Dosage and Administration of Fusion Polypeptide for the Treatment of Myasthenia Gravis

Abstract

Provided is a method for treating myasthenia gravis (MG) in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective dose of a fusion protein comprising an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds human serum albumin, wherein the engineered polypeptide that specifically binds human complement component C5 is fused via a peptide linker to the engineered polypeptide that specifically binds human serum albumin, the engineered polypeptide that specifically binds human complement component C5 comprises three complementarity determining regions CDR1, CDR2, and CDR3 respectively comprising the amino acid sequences shown in SEQ ID NOs: 5, 6, and 7, and the engineered polypeptide that specifically binds human serum albumin comprises three complementarity determining regions CDR1, CDR2, and CDR3 respectively comprising the amino acid sequences shown in SEQ ID NOs: 1, 2, and 3.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority to U.S. Application No. 63 / 348,622, filed on June 3, 2022, which is incorporated herein by reference for all purposes.

Background Art

[0002] The complement system acts in concert with other immune systems of the body to defend against the invasion of cellular and viral pathogens. There are at least 25 complement proteins, seen as a complex collection of plasma proteins and membrane cofactors. Plasma proteins constitute approximately 10% of the globulins in vertebrate serum. Complement components achieve their immune defense functions by interacting a series of complex but precise enzymatic cleavage and membrane - binding events. The resulting complement cascade produces products with opsonin, immunomodulatory, and lytic functions.

[0003] Myasthenia gravis (MG) is a rare, debilitating, acquired autoimmune neuropathy of the neuromuscular junction (NMJ), which is caused by the failure of neuromuscular transmission resulting from autoantibodies (autoAbs) binding to proteins involved in signal transduction at the NMJ. These proteins include the nicotinic acetylcholine receptor (AChR), or less frequently, muscle - specific tyrosine kinase (MuSK) involved in AChR clustering.

[0004] MG can cause life - threatening respiratory failure, called myasthenic crisis. The prevalence of MG is 14 - 20 per 100,000 in the United States, affecting approximately 60,000 Americans. It affects men and women at the same rate, but the incidence peaks in women in their 30s, while the peak age of onset in men is in their 60s or 70s. Approximately 15% - 20% of patients experience myasthenic crisis during the course of the disease, and 75% require hospitalization and ventilatory support within 2 years of diagnosis. The mortality rate due to MG is approximately 4%, mostly due to respiratory failure.

[0005] Myasthenia gravis is characterized clinically by weakness and fatigability of voluntary skeletal muscles. MG can initially present with weakness of the extraocular muscles, called ocular MG (oMG), which affects the movement of the eyes and eyelids. 10% of the subjects have a disease limited to the extraocular muscles. 90% of the subjects have generalized MG with muscle weakness involving the muscles of the neck, head, spine, medulla, respiratory system, or extremities. Bulbar weakness refers to the muscles controlled by nerves arising from the bulbous part of the brainstem and presents as difficulty in conversation, chewing, swallowing, and head control.

[0006] Patients with generalized myasthenia gravis (gMG) differ from the ocular myasthenia gravis (oMG) population in that the neuromuscular inflammation and resulting clinical findings are not limited to the extraocular muscles but involve all voluntary muscle groups, i.e., the medulla, respiratory system, head, neck, trunk, or peripheral muscles, regardless of the presence or absence of eye involvement. Severe weakness and devastating consequences, including slurred speech, dysarthria, dysphagia, visual impairment, shortness of breath (both during exertion and at rest), weakness of the upper and lower extremities, movement disorders, marked decline in the ability to perform activities of daily living (ADL), extreme fatigue, and episodes of pulmonary insufficiency requiring mechanical ventilation, are characteristic of gMG. Compared to patients with isolated oMG, patients with gMG have a higher prevalence and a higher disease burden. gMG is a rare disease with an estimated prevalence of 145 - 278 per million. Patients with gMG suffer from a devastating inflammatory neuromuscular disorder with limited treatment options.

[0007] Hospitalization for gMG exacerbation is common, and there is a need for respiratory assistance, including mechanical ventilation secondary to respiratory failure (e.g., myasthenic crisis), and placement of a gastrointestinal tube for nutritional supplementation and prevention of aspiration related to dysphagia. Patients with more advanced gMG have been reported to experience an increase in mortality of up to 40% within 10 years after diagnosis.

[0008] Although there is no cure for MG, there are therapies that reduce muscle weakness and improve neuromuscular function. Currently available treatments for myasthenia gravis aim to regulate neuromuscular transmission, inhibit the production or effects of pathogenic antibodies, or inhibit inflammatory cytokines. Currently, there is no specific treatment targeting the pathophysiology underlying NMJ damage, specifically the anti-AChR antibody-AChR interaction that results in classical pathway and complement activation via inflammation, ultimately destroying the NMJ. There is no specific treatment to correct the autoimmune deficiency in MG. Usually, immunosuppressive therapy (IST), which represents the current standard treatment using a combination of cholinesterase inhibitors, corticosteroids, and immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine, and mycophenolate mofetil [MMF]), allows the majority of subjects with MG to fairly control their disease. However, these therapies may not be optimal for all patients, and there is a cohort of subjects who do not respond adequately to IST or are intolerant to IST, as well as those who require repeated treatments with plasma exchange (PE) and / or intravenous immunoglobulin (IVIg) to maintain clinical stability.

[0009] In difficult-to-control cases, patients with gMG experience severe pathological conditions as a result, including persistent inflammation, tissue destruction, and profound muscle weakness, movement disorders, shortness of breath, lung failure, extreme fatigue, risk of dysphagia, and marked ADL impairment. These patients are typically diagnosed in the prime of adulthood, with a median onset age in the range of 36 - 60 years. As a result of the pathological conditions associated with gMG, many patients are unable to work or have reduced work capacity, have difficulty taking care of themselves or others, and require assistance to talk, eat, walk, breathe, and perform ADL.

[0010] Uncontrolled terminal complement activation is involved in experimental animal models of autoimmune gMG and other forms of autoimmune neuropathy in humans. Autoantibodies recognize targeted nerve or muscle tissue, including AChR, resulting in uncontrolled terminal complement activation on the nerve or muscle surface.

[0011] Autoantibody-driven uncontrolled terminal complement activation with membrane attack complex (MAC)-dependent lysis and activation, and C5a-dependent inflammation in the NMJ result in AChR loss and failure of neuromuscular transmission. Consistent with this model, both complement component C3 fragments (C3a and C3b) and MAC C5b-9 have been found at the NMJ of MG patients.

[0012] There is no cure for MG and standard treatments are not effective in all patients, so there is a need to provide improved methods for treating these patients. SUMMARY OF THE INVENTION

[0013] In one aspect, the present disclosure provides a method of treating myasthenia gravis (MG) in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective dose of a fusion protein comprising an engineered polypeptide that specifically binds to human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused via a peptide linker to the engineered polypeptide that specifically binds to human serum albumin, the engineered polypeptide that specifically binds to human complement component C5 comprises three complementarity-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 5, 6, and 7, and the engineered polypeptide that specifically binds to human serum albumin comprises three complementarity-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3.

[0014] In some embodiments, the polypeptide that specifically binds to human serum albumin comprises a VHH domain. In some embodiments, the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 4. In some embodiments, the polypeptide that specifically binds to human serum albumin comprises the amino acid sequence of SEQ ID NO: 4.

[0015] In some embodiments, the polypeptide that specifically binds to human complement component C5 comprises a VHH domain. In some embodiments, the polypeptide that specifically binds to human complement component C5 comprises an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 8. In some embodiments, the polypeptide that specifically binds to human complement component C5 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the peptide linker comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the fusion protein comprises an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 9. In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 9.

[0016] In some embodiments, the C-terminal residue of the polypeptide that specifically binds to human serum albumin is fused via a linker to the N-terminal residue of the polypeptide that specifically binds to human complement component C5.

[0017] In some embodiments, the subject is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti - AChR). In some embodiments, MG is generalized myasthenia gravis (gMG). In some embodiments, the subject has been diagnosed with MG, such as anti - AChR positive gMG, for at least 3 months. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject has an American Myasthenia Gravis Foundation (MGFA) clinical classification of II - IV. In some embodiments, the patient has a Myasthenia Gravis Activities of Daily Living (MG - ADL) score of 5 or more.

[0018] In some embodiments, the subject is receiving administration of one or more additional pharmaceutical compositions. In some embodiments, the pharmaceutical composition is an acetylcholinesterase inhibitor, immunosuppressive therapy (IST), or immunoglobulin. In some embodiments, IST is selected from the group consisting of corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).

[0019] In some embodiments, the subject has not been administered B - cell depletion therapy in the past 6 months. In some embodiments, the B - cell depletion therapy is rituximab or ocrelizumab. In some embodiments, prior to administration of the fusion protein, the subject has not been administered an FcRn inhibitor within 5 half - lives of FcRn. In some embodiments, prior to administration of the fusion protein, the subject has not been administered a complement inhibitor within 5 half - lives of the complement inhibitor.

[0020] In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject has a body mass index of 18.5 kg / m 2 or more to 40 kg / m 2 less (e.g., 18.5 kg / m 2 to 39.5 kg / m 2 , 20 kg / m 2 to 35 kg / m 2 , 25 kg / m2 ~30 kg / m 2 、 25 kg / m 2 ~39.5 kg / m 2 、 and 18.5 kg / m 2 ~35 kg / m 2 It is. In some embodiments, the therapeutically effective dose is based on the weight of the subject.

[0021] In some embodiments, the fusion protein is administered once on the first day of the dosing cycle at a loading dose of 600 mg to patients weighing less than 80 kg, and then weekly at a maintenance dose of 300 mg. In some embodiments, the fusion protein is administered weekly at a dose of 300 mg for up to 2 years after the dosing cycle. In some embodiments, the fusion protein is administered once on the first day of the dosing cycle at a loading dose of 900 mg to patients weighing 80 kg or more, and then weekly at a maintenance dose of 600 mg. In some embodiments, the fusion protein is administered weekly at a dose of 600 mg for up to 2 years after the dosing cycle.

[0022] In some embodiments, the fusion protein is administered subcutaneously to the subject. In some embodiments, the fusion protein is administered to the subject using a prefilled syringe. In some embodiments, the prefilled syringe includes a passive needle safety device. In some embodiments, the fusion protein is administered to the subject using an autoinjector.

[0023] In some embodiments, as a result of treatment, the patient experiences a change from the baseline MG-ADL score. In some embodiments, as a result of treatment, the patient experiences a change from the baseline MG-ADL score after 26 weeks. In some embodiments, as a result of treatment, the patient experiences a decrease in the MG-ADL score after 26 weeks. In some embodiments, the decrease is at least 3.0 points. In some embodiments, the decrease is at least 4.0 points.

[0024] In some embodiments, treatment causes the patient to experience a change from the baseline Quantitative Myasthenia Gravis (QMG) score. In some embodiments, treatment causes the patient to experience a change from the baseline QMG score after 26 weeks. In some embodiments, treatment causes the patient to experience a decrease in the QMG score after 26 weeks. In some embodiments, the decrease is at least 2.0 points. In some embodiments, the decrease is at least 5.0 points.

[0025] In some embodiments, treatment causes the patient to experience a change from the baseline Myasthenia Gravis Composite (MGC) score. In some embodiments, treatment causes the patient to experience a change from the baseline MGC score after 26 weeks. In some embodiments, treatment causes the patient to experience a decrease in the MGC score after 26 weeks.

[0026] In some embodiments, treatment causes the subject to experience a change from the baseline free or total C5 blood concentration. In some embodiments, treatment causes the patient to experience a change from the baseline Myasthenia Gravis Quality of Life 15 (MG-QoL15r) score after 26 weeks. In some embodiments, treatment causes the patient to experience a change from the baseline EQ-5D-5L score after 26 weeks. In some embodiments, treatment causes the patient to experience a change from the baseline SF-36 score after 26 weeks. In some embodiments, treatment causes the patient to experience a change from the baseline Neuro-QoL Fatigue (Quality of Life in Neurological Disorders Fatigue Short Form) score after 26 weeks. In some embodiments, treatment causes the patient to experience an MG-ADL score of 1 or less after 26 weeks. In some embodiments, treatment causes the patient to experience a change in the post-intervention MGFA status after 26 weeks.

[0027] In some embodiments, treatment causes the patient to experience a reduced incidence of clinical worsening after 26 weeks. In some embodiments, treatment causes the patient to experience a reduced incidence of hospitalization after 26 weeks. In some embodiments, treatment causes the patient to experience a reduced incidence of the need for rescue therapy after 26 weeks. In some embodiments, treatment causes a change in the concentration of one or more inflammatory biomarkers. In some embodiments, the one or more inflammatory biomarkers include MMP-10 or IL-6. In some embodiments, treatment causes a change in the concentration of a complement protein or complement pathway regulator. In some embodiments, the treatment effect is maintained until week 26 after the start of treatment. In some embodiments, the treatment effect is maintained until week 96 after the start of treatment.

[0028] In another aspect, the present disclosure provides a method of treating gMG in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective dose of a fusion protein comprising an engineered polypeptide that specifically binds to human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, the polypeptide that specifically binds to human complement component C5 comprises three complementarity determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 5, 6, and 7, the polypeptide that specifically binds to human serum albumin comprises three complementarity determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, the subject is positive for anti-AChR, the subject is 18 years of age or older, the fusion protein is administered to patients weighing less than 80 kg once on day 1 of the dosing cycle at a loading dose of 600 mg, on day 8 of the dosing cycle and then weekly at a maintenance dose of 300 mg, the fusion protein is administered weekly at a dose of 300 mg for up to 2 years after the dosing cycle, or the fusion protein is administered to patients weighing 80 kg or more once on day 1 of the dosing cycle at a loading dose of 900 mg, on day 8 of the dosing cycle and then weekly at a maintenance dose of 600 mg, the fusion protein is administered weekly at a dose of 600 mg for up to 2 years after the dosing cycle, and the subject has an improvement from baseline in at least one measurement of gMG severity selected from the group consisting of MG-ADL, QMG, MGC, MG-QoL15r, EQ-5D-5L, SF-36, and Neuro-QoL Fatigue.

Brief Description of the Drawings

[0029]

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[0030] DEFINITIONS As used herein, the term “antibody” includes whole antibodies and any antigen-binding fragment (i.e., “antigen-binding portion”) or single-chain version thereof. An “antibody” refers, in one preferred embodiment, to a glycoprotein comprising at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region. The heavy chain constant region is composed of three domains CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as V L ), and a light chain constant region. The light chain constant region is composed of one domain CL. V H and V L regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed with regions called more conserved framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain the binding domains that interact with the antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Clq).

[0031] "Heavy chain antibody" refers to an antibody consisting of two heavy chains and lacking the two light chains found in conventional antibodies. Camelids (members of the biological family Camelidae, the only family currently living within the suborder Tylopoda; extant camelids include the dromedary, Bactrian camel, wild or feral camels, llamas, alpacas, vicuñas, and guanacos) are the only mammals that possess single-chain VHH antibodies. Approximately 50% of the antibodies in camelids are heavy chain antibodies, and the other 50% are of the normal or conventional mammalian heavy chain / light chain antibody type.

[0032] "VHH domain" refers to the variable domain present in naturally occurring heavy chain antibodies, and these are distinguished from the heavy chain variable domain (referred to herein as the "VH domain") present in conventional four-chain antibodies and the light chain variable domain (referred to herein as the "VL domain") present in conventional four-chain antibodies.

