the clinical symptoms of CIDP.

[0740] 12. a. Patients who received a live attenuated vaccine less than 28 days prior to screening. This does not exclude patients who received inactivated vaccines, subunit vaccines, polysaccharide vaccines, or conjugate vaccines at any time prior to screening.

[0741] 13. Patients with a history of malignant tumors, unless they are considered cured with adequate treatment and have shown no signs of recurrence for ≥3 years prior to the first administration of IMP. Patients with the following cancers may be included at any time:

[0742] • Basal cell or squamous cell skin cancer that has received adequate treatment

[0743] • Cervical carcinoma in situ

[0744] • Breast carcinoma in situ, or

[0745] • Incidental histological discovery of prostate cancer (TNM [tumor, nodule and metastasis classification] T1a or T1b stage).

[0746] 14. Patients who have previously participated in the Aigamod trial and have received at least one IMP administration.

[0747] 15. Patients with a known history of hypersensitivity to any component of IMP.

[0748] 16. Patients with clinical signs of other major serious illnesses or who have recently undergone or are planning to undergo major surgery, or any other reason that could confound the test results or put the patient under excessive risk.

[0749] 1.3.3 Prohibited Drugs

[0750] Continue CIDP treatment during the screening period, but discontinue it from the start of the break-in period (RI-V1):

[0751] • Intravenous or subcutaneous immunoglobulin therapy;

[0752] • Pulsed corticosteroids and oral daily corticosteroids ≤10 mg / day.

[0753] Throughout the trial, the following drugs or treatments are not permitted from the time of ICF signing at the time of screening:

[0754] • Plasma removal surgery;

[0755] • Total lymphatic irradiation;

[0756] • Any other IgG therapy;

[0757] • Any stem cell-based therapy, including bone marrow transplantation, such as autologous stem cell transplantation (ASCT) and allogeneic cell transplantation.

[0758] • Any cytokine or anti-cytokine therapy;

[0759] • Systemic corticosteroids, including oral ones, for any other indication besides CIDP;

[0760] • Cyclophosphamide, interferon, tumor necrosis factor-α inhibitors, fingolimod, methotrexate, azathioprine, mycophenolate mofetil, or any other immunomodulatory or immunosuppressive drugs or procedures;

[0761] • Rituximab, alemtuzumab, or any other monoclonal antibody used for immune modulation;

[0762] • Any research drugs or experimental procedures;

[0763] • Live attenuated vaccine

[0764] Note: It is not prohibited to receive inactivated vaccines, subunit vaccines, polysaccharide vaccines, or conjugate vaccines at any time prior to screening.

[0765] • Use of complementary therapies including traditional Chinese medicine and herbal remedies that include any of the following: naturally derived glucocorticoids; drugs with immunosuppressive, immunomodulatory, peripheral or central nervous system effects based on clinical indications; or procedures (e.g., acupuncture) for any neurological condition that are agreed not to be used during the trial and are within 4 weeks or 5 half-lives (whichever is longer) prior to IMP administration.

[0766] 1.4 Research Intervention

[0767] The pharmaceutical product (IMP) used in this study is:

[0768] -Open Tag Phase A-Agamod PH20 SC

[0769] - Double-blind Phase B trial – Egamod PH20 SC and placebo.

[0770] Aigamod is a modified human IgG1 Fc fragment with increased affinity for human FcRn.

[0771] rHuPH20 is an enzyme used in SC administration to increase the dispersion and absorption of co-administered therapeutic agents.

[0772] Aigamod and rHuPH20 are co-formulated and administered as a single SC injection.

[0773] The egamod PH20 SC formulation is provided in vials with egamod at concentrations of 165 mg / mL or 180 mg / mL and rHuPH20 at a concentration of 2000 U / mL (also known as ARGX-113 / rHuPH20). Each dose of egamod PH20 SC contains 1000 mg of egamod. It should be noted that there is a transition period during which both egamod PH20 SC formulations are used (with egamod concentrations of 165 mg / mL or 180 mg / mL). After this transition period, all patients receive the egamod PH20 SC formulation with the higher egamod concentration (180 mg / mL). The formulation with the higher egamod concentration (180 mg / mL) reduces the volume of administration per SC injection.

[0774] The placebo is provided as a mediator (containing 2000 U / mL rHuPH20) in vials as a ready-to-use SC formulation. For both egamod PH20 SC formulations (egamod concentrations of 165 mg / mL or 180 mg / mL), a corresponding placebo is provided, containing the same volume of the active pharmaceutical product in the same vial.