[0033] VHH domains have a number of unique structural and functional properties that enable the creation of isolated VHH domains (as well as sdAbs based on VHH domains that share these structural and functional properties with naturally occurring VHH domains) and proteins containing VHH domains that are highly advantageous for use as functional antigen-binding domains or proteins. For example, VHH domains and sdAbs that bind antigens without the presence of VL can function as a single relatively small functional antigen-binding structural unit, domain, or protein. The small size of these molecules distinguishes VHH domains from the VH and VL domains of conventional four-chain antibodies. Using VHH domains and sdAbs as a single antigen-binding protein or as an antigen-binding domain (e.g., as part of a larger protein or polypeptide) offers a number of significant advantages over the use of conventional VH and VL domains and scFv or conventional antibody fragments (such as Fab or F(ab’)2 fragments). For example, only a single domain is required to bind an antigen with high affinity and high selectivity, so there is no need for two separate domains, nor is it necessary to ensure that these two domains are present in a specific spatial structure and configuration (e.g., via the use of a specific linker, as in scFv). VHH domains and sdAbs can also be expressed from a single gene and do not require post-translational folding or modification. VHH domains and sdAbs can be easily engineered into multivalent and multispecific formats. VHH domains and sdAbs are also very soluble and do not tend to aggregate (Ward, E. et al., Nature, 341:544-6, 1989), and they are very stable to heat, pH, proteases, and other denaturing agents or conditions (Ewert, S. et al., Biochemistry, 41:3628-36, 2002). VHH domains and sdAbs can be prepared relatively easily and inexpensively, even on the scale required for production. For example, VHH domains, sdAbs, and polypeptides containing VHH domains or sdAbs can be produced using microbial fermentation using methods known in the art and do not require the use of mammalian expression systems, for example, like conventional antibody fragments.VHH domains and sdAbs are relatively small compared to conventional four-chain antibodies and their antigen-binding fragments (approximately 15 kDa, or one-tenth the size of a conventional IgG), and thus exhibit higher penetration into tissues (including, but not limited to, solid tumors and other dense tissues) than conventional four-chain antibodies and their antigen-binding fragments. VHH domains and sdAbs can exhibit so-called "cavity binding" properties (e.g., due to their extended CDR3 loops), allowing access to targets and epitopes that are inaccessible to conventional four-chain antibodies and their antigen-binding fragments. For example, it has been shown that VHH domains and sdAbs can inhibit enzymes (WO97 / 49805, Transue, T. et al., Proteins, 32:515-22, 1998, Lauwereys, M. et al., EMBO J., 17:3512-20, 1998).

[0034] As used herein, the term "single domain antibody" or "sdAb" refers to an antibody or fragment thereof consisting of a single monomeric variable antibody domain. This is not limited to a particular biological origin or a particular method of preparation. sdAbs can be obtained, for example, by (1) isolating the VHH domain of a naturally occurring heavy chain antibody, (2) expressing a nucleotide sequence encoding a naturally occurring VHH domain, (3) "humanizing" a naturally occurring VHH domain, or expressing a nucleic acid encoding such a humanized VHH domain, (4) "camelizing" a naturally occurring VH domain from any animal species, particularly mammalian species such as humans, or expressing a nucleic acid encoding such a camelized VH domain, (5) "camelizing" a "domain antibody" ("Dab"), or expressing a nucleic acid encoding such a camelized VH domain, (6) using synthetic or semi-synthetic techniques for preparing engineered polypeptides or fusion proteins, (7) using techniques for nucleic acid synthesis to prepare a nucleic acid encoding an sdAb, followed by expressing the nucleic acid thus obtained, and / or (8) by any combination of the above.

[0035] The fusion polypeptide or fusion protein described herein can comprise an amino acid sequence of a "humanized" naturally-occurring VHH domain, for example, by substituting one or more amino acid residues within the amino acid sequence of a naturally-occurring VHH sequence with one or more of the amino acid residues present at the corresponding positions within the VH domain derived from human.

[0036] The fusion polypeptide or fusion protein described herein can comprise an amino acid sequence of a naturally-occurring VH domain that has been "camelized" (i.e., by substituting one or more amino acid residues within the amino acid sequence of a naturally-occurring VH domain with one or more of the amino acid residues present at the corresponding positions within the VHH domain of a camelid antibody). This can be done in a manner known in the art. Such camelization may preferentially occur at amino acid positions present at the VH-VL interface and at so-called "camelid-signature residues" (WO94 / 04678). The VH domain or sequence used as the parental sequence or starting material for generating or designing the camelized sequence can be, for example, a VH sequence derived from a mammal, and in certain embodiments, a human VH sequence. However, it should be noted that such camelized sequences are not strictly limited to polypeptides obtained using polypeptides comprising a native parental VH domain, since such camelized sequences can be obtained in any suitable manner known in the art.

[0037] Both "humanization" and "camelization" are each of a naturally-occurring VHH domain or V HProvided is a nucleotide sequence encoding a domain, and then one or more codons within the nucleotide sequence can be varied in a manner known to those skilled in the art so that the new nucleotide sequences each encode a humanized or camelized sequence. Also, based on the amino acid sequence or nucleotide sequence of a naturally occurring VHH domain or VH domain, a nucleotide sequence encoding a desired humanized or camelized sequence can be newly designed and synthesized using techniques for nucleic acid synthesis known in the art, and then the nucleotide sequence thus obtained can be expressed in a manner known in the art.

[0038] As used herein, the terms "antigen" or "antigen target" refer to a molecule or part of a molecule that can be bound by an antibody, one or more Ig binding domains, or other immunoconjugate moieties, including, for example, an engineered polypeptide or fusion polypeptide disclosed herein. An antigen can be used in an animal to produce an antibody capable of binding to an epitope of the antigen. An antigen may have one or more epitopes.

[0039] As used herein, the term "antigen-binding fragment" (or simply "antibody fragment") of an antibody refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen. Such "fragments" are, for example, about 8 to about 1500 amino acids in length, preferably about 8 to about 745 amino acids in length, preferably about 8 to about 300, such as about 8 to about 200 amino acids, or about 10 to about 50, or 100 amino acids in length. It has been shown that the antigen-binding function of an antibody can be performed by a fragment of the full-length antibody. Examples of binding fragments included in the term "antigen-binding fragment" of an antibody include (i) a Fab fragment which is a monovalent fragment consisting of V L , V H , CL, and CH1 domains, (ii) an F(ab')2 fragment which is a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region, (iii) an Fd fragment consisting of V H and CH1 domains, (iv) the V L of a single arm of the antibody and VH An Fv fragment consisting of domains, (v)V H A dAb fragment consisting of domains (Ward et al., (1989) Nature 341:544-546), and (vi) an isolated complementarity determining region (CDR), or (vii) a combination of two or more isolated CDRs optionally joined by a synthetic linker. Further, the two domains of the Fv fragment, V L and V H are encoded by separate genes, but these can be joined using recombinant methods by a synthetic linker that enables the V L region and the V H region to pair and form a single protein chain that forms a monovalent molecule (known as single-chain Fv (sFv), see, for example, Bird et al. (1988) Science 242:423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are intended to be included within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and these fragments are screened for utility in the same manner as intact antibodies. The antigen-binding portion can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0040] As used herein, the term "binding domain" refers to a portion of a protein or antibody that contains amino acid residues that interact with an antigen. Binding domains include, but are not limited to, antibodies (e.g., full-length antibodies) and antigen-binding portions thereof. A binding domain confers specificity and affinity for an antigen to a binder. The term also encompasses any protein having a binding domain that is homologous or nearly homologous to an immunoglobulin binding domain.

[0041] As used herein, the phrase "clinical worsening" refers to a patient experiencing an MG crisis defined as weakness due to MG severe enough to require intubation or delay extubation after surgery, where respiratory failure is due to weakness of the respiratory muscles and severe bulbar (oropharyngeal) muscle weakness is associated with weakness of the respiratory muscles or is characteristic in the patient, or where there is a significant symptomatic worsening from baseline by 3 points or a score of 2 points in any one of the individual MG - activities of daily living (MG - ADL) items other than diplopia or ptosis, or where administration of rescue therapy is provided to a patient whose health is at risk in the opinion of the treating investigator or a physician designated by the treating investigator in circumstances where rescue therapy would not be given (e.g., an emergency).

[0042] The term "epitope" or "antigenic determinant" refers to the site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes can be formed from both contiguous and non - contiguous amino acids juxtaposed by the three - dimensional folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon exposure to denaturing solvents, whereas epitopes formed by three - dimensional folding are typically lost upon treatment with denaturing solvents. Epitopes typically contain at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in their unique spatial structure. Methods for determining which epitope is bound by a given antibody (i.e., epitope mapping) are well - known in the art and include, for example, immunoblot and immunoprecipitation assays that test overlapping or contiguous peptides from an antigen for reactivity with a given antibody. Methods for determining the spatial structure of an epitope include techniques in the art and techniques described herein, such as X - ray crystallography and two - dimensional nuclear magnetic resonance (e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G.E. Morris, Ed. (1996)).

[0043] The term "bispecific" refers to the fusion polypeptides of the present disclosure that are capable of binding to two antigens.

[0044] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a reduction, improvement, alleviation, mitigation, delay, and / or remission of one or more of the symptoms, signs, or causes of a disease, or any other desired modification of a biological system. In one example, an "effective amount" is the amount of a fusion polypeptide or fragment thereof that has been clinically proven to alleviate at least one symptom of MG. The effective amount can be administered in one or more administrations.

[0045] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, such as improvement of at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement over a baseline, i.e., an improvement over a measurement or observation made prior to initiation of treatment by the method. Effective treatment may refer to alleviation of at least one symptom of MG.

[0046] The term "fused to" as used herein refers to a polypeptide made by combining more than one sequence, typically by cloning one sequence, e.g., a coding sequence, into an expression vector in-frame with one or more second coding sequences(s) such that the two (or more) coding sequences are transcribed and translated into a single continuous polypeptide. In addition to being made by recombinant techniques, portions of a polypeptide can be "fused" to each other using chemical reactions or other means known in the art for making custom polypeptides.

[0047] As used herein, the terms "introduction" and "introduction phase" are used interchangeably and refer to the first phase of treatment in a clinical trial.

[0048] As used herein, the term "loading dose" refers to the initial dose administered to a patient. In some embodiments, the loading dose is 500-1000 mg of the fusion polypeptide. In some embodiments, the loading dose is 600-900 mg, 700-900 mg, or 600-800 mg of the fusion polypeptide. In some embodiments, the loading dose is 800-1000 mg, 600-700 mg, or 700-1000 mg of the fusion polypeptide. In some embodiments, the loading dose is approximately 600 mg, approximately 700 mg, approximately 800 mg, or approximately 900 mg of the fusion polypeptide. The loading dose can be adjusted based on body weight.

[0049] In some embodiments, a patient weighing 40 kg or more but less than 80 kg is administered 200-700 mg, 300-600 mg, approximately 600 mg, or 300 mg of the fusion polypeptide. In some embodiments, a patient weighing 80 kg or more is administered 500-1000 mg, 600-900 mg, approximately 600 mg, or 900 mg of the fusion polypeptide.

[0050] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second stage of treatment in a clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until untreatable toxicity or disease progression occurs. The maintenance phase of fusion polypeptide dosing can continue for 1 week to the lifetime of the subject. According to other embodiments, the maintenance phase continues for 26 - 52, 26 - 78, 26 - 96, 26 - 104, 26 - 130, 26 - 156, 26 - 182, 26 - 208 weeks, or longer. In other embodiments, the maintenance phase continues for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 96, 104, 130, 156, or 182 weeks. According to other embodiments, the maintenance phase continues for 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years, or longer. In certain embodiments, the maintenance phase continues for the remainder of the subject's lifetime.

[0051] As used herein, the term "maintenance dose" or "maintenance phase" refers to the dose administered to a patient after a loading dose. In some embodiments, the loading dose is 200 - 700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 300 - 700 mg, 400 - 600 mg, or 300 - 700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 200 - 600 mg, 200 - 500 mg, or 400 - 700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is approximately 300 mg, approximately 200 mg, or approximately 400 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 600 mg, 500 mg, or 700 mg of the fusion polypeptide. The maintenance dose can be adjusted based on body weight.

[0052] In some embodiments, a fusion polypeptide of 200 - 400 mg, 300 - 400 mg, about 300 mg, or 200 mg is administered to a patient weighing 40 kg or more and less than 80 kg. In some embodiments, a fusion polypeptide of 500 - 700 mg, 600 - 700 mg, about 600 mg, or 700 mg is administered to a patient weighing 80 kg or more.

[0053] As used herein, the phrase "requiring chronic plasma exchange" to maintain clinical stability refers to the use of plasma exchange therapy regularly on a patient at least every three months over the past 12 months to manage muscle weakness.

[0054] As used herein, the term "peptide linker" refers to one or more amino acid residues inserted or included between engineered polypeptides of a fusion polypeptide(s). A peptide linker can be inserted or included, for example, at the transition between the engineered polypeptides of a fusion polypeptide at the sequence level.

[0055] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition that can induce a desired therapeutic effect when administered to a patient.

[0056] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing the delivery of an engineered polypeptide or fusion polypeptide of the present disclosure.

[0057] An antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or an engineered polypeptide or fusion polypeptide disclosed herein is said to "specifically" bind to an antigen when the molecule preferentially recognizes its antigen target in a complex mixture of proteins and / or macromolecules. As used herein, the term "specifically binds" means that an antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or an engineered polypeptide or fusion polypeptide of the present disclosure binds to an antigen containing an epitope with an affinity of at least about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, or greater K D d, and / or the ability to bind to an epitope with an affinity that is at least 2-fold greater than its affinity for non-specific antigens.

[0058] As used herein, the terms "subject" or "patient" refer to a human patient (e.g., a patient having myasthenia gravis (MG)). As used herein, the terms "subject" and "patient" are interchangeable.

[0059] As used herein, the terms "treatment" or "treating" refer to both therapeutic treatment and prophylactic or preventive measures. Those in need of treatment include those having a disorder, those at risk of having a disorder, or those in whom a disorder is to be prevented.

[0060] As used herein, the term "treatment effect" refers to a decrease in the myasthenia gravis activities of daily living (MG-ADL) score, myasthenia gravis (QMG) score, myasthenia gravis (MG) quality of life questionnaire (MGQOL15R) score, neuro-QOL-fatigue score, or another score evaluating the severity of MG, compared to the baseline before the start of treatment. The reduction may be 1 point or more. (Mode for Carrying Out the Invention)

[0061] In the present disclosure, a method for treating myasthenia gravis (MG) in a subject in need thereof is provided by administering a fusion polypeptide comprising an engineered polypeptide that specifically binds to human complement component C5 fused to a polypeptide that specifically binds to human serum albumin via a peptide linker.

[0062] In certain embodiments, the fusion polypeptide comprises an engineered polypeptide that specifically binds to human serum albumin having the sequence of SEQ ID NO: 4, fused to a polypeptide that specifically binds to human complement component 5 having the amino acid sequence of SEQ ID NO: 8.

[0063] Fusion polypeptide that specifically binds complement component C5 and serum albumin Fusion polypeptides are described herein that comprise an engineered polypeptide that specifically binds albumin and complement component C5, and the engineered polypeptides are either directly fused or linked via one or more suitable linkers or spacers. The peptide linker can be inserted or included, for example, at the transition between the engineered polypeptides of the fusion polypeptide at the sequence level. The identity and sequence of the amino acid residues in the linker may vary depending on the desired secondary structure. For example, glycine, serine, and alanine are useful for linkers with the highest flexibility. Any amino acid residue can be considered a linker in combination with one or more other amino acid residues that may be the same or different from the first amino acid residue, as needed to construct a larger peptide linker depending on the desired properties. In other embodiments, the linker is GGGGGAGGGGAGGGGS (SEQ ID NO: 10). One of ordinary skill in the art can select the linker, for example, to reduce or eliminate post-translational modifications, such as glycosylation, such as xylosylation.

[0064] In some embodiments, the C-terminal residue of the albumin-binding domain of the fusion polypeptide can be fused directly or via a peptide to the N-terminal residue of the complement component C5-binding domain.

[0065] In some embodiments, the polypeptide that specifically binds to human serum albumin comprises three complementarity determining regions, CDR1, CDR2, and CDR3, wherein CDR1 has the amino acid sequence of GRPVSNYA (SEQ ID NO: 1), CDR2 has the amino acid sequence of INWQKTAT (SEQ ID NO: 2), and CDR3 has the amino acid sequence of AAVFRVVAPKTQYDYDY (SEQ ID NO: 3).

[0066] In some embodiments, the polypeptide that specifically binds to human complement component 5 comprises three complementarity determining regions, CDR1, CDR2, and CDR3, wherein CDR1 has the amino acid sequence of GRAHSDYAMA (SEQ ID NO: 5), CDR2 has the amino acid sequence of GIGWSGGDTLYADSVRG (SEQ ID NO: 6), and CDR3 has the amino acid sequence of AARQGQYIYSSMRSDSYDY (SEQ ID NO: 7).

[0067] In some embodiments, the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identity to the VHH sequence: EVQLVESGGGLVKPGGSLRLSCAASGRPVSNYAAAWFRQAPGKEREFVSAINWQKTATYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAAVFRVVAPKTQYDYDYWGQGTLVTVSS (SEQ ID NO: 4).

[0068] In some embodiments, the polypeptide that specifically binds to human serum albumin has the amino acid sequence of SEQ ID NO: 4.

[0069] In some embodiments, the polypeptide that specifically binds to complement component C5 comprises an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identity to the VHH sequence: EVQLVESGGGLVQPGGSLRLSCAASGRAHSDYAMAWFRQAPGQEREFVAGIGWSGGDTLYADSVRGRFTNSRDNSKNTLYLQMNSLRAEDTAVYYCAARQGQYIYSSMRSDSYDYWGQGTLVTVSS (SEQ ID NO: 8).

[0070] In some embodiments, the polypeptide that specifically binds to human complement component C5 has the amino acid sequence of SEQ ID NO: 8.

[0071] In some embodiments, the fusion polypeptide comprises complement component C5 binding that comprises the amino acid sequence of SEQ ID NO: 8 or a fragment thereof, and the polypeptide that specifically binds to human serum albumin comprises the amino acid sequence of SEQ ID NO: 4 or a fragment thereof. In some embodiments, the fusion polypeptide may have an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identity to the following sequence: EVQLVESGGGLVKPGGSLRLSCAASGRPVSNYAAAWFRQAPGKEREFVSAINWQKTATYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAAVFRVVAPKTQYDYDYWGQGTLVTVSSGGGGAGGGGAGGGGSEVQLVESGGGLVQPGGSLRLSCAASGRAHSDYAMAWFRQAPGQEREFVAGIGWSGGDTLYADSVRGRFTNSRDNSKNTLYLQMNSLRAEDTAVYYCAARQGQYIYSSMRSDSYDYWGQGTLVTVSS (SEQ ID NO: 9).

[0072] In some embodiments, the fusion polypeptide has the amino acid sequence of SEQ ID NO: 9. In the sequence of SEQ ID NO: 9, the C-terminus of the sequence that specifically binds human serum albumin (SEQ ID NO: 4) is fused to the GGGGGAGGGGAGGGGS (SEQ ID NO: 10) linker, which is fused to the N-terminus of the polypeptide that specifically binds human complement component C5 (SEQ ID NO: 8).

[0073] The fusion polypeptides disclosed in this specification can be prepared by expressing at least one nucleic acid molecule comprising a nucleotide sequence encoding the fusion polypeptide in a host cell. The host cell can be derived from a mammal, a plant, or a microorganism. In addition to known mammalian host cells, yeast host cells such as Pichia pastoris, Saccharomyces cerevisiae, and / or plant host cells can be used.

[0074] This polypeptide was tested in a Phase I randomized double-blind placebo-controlled single and multiple ascending dose trial in which 97 healthy subjects participated (EudraCT 2018-004500-19, NCT04920370). Single doses of the polypeptide ranged from 30 mg to 1700 mg SC and included 1700 mg SC in combination with recombinant human hyaluronidase and 300 mg intravenous (IV) administration. Multiple doses were in the range of 100 - 300 mg SC Q1W for 3 doses, 600 mg SC Q1W after an initial (loading) dose of 900 mg, for a total of 8 doses. A detailed analysis of the data from this Phase 1 trial is still pending, but preliminary findings indicate a favorable safety and tolerability profile. All adverse events (AEs) were mild or moderate in severity and no serious adverse events (SAEs) were observed.

[0075] The objective of the pivotal Phase 3 trial described in this protocol is to test the safety and efficacy of the polypeptide(s) described herein, administered via SC injection using a prefilled syringe with safety device (PFS-SD), for the treatment of adults with AChR+ gMG.

[0076] Method for treating myasthenia gravis Methods for treating MG in a human patient (e.g., generalized MG (gMG), e.g., gMG when the patient is positive for anti-AChR antibodies) are provided herein, the methods comprising administering to the patient a fusion polypeptide comprising an engineered polypeptide that specifically binds human complement component C5 fused to a polypeptide that specifically binds human serum albumin via a peptide linker, according to a specific clinical dosing regimen (i.e., at a specific dosage and according to a specific dosing schedule).

[0077] In some embodiments, MG includes gMG. In some embodiments, gMG is a subject or patient who is positive for autoantibodies that bind to AChR and who, while receiving current standard treatments for MG such as cholinesterase inhibitor therapy and IST, continue to exhibit significant systemic weakness or bulbar signs and symptoms of MG, or require chronic plasma exchange or chronic IVIg to maintain clinical stability.

[0078] In one embodiment, the fusion polypeptide is administered once on day 1 of the dosing cycle, once on day 8 of the dosing cycle, and then weekly thereafter. In some embodiments, the fusion polypeptide is administered weekly after the dosing cycle for a duration of up to 2 years (e.g., at a dose of 300 mg or 600 mg). In some embodiments, the fusion polypeptide is administered weekly after the dosing cycle for the duration of the subject's lifetime (e.g., at a dose of 300 mg or 600 mg).

[0079] In another embodiment, the fusion polypeptide is administered in one or more dosing cycles. In one embodiment, the dosing cycle is 26 weeks. In another embodiment, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, the treatment is continued throughout the lifetime of the human patient.

[0080] In some embodiments, the dosage of the fusion polypeptide is based on the patient's body weight. In one embodiment, a fusion polypeptide of 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, or 650 mg is administered to a patient weighing less than 80 kg.

[0081] In some embodiments, the fusion polypeptide is administered to a patient weighing less than 80 kg in an amount of 500 mg to 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, or 700 mg) on the first day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing less than 80 kg in an amount of 600 mg on the first day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing less than 80 kg in a maintenance dose of 200 mg to 400 mg (e.g., 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg) on the eighth day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing less than 80 kg in a maintenance dose of 600 mg on the eighth day of the dosing cycle.

[0082] In some embodiments, a fusion polypeptide of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, or 1000 mg is administered to a patient weighing 80 kg or more.

[0083] In some embodiments, the fusion polypeptide is administered to a patient weighing 80 kg or more in an amount of 800 mg to 1000 mg (e.g., 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, or 1000 mg) on the first day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing 80 kg or more in an amount of 900 mg on the first day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing 80 kg or more at a maintenance dose of 500 mg to 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, or 700 mg) on the eighth day of the dosing cycle. In some embodiments, the fusion polypeptide is administered to a patient weighing 80 kg or more at a maintenance dose of 600 mg on the eighth day of the dosing cycle.

[0084] In some embodiments, the fusion polypeptide is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily. In another embodiment, the fusion polypeptide is administered twice a day. In another embodiment, the fusion polypeptide is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the fusion polypeptide is administered as a loading dose on day 1, followed by a different maintenance dose on day 8, and then weekly thereafter.

[0085] In some embodiments, the fusion polypeptide is administered using a prefilled syringe. In other embodiments, the fusion polypeptide is administered using an autoinjector device. For example, the autoinjector device may include a single vial system such as a pen-type injector device for solution delivery. Such devices are commercially available from manufacturers such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D® Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, DosePro®, Medi-Ject®, etc., for example, those made or developed by Becton Dickinson (Franklin Lakes, NJ), Ypsomed (Burgdorf, Switzerland, www.ypsomed.com; Bioject, Portland, OR.; National Medical Products, Weston Medical (Peterborough, UK), Medi-Ject Corp (Minneapolis, MN), and Zogenix, Inc, Emeryville, CA. Approved devices that include a dual vial system include pen-type injector systems for reconstituting lyophilized drugs in a cartridge for reconstituted solution delivery such as HumatroPen®. In one embodiment, the autoinjector is a disposable injection device of YpsoMate 2.25 or YpsoMate 2.25 Pro (Ypsomed).

[0086] In some embodiments, patients being treated according to the methods described herein are vaccinated against meningococcal infection within 3 years prior to or at the start of the investigational drug. In one embodiment, patients who start treatment less than 2 weeks after receiving the meningococcal vaccine receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. In another embodiment, patients being treated according to the methods described herein are vaccinated against meningococcal serogroups A, C, Y, W135, and / or B.

[0087] Outcome In some embodiments, treatment of MG includes improvement or amelioration of one or more symptoms associated with MG. Symptoms associated with MG include muscle weakness and easy fatigability. Muscles primarily affected by MG include those controlling eye and eyelid movement, facial expression, chewing, conversation, swallowing, breathing, neck movement, and limb movement.

[0088] In some embodiments, treatment of MG includes improvement of clinical markers of MG progression. These markers include MG-ADL score, QMG score of disease severity, MGC, NIF, forced vital capacity, post-MGFA intervention status, and other quality of life measurements. In some embodiments, MG-ADL is the primary score for measuring improvement in MG.

[0089] MG-ADL is an 8-item questionnaire focusing on the related symptoms and functional performance of activities of daily living (ADL) in MG subjects (Table 1). The 8 items of MG-ADL were derived from the components based on the symptoms of the original 13-item QMG to evaluate the physical impairments secondary to the eye disorders (2 items), bulbar disorders (3 items), respiratory disorders (1 item), and gross motor or limb disorders (2 items) related to the impact of MG. In this measure of functional status, each response is graded from 0 (normal) to 3 (most severe). The total MG-ADL score ranges from 0 to 24. In one embodiment, a clinically significant improvement in a patient's MG-ADL is, for example, a decrease of 3 points or more in the score after 26 weeks of treatment.

[0090] The current QMG scoring system consists of 13 items: eyes (2 items), face (1 item), medulla oblongata (2 items), gross motor (6 items), axis (1 item), and respiration (1 item). Each item is graded from 0 to 3, with 3 being the most severe (Table 2). The total QMG score ranges from 0 to 39. The QMG scoring system is an objective assessment of treatment for MG and is based on a quantitative examination of the sentinel muscle groups. The MGFA Task Force recommends using the QMG score in prospective trials of MG treatment (Benatar, M. et al., Muscle Nerve, 45:909-17, 2012). In one embodiment, a clinically significant improvement in a patient's QMG is, for example, a decrease in score of 5 points or more after 26 weeks of treatment.

Table 1-1

Table 2-1

[0091] The MGC is a validated assessment tool for measuring the clinical status of subjects with MG (16). The MGC evaluates 10 important functional areas most frequently affected by MG, and the scale is weighted for clinical significance incorporating the results reported by the subject (Table 3; Burns, T. et al., Muscle Nerve, 54:1015-22, 2016). The MGC is performed at screening, day 1, weeks 1-4, 8, 12, 16, 20, and 26, or ET (visits 1-6, 8, 10, 12, 14, and 17, or ET). In one embodiment, a clinically significant improvement in a patient's MGC is, for example, a decrease in score of 3 points or more after 26 weeks of treatment.

Table 3

[0092] The Revised Myasthenia Gravis Quality of Life 15-Item Scale (MG-QOL15r) is a health-related QoL assessment tool specific to patients with MG (Table 4). The MG-QOL15r is designed to provide information on the perceptions of patients with disabilities and physical impairments, to determine the degree to which disease symptoms are tolerated, and to be easily administered and interpreted. The MG-QOL15r is completed by the patient. Higher scores indicate a greater degree of MG-related dysfunction and dissatisfaction. A clinically significant improvement in a patient's MG-QOL 15 is a decrease in score after 26 weeks of treatment. [Table 4]

[0093] Neuro-QOL Fatigue is a brief, 19-item survey of fatigue that is completed by the subject or patient and has high reliability and evidence. Higher scores indicate greater fatigue and a greater impact of MG on activities (Table 5; Gershon, R. et al., Qual. Life Res., 21:475-86, 2012). A clinically significant improvement in a patient's Neuro-QQL Fatigue score is reflected as an increase in score after 26 weeks of treatment. [Table 5-1] [Table 5-2]

[0094] The EuroQol 5 - Dimension 5 - Level (EQ - 5D - 5L) is a self - reported, health - related quality of life questionnaire. The EQ - 5D - 5L basically consists of two pages: the EQ - 5D descriptive system and the EQ Visual Analogue Scale (EQ VAS). This scale measures QOL on a scale of five elements including mobility, self - care, usual activities, pain / discomfort, and anxiety / depression. Each level is rated based on a scale representing the degree of problems in that area (e.g., no problems walking, having mild problems, having moderate problems, having severe problems, or unable to walk). Patients are asked to indicate their health status by checking the box next to the most appropriate description in each of the five dimensions. This decision results in a single - digit number representing the level selected for that dimension. The five - digit numbers can be combined to form a five - digit number that describes the patient's health status. Clinically significant improvement in a patient's EQ 5D is reflected as a decrease in the score in each category after 26 weeks of treatment. This tool also has an overall health scale (EQ VAS), and the assessor selects a number from 1 to 100 to describe their health status, with 100 being the best imaginable. The EQ VAS records the patient's self - reported health status on a vertical visual analogue scale, labeled with "the best health state imaginable" and "the worst health state imaginable" for the assessment items. The VAS can be used as a quantitative measure of the change in health status reflecting the patient's own judgment. Clinically significant improvement in a patient's EQ VAS is reflected as an increase in the score after 26 weeks of treatment. Convergent validity was demonstrated by the correlation between the EQ - 5D - 5L and the dimensions of the World Health Organization's five - well - being questionnaire (r = 0.43, p < 0.001) (see Janssen, M. et al., Qual. Life Res., 22:1717 - 27, 2013).The EQ-5D-5L approach has high mean test-retest reliability using interclass coefficients with means of 0.78 and 0.73 (Brooks, R., Health Policy, 37:53-72, 1996, Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).

[0095] Subjects with increasingly severe MG are at risk of potentially fatal respiratory complications, including profound respiratory muscle weakness. Respiratory function is closely monitored for evidence of respiratory failure in MG subjects, and ventilatory support is recommended if there is a consistent decrease in serial measurements of forced vital capacity (FVC) or NIF, loss of upper airway integrity (difficulty handling oral secretions, swallowing, or speaking), or if respiratory failure is present. FVC, as one of the test items in QMG, is performed when QMG is carried out. NIF is performed using a NIF meter.

[0096] The clinical state of MG is evaluated using the MGFA post-intervention state (MGFA-PIS). Changes in the state categories of improved, unchanged, worsened, deteriorated, and died of MG, as well as minimal manifestation (MM), can be evaluated (Table 6).

Table 6

[0097] Patients administered the fusion polypeptide may exhibit a reduced MG-ADL. In some embodiments, the subject has an initial MG-ADL score of 5 points or more. In some embodiments, the subject has an initial MG-ADL score greater than 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 points. In some embodiments, after the course of treatment with the fusion polypeptide, the subject's MG-ADL score is reduced to less than 5 points. In some embodiments, the MG-ADL score is reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, or at least 24 points after treatment with the fusion polypeptide. In some embodiments, the patient's MG-ADL score is reduced by at least 2 points after the course of treatment with the fusion polypeptide. In some embodiments, the patient's MG-ADL is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 points after the course of treatment with the fusion polypeptide.