[0775] Apply a fixed dose of edemamod PH20 SC or PBO PH20 SC to the peritoneal skin area.

[0776] 1.5 Test Evaluation and Procedures

[0777] Each participant was instructed to attend each study visit on the designated dates according to the activity schedule shown in Tables 9 and 10.

[0778] 1.5.1 Clinically significant signs of deterioration during the break-in period and clinical signs of improvement during Phase A. The definition of aINCAT deterioration during phase B.

[0779] ECMD

[0780] ECMD is defined as meeting any one of the following criteria only during the break-in period:

[0781] • At the first visit during the adjustment period (RI-V1), the total aINCAT score increased by ≥1 point; and / or

[0782] • At RI-V1, I-RODS decreases by ≥4 points (using percentile measures); and / or

[0783] • At RI-V1, the average grip strength of one hand using a handheld grip dynamometer decreased by ≥8 kPa.

[0784] Any patient who exhibits ECMD at the trial center during the adjustment period will be immediately admitted to Phase A.

[0785] ECI during Phase A for non-treatment-naïve patients

[0786] Patients who show improvement in their aINCAT score during Phase A (a decrease of ≥1 point relative to Phase A baseline [D1A]) and whose aINCAT score worsens during the adjustment period (an increase of ≥1 point relative to the first visit during the adjustment period [RI-V1]) are eligible for Phase B. These patients are only admitted to Phase B upon confirmation of improvement in their aINCAT score.

[0787] Patients whose aINCAT score remains unchanged during the break-in period and who experience I-RODS and / or worsening grip strength during the break-in period may proceed to Phase B under the following circumstances:

[0788] • When it is confirmed that the aINCAT score has improved relative to D1A (reduced by ≥1 point).

[0789] • When no change in aINCAT score is observed during phase A, and:

[0790] ○ If only a deterioration in I-RODS (a decrease of ≥4 points) is observed during the break-in period, then it is confirmed that I-RODS improved during Phase A (an increase of ≥4 points relative to D1A).

[0791] ○ If only a deterioration in grip strength (a decrease of ≥8 kPa) is observed during the break-in period, then it is confirmed that grip strength has improved during stage A (an increase of ≥8 kPa relative to D1A). ...

Claims

1. A method for treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a subject with such need, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist.

2. The method of claim 1, wherein the FcRn antagonist comprises two, three, or four FcRn binding regions.

3. The method according to claim 1 or 2, wherein the FcRn antagonist comprises or is composed of the following: Variant Fc region or its FcRn binding fragment.

4. The method of claim 3, wherein the variant Fc region or its FcRn binding fragment binds to FcRn with higher affinity at pH 6.0 compared to the corresponding wild-type Fc region.

5. The method according to claim 3 or 4, wherein the variant Fc region or its FcRn binding fragment binds to FcRn with higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

6. The method according to any one of claims 3 to 5, wherein the variant Fc region comprises or consists of the following: The first Fc domain and the second Fc domain form homodimers or heterodimers.

7. The method according to claim 6, wherein the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively.

8. The method according to claim 6 or 7, wherein the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F and Y respectively located at EU positions 252, 254, 256, 433, 434 and 436.

9. The method according to any one of claims 6 to 8, wherein the first Fc domain and / or the second Fc domain comprises 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.

10. The method according to any one of claims 6 to 9, wherein the first Fc domain and the second Fc domain comprise amino acid sequences independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:

4.

11. The method according to any one of claims 1 to 10, wherein the FcRn antagonist is iatrogen.

12. The method of claim 1, wherein the FcRn antagonist is an anti-FcRn antibody.

13. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of 200 mg to 20,000 mg.

14. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a dose of 2 mg / kg to 200 mg / kg.

15. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of about 800 mg to about 1200 mg.

16. The method of claim 15, wherein the FcRn antagonist is administered to the subject at a fixed dose of about 1000 mg.

17. The method according to any one of claims 1 to 16, wherein the FcRn antagonist is administered subcutaneously.

18. The method according to any one of claims 1 to 17, wherein the FcRn antagonist is administered to the subject once a week.

19. The method according to any one of claims 1 to 17, wherein the FcRn antagonist is administered to the subject once every two weeks.

20. The method according to any one of claims 1 to 17, wherein the FcRn antagonist is administered to the subject once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

21. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1000 mg.

22. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered during the induction period and then during the maintenance period, wherein the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg during the induction period, and wherein the FcRn antagonist is administered subcutaneously once every two weeks at a fixed dose of about 1000 mg during the maintenance period.

23. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is first administered subcutaneously at a fixed dose of about 1000 mg once a week, and subsequently administered subcutaneously at a fixed dose of about 1000 mg every two weeks based on clinical assessment.

24. The method of claim 23, wherein after symptom exacerbation, a fixed dose of about 1000 mg is resumed once a week via subcutaneous administration.

25. The method according to any one of claims 1 to 16, wherein the FcRn antagonist is administered intravenously.

26. The method of claim 25, wherein the FcRn antagonist is administered intravenously once weekly or every two weeks.

27. The method of claim 25 or 26, wherein the FcRn antagonist is administered at a dose of about 3 mg / kg to about 60 mg / kg.

28. The method of claim 27, wherein the FcRn antagonist is administered at a dose of 5 mg / kg.

29. The method of claim 27, wherein the FcRn antagonist is administered at a dose of 10 mg / kg.

30. The method of claim 27, wherein the FcRn antagonist is administered at a dose of 25 mg / kg.

31. The method according to any one of claims 1 to 21 and 25 to 30, wherein the FcRn antagonist is first administered intravenously and then subcutaneously.

32. The method according to any one of claims 1 to 31, wherein the FcRn antagonist is administered for 61 weeks or less.

33. The method according to any one of claims 1 to 31, wherein the FcRn antagonist is administered for 52 weeks or less.

34. The method according to any one of claims 1 to 31, wherein the FcRn antagonist is administered for 48 weeks or less.

35. The method according to any one of claims 1 to 31, wherein the FcRn antagonist is administered for at least 12 weeks.

36. The method according to any one of claims 1 to 24, wherein the FcRn antagonist is administered subcutaneously once a week for at least 4 weeks.

37. The method of claim 36, wherein the FcRn antagonist is administered subcutaneously once weekly until the subject shows signs of clinical improvement (ECI).

38. The method of claim 36 or 37, wherein the FcRn antagonist is administered subcutaneously once weekly until the subject exhibits ECI between two consecutive measurements.

39. The method of claim 37 or 38, wherein ECI is a clinical improvement in one or more of the Rasch Inflammatory Total Disability Scale (I-RODS), mean grip strength, or Inflammatory Neuropathy Etiology and Treatment (INCAT) score.

40. The method of claim 36, wherein the FcRn antagonist is administered subcutaneously once weekly until the subject exhibits clinically meaningful signs of deterioration (ECMD).

41. The method of claim 40, wherein the ECMD is one or more of the following: an increase of ≥1 point in the adjusted INCAT (aINCAT) score, a decrease of ≥4 points in I-RODS (using percentile measurement), or a decrease of ≥8 kPa in the average grip strength of one hand using a handheld grip dynamometer.

42. The method of claim 40 or 41, wherein the ECMD is an increase of ≥1 point in the aINCAT score.

43. The method according to any one of claims 40 to 42, wherein the ECMD is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

44. The method according to any one of claims 40 to 43, wherein the ECMD is an increase of ≥1 point in the aINCAT score twice within two weeks.

45. The method according to any one of claims 40 to 44, wherein the ECMD is an increase of ≥2 points in the aINCAT score.

46. ​​The method according to any one of claims 1 to 45, wherein the subject has been diagnosed with CIDP according to the EFNS / PNS 2010 diagnostic criteria.

47. The method according to any one of claims 1 to 46, wherein the subject suffers from typical CIDP.

48. The method according to any one of claims 1 to 46, wherein the subject has a CIDP variant.

49. The method of claim 48, wherein the subject has distal CIDP.

50. The method of claim 48, wherein the subject has multifocal CIDP.

51. The method of claim 48, wherein the subject has focal CIDP.

52. The method of claim 48, wherein the subject suffers from motor CIDP.

53. The method of claim 48, wherein the subject suffers from sensory CIDP.

54. The method according to any one of claims 1 to 53, wherein the subject suffers from progressive CIDP.

55. The method according to any one of claims 1 to 53, wherein the subject suffers from recurrent CIDP.

56. The method according to any one of claims 1 to 55, wherein the subject has an aINCAT score of 2 or higher prior to administration of the FcRn antagonist.

57. The method according to any one of claims 1 to 55, wherein the subject has an aINCAT score of 5 or higher prior to administration of the FcRn antagonist.