[0098] According to some embodiments, the course of treatment with the fusion polypeptide lasts for 26 weeks. According to some embodiments, the course of treatment lasts for 26 - 52, 26 - 78, 26 - 96, 26 - 104, 26 - 130, 26 - 156, 26 - 182, 26 - 208 weeks, or longer. In some embodiments, the course of treatment lasts for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 96, 104, 130, 156, or 182 weeks. According to some embodiments, the course of treatment lasts for 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years, or longer. In some embodiments, the course of treatment lasts for the remainder of the subject's life.

[0099] According to some embodiments, during the course of treatment, one or more symptoms or scores related to MG improve during the course of treatment and are maintained at the improved level throughout the treatment. The MG - ADL, for example, can be improved after 26 weeks of treatment with the fusion polypeptide and then remain at the improved level over the duration of the treatment, i.e., 96 weeks of treatment with the fusion polypeptide.

[0100] In some embodiments, the first sign of improvement occurs by 26 weeks of treatment with the fusion polypeptide. According to some embodiments, the first sign of improvement occurs between weeks 1 - 26, 26 - 52, 52 - 78, 26 - 96, 78 - 104, 104 - 130, 130 - 156, 156 - 182, or 182 - 208 of treatment with the fusion polypeptide. In some embodiments, the first sign of improvement occurs at week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 96, 104, 130, 156, or 182.

[0101] In some embodiments, the subject has been diagnosed with MG for at least 3 months. In some embodiments, MG includes refractory gMG. In some embodiments, refractory gMG is characterized by a subject or patient who is positive for autoantibodies that bind to AChR and who, while receiving current standard treatments for myasthenia gravis such as cholinesterase inhibitor therapy and IST, continues to exhibit marked systemic weakness or bulbar signs and symptoms of MG, or requires chronic plasma exchange or chronic IVIg to maintain clinical stability. In some embodiments, refractory gMG is characterized by a subject or patient who, while receiving current standard treatments for MG such as cholinesterase inhibitor therapy and IST, continues to exhibit marked systemic weakness or bulbar signs and symptoms of myasthenia gravis, or requires chronic plasma exchange or chronic IVIg to maintain clinical stability. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject has an American Myasthenia Gravis Foundation (MGFA) clinical classification between II and IV.

[0102] In some embodiments, the subject has been administered one or more additional pharmaceutical compositions. In some embodiments, the pharmaceutical composition is an acetylcholinesterase inhibitor, IST, or an immunoglobulin. In some embodiments, IST is selected from the group consisting of corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).

[0103] In some embodiments, the subject has not received B cell depletion therapy in the past 6 months. In some embodiments, the B cell depletion therapy is rituximab or ocrelizumab. In some embodiments, the subject has not been administered an FcRn inhibitor within 5 half-lives of FcRn prior to administration of the fusion polypeptide.

[0104] Kits and unit dosage forms Also provided herein is a kit comprising a pharmaceutical composition comprising a fusion polypeptide described herein, such as a fusion polypeptide having the amino acid sequence of SEQ ID NO:9, and a therapeutically effective amount of a pharmaceutically acceptable carrier suitable for use in the foregoing method. The kit may also optionally include instructions, such as an administration schedule, for enabling a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to a patient having MG. The kit may also include a syringe.

[0105] The kit may optionally include a plurality of packages of single-dose pharmaceutical compositions, each containing an effective amount of the fusion polypeptide for a single administration by the method provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) may also be included in the kit. The kit may provide one or more prefilled syringes containing an amount of the fusion polypeptide. The kit may include one or more autoinjectors containing an amount of the fusion polypeptide.

[0106] The following examples are illustrative only and are not to be construed as limiting the scope of the disclosure in any way, as many types and equivalents will be apparent to those skilled in the art upon reading the disclosure. The contents of all references, Genbank entries, patents, and published patent applications cited throughout this application are hereby expressly incorporated herein by reference.

Examples

[0107] The following examples illustrate specific embodiments of the disclosure and various uses thereof. These are described for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

[0108] Example 1. A Phase 3, randomized, double-blind, placebo-controlled, parallel, multi-center trial to evaluate the safety and efficacy of a C5-binding polypeptide in adults with gMG This study evaluates the safety, tolerability, pharmacokinetics, and efficacy of the fusion polypeptide described in this specification in the treatment of MG. The specific objectives of this study and the corresponding evaluation items are outlined in Table 7.

[0109] 1. Objectives, Estimands, and Evaluation Items of the Study [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0110] 2. Primary Estimand(s) The estimands corresponding to the primary objectives were defined as follows: This study compares the fusion polypeptide described in this specification with placebo in adults with AChR+gMG. For the primary objective, the question of interest is whether the fusion polypeptide described in this specification is superior to placebo in improving the total MG-ADL score at week 26, regardless of whether the participant experiences any of the following intermediate events: clinical worsening, use of rescue therapy, change in concomitant gMG therapy, use of prohibited drugs and therapies, or discontinuation of the study intervention. The difference between treatment groups in the mean change from baseline in the total MG-ADL score at week 26 was evaluated.

[0111] 3. Primary Secondary Estimand For the primary secondary objective, the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the total Quantitative Myasthenia Gravis Score (QMG) for disease severity at week 26, regardless of whether the participant experiences any of the following intermediate events: clinical worsening, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medications and therapies, or discontinuation of the trial intervention. The difference between treatment groups in the mean change from baseline in the QMG total score at week 26 was evaluated.

[0112] 3.1 Secondary Estimand Another secondary objective is to evaluate the efficacy of the fusion polypeptide described herein in the treatment of gMG compared to placebo, based on the level of improvement in the QMG total score, the level of improvement in the MG-ADL total score, and the change in the Myasthenia Gravis Composite (MGC) total score.

[0113] The estimands corresponding to these secondary objectives were defined as follows: The question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the QMG total score at week 26 by 5 points or more from baseline, regardless of whether the participant experiences any of the following intermediate events: clinical worsening, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medications and therapies, or discontinuation of the trial intervention. The odds ratio for a reduction of 5 points or more from baseline in the QMG total score at week 26 (comparing the fusion polypeptide described herein to placebo) was calculated.

[0114] The question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the total MG-ADL score at week 26 by 3 points or more from baseline, regardless of whether the participant experiences any of the following intermediate events: clinical worsening, use of rescue therapy, change in concomitant gMG therapy, use of prohibited drugs and therapies, or discontinuation of the trial intervention. The odds ratio for a reduction of 3 points or more from baseline in the total MG-ADL score at week 26 (comparing the fusion polypeptide described herein to placebo) was calculated.

[0115] The question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the total MGC score at week 26, regardless of whether the participant experiences any of the following intermediate events: clinical worsening, use of rescue therapy, change in concomitant gMG therapy, use of prohibited drugs and therapies, or discontinuation of the trial intervention. The difference between treatment groups in the mean change from baseline in the total MGC score at week 26 was evaluated.

[0116] 4. Study Design 4.1. Overall Design A Phase 3, randomized, double-blind, placebo-controlled, parallel, multi-center trial is described herein to evaluate the safety and efficacy of the fusion polypeptide described herein in adults with generalized myasthenia gravis (gMG). This trial was conducted in North America, South America, Europe, Asia, and the Pacific region. Approximately 200 eligible participants were stratified at baseline by geographic region and weight (less than 80 kg and 80 kg or more) and randomized 1:1 to treatment with the fusion polypeptide described herein or placebo, both administered via subcutaneous (SC) injection weekly using PFS-SD. Randomization of participants with a total MG-ADL score of less than 7 and participants receiving concomitant regular (chronic) intravenous (IVIg) or SC immunoglobulin (SCIg) therapy is restricted as specified in Section 4.1.2.

[0117] This trial consists of three periods: screening (for at least 4 weeks), randomized controlled trial (RCT) (26 weeks), and open-label extension (OLE) (96 weeks) (Figure 1). Eligible participants were screened for trial eligibility up to 4 weeks prior to Day 1. Participants with confirmed gMG and positive serological testing for AChR antibodies were included if the severity of their disease was classified between II and IV according to the clinical criteria established by the Myasthenia Gravis Foundation of America (MGFA) (Jaretzki et al., Neurology, 55:16-23, 2000), and if the total MG-ADL score was 5 or greater. MGFA classes II-IV include a broad population of participants, excluding only those with only ocular symptoms or signs (class I) and those requiring intubation (class V).

[0118] Participants who met all eligibility criteria were randomized during the RCT period and received the fusion polypeptide or placebo described herein at a loading dose based on body weight on Day 1, followed by maintenance therapy based on body weight with the fusion polypeptide or placebo described herein on Week 1 (Day 8), and then once weekly (Q1W) for a total of 26 weeks. Doses during the RCT period were based on the body weight of the participant at randomization. During the first 5 visits, the participant, and if applicable, the participant's caregiver, received training on the administration of the study intervention by the designated study site staff. Once the training was completed and certified, the participant could self-administer the treatment at home, unless the scheduled dose fell on the same day as the next clinic visit. In this case, the participant was required to administer the study intervention at the clinic under the supervision of the clinic staff and have their injection skills monitored. The participant makes every effort to maintain the weekly dosing interval. However, a deviation of ±1 day is allowed if unavoidable.

[0119] Participants who completed the 26-week RCT period continue the trial for the earliest of 96 weeks of the OLE period (Figure 1), or until the product is registered or approved (in accordance with country-specific regulations), or until the fusion polypeptide described herein is made available via a post-trial access program (as permitted by regional laws and regulations). Participants transition to open-label treatment with the fusion polypeptide described herein after completion of the Day 183 assessment. To maintain blinding of participants with respect to treatment assignment in the previous RCT period, the first dose upon entering the Day 183 OLE period was administered by the investigator at the trial site. Participants who were in the placebo group during the RCT period receive a blinded weight-based loading dose of the fusion polypeptide described herein. Participants who were in the fusion polypeptide group during the RCT period receive a maintenance dose based on weight and one additional injection of placebo matching the number of injections required for the weight-based loading dose. Participants resume the weekly self-administered maintenance dose the following week (Day 190). Doses during the OLE period are based on the participant's weight at Day 183 and were re-evaluated approximately every 6 months as specified in the schedule of activities (SoA).

[0120] The final trial assessment was conducted at the EoS visit at Week 122, 3 weeks after the last dose of the trial intervention at Week 119. If a participant withdraws from the trial or completes the trial before Week 122 of the OLE period, the participant is recommended to return for an early termination (ET) visit 3 weeks after the final dose of the trial intervention was administered. The overall trial period for an individual participant is approximately 126 weeks (from screening visit to EoS visit).

[0121] Participants who are treated with an AChE inhibitor containing corticosteroids or immunosuppressive therapy (IST) at the time of screening visit may continue therapy throughout the RCT and OLE periods. However, during the RCT period, the dosing of AChE inhibitor or IST shall not be changed, interrupted, or a new AChE inhibitor or IST added, unless medically necessary as determined by the Investigator. Unapproved ISTs are listed in Section 6.5.2. During the OLE period, i.e., after the 26-week RCT, treatment with AChE inhibitor or IST can be changed at the discretion of the Investigator.

[0122] Throughout the trial, rescue therapy is permitted if the participant's health is at risk without such therapy (e.g., in an emergency situation), or if the participant experiences a clinical worsening as defined in Section 4.2.1. Rescue therapy includes plasma pheresis (PP), plasmapheresis (PE), IVIg, SCIg, or short-term use of high-dose corticosteroids (Section 6.5.3). The therapy used for an individual participant is determined at the discretion of the Investigator within these boundaries.

[0123] Trial staff designated as clinical evaluators must receive appropriate training and be certified in the conduct of MG-ADL and other relevant disease assessments (Section 4.2.2). Clinical evaluators may be neurologists (including trained neurology residents) or other qualified research team members assigned by the Investigator. Section 4.2.2 describes in more detail the responsibilities for clinical and trial assessments.

[0124] 4.1.1. Screening Period (4 weeks or more) After obtaining informed consent, participants were screened for eligibility over a period of up to 4 weeks (within 28 days) through a review of demographic data, medical history, physical examination, and clinical laboratory tests. The medical history included the date of diagnosis of MG, the first clinical symptoms (ocular or gMG), the time to signs of gMG (if the first clinical signs were limited to ocular symptoms or signs), the maximum MGFA classification and need for ventilatory support since diagnosis, the dates of exacerbation or crisis of gMG, the diagnosis of thymoma or thymic carcinoma, thymectomy if applicable, and hospitalizations related to MG in the 2 years prior to screening. Treatments and physical therapies related to MG in the 2 years prior to screening were also recorded. Additional information regarding such treatments in the initial few years should be documented if available.

[0125] Participants receive vaccination against Neisseria meningitidis (meningococcus) during screening or at the start of treatment as prophylaxis against meningococcal infection. If the participant has received vaccination against meningococcus including serotypes A, C, W135, Y (and if possible, serotype B) within 3 years prior to randomization and such vaccination has been documented or confirmed by the treating physician, vaccination is not required. Participants who start the trial intervention less than 2 weeks after receiving the meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after vaccination (see Section 6.5.4).

[0126] If a participant experiences a clinical exacerbation including a crisis of myasthenia gravis during the screening period, it is necessary to notify the sponsor of the clinical trial.

[0127] 4.1.2 Randomization At the time of randomization, all participants were re-evaluated for eligibility based on the inclusion and exclusion criteria of the trial. On Day 1, all vaccinated participants who continued to meet the eligibility criteria were randomized 1:1 to the fusion polypeptide or placebo described herein. Randomization was performed using a centralized interactive response technology (IRT) application. Randomization was stratified by geographical region and body weight (<80 kg and ≥80 kg) as specified in the statistical analysis plan (SAP). Randomization of participants with a total MG-ADL score of less than 7 and participants receiving concomitant regular (chronic) IVIg or SCIg was limited to approximately 10% each.

[0128] 4.1.3 Randomized control treatment period (26 weeks) The fusion polypeptide and placebo described herein were administered via SC injection. The trial intervention consisted of a loading dose followed by a weekly maintenance dose (Table 2). Both the loading dose and the maintenance dose were based on the body weight of the randomized participants (<80 kg or ≥80 kg). Assessments of disease status, efficacy, safety, and outcome measures, as well as other procedures, were performed at the regular study visits specified in the SoA of Figures 2A - 2C.

[0129] It is permitted through the trial if the health of the participant is at risk without such therapy (e.g., in an emergency situation), or if the participant experiences a clinical exacerbation including a crisis related to gMG as defined in Section 4.2.1. Management of clinical exacerbations always includes treatment directed at the precipitating condition, e.g., infection, if applicable. The trial responsible physician or designee determines whether the participant meets the definition of a clinical exacerbation and intervenes accordingly. Rescue therapy may consist of PP, PE, IVIg, SCIg, or high-dose corticosteroids. If PE or PP is used as rescue therapy on a non-dosing day, supplemental dosing of the trial intervention is required (see Section 6.5.3.1 for details). Appropriate intervention for an individual participant is selected at the discretion of the trial responsible physician within these boundaries (see further Section 6.5.3). Current treatment guidance should be considered (Narayanaswami et al., Neurology, 96:114-122, 2021, Sanders et al., Neurology, 87:419-425, 2016). After the intervention, treatment should return to the standard treatment given prior to the exacerbation.

[0130] 4.1.4 Open-label Follow-up Period (96 Weeks) After completion of the trial assessment at the 26th week (Day 183) visit during the RCT period, participants receive open-label treatment with the fusion polypeptide described herein. To maintain blinding of the participant to their previous treatment assignment during the RCT period, the blinded dose based on body weight was administered on Day 183 by a designated trial implementation facility staff member who is not permitted to participate in either safety or efficacy assessments (see Section 0 regarding blinding). Participants who were in the placebo group during the RCT period receive a body weight-based loading dose of the fusion polypeptide described herein to ensure rapid and complete C5 inhibition prior to the next scheduled maintenance dose. Participants who were in the fusion polypeptide group during the RCT period receive a body weight-based maintenance dose and one additional injection of placebo that matches the number of injections required for the body weight-based loading dose. The weekly open-label maintenance dose resumes the following week (Day 190).

[0131] The OLE period for each participant begins when the participant receives the trial intervention on the 183rd day and continues for 96 weeks, or until the fusion polypeptide described herein is registered or approved (in accordance with country-specific regulations), or until the fusion polypeptide described herein can be provided through the post-trial access program by the sponsor of the clinical trial (as permitted by regional laws and regulations), whichever comes first.

[0132] Evaluations of disease status, efficacy safety and outcome measures, and other procedures were performed at the scheduled visits specified in the SoA of Figures 3A - 3D.

[0133] 4.1.5 Conduct of Trial Visits There are two types of scheduled trial visits: clinic visits and remote visits. ● Clinic visits: Scheduled trial visits conducted at the clinical trial facility, including all relevant activities in accordance with the SoA. ● Remote visits: Scheduled trial visits conducted when the participant is not at the clinical trial facility. Data for the scheduled evaluations are collected via remote collaboration means, which may include one or a combination of the following methods: virtual meetings with the staff of the clinical trial facility via digital devices, telephone, or video conferencing platforms. The method of collaboration means needs to comply with regional and institutional data privacy regulatory requirements.

[0134] Only in exceptional circumstances, such as when the occurrence of the COVID-19 pandemic prevents the participant from attending the clinic visit, the principal investigator of the clinical trial will collect the scheduled evaluations remotely, to the extent possible, to avoid data gaps. At a minimum, the information collected remotely includes MG-ADL, concomitant medications including physical and other non-pharmacological therapies, and the hospitalization status of the participant. For details of the specific potential risks and mitigation measures implemented in consideration of the COVID-19 pandemic, see Table 7.

[0135] If any symptoms or signs reported during a remote visit indicate a worsening of SAE or clinically relevant MG symptoms, further evaluation of the participant was initiated at the test facility or emergency medical facility. Suspected SAE or worsening of MG symptoms must be immediately notified to the principal investigator of the clinical trial. Information related to such incidents needs to be captured as described in the guidelines and training materials for completing the electronic case report form (eCRF).

[0136] Only under exceptional circumstances, additional (unscheduled) visits other than the designated visits may be permitted at the discretion of the principal investigator of the clinical trial. Procedures, tests, and evaluations during unscheduled visits are carried out at the discretion of the principal investigator of the clinical trial, and if applicable, the corresponding data should be indicated as scheduled visits as described in the guidelines and training materials for completing the eCRF. The justification for such visits must be documented in the eCRF.

[0137] However, participants may request additional training on the management of trial interventions by the designated personnel at the trial site, and these retraining visits are not considered as visits to the clinic. The personnel designated to train participants and caregivers in the management of trial interventions shall not perform any other roles in the trial, specifically, they are not permitted to participate in the assessment of safety or efficacy (see Section 6.3.2 regarding blinding).

[0138] 4.2 Definition of Standard Protocol A complete glossary is provided in Section 10.12.

[0139] 4.2.1 Clinical Worsening of Myasthenia Gravis Throughout the trial, it is permitted when the health status of the participant is at risk without such therapy (e.g., in an emergency situation), or when the participant experiences a clinical worsening including a crisis related to gMG. For the purposes of this trial, clinical worsening is defined as any of the following: ●An increase of 3 points or more in the total MG-ADL score, or an increase of 2 points or more in the subscore of any individual MG-ADL item other than diplopia or ptosis, due to worsening of symptoms or signs related to gMG, was judged clinically significant by the principal investigator of the clinical trial. ●Weakening related to gMG is severe enough that, for example, intubation becomes necessary or extubation is delayed after subsequent surgery, etc. Respiratory insufficiency must be related to weakness of the respiratory or bulbar (oropharyngeal) muscles.

[0140] Participants are required to notify potential signs and symptoms of clinical worsening and are instructed to contact the principal investigator of the clinical trial if they occur. If there is suspicion of clinical deterioration, it should be evaluated, if possible, within 48 hours of notification to the principal investigator of the clinical trial. At the time of hospitalization due to clinical worsening, the principal investigator of the clinical trial or the designee of the principal investigator of the clinical trial shall conduct the clinical evaluations and clinical laboratory evaluations specified in the SoA. Additional evaluations may be conducted, and the hospitalization for additional evaluations may be scheduled at the discretion of the principal investigator of the clinical trial or the designee.

[0141] The principal investigator of the clinical trial or the designee shall determine whether the criteria for clinical worsening are met and intervene accordingly. Rescue therapy may consist of PP, PE, IVIg, SCIg, or high-dose corticosteroids. If PE or PP is used as rescue therapy on a non-dosing day, supplementary dosing is required (see Section 6.5.3.1 and Figure 5 for details). The appropriate intervention for each individual participant is selected at the discretion of the principal investigator of the clinical trial within these boundaries. Current treatment guidance should be considered. Management of clinical worsening should always include treatment directed at precipitating conditions, such as infections, if applicable. After the intervention, the treatment should return to the standard treatment given before the clinical worsening.

[0142] Information related to clinical worsening must be collected from the signing of the informed consent form (ICF) until EoS or ET hospital visit and documented in the eCRF. The information collected must include the administration of rescue therapy (if applicable), an explanation of the selected therapy, and, if applicable, supplementary dosing of the study intervention.

[0143] 4.2.2 gMG Clinical Evaluation The clinical evaluator may be a neurologist or other qualified study team member assigned by the principal investigator as specified in Table 8. The clinical evaluator is a trained and certified study staff member for the conduct of the MG-ADL profile and other relevant evaluations regarding disease severity as specified in Table 8. Only the clinical evaluator can administer these evaluations. The training and certification of the clinical evaluators for this study can be carried out either through a meeting of the principal investigator or an online training program.

[0144] Throughout the study, the MG evaluations should be performed in the morning and at approximately the same time, preferably by the same evaluator for each participant. The MG-ADL profile should always be performed first, followed by QMG, MGC, and then other evaluations of the disease state.

Table 8

[0145] 4.3. Scientific Rationale for the Study Design The goal of this study is to evaluate the safety and efficacy of the fusion polypeptide described herein compared to placebo in the treatment of adults with gMG, based on the ability of the participants to perform activities of daily living and the muscle strength of the participants. The primary objective and the main secondary objective reflect this goal: ● The MG-ADL profile is a valid and sensitive means to assess the impact of gMG and measure changes related to the treatment of disease severity. A two-point decrease compared to baseline in MG-ADL is considered an indicator of clinical improvement (Muppidi et al., Muscle Nerve, 44:727-731, 2011). ● QMG involves quantitative testing of sentinel muscle groups and provides a valid objective score of muscle strength (Jaretzki et al., Neurology, 55:16-23, 2000).

[0146] This study investigates other measures of treatment efficacy and evaluates the safety and tolerability of the test intervention, the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of the fusion polypeptides described herein, and biomarkers of complement activity related to the mechanism of action of the fusion polypeptides described herein.

[0147] The length of the RCT period and the determination of primary and secondary assessment items at week 26 are designed to demonstrate persistent changes in symptoms and signs that are important in chronic diseases such as gMG.

[0148] The eligibility criteria and outcome measures are selected based on a review of comparable clinical trials provided by the Task Force on MG Trial Design of the Medical Scientific Advisory Committee of the MGFA (Benatar et al., Muscle Nerve, 45:909-917, 2012), and advice from experts in the field of gMG research.

[0149] This study includes adults (18 years of age and older) with gMG corresponding to MGFA classification grades II, III, or IV to evaluate the treatment potential of the fusion polypeptides described herein in a broad participant population having mild, moderate, or severe disease, respectively. If successful, the fusion polypeptides described herein will provide these participants with a treatment option that they can administer to themselves at home at convenient weekly dosing intervals.

[0150] The dosing regimen based on body weight was selected based on modeling and dosing simulations using clinical PK, PD, and anti-drug antibody (ADA) data from the first-in-human Phase 1 trial of the fusion polypeptide described herein.

[0151] 4.3.1 Design Incorporating Patient Input Six members of the patient insights group provided their input. Patients described their experiences and challenges in previous clinical studies and shared ideas on how to improve the conduct of clinical trials. These patients specifically commented on topics including completing questionnaires as needed prior to their clinic visit, limiting the withholding of AChE inhibitor treatment to relevant assessments, and prioritizing these assessments for early completion during their clinic visit. In response to recommendations from this patient group, the trial site encouraged taking a 5 - 10 minute break between assessment blocks and a 45 - 60 minute break if the clinic visit duration exceeded 4 hours.

[0152] 4.4. Justification of Dosage In this Phase 3 trial (Table 12), the dosing regimen of the fusion polypeptide described herein leverages previous experience in the treatment of complement-mediated diseases (including gMG) with the C5 inhibitors eculizumab and ravulizumab. Using PK / PD data from healthy participants in a healthy volunteer trial (HV - 101), a population PK / PD model was developed and dosing simulations were generated to determine the dosing regimen predicted to achieve rapid and complete terminal complement inhibition (Table 12).

[0153] Targeting sustained terminal complement inhibition in patients with gMG has shown a favorable benefit / risk profile following therapeutic administration with eculizumab and ravulizumab. Based on the PK, PD, ADA, safety, and efficacy data obtained during the development of eculizumab and ravulizumab, and on the overall approved treatment with eculizumab, the proposed body weight-based dosing regimen is expected to be beneficial for the treatment of participants with gMG.

[0154] The delayed dose is defined as the dose administered after the scheduled day has passed and is administered as soon as possible and by the next scheduled dose. Replacement of missed doses is determined individually.

[0155] If PP or PE is used as a rescue therapy on a non-dosing day, supplementary dosing is required. If PP or PE is performed on the same day as the scheduled administration of the test intervention, supplementary dosing is not required, but if possible, the scheduled dose of the test intervention is administered within 60 minutes after completion of PP or PE. If PP or PE is performed between two scheduled doses of the test intervention, supplementary dosing of the test intervention is recommended within 4 hours after the PP or PE session if possible (see Section 6.5.3.1 for details).

[0156] To maintain the blinding of treatment assignment during the RCT period, participants who were in the placebo group during the RCT period receive a blinded loading dose based on the weight described herein at the start of the 183-day OLE period. Participants who were in the fusion polypeptide group during the RCT period receive a blinded maintenance dose and one additional injection of placebo that matches the number of injections required for the weight-based loading dose. The weekly unblinded maintenance dose resumes the following week (Day 190).

[0157] The safety and tolerability of the fusion polypeptides described herein have been established across a wide range of PK exposures, including those expected under the proposed gMG dosing regimen, in healthy volunteers.

[0158] 4.5. Definition of End of Trial A participant is considered to have completed the trial if they have completed all scheduled trial visits during the RCT period and the OLE period. If the trial ends early, or if the test intervention is registered or approved in accordance with country-specific regulations, a participant is also considered to have completed the trial if they have completed all scheduled trial visits during the relevant trial period, including EoS visits until the end of the trial.

[0159] The end of the trial is defined as the date of the last visit of the last participant in the trial or the last scheduled procedure indicated in the SoA of the last participant in the trial.

[0160] 5. Trial Population Prior approval of protocol deviations from the recruitment and registration criteria, also known as protocol waiver or exclusion, is not permitted.

[0161] 5.1 Inclusion Criteria Participants are eligible to participate in the clinical trial if all of the following criteria are met: Age Must be 18 years of age or older at the time of signing the informed consent

[0162] Participant and Disease Characteristics 1. Documented diagnosis of gMG at least 3 months (90 days) prior to screening based on clinical disease characteristics and at least one of the following confirmatory tests. Test results are collected from existing participant records or obtained during screening, unless otherwise specified. a. Positive reaction in an AChE inhibitor test, e.g., edrophonium chloride test, or b. Abnormal neuromuscular transmission demonstrated by repetitive nerve stimulation or single fiber electromyography, or c. Previous improvement of symptoms or signs related to MG with treatment using oral AChE inhibitors, as confirmed by the treating physician 2. Serological test for AChR autoantibodies at screening is positive (if applicable, previous test results need to be confirmed by the central laboratory during screening) 3. MGFA classification II-IV at screening 4. MG-ADL total score at screening and on Day 1 before randomization is 5 or more Participants who are receiving treatment with any of the drugs listed in Table 9 must have been administered a stable dose for a specific period prior to screening, without any changes to the expected regimen during the screening or RCT period.

Table 9

[0163] 5.2 Exclusion Criteria If any of the following criteria apply, the participant will be excluded from the study: 11. In the opinion of the trial responsible physician or medical monitor, any medical conditions (e.g., heart, lung, kidney, tumor, neurological, or psychiatric disorders) or risk factors that may prevent the participant from participating in the trial, pose any additional risks to the participant, or confound the assessment of the safety or efficacy of the trial intervention 12. History of thymectomy or any other thymus surgery within 12 months prior to screening ​13. Untreated thymic malignancies, cancers, or thymomas Participants with a history of treated thymic malignancies or cancers are eligible if they meet all of the following conditions: a. Treatment completed more than 5 years prior to screening visit b. No recurrence within 5 years prior to screening visit c. No radiographic signs of recurrence on computed tomography (CT) or magnetic resonance imaging (MRI) scan with intravenous contrast, performed within 6 months of randomization on Day 1 Participants with a history of treated benign thymomas are eligible if they meet all of the following conditions: d. Histopathological or equivalent records confirming diagnosis of benign thymoma e. Treatment completed more than 12 months prior to screening visit f. No known recurrence within 12 months prior to screening visit g. No radiographic signs of recurrence on CT or MRI scan with intravenous contrast, performed within 6 months of randomization on Day 1 h. If appropriate records confirming diagnosis of benign thymoma are not available, participants must meet the eligibility criteria for thymic malignancies or cancers as described above. 14. History of meningococcal infection 15. History of any persistent or recurrent infection in the past 12 months that may pose an additional risk to the participant 16. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization on Day 1 17. History of allergy to any component included in the study intervention, including device components (see Table 10 and Section 0) 18. History of malignancy within 5 years of screening. Exceptions that do not require exclusion from the study are skin cancers other than melanoma and primary cervical cancer of the cervix, which have already been treated and for which there is no evidence of recurrence. A known or suspected history of alcohol or substance use disorder based on the current diagnostic criteria provided in the Diagnostic and Statistical Manual of Mental Disorders (DSM) within 12 months prior to screening.

[0164] Pre / Concomitant Therapy 20. Concomitant therapy with any of the following drugs, or pre-treatment for the period specified below is not permitted: ● Complement inhibitors: Received within less than 5 half-lives prior to randomization on Day 1. Participants who have received pre-treatment with a complement inhibitor for 5 half-lives or more prior to randomization on Day 1 can be enrolled, but they must be sufficiently tolerant of such treatment without side effects that may interfere with participation in the trial, pose any additional risks to the participants, or confound the assessment of the safety or efficacy of the trial intervention, as per the opinion of the principal investigator of the clinical trial or the medical monitor. ● Human neonatal Fc receptor (FcRn) inhibitors: Received within less than 5 half-lives prior to randomization on Day 1. Participants who have received pre-treatment with an FcRn inhibitor for 5 half-lives or more prior to randomization on Day 1 can be enrolled, but their total immunoglobulin G (IgG) levels must exceed the lower limit of normal (LLN) before they are randomized. ● Rituximab, ocrelizumab, or other B-cell depletion therapies: Received or scheduled within 6 months (180 days) prior to randomization on Day 1. The sponsor of the clinical trial does not recommend any interruption of treatment solely for the purpose of obtaining eligibility to participate in this trial.