58. The method according to any one of claims 1 to 57, wherein the subject had an I-RODS percentile score of 10 or higher, optionally 20 or higher, optionally 30 or higher, optionally 40 or higher, optionally 50 or higher before administration of the FcRn antagonist.

59. The method according to any one of claims 1 to 58, wherein the subject is newly diagnosed with CIDP.

60. The method according to any one of claims 1 to 58, wherein the subject is untreated.

61. The method according to any one of claims 1 to 58, wherein the subject has previously received treatment for CIDP.

62. The method of claim 61, wherein the subject has previously received steroid treatment.

63. The method of claim 61 or 62, wherein the subject has previously received IVIg or SCIg treatment.

64. The method according to any one of claims 1 to 63, wherein the subject still has an active disease despite treatment with corticosteroids or immunoglobulins.

65. The method according to any one of claims 1 to 64, wherein the subject is a CIDP patient characterized by the presence of anti-NF155 antibody.

66. The method according to any one of claims 1 to 65, wherein the subject is a CIDP patient characterized by the presence of anti-CNTN1 antibody.

67. The method according to any one of claims 1 to 66, wherein the subject is a CIDP patient characterized by the presence of anti-Caspr1 antibody.

68. The method according to any one of claims 1 to 67, wherein the subject is a CIDP patient characterized by the presence of anti-NF140 / 186 antibodies.

69. The method according to any one of claims 1 to 68, wherein the subject is a CIDP patient characterized by the presence of anti-GM-1 antibody.

70. The method according to any one of claims 1 to 69, wherein the subject is a CIDP patient characterized by the presence of anti-LM-1 antibody.

71. The method according to any one of claims 1 to 70, wherein disease activity control, partial remission, or complete remission is achieved after administration of the FcRn antagonist.

72. The method of claim 71, wherein complete mitigation is achieved.

73. The method of claim 71 or 72, wherein the disease activity control, partial remission, or complete remission is achieved within 12 weeks or less, optionally within 8 weeks or less, optionally within 6 weeks or less, optionally within 4 weeks or less, optionally within 3 weeks or less after the first administration of the FcRn antagonist.

74. The method according to any one of claims 71 to 73, wherein the subject's disease activity control, partial remission, or complete remission is maintained for at least 2 months.

75. The method according to any one of claims 71 to 73, wherein the subject's disease activity control, partial remission, or complete remission is maintained for at least 6 months.

76. The method of claim 71, wherein once the disease activity is controlled, partially relieved, or completely relieved, continued administration of the FcRn antagonist prevents symptom exacerbation.

77. The method of claim 76, wherein the absence of symptom exacerbation is measured using any of the following: INCAT score; Medical Research Council (MRC) total score; I-RODS; average grip strength test; or timed stand-up walking (TUG) test.

78. The method according to any one of claims 1 to 77, wherein the treatment prevents or delays recurrence.

79. The method of claim 78, wherein the treatment to prevent or delay recurrence lasts for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks.

80. The method of claim 78 or 79, wherein the treatment to prevent or delay recurrence continues for the duration of treatment with the FcRn antagonist.

81. The method of claim 78 or 79, wherein the treatment prevents or delays relapse after treatment with the FcRn antagonist is discontinued.

82. The method of claim 81, wherein the treatment prevents or delays recurrence for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks after the treatment is stopped.

83. The method of claim 81, wherein the treatment continues to prevent or delay recurrence for at least 20 weeks after the treatment is discontinued.

84. The method according to any one of claims 1 to 83, wherein the treatment reduces the risk of recurrence by at least 60%.

85. The method according to any one of claims 1 to 84, wherein the subject shows symptom improvement after administration of the FcRn antagonist, as measured using the INCAT score, preferably as measured using the aINCAT score.

86. The method of claim 85, wherein the subject shows a reduction of 1 or more points in aINCAT score.

87. The method of claim 85, wherein the subject shows a reduction of 2 or more points in aINCAT score.

88. The method according to any one of claims 1 to 87, wherein the subject shows symptom improvement after administration of the FcRn antagonist, as measured using the MRC total score.

89. The method according to any one of claims 1 to 88, wherein the subject shows symptom improvement after administration of the FcRn antagonist, as measured using the I-RODS.

90. The method of claim 89, wherein the subject shows an increase of 4 or more points in the I-RODS percentile metric score.

91. The method according to any one of claims 1 to 90, wherein the subject shows symptom improvement after administration of the FcRn antagonist, as measured using the mean grip strength test.

92. The method of claim 91, wherein the subject exhibits an increase in average grip strength ≥8 kPa.

93. The method according to any one of claims 1 to 92, wherein the subject shows symptom improvement after administration of the FcRn antagonist, as measured using the TUG test.

94. The method according to any one of claims 85 to 93, wherein symptom improvement is achieved within 12 weeks or less, optionally within 8 weeks or less, optionally within 6 weeks or less, optionally within 4 weeks or less, optionally within 3 weeks or less after the first administration of the FcRn antagonist.

95. The method according to any one of claims 1 to 94, wherein the subject exhibits decreased serum levels of total IgG, autoantibodies, cytokines / chemokines, or immune complexes after administration of the FcRn antagonist.

96. The method of claim 95, wherein the serum levels of total IgG, the autoantibody, the cytokines / chemokines, or the immune complexes are measured at 4, 12, 24, or 48 weeks after administration of the FcRn antagonist.

97. The method of claim 95 or 96, wherein the subject exhibits a decrease in serum levels of one or more autoantibodies selected from the group consisting of: anti-GM1, anti-LM-1, anti-NF-155, anti-CNTN1, anti-Caspr-1 antibody, and anti-myelinated nerve antibody after administration of the FcRn antagonist.

98. The method according to any one of claims 1 to 97, wherein the subject does not show a decrease in serum albumin levels after administration of the FcRn antagonist.

99. The method according to any one of claims 1 to 98, wherein the subject does not show an increase in serum cholesterol after administration of the FcRn antagonist.

100. The method according to any one of claims 1 to 99, wherein the subject exhibits ECI after administration of the FcRn antagonist.

101. The method of claim 100, wherein the subject exhibits ECI within 31 to 51 days after first receiving the FcRn antagonist.

102. The method of claim 100 or 101, wherein the subject exhibits ECI within 43 days of first receiving the FcRn antagonist.

103. The method according to any one of claims 1 to 102, further comprising administering an effective amount of one or more additional therapeutic agents to the subject.

104. The method of claim 103, wherein the additional therapeutic agent is a corticosteroid.

105. The method according to any one of claims 1 to 104, wherein the method is used to assist in the diagnosis of CIDP.

106. An FcRn antagonist used for treating CIDP according to any one of claims 1 to 105.

107. Use of an FcRn antagonist in the manufacture of a medicament for treating CIDP, wherein the treatment is performed according to any one of claims 1 to 105.

108. A method for treating CIDP in subjects within a patient population, the method comprising: The patient population was given 1008 mg / 11,200 units of egamod PH20 or a biosimilar thereof once weekly, and 66.5% of the subjects in the patient population exhibited ECI after administration of the egamod PH20 or a biosimilar thereof.

109. The method of claim 108, wherein the patient population achieves the ECI within 31 to 51 days after first receiving the edamod PH20 or a biosimilar thereof.

110. The method of claim 108 or 109, wherein the patient population achieves the ECI within 43 days of first receiving the edamod PH20 or a biosimilar thereof.

111. The method according to any one of claims 108 to 110, wherein the patient population comprises 322 subjects.

112. The method according to any one of claims 108 to 110, wherein anti-egamod α antibodies were detected in 6% of the patient population after administration of the egamod PH20 for up to 12 weeks.

113. The method of claim 112, wherein neutralizing anti-egamod α antibodies were detected in 0.3% of the patient population after administration of the egamod PH20 for up to 12 weeks.

114. The method according to any one of claims 108 to 110, wherein the subjects in the patient population remain relapse-free for a significantly longer period than subjects who have not received iatrovid PH20 or its biosimilar form.

115. The method of any one of claims 108 to 110, wherein the subjects in the patient population experienced a longer time to clinical deterioration that was statistically significant compared to subjects who did not receive iamod PH20 or a biosimilar thereof, wherein the clinical deterioration was an increase of ≥1 point in the aINCAT score.

116. The method of claim 115, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

117. The method of claim 115 or 116, wherein the clinical deterioration is an increase of ≥2 points in the aINCAT score.

118. The method according to any one of claims 115 to 117, wherein the longer time to clinical deterioration is demonstrated by a risk ratio of 0.

394.

119. The method according to any one of claims 108 to 110, wherein the subjects in the patient population treated with egamod PH20 or a bioanalyte thereof exhibited a 61% reduction in the risk of exacerbation in patients with CIDP.