[0165] Pre / Concurrent Clinical Trial Experience 21. Participation in another trial investigating drugs, biological products, devices, or combination products, procedures, or any other intervention within the longer of either within 5 half-lives (if known) of treatment or within 30 days prior to the first dose of the trial intervention. 22. Concurrent participation in another trial involving drugs, biological products, devices, combination products, procedures, or any other intervention.

[0166] Diagnostic Evaluation 23. History of human immunodeficiency virus (HIV) infection or positive serological test for HIV-1 or HIV-2 24. Evidence of hepatitis B (positive hepatitis B surface antigen [HBsAg] or positive core antibody [anti-HBc] and negative surface antibody [anti-HBs]) or hepatitis C virus infection (positive HCV antibody, excluding participants who have proven successful treatment). If possible in the region, sustained virological response (SVR) should be documented or established at screening. 25. Participants with a positive pregnancy test at screening or on Day 1 26. Fever recorded by a body temperature of 38°C (100.4°F) or higher within 7 days before randomization on Day 1 27. Abnormal test results at screening visit, including: a. Alanine aminotransferase (ALT) more than 2 × upper limit of normal (ULN) b. Direct bilirubin more than 2 × ULN c. Estimated glomerular filtration rate less than 30 mL / min / 1.73 m 2 or dialysis participants d. Other clinically significant test abnormalities that, in the opinion of the principal investigator of the clinical trial, would make participation in the trial inappropriate or place the participant at excessive risk.

[0167] Other exclusion criteria 28. Being pregnant, breastfeeding, or planning to become pregnant during the course of the trial 29. The participant or caregiver is unable or unwilling to manage the trial intervention 30. Unable or unwilling to comply with the requirements and restrictions of the protocol, including attending scheduled trial visits

[0168] 5.3. Considerations regarding lifestyle There are no restrictions in this trial.

[0169] 5.4. Screening failure Screening failure is defined as registered participants who consented to participate in the clinical trial but were not subsequently randomly assigned to the trial intervention. Minimal information on screening failures is required to ensure transparent reporting, meet the disclosure requirements of the consolidated standards for clinical trial reports, and respond to inquiries from regulatory authorities. The minimal information includes demographic data on participants during the screening period, details of screening failures (e.g., failed eligibility criteria), and AEs, as well as relevant concomitant medications.

[0170] Clinical tests with results outside the criteria range at screening can be repeated at the discretion of the principal investigator for the purpose of further determining eligibility. Individuals who do not meet the participation criteria for this trial for any other reason (screening failure) are expected to be resolved or, if resolved, can be re-screened after consultation with the medical monitor. Participants re-screened outside the screening window are required to sign a new ICF (Section 10.1.3).

[0171] 6. Test Intervention and Medical Device The test intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to the trial participants in accordance with the trial protocol. For the purposes of this trial, the test intervention refers to the combination product consisting of PFS-SD containing the fusion polypeptide or placebo described herein.

[0172] 6.1 Investigational Intervention(s) Administered PFS-SD is a single-use disposable device for subcutaneous delivery of the fusion polypeptide or placebo described herein. The prefilled glass syringe is equipped with attached safety features to prevent needle stick injuries and improve its ergonomic use. The safety features are designed to automatically retract the needle into the syringe after injection. Details of the test intervention are presented in Table 10.

[0173] All investigational products are manufactured in accordance with current pharmaceutical manufacturing and quality control standards.

Table 10-1

Table 10-2

[0174] 6.1.1 Packaging and Labeling of Test Intervention(s) The fusion polypeptides and placebo PFS-SD described in this document were packaged and labeled in accordance with Section 6.1.2.1.

[0175] 6.1.2 Medical Device Components The PFS-SD combination product is a single-use disposable device consisting of a fusion polypeptide or placebo formulation (2 mL) in a prefilled syringe equipped with a needle safety device (BD UltraSafe Plus™ Passive). PFS-SD is designed to provide an automated safety mechanism that enables SC administration of the fusion polypeptide or placebo and reduces the risk of accidental needlestick injury by retracting the needle into the syringe after injection. Participants, and where applicable, the participant's caregiver, will be trained in the use of PFS-SD so that they can self-administer the injection during the study.

[0176] PFS-SD constitutes a container closure system that is the total of the packaging components that contain and protect the fusion polypeptide or placebo together (Figure 5). The main parts of the device components are provided in Table 11.

Table 11

[0177] Any defects in medical devices, including malfunction, user error, and inappropriate labeling, are to be documented and reported by the study responsible physician (see Section 0) and appropriately addressed by the study sponsor.

[0178] All adverse events (ADEs) must be documented, and all serious adverse events (SADEs) must be documented and reported regardless of whether they are related to a device defect (Section 10.4).

[0179] 6.1.2.1 Device Packaging and Labeling The PFS-SD is packaged in a carton with an insert that holds the device in a predetermined position within the carton. Each PFS-SD is attached with a single panel label that contains a unique identification kit number and other minimally required information such as the sponsor's name, product description, protocol number, lot number, etc. to enable traceability of the device. The secondary packaging (carton) is labeled with either a single panel or booklet label that contains, as required, investigational biological warning statements and a "For Clinical Trials Only" statement, as well as other required information.

[0180] 6.1.3. Dosage Administration The dosing regimen for the test intervention during the RCT period is based on the participant's weight at randomization on Day 1 (Table 12).

Table 12

[0181] For details of dosing during the transition from the RCT period to the OLE period, refer to Section 4.1.4. As described in Section 0, the maintenance dose is adjusted at the start of the OLE period and may then be adjusted approximately every 6 months if the participant's weight group (less than 80 kg or 80 kg or more) changes. If applicable, adjustment of the maintenance dose does not require administration of an additional loading dose.

[0182] The first dose of the test intervention on Day 1 (baseline) and Day 8 (week 1) shall be administered only by trained and certified personnel at the study site specifically designated for the conduct of the test intervention and the training of participants and caregivers in the conduct of the test intervention. During the first four weeks of the study, participants, and where applicable, caregivers, will be trained on how to administer the test intervention under the supervision of the designated study site personnel. After completion of the training and certification by the training personnel, participants will receive a kit containing the test intervention and accessories so that they can self-administer the test intervention at home. At any time, participants may request additional training on the administration of the test intervention by the designated study site personnel, and these retraining visits to the clinic are not considered clinic visits. Participants must make every effort to maintain the weekly dosing interval. However, a deviation of ±1 day is allowed if unavoidable. Participants must document each test intervention administration in the eDiary (Section 6.4).

[0183] Once training is completed and certified, participants must self-administer the treatment at home unless the scheduled dose falls on the same day as the next clinic visit. On such a day, participants are required to administer the test intervention at the clinic under the supervision of the designated clinic staff and have their injection skills monitored. If future clinic visits fall outside the ±1-day window for the administration of the test intervention, participants must administer the test intervention at home to maintain the regular weekly dosing interval. In such situations, it is not necessary to conduct the planned PK / PD or ADA assessments at the clinic visit.

[0184] The injection sites include the abdomen and the anterior thigh. The caregiver performing the test intervention may also select the back of the participant's upper arm for injection. The injection sites need to be rotated so that the participant receives the test intervention at different anatomical sites in consecutive weeks. The participant and the caregiver must follow the IFU. The IFU describes the injection technique including the activation of the safety device when the plunger of the PFS-SD is fully depressed. The needle retraction is a safety feature to prevent needle stick injuries after injection.

[0185] If a malfunction of the PFS-SD occurs where no dose or only a partial dose is delivered, the participant should use a new PFS-SD to confirm that the required dose has been administered and record the event in the eDiary (see Section 10.5). The participant must report any malfunction or inadequate device as specified in the IFU, regardless of the need to use a new PFS-SD. Any malfunction or inadequate device must be returned to the trial site upon the next clinic visit (see Sections 8.5.5 and the investigational medicinal product management procedure for detailed reporting requirements for device malfunctions and inadequacies).

[0186] 6.2. Preparation / Handling / Storage / Responsibility for Instructions 1. The principal investigator or designee must confirm that appropriate temperature conditions are maintained during transportation for all test interventions received. The principal investigator must report any discrepancies and resolve them before using the test interventions. The test interventions are shipped and must be stored at 2°C to 8°C (36°F to 46°F) at all times until the test intervention is administered. Details of reporting for temperature deviations are described in the investigational medicinal product management procedure. 2. Only the staff of the approved implementation facility can provide or manage the test intervention. Only the caregivers trained and certified by the randomly selected participants or the responsible persons of the clinical trial implementation facility for the trial can receive and manage the test intervention. The approved caregivers can only administer the test intervention to the participants they care for. All test interventions must be stored in a safe, environmentally controlled, manually or automatically monitored area according to the labeled storage conditions. Access to the test intervention must be limited to the principal investigator of the clinical trial and the staff of the approved implementation facility. 3. The staff of the approved implementation facility shall explain to the participants and caregivers the proper handling and storage methods of the test intervention kit for off-site administration. The principal investigator of the clinical trial, the institution, or the responsible person of the medical institution (if applicable) shall be responsible for the explanation, adjustment, and maintenance of records of the test intervention (i.e., receipt, adjustment, and final disposition records). a. This responsibility includes promptly reporting to the sponsor of the clinical trial any temperature deviation and any complaint regarding the product. A complaint regarding the product is defined as any written, electronic, or oral communication alleging a defect related to the identification, quality, durability, reliability, usability, safety, effectiveness, or performance of the product or material that affects its performance after the product or clinical trial material and / or its packaging components have been released for distribution to the end user. 4. Further guidance on preparation, handling, storage, and explanation responsibilities, and information on the final disposition of unused test interventions are provided in the investigational product management procedures and the IFU.

[0187] 6.3. Measures to Minimize Bias: Randomization and Blinding 6.3.1. Randomization Participants are randomized on Day 1 after the investigator has confirmed that the participant is eligible. Participants are stratified by geographical region (e.g., North America, Europe) and weight group (less than 80 kg or 80 kg or more) as specified in the SAP and randomized 1:1 to the fusion polypeptide described herein or placebo using an intensive IRT.

[0188] 6.3.2. Blinding The PFS-SD containing the fusion polypeptide or placebo described herein is provided in the same test intervention kit and has the same label for all participants during the RCT period. To hide the color difference between the fusion polypeptide and placebo described herein, the PFS-SD was covered with yellow transparent tape. Since the viscosity of the fusion polypeptide described herein also differs from that of the placebo formulation, a moderately different injection force is required for its administration. To maintain blinding despite this viscosity difference, the trial site needs to designate independent staff who can: ● Administer the test intervention during the participant's visit to the first clinic ● Train the participant and, if applicable, the caregiver for self-administered doses

[0189] These designated staff can be nurses, study coordinators, or research assistants trained to manage the test intervention. They remain blinded to the test intervention assigned to the participant and are not permitted to communicate observations related to the injection force required to administer the intervention to the study participant, caregiver, other site personnel, study sponsor staff, or designees, or other personnel involved in the conduct of the study. They are not permitted to perform any other roles in the study, specifically not to participate in the assessment of safety or efficacy.

[0190] The investigator responsible for the clinical trial shall receive only blinded information, unless non-blinded information is determined to be necessary for safety reasons. In the event of an emergency, the investigator responsible for the clinical trial shall bear the sole responsibility for determining whether unblinding the participant's intervention assignment is justified. When making such a decision, the safety of the participant must always be considered first. If the investigator responsible for the clinical trial determines that unblinding is justified, the investigator responsible for the clinical trial shall make every effort to contact the sponsor before unblinding the participant's intervention assignment, unless there is a risk of delay in the participant's emergency treatment. If unblinding is determined to be necessary, the investigator responsible for the clinical trial may use the IRT to unblind the participant's intervention assignment. If the participant's intervention assignment is unblinded, the sponsor must be notified within 24 hours after unblinding.

[0191] If a serious unexpected adverse reaction (SUSAR) or a serious unexpected device-related adverse event (USADE) is suspected, the requirements of Section 0 and the reporting guidance in Section 0 must be followed. Blinding is maintained for those responsible for the continued conduct of the trial (e.g., monitors, investigators responsible for the clinical trial), as well as those responsible for data analysis and interpretation of the results. Except in these emergency situations, non-blinded information may only be accessed by those involved in safety reporting to the healthcare institution, the institutional ethics committee (IEC) within the medical institution, and / or the institutional review board (IRB) within the facility.

[0192] 6.4. Compliance with the Test Intervention If the participant receives the dose at the test site by the staff of the designated test site (described in Section 6.1.3), the date and time of each dose administered at the clinic shall be recorded in the source document and the eCRF.

[0193] When the participant or caregiver performs the trial intervention at home, compliance with the trial intervention is evaluated by assessing the entries made by the participant into their electronic diary (eDiary) during their visit to each clinic. The results of the assessment need to be recorded in the source document. If necessary, the responsible person at the implementing facility can contact the participant remotely using telecommunication technologies such as the telephone to inquire about the maintenance of the trial intervention. Deviations from the prescribed dosing regimen(s) need to be recorded in the eCRF.

[0194] Maintain a record of the amount of the trial intervention dispensed and administered to each participant and reconcile it with the trial intervention and compliance records. The start and end dates of the intervention, including the date of any delay in the intervention or dose change, also need to be recorded in the eCRF.

[0195] 6.5. Concomitant Therapy Medications (including vitamins and herbal preparations) and procedures (including therapeutic interventions such as surgery or physical therapy) received by the participant within 28 days prior to the start of screening up to the first dose of the trial intervention are recorded in the participant's eCRF. Information regarding previously prescribed medications or procedures performed also needs to be documented in the eCRF as it relates to the eligibility criteria (Sections 5.1 and 5.2). MG-specific medications or therapies within 2 years prior to screening (e.g., thymectomy, IST including corticosteroids, and rescue therapies) are recorded. Additional information regarding such medications or therapies for the initial few years, if available, should also be documented. In addition, the history of meningococcal vaccine inoculation needs to be collected for the 3 years prior to the first dose of the trial intervention.

[0196] Participants are permitted to continue any previously prescribed therapies for gMG, including IST, except for the agents listed in Section 6.5.2. Combination therapies for gMG must have been stable over a defined period prior to screening (see Section 5.1) and may not be modified prior to randomization without the sponsor's consent, unless a modification is deemed necessary by the Investigator to address clinical worsening or to reduce side effects that require adjustment of the therapy. The sponsor must be notified of any such modifications during the screening period in order to determine whether they will affect the participant's eligibility for the trial.

[0197] Any medications (including over-the-counter or prescription drugs, vitamins, and herbal supplements, vaccinations) or procedures that the participant is receiving at the time of registration or during the trial must be recorded, together with: ● Reason for use (indication) ● Dates of administration or procedure, including start and end dates ● Dose and frequency of administration or procedure If there are any questions regarding combination therapies or previous therapies, the medical monitor should be contacted.

[0198] 6.5.1. Permitted Agents and Therapies Palliative and supportive care during the trial is permitted.

[0199] Participants receiving treatment with any of the agents listed in Table 9 must have been receiving this treatment at a stable dose for a period specified prior to the screening visit. During the screening or RCT period, the dosage of AChE inhibitor or IST may not be changed, interrupted, or a new AChE inhibitor or IST added, unless medically necessary as determined by the Investigator. For example, rescue therapies, including PP, PE, IVIg, SCIg, or high-dose corticosteroids, for participants experiencing worsening of gMG symptoms or signs in myasthenic crisis are permitted (see Section 6.5.3 for details).