120. A method for treating a subject with CIDP, the method comprising: The subject was given 1008 mg / 11,200 units of edamod PH20 or a biosimilar thereof once weekly, and the subject exhibited ECI after administration of said edamod PH20 or a biosimilar thereof.

121. The method of claim 120, wherein the subject achieves the ECI within 31 to 51 days after first receiving the edamame PH20 or a biosimilar thereof.

122. The method of claim 120 or 121, wherein the subject achieves the ECI within 43 days of first receiving the edamame PH20 or a biosimilar thereof.

123. The method according to any one of claims 120 to 122, wherein the subject remains relapse-free for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks after administration of the edema PH20 or its biosimilar form.

124. The method of any one of claims 120 to 123, wherein the subject exhibits a reduced risk of displaying ECMD.

125. The method of claim 124, wherein the ECMD is an increase of ≥1 point in the aINCAT score.

126. The method of claim 124 or 125, wherein the ECMD is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

127. The method according to any one of claims 124 to 126, wherein the ECMD is an increase of ≥1 point in the aINCAT score twice within two weeks.

128. The method according to any one of claims 124 to 127, wherein the ECMD is an increase of ≥2 points in the aINCAT score.

129. A method for treating CIDP in a patient population, the method comprising: Once weekly administration of 1008 mg / 11,200 units of egamod PH20 or its biosimilar, wherein, following administration of said egamod PH20 or its biosimilar, the mean percentage reduction in total IgG levels relative to baseline in the patient population ranged between 66.8% and 71.6%.

130. The method of claim 129, wherein after administration of the edamamed PH20 or a biosimilar thereof four times a week, the average percentage reduction in total IgG levels in the patient population relative to baseline ranges between 66.8% and 71.6%.

131. The method of claim 129 or 130, wherein the average percentage reduction in total IgG levels relative to baseline is maintained from week 4 throughout the treatment period.

132. The method according to any one of claims 129 to 131, wherein the patient population comprises 322 subjects.

133. A method for treating a subject with CIDP, the method comprising: Once weekly administration of 1008 mg / 11,200 units of igamaide PH20 or its biosimilar, wherein the subjects showed a decrease in serum total IgG levels between 66.8% and 71.6% after administration of igamaide PH20 or its biosimilar compared to baseline values ​​prior to administration.

134. The method of claim 133, wherein the subject showed a reduction in serum total IgG levels between 66.8% and 71.6% after administration of the edamame PH20 or a biosimilar thereof four times per week.

135. The method of claim 133 or 134, wherein the reduction in serum total IgG levels is maintained until the once-weekly administration of the icomod PH20 or a bioanalyte thereof is discontinued.

136. A method for treating CIDP in a patient population, the method comprising: The subjects in the patient population who received 1008 mg / 11,200 units of egamod PH20 or its biosimilars once a week experienced a longer time to clinical deterioration compared with subjects who did not receive egamod PH20 or its biosimilars, wherein the clinical deterioration was defined as an increase of ≥1 point in the aINCAT score.

137. The method of claim 136, wherein the longer time to clinical deterioration is demonstrated by a risk ratio of 0.

394.

138. The method of claim 136 or 137, wherein the patient population comprises 221 subjects.

139. A method of treating CIDP in a subject with this need, the method comprising administering, once weekly, a clinically proven safe and clinically proven effective amount of egamod PH20 to the subject subcutaneously.

140. The method of claim 139, wherein the clinically proven safe and clinically proven effective amount of icomod PH20 is administered subcutaneously over approximately 30 to 90 seconds.

141. The method according to claim 139 or 140, wherein the clinically proven safe and clinically proven effective amount of egamod PH20 is 1008 mg / 11,200 units.

142. The method according to any one of claims 139 to 141, wherein the subject shows signs of improvement after administration of the edamamed PH20.

143. The method of claim 142, wherein the subject shows signs of improvement between two consecutive measurements.

144. The method of claim 142 or 143, wherein the improvement indicator is selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in average grip strength.

145. The method according to any one of claims 139 to 144, wherein the subject experiences a longer time to clinical deterioration after administration of the igamadiol PH20 compared to a subject who has not received igamadiol PH20.

146. The method of claim 145, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score.

147. The method of claim 145 or 146, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

148. The method according to any one of claims 145 to 147, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score twice within two weeks.

149. The method according to any one of claims 145 to 148, wherein the clinical deterioration is an increase of ≥2 points in the aINCAT score.

150. A method for treating CIDP in a patient population, the method comprising subcutaneous administration once weekly of a clinically proven safe and effective amount of egamod PH20.

151. The method of claim 150, wherein the clinically proven safe and clinically proven effective amount of icomod PH20 is administered subcutaneously over approximately 30 to 90 seconds.

152. The method according to claim 150 or 151, wherein the clinically proven safe and clinically proven effective amount of egamod PH20 is 1008 mg / 11,200 units.

153. The method according to any one of claims 150 to 152, wherein, after administration of the icotinamide PH20, 69% of the subjects in the patient population showed signs of improvement during two consecutive measurements.

154. The method of claim 153, wherein the improvement indicator is selected from: an improvement of ≥1 point in aINCAT, an improvement of ≥4 points in I-RODS, or an improvement of ≥8 kPa in average grip strength.

155. The method according to any one of claims 150 to 154, wherein the subjects in the patient population experienced a longer time to clinical deterioration compared to subjects who did not receive iatrovid PH20, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score.

156. The method of claim 155, wherein the clinical deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

157. The method of claim 155 or 156, wherein the clinical deterioration is an increase of ≥2 points in the aINCAT score.

158. The method according to any one of claims 155 to 157, wherein the longer time to clinical deterioration is demonstrated by a risk ratio of 0.

394.

159. The method according to any one of claims 155 to 157, wherein the patient population comprises 221 subjects.

160. An edamod PH20 for use in treating a subject with CIDP, wherein a clinically proven safe and clinically proven effective amount of the edamod PH20 is administered subcutaneously to the subject once weekly or every other week.

161. The egamod PH20 used according to claim 160, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 is administered subcutaneously once a week.

162. The egamod PH20 used according to claim 160, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 is initially administered subcutaneously once a week and subsequently administered subcutaneously once every other week based on clinical evaluation.

163. The use of α-gamod PH20 according to claim 162, wherein once-weekly subcutaneous application is resumed after symptom exacerbation.

164. The edamame PH20 used according to any one of claims 160 to 163, wherein the clinically proven safe and clinically proven effective amount of the edamame PH20 is administered subcutaneously over approximately 30 to 90 seconds.

165. The egamod PH20 used according to any one of claims 160 to 164, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 comprises 1000 mg of egamod α.

166. The use of edamamed PH20 according to any one of claims 160 to 165, wherein the subject still has an active disease despite treatment with corticosteroids or immunoglobulins.

167. The use of igamaide PH20 according to any one of claims 160 to 166, wherein the subject received prior CIDP therapy prior to initiating igamaide PH20 treatment, and wherein the igamaide PH20 was administered before the clinical effect of the prior CIDP therapy diminished.

168. The Aigamod PH20 used according to claim 167, wherein the prior CIDP therapy is a corticosteroid or immunoglobulin.

169. The edamamed PH20 used according to any one of claims 160 to 168, wherein the subject shows a decrease in serum total IgG levels between 66.8% and 71.6% after administration of the edamamed PH20 compared to baseline values ​​prior to administration.

170. The edamamed PH20 used according to claim 169, wherein the subject showed a decrease in serum total IgG levels between 66.8% and 71.6% after administration of the edamamed PH20 four times a week.

171. The edamamed PH20 used according to claim 169 or 170, wherein the reduction in serum total IgG levels is maintained until the once-weekly administration of the edamamed PH20 is discontinued.

172. The eigamod PH20 used according to any one of claims 160 to 171, wherein when administered to a patient population of CIDP subjects, the eigamod PH20 induces an ECI response in 66.5% of the subjects in the patient population.

173. The use of edamame PH20 according to any one of claims 160 to 172, wherein the subject exhibits ECI after administration of the edamame PH20.

174. The edamame PH20 used according to claim 173, wherein the subject exhibits ECI within 31 to 51 days after first receiving the edamame PH20.

175. The edamamed PH20 used according to claim 173 or 174, wherein the subject exhibits ECI within 43 days of first receiving the edamamed PH20.

176. The eigamod PH20 used according to any one of claims 160 to 175, wherein the subject remained relapse-free for a significantly longer period after administration of the eigamod PH20 compared to subjects who did not receive the eigamod PH20.

177. The use of igamaide PH20 according to any one of claims 160 to 176, wherein the subject exhibits a reduced risk of showing signs of clinical deterioration after administration of the igamaide PH20.