[0200] If the participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours before the MGC and QMG assessments. Treatment with an AChE inhibitor can be restarted when the QMG and MGC assessments are completed.

[0201] 6.5.2. Unapproved Drugs and Therapies The following concomitant medications are prohibited during the trial. ● Other complement inhibitors ● FcRn inhibitors Rituximab, ocrelizumab, and other B cell depletion therapies

[0202] 6.5.3. Rescue Therapy Rescue therapies, including short-term use of PP / PE, IVIg, SCIg, or high-dose corticosteroids, are permitted if such therapy is required to prevent risk to the participant's health in the absence of such therapy (e.g., in an emergency situation) or if the participant experiences a clinical exacerbation (as defined in Section 4.2.1). Appropriate interventions for individual participants are selected at the discretion of the study physician within these boundaries, taking into account current treatment guidance. Participants who require rescue medication may continue in the trial. However, the study physician should notify the sponsor or their designee within 24 hours of the start of rescue therapy. After the intervention, treatment should return to the standard treatment given prior to the clinical exacerbation. Additional PK / PD / ADA blood samples should be collected before and after rescue therapy. If PE or PP is used as rescue therapy on a non-dose day, supplemental dosing of the study intervention is required (see Section 6.5.3.1 for details).

[0203] The description, date, and dosing schedule of rescue therapy must be recorded in the participant's eCRF.

[0204] 6.5.3.1. PP / PE If the PP / PE rescue therapy is carried out on a day that does not coincide with the administration of the test intervention, a supplementary dose of the test intervention is required. If the PP / PE is carried out on the dosing day, a supplementary dose of the test intervention is not required, but the PP / PE session must be carried out before the administration of the test intervention.

[0205] If the PP / PE is carried out on a day that does not coincide with the administration of the test intervention, and if feasible, for participants with a body weight <80 kg, one supplementary dose of PFS-SD should be administered within 4 hours after each second PP / PE session, or for participants with a body weight ≥80 kg, within 4 hours after each PP / PE session (Table 13). [Table 13]

[0206] If the supplementary dosing cannot be carried out according to the schedule in the table, a supplementary dose equivalent to 300 mg of the fusion polypeptide or placebo (one PFS-SD) should be administered before or together with the next weekly maintenance dose of the test intervention.

[0207] 6.5.4. Vaccination and Prophylactic Administration of Antibiotics To reduce the risk of meningococcal infection, all participants must be vaccinated against Neisseria meningitidis serogroups A, C, W135, Y (and serogroup B if available) within 3 years before Day 1. Participants who do not meet this requirement should be vaccinated against these Neisseria meningitidis serogroups before receiving the first dose of the test intervention. If Day 1 occurs <2 weeks after vaccination, the participants should receive prophylactic antibiotics until 2 weeks after vaccination. Vaccination must comply with the national / regional guidelines.

[0208] If applicable, the vaccination against Neisseria meningitidis and the use of prophylactic antibiotics are recorded in the participant's eCRF. All participants should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary.

[0209] To raise awareness of risks and facilitate the prompt disclosure of any potential signs or symptoms of infection, participants are provided with a patient safety card that they must carry at all times (see Section 8.3.10).

[0210] Participants should be vaccinated or revaccinated against other pathogens in accordance with national vaccination guidelines or local standard of care.

[0211] 6.6. Dose Modification The dosing schedule for the study intervention, including loading and maintenance doses, is based on the participant's weight. The weight at randomization is determined, and the dose is administered during the RCT period. The dosing schedule is adjusted at the start of the OLE period and then approximately every six months if the participant's weight group (<80 kg or ≥80 kg) changes. If applicable, adjustment of the maintenance dose does not require administration of an additional loading dose.

[0212] 6.7. Intervention after Study Completion At the completion of the last study visit, participants return to the care of their attending physician.

[0213] 7. Interruption of Study Intervention and Participant Discontinuation / Withdrawal 7.1. Interruption of Study Intervention Rarely, a participant may need to permanently interrupt the study intervention. If the study intervention is definitively interrupted, the participant should remain in the study for safety evaluation.

[0214] The principal investigator of the clinical trial shall notify the medical monitor as soon as possible regarding the interruption or consideration of interruption of the trial intervention. If a participant permanently discontinues treatment, the principal investigator of the clinical trial shall follow up with the participant regarding safety and, if the participant consents, attempt to conduct the evaluations designated for ET visits (see SoA). If it is not possible to arrange an ET visit, the principal investigator of the clinical trial shall attempt to conduct a telephone follow-up three weeks after the last dose of the trial intervention has been administered. The time and scope of the contact shall be recorded in the eCRF.

[0215] If any of the following occur, the participant should consider interruption of the trial intervention. ● For example, severe allergic reactions with bronchospasm or other respiratory reactions requiring ventilatory support, symptomatic hypotension, or serum sickness-like reactions occurring within 14 days after administration of the trial intervention ● An AE that, in the opinion of the principal investigator of the clinical trial, poses a risk that continued participation in the trial cannot be tolerated ● Severe uncontrolled infections ● Unapproved concomitant medications ● Pregnancy or a plan to become pregnant ● The principal investigator of the clinical trial or the sponsor of the trial determines that interruption is in the best interest of the participant

[0216] The reason for treatment interruption shall be recorded in the eCRF. If the trial intervention is interrupted due to the participant's pregnancy, the principal investigator of the clinical trial shall attempt reasonable follow-up in accordance with local laws and regulations until the outcome of the pregnancy is known.

[0217] Participants who discontinue the trial intervention shall not be replaced.

[0218] 7.2. Withdrawal of Participants from the Trial ● Before conducting the screening procedure, every effort should be made to ensure that future participants intend to comply with the requirements for trial participation. a. If feasible, the principal investigator of the clinical trial should contact the sponsor and the trial site before withdrawing a participant or interrupting the trial intervention. The reasons for participant withdrawal must be recorded in the source documents and eCRF. b. A participant may withdraw from the trial at any time upon their own request, or may be withdrawn at any time at the discretion of the principal investigator of the clinical trial for reasons of safety, behavior, compliance, or administrative reasons. Participant withdrawal is not expected to be common. - If feasible, at the time of trial interruption, as indicated in the SoA, an ET visit should be conducted. For data collected during trial interruption and follow-up, and any additional evaluations that need to be completed, please refer to the SoA. Once the ET visit is completed, the participant is permanently withdrawn from both the trial intervention and the trial. - If a participant withdraws consent for future disclosure of information, the sponsor may retain and continue to use any data collected prior to such withdrawal of consent. - If a participant withdraws from the trial, the participant may request destruction of any samples that have been taken but not yet tested, and the principal investigator of the clinical trial must document this in the trial records of the trial site. Participants who withdraw from or are withdrawn from the trial are not replaced.

[0219] 7.3. Loss to Follow-up A participant is considered lost to follow-up if they cannot be repeatedly contacted for scheduled visits to the trial site and cannot be reached by the trial site.

[0220] If a participant cannot return to the clinic for a required trial visit, the following measures must be taken. 1. The trial site should attempt to contact the participant, reschedule the missed visit as soon as possible, advise the participant of the importance of maintaining the assigned visit schedule, and confirm whether the participant wishes to continue with the trial and should continue. 2. Before a participant is considered lost to follow-up, the Investigator or designee must make every effort to re - establish contact with the participant (if possible, three telephone calls and, if necessary, a registered or equivalent local method to the participant's last known mailing address). These attempts at contact should be recorded in the participant's medical record. 3. If the participant remains unavailable for contact, they will be considered lost to follow - up. Interruption of a specific study site or of the study as a whole is addressed as part of Section 10.1.9.

[0221] 8. Evaluation and Procedures of the Study 1. The evaluation of the study and its timing are summarized in the SoA. Adherence to the study design requirements is essential and required for the conduct of the study. Waivers or deviations from the protocol are not permitted. 2. Refer to Section 4.1.5 for the definition of study visits. 3. For the determination of whether a participant should continue or discontinue a study intervention, safety concerns should be discussed immediately with the sponsor upon their occurrence or recognition. 4. All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The Investigator is to maintain a log to record details of all screened participants and, where applicable, to confirm eligibility or record the reasons for screening failure. 5. Procedures that are part of a participant's regular clinical management (e.g., blood counts) and are obtained before ICF signature may be used for screening or baseline purposes provided that the procedures meet protocol - specified criteria and are performed within the time frame defined in the SoA. 6. Refer to Section 10.2 for the list of clinical tests. For safety reasons or due to technical problems related to sample collection, processing, or analysis, repeat or unscheduled samples may be obtained.

[0222] 8.1. Efficacy evaluation 8.1.1. MG-ADL The MG-ADL profile is a questionnaire that focuses on activities of daily living that are likely to be impaired by gMG. The 8 items of MG-ADL evaluate the physical impairments secondary to ocular function (2 items), oropharyngeal function (3 items), respiratory function (1 item), and limb function (2 items). Each response is graded from 0 (normal) to 3 (most severe). The total score of MG-ADL ranges from 0 to 24, and a higher score indicates a greater impairment. The recall period for the MG-ADL profile is the previous 7 days, or the time elapsed since the last visit if the interval between visits is shorter than 7 days.

[0223] The MG-ADL profile must be administered by a properly trained clinical evaluator. MG-ADL should be performed in the morning and at approximately the same time of day throughout the trial. For consistency, the same evaluator should administer the questionnaire throughout the trial. It is expected that it will take ≤10 minutes to complete the paper form. If multiple efficacy evaluations are scheduled, MG-ADL should be performed first, followed by QMG, MGC, and the remaining tests in this order.

[0224] 8.1.2. QMG The QMG total score provides a quantitative assessment of function in the sentinel muscle groups. The QMG total score consists of 13 items, namely, ocular (and facial) function (3 items), oropharyngeal function (2 items), limb (and head lift) function (7 items), and respiratory function (1 item). The strength in each of the muscle groups is graded from 0 to 3, with 3 indicating severe impairment. The QMG total score ranges from 0 to 39. The MGFA recommends that the QMG total score be used as one of the outcome measures in prospective intervention trials in MG (Benatar et al., Muscle Nerve, 2012;45:909-917, 2012). The QMG total score must be performed by a neurologist or other appropriately qualified test team member, such as a senior neurology trainee in training, physician assistant, or clinical nurse. The QMG should be performed throughout the test in the morning and at approximately the same time of day. Vital capacity may be measured by a qualified physical therapist. For consistency, the same evaluator should perform the evaluations throughout the test. If the participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the evaluation. The time from the last dose to the QMG evaluation should be documented and kept similar between visits. If multiple efficacy evaluations are scheduled, the QMG must be performed after the MG-ADL and before the MGC and other remaining tests.

[0225] 8.1.3.MGC The MGC evaluates the clinical state of MG by combining the test items reported by the participant and the test items reported by the principal investigator of the clinical trial, and measuring both the symptoms and objective signs of the disease. The MGC generally evaluates 10 functional areas affected by MG. The evaluation scale is weighted for clinical significance (see, for example, Burns et al. Neurology 74:1434-1440, 2010). The total MGC score ranges from 0 to 50. The total MGC score ranges from 0 to 50.

[0226] The MGC must be performed by a neurologist or other appropriately qualified test team member, such as a senior neurology trainee in training, physician assistant, or clinical nurse. The MGC should be performed throughout the test in the morning and at approximately the same time of day. For consistency, the same evaluator should perform the evaluations throughout the test. If the participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the evaluation. The time from the last dose to the MGC evaluation should be documented and kept similar between visits. If multiple efficacy evaluations are scheduled, the MGC must be performed after the MG-ADL and QMG but before the other tests.

[0227] 8.1.4. MG-QoL15r The Revised 15-Item Myasthenia Gravis Quality of Life Scale (MG-QoL15r) assesses quality of life (QoL) as it is specifically relevant to participants with MG. The MG-QoL15r provides information on participants' perceptions of impairment and physical disability and is designed to determine the degree to which disease symptoms are tolerated (Burns et al., Muscle Nerve, 54:1015-1022, 2016). The MG-QoL15r is completed by participants. Higher scores indicate greater MG-related dysfunction and dissatisfaction with the current disease state.

[0228] 8.1.5. Neuro-QoL Fatigue (Short Form) This study uses the 8-item short form of Neuro-QoL (trademark) Fatigue. The Quality of Life in Neuropathic Fatigue (Neuro-QoL Fatigue) scale is one of the Quality of Life in Neurological Disorders - Fatigue (Neuro-QoL) scales developed through a research initiative in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS). This is a brief survey completed by participants (Cella Measuring Quality of Life in Neurological Disorders; Final Report of the Neuro-QOL Study September 2010. 2010). Higher scores indicate greater fatigue and a greater impact of MG on activities of daily living.

[0229] 8.1.6. EuroQol 5D-5L The EuroQol 5 Dimensions - 5 Levels (EQ-5D-5L) is a self-administered standardized instrument for measuring health-related quality of life used across a wide range of health states. The EQ-5D-5L describes mobility, self-care, usual activities, pain and discomfort, and anxiety and depression by using five response levels ranging from 'no problems' to being unable to perform the activity or 'extreme problems'.

[0230] 8.1.7. Short-Form Health Survey The Short-Form Health Survey (36-item version) (SF-36) is a 36-item self-report of health-related quality of life (Stewart et al., Med. Care, 26:724-735, 1988; Ware et al., Med. Care, 30:473-483, 1992). It includes eight subscales that measure different domains, including physical function, role limitation due to physical problems, bodily pain, general health perception, vitality, social function, role limitation due to emotional problems, and mental health. Two summary scores are the physical component summary and the mental component summary.

[0231] 8.1.8. Minimal Symptom Expression Minimal Symptom Expression (MSE) is an efficacy endpoint in gMG studies that uses outcome measures reported by MG-ADL participants to determine improvement during treatment. MSE is achieved when the total MG-ADL score is reduced to 0-1.

[0232] 8.1.9. MGFA Postintervention Status Improvement during treatment is also evaluated by using a modified version of the MGFA Postintervention Status (MGFA-PIS) (Jaretzki et al., Neurology, 55:16-23, 2000). Improvement, no change, or worsening, as well as postintervention status (PIS) categories of minimal manifestations (MM), are recorded. The MM subscore is not used.

[0233] The PIS, including achievement of MM, must be determined by a neurologist or an appropriately qualified neurology trainee in the study who is experienced in the assessment of participants with MG. For consistency, the same assessor should perform the assessments throughout the trial.

[0234] 8.2. Device Use Evaluation 8.2.1. Device User Experience Questionnaire The experience of participants using PFS-SD, or, where applicable, their caregivers, is evaluated using a 4-item questionnaire. The questionnaire assesses the user's overall confidence, convenience, and comfort regarding the SC injection of the study intervention. The device also collects information on whether the participant would recommend this self-administration route to another patient. Each item is answered on a 5-point Likert scale.

[0235] 8.3. Safety Assessment All time points for safety assessments are provided in the SoA.

[0236] 8.3.1. Physical Examination ● A complete physical examination includes, minimally, an assessment of the cardiovascular, respiratory, digestive, and nervous systems. ● If necessary, a brief physical examination is performed based on the participant's health status and the clinical judgment of the principal investigator of the clinical trial. If the participant has any complaints or clinical findings attributable to the nervous system, a symptom-based neurological examination should be performed. If neurological findings are revealed, a complete neurological examination should immediately follow and be repeated as necessary in future evaluations based on the clinical judgment of the principal investigator of the clinical trial. A complete neurological examination includes an assessment of mental status, cranial nerve examination, motor examination, reflex status, sensory examination, as well as tests of coordination and gait.

[0237] 8.3.2. Vital Signs 1. Body temperature (degrees Celsius [°C]), respiratory rate, pulse rate (heartbeats per minute), pulse oximetry (oxygen saturation), and systolic and diastolic blood pressure (mmHg) are evaluated. 2. Vital signs (taken before blood sampling for clinical tests) consist of a single pulse check and a single blood pressure measurement. 3. Before pulse and blood pressure measurements, the participant should rest in a quiet environment for at least 5 minutes without being disturbed (e.g., by TV, mobile phone, etc.). Ideally, the same arm of each participant should be used for the measurements. Pulse and blood pressure should be evaluated in supine or seated participants and by using an automated device. Manual measurement of pulse and blood pressure should only be used when an automated device is not available.

[0238] 8.3.3. Electrocardiogram ● A single 12-lead electrocardiogram (ECG) is performed as outlined in the SoA to obtain a combination of heart rate, PR interval (time from the start of the P wave to the start of the QRS complex), Q wave, R wave, and S wave (QRS) intervals, interval from the start of the Q wave to the end of the T wave (QT), and corrected QT interval (QTc). The QT interval is corrected for heart rate using the Fridericia formula. ● The participant should be supine for about 5 - 10 minutes before ECG collection and should be supine and awake during ECG collection. ● The principal investigator of the clinical trial is responsible for reviewing the ECG, assessing whether the ECG is within the normal range, and determining the clinical significance of the results. The results are recorded in the eCRF. Clinically significant findings should be recorded on the AE form.

[0239] 8.3.4. Clinical Safety Test Evaluation 1. The principal investigator of the clinical trial reviews the laboratory report, documents this review, and must record any clinically relevant changes that occur during the trial in the AE section of the eCRF. The laboratory report must be submitted together with the source document. Clinically significant abnormal test findings are not related to underlying diseases unless determined by the principal investigator of the clinical trial to be more severe than expected for the participant's condition. 2. All clinical tests with abnormal values that are considered clinically significant by the principal investigator of the clinical trial during the trial or within 3 weeks after the last dose of the trial intervention should be repeated until the values return to normal or baseline, or until they are no longer considered clinically significant by the principal investigator of the clinical trial or the medical monitor. If such values do not return to normal / baseline within a period reasonably determined by the principal investigator of the clinical trial, the cause of the disease should be identified and the sponsor of the clinical trial should be notified. All laboratory evaluations required by all protocols defined in Section 10.2 must be collected in accordance with the laboratory manual and the SoA. Any changes to participant management or laboratory evaluations that are considered clinically significant by the principal investigator of the clinical trial must be recorded on the AE or SAE form. Where possible, out-of-range values should be entered, for example, in a free text field.

[0240] 8.3.4.1. Virus Serology Testing for HIV-1 and HIV-2 is required for all participants prior to randomization. Participants who are positive for HIV antibodies will not be randomized.

[0241] Similarly, participants who are positive for HBsAg, positive anti-HBc with negative anti-HBs, or HCV antibodies will not be randomized unless treatment success and, if available locally, SVR are documented.

[0242] 8.3.4.2. Urine Test Urine samples are analyzed for the parameters listed in Section 0. Microscopic examination of urine samples is performed if the results of macroscopic analysis are abnormal.

[0243] 8.3.4.3. Follicle-Stimulating Hormone Follicle-stimulating hormone (FSH) may be obtained to confirm the postmenopausal state in female participants considered to be postmenopausal. High FSH levels within the postmenopausal range may be used to confirm the postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT).

[0244] This test is not required for participants who may be pregnant.

[0245] 8.3.5. Hospitalization Status Information regarding hospitalization defined as hospitalization in a medical facility (hospital, rehabilitation center, or hospice) is collected regardless of the relationship with MG. The date of admission, date of discharge, reason for admission, relationship with MG, and other relevant information are recorded on the eCRF.

[0246] 8.3.6. Monitoring of Suicide Ideation and Behavioral Risk NINDS is developing a set of data collected in clinical trials for neurological indications in collaboration with regulatory authorities.

[0247] Participants receiving a study intervention should be carefully monitored and observed for suicide ideation, behavior, or any other abnormal changes in behavior, particularly at the start and end of the intervention, or at the time of dose change. Interruption of the study intervention should be considered in participants who experience signs of suicide ideation or behavior.

[0248] Family members and caregivers of participants being treated with a study intervention should be warned about the need to monitor the participant for abnormal changes in behavior, including the emergence of suicide ideation or behavior, and the need to report such symptoms immediately to the study physician responsible for the trial.

[0249] Suicide ideation and behavior are evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS) at baseline. Post-intervention emergence of suicide ideation and behavior is monitored using the C-SSRS after the final visit.

[0250] The C-SSRS is administered by the study physician responsible for the trial or a duly trained designee at the time of the visit specified in the SoA to ensure that participants experiencing suicide ideation or behavior are recognized, appropriately managed, or referred for further evaluation. Additional C-SSRS evaluations are permitted as needed.

[0251] 8.3.7. Injection Site Reactions Injection site reactions can occur when any drug is administered subcutaneously. Monitoring of injection site reactions is part of the regular safety assessment for this trial. Injection site reactions can include erythema, pruritus (itching), pain, and bruising at the site of administration of the study intervention. These reactions are typically observed during or immediately after injection, but can occur with a delay of up to 2 or 3 days. Injection site reactions should not be recorded as AEs unless clinically significant as determined by the investigator in charge of the trial.

[0252] 8.3.8. Systemic Reactions Systemic injection-related reactions can be mediated by immune or non-immune mechanisms and generally occur during or within a few hours after administration of a drug or biologic therapy. Immune-mediated reactions can include allergic reactions such as fever, chills, flushing, changes in heart rate and blood pressure, dyspnea, generalized skin rash, or anaphylaxis. Non-immune-mediated reactions can cause less specific symptoms such as headache, dizziness, nausea, vomiting, or diarrhea. Monitoring of these reactions is part of the regular safety assessment for this trial.

[0253] 8.3.9. Pregnancy Serum or urine pregnancy tests are performed on all participants who are capable of becoming pregnant. A negative serum pregnancy test at screening visit and a negative urine pregnancy test on Day 1 are required for eligibility to participate in the trial.

[0254] Pregnancy data are collected from participants who are capable of becoming pregnant and from the pregnant partners of participants from the first dose of the study intervention and at the time points specified in the SoA. Any female participant who becomes pregnant while participating in the trial will discontinue the study intervention or withdraw from the trial. If pregnancy is reported, the investigator in charge of the trial must notify the sponsor within 24 hours of recognition of the pregnancy and follow the procedures outlined.

[0255] 8.3.10. Patient Safety Card Before the first dose of the study intervention, participants receive a Patient Safety Card that they must carry at all times until 5.5 terminal half-lives (92 days) after the last dose of the study intervention. The Patient Safety Card is provided to raise participants' awareness of the risk of meningococcal infection, to facilitate the rapid recognition and disclosure of any potential signs or symptoms of such an infection during the study, and to inform participants of the measures that must be taken if they experience these symptoms or signs.

[0256] At each clinic visit throughout the study, the study staff ensures that the participant has the Patient Safety Card and reviews the information provided on the card.

[0257] 8.4. Adverse Events and Serious Adverse Events Any AE and / or any SAE reported in this study will undergo a causality assessment by the principal investigator for causality with the study intervention, including both the drug and device components.

[0258] The definitions of AE and SAE can be found in Section 10.3.

[0259] All AEs are reported by the participant (or, where appropriate, a caregiver, proxy, or legally authorized representative of the participant) to the principal investigator or a qualified designee.

[0260] The principal investigator and any qualified designee are responsible for detecting, documenting, and recording events that meet the definition of AE or SAE and for following up on AEs that are considered serious or that interrupt the participant's study intervention, whether related to the study intervention or study procedure (Section 7).

[0261] Procedures for recording, evaluating, following up on, and reporting AEs and SAEs are outlined in Section 10.3.

[0262] 8.4.1. Period and Frequency for Collecting AE and SAE Information AE and SAE are collected from the signature of the ICF at the time specified by the SoA.

[0263] All SAEs are recorded and reported immediately to the sponsor of the clinical trial, which, as shown in Section 10.3, must not exceed 24 hours under any circumstances. The principal investigator of the clinical trial shall submit any updated SAE data to the sponsor of the clinical trial within 24 hours of the date on which the clinical trial site became aware of the event.

[0264] The principal investigator of the clinical trial has no obligation to actively seek AE or SAE data after the end of participation in the trial. However, at any time after a participant has been withdrawn from the trial, if the principal investigator becomes aware of any SAE, including death, and considers the event to be reasonably related to the trial intervention or participation in the trial, the principal investigator must notify the sponsor of the clinical trial promptly.

[0265] 8.4.2. Methods for Detecting AEs and SAEs The methods for recording, evaluating, and assessing the causal relationship of AEs and SAEs, as well as the procedures for completing and submitting SAE reports, are provided in Section 10.3.

[0266] Care is taken not to introduce bias when detecting adverse device effects (ADEs) or serious adverse device effects (SADEs) by the device. Unconstrained and non-leading verbal questioning of participants is the preferred method for inquiring about the occurrence of ADEs or SADEs. The principal investigator of the clinical trial should attempt to associate each ADE or SADE with one unit (kit) of the test device. When an ADE or SADE is suspected, the unique identification kit serial number and lot number should be obtained immediately and recorded along with the corresponding event.

[0267] 8.4.3. Follow-up of AEs and SAEs After the initial AE / SAE report, the principal investigator of the clinical trial is required to actively follow up on each participant during subsequent visits / communications. All SAEs are followed up until resolved, stabilized, the event is otherwise explained, or the participant becomes untraceable (as defined in Section 7.3). Further information on the follow-up procedure is provided in Section 10.3.

[0268] 8.4.4 Regulatory reporting requirements for SAEs a. Prompt notification by the principal investigator of the clinical trial to the sponsor of the SAE is essential to fulfill the legal obligations and ethical responsibilities regarding the safety of the participants and the safety of the test intervention during the clinical trial. b. The sponsor has the legal responsibility to notify both the local regulatory authority and other regulatory authorities regarding the safety of the test intervention during the clinical trial. The sponsor complies with country-specific regulatory requirements regarding safety reporting to regulatory authorities, IRB / IEC, and the principal investigator of the clinical trial. c. The sponsor is required to submit individual SUSAR reports (as defined in Section 10.3.2) in the form of MedWatch 3500 or the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Form I to the health authority and the principal investigator of the clinical trial as necessary. The forms submitted to the principal investigator of the clinical trial are blinded to treatment assignment. In limited circumstances, for example, in the case of urgent safety issues that may compromise the safety of the participant, the blinding may be broken. d. The principal investigator of the clinical trial who receives a principal investigator safety report from the sponsor that describes an SAE or other specific safety information (e.g., summary or list of SAEs) reviews the information and notifies the IRB / IEC if appropriate according to local requirements.

[0269] 8.4.5 Adverse events of special interest Meningococcal infection is recorded as an adverse event of special interest (AESI) for this trial.

[0270] 8.5 Defects in medical devices, adverse effects due to devices, unexpected serious adverse effects due to devices, and serious adverse effects due to devices The definitions of machine-related safety events (medical device defects, ADEs, SADEs, and USADEs) can be found in Section 0.

[0271] All ADEs must be reported to the principal investigator or qualified designee by the participant or, where appropriate, by the caregiver, study site staff operating the device, or any other person who may cause an adverse medical event related to the device or its use. The principal investigator and any qualified designee are responsible for detecting, documenting, and recording events that meet the definition of an ADE or SADE and for following up on any serious ADEs that are considered related to the study intervention or procedure and that cause the participant to discontinue the study intervention (see Section 7).

[0272] Procedures for recording, evaluating, following up, and reporting ADEs and SADEs are outlined in Section 10.4.

[0273] 8.5.1. Period and Frequency for Collecting ADE and SADE Information All ADEs and SADEs are collected from the date of ICF signature as specified in the SoA.

[0274] All SADEs are recorded and reported immediately to the sponsor, which must not exceed 24 hours under any circumstances, as shown in Section 10.4. The principal investigator submits any updated SADE data to the sponsor within 24 hours of the date the study site became aware of the event.

[0275] The principal investigator has no obligation to actively seek ADE or SADE data after the end of the study participation. However, at any time after the participant is withdrawn from the study, if the principal investigator becomes aware of any SADE, including death, and reasonably believes the event is related to the study intervention or participation, the principal investigator must promptly notify the sponsor.

[0276] 8.5.2. Method for Detecting ADE and SADE The method for recording, evaluating, and assessing the causal relationship of ADE and SADE, as well as the procedures for filling out and submitting the SADE report, are provided in Section 10.4.

[0277] Care is taken not to introduce bias when detecting ADE or SADE. Unconstrained and non-leading oral questions of participants are the preferred method for inquiring about the occurrence of ADE or SADE. The principal investigator of the clinical trial should attempt to associate each ADE or SADE with one unit (kit) of the test article. When an ADE or SADE is suspected, the unique identification kit serial number and lot number should be immediately obtained and recorded along with the corresponding event.

[0278] 8.5.3. Follow-up of ADE and SADE After the first ADE or SADE report, the principal investigator of the clinical trial should actively follow up each participant during subsequent hospital visits / communications. All SADEs are followed up until they are resolved, stabilized, the event is otherwise explained, or the participant becomes untraceable (as defined in Section 7.3). Further information on the follow-up procedures is provided in Section 10.4.

[0279] 8.5.4. Regulatory Reporting Requirements for SADE ● Prompt notification by the principal investigator of the clinical trial to the sponsor of the clinical trial of SADE is essential to fulfill the legal obligations and ethical responsibilities regarding the safety of participants and the safety of the test intervention during the clinical trial. ● The sponsor of the clinical trial has the legal responsibility to notify both the local regulatory authority and other regulatory authorities regarding the safety of the test intervention during the clinical trial. The sponsor of the clinical trial complies with the country-specific regulatory requirements regarding safety reports to the regulatory authority, IRB / IEC, and the principal investigator of the clinical trial. ● The sponsor shall submit each individual USADE report (as defined in Section 10.4.2) in the form of a MedWatch 3500 or CIOMS I form, as appropriate, to the health authority and the principal investigator of the trial. Forms submitted to the principal investigator of the trial shall be blinded to treatment assignment. In limited circumstances, for example, in the case of an urgent safety issue that may compromise the safety of the participants, the blinding may be broken. ● The principal investigator who receives a principal investigator safety report from the sponsor that describes a SADE or other specific safety information (e.g., summary or list of SADEs) shall review the information and notify the IRB / IEC, as appropriate, in accordance with local requirements.

[0280] 8.5.5. Defects in Medical Devices To fulfill regulatory reporting obligations worldwide, the principal investigator is responsible for identifying and documenting events that meet the definition of a defect in a medical device that occurs during the trial. Defects in medical devices include malfunctions, user errors, and inappropriate labeling (Section 10.4.3).

[0281] Defects that meet the definition of an ADE or SADE (see Sections 10.4.1 and 10.4.2) also follow the detection, follow-up, and reporting processes outlined in Sections 8.5.3 and 10.4 of the protocol.

[0282] 8.5.5.1 Period for Detecting Defects in Medical Devices ● Defects in medical devices shall be identified, documented, and reported throughout all periods of the trial during which the medical device is used, regardless of the occurrence of resulting ADEs / SADEs. ● The principal investigator has no obligation to actively seek device defect data after the end of trial participation. However, at any time after a participant is withdrawn from the trial, if the principal investigator becomes aware of a defect in any medical device, including death, and such defect is reasonably considered to be related to the investigational medical device, the principal investigator shall promptly notify the sponsor. The method for documenting defects in medical devices is provided in Section 10.4.

[0283] 8.5.5.2. Tracking and Investigation of Defects in Medical Devices ● The principal investigator is responsible for ensuring that all device defects occurring after the signing of the ICF are reported, either through the 30-day period following the last dose of the trial intervention or at the end of the trial, whichever is later. ● After the initial defect report, the principal