178. The α-carboxamide PH20 used according to claim 177, wherein the clinical sign of deterioration is an increase of ≥1 point in the aINCAT score.

179. The use of α-gamod PH20 according to claim 177 or 178, wherein the clinical sign of deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

180. The use of α-gamod PH20 according to any one of claims 177 to 179, wherein the clinical sign of deterioration is an increase of ≥1 point in the aINCAT score twice within two weeks.

181. The use of α-gamod PH20 according to any one of claims 177 to 180, wherein the clinical sign of deterioration is an increase of ≥2 points in the aINCAT score.

182. An ethamod PH20 for use in treating subjects in a patient population, said treatment comprising subcutaneous administration of a clinically proven safe and clinically proven effective amount of said ethamod PH20 once weekly or every other week.

183. The egamod PH20 used according to claim 182, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 is administered subcutaneously once a week.

184. The egamod PH20 used according to claim 182, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 is initially administered subcutaneously once a week and subsequently administered subcutaneously every other week based on clinical evaluation.

185. The use of α-gamod PH20 according to claim 184, wherein once-weekly subcutaneous application is resumed after symptom exacerbation.

186. The edamame PH20 used according to any one of claims 182 to 185, wherein the clinically proven safe and clinically proven effective amount of the edamame PH20 is administered subcutaneously over approximately 30 to 90 seconds.

187. The egamod PH20 used according to any one of claims 182 to 186, wherein the clinically proven safe and clinically proven effective amount of the egamod PH20 comprises 1000 mg of egamod α.

188. The use of α-gamod PH20 according to any one of claims 182 to 186, wherein the subjects in the patient population still have active disease despite treatment with corticosteroids or immunoglobulins.

189. The use of igamaide PH20 according to any one of claims 182 to 188, wherein the subjects in the patient population received prior CIDP therapy prior to initiating igamaide PH20 treatment, and wherein the igamaide PH20 was administered before the clinical effect of the prior CIDP therapy diminished.

190. The Aigamod PH20 used according to claim 189, wherein the prior CIDP therapy is a corticosteroid or immunoglobulin.

191. The eigamod PH20 used according to any one of claims 182 to 190, wherein after administration of the eigamod PH20, the average percentage reduction in total IgG levels relative to baseline in the patient population ranges between 66.8% and 71.6%.

192. The eigamod PH20 used according to claim 191, wherein after administration of the eigamod PH20 four times a week, the average percentage reduction in total IgG levels in the patient population relative to baseline ranges between 66.8% and 71.6%.

193. The edamamed PH20 used according to claim 191 or 192, wherein the mean percentage reduction in total IgG levels relative to baseline is maintained from week 4 throughout the treatment period.

194. The eigamod PH20 used according to any one of claims 182 to 193, wherein 66.5% of the subjects in the patient population exhibited ECI after administration of the eigamod PH20.

195. The egamod PH20 used according to claim 194, wherein the patient population achieves the ECI within 31 to 51 days after first receiving the egamod PH20.

196. The use of egamod PH20 according to claim 194 or 195, wherein the patient population achieves the ECI within 43 days of first receiving the egamod PH20.

197. The use of eigamod PH20 according to any one of claims 182 to 196, wherein the subjects in the patient population remain relapse-free for a significantly longer period than subjects who have not received eigamod PH20.

198. The egamod PH20 used according to any one of claims 182 to 197, wherein the subjects in the patient population treated with egamod PH20 showed a 61% reduction in the risk of deterioration.

199. The use of igamaide PH20 according to any one of claims 182 to 198, wherein the subjects in the patient population showed a reduced risk of showing signs of clinical deterioration after administration of the igamaide PH20.

200. The use of α-gamod PH20 according to claim 199, wherein the clinical sign of deterioration is an increase of ≥1 point in the aINCAT score.

201. The α-carboxamide PH20 used according to claim 199 or 200, wherein the clinical sign of deterioration is an increase of ≥1 point in the aINCAT score between two consecutive measurements.

202. The use of α-gamod PH20 according to any one of claims 199 to 201, wherein the clinical sign of deterioration is an increase of ≥1 point in aINCAT score twice within two weeks.

203. The use of α-gamod PH20 according to any one of claims 199 to 202, wherein the clinical sign of deterioration is an increase of ≥2 points in the aINCAT score.

204. The use of Aigamod PH20 according to any one of claims 182 to 203, wherein the patient population comprises 322 subjects.

205. The method or use according to any one of claims 1 to 204, wherein the subject is an adult.

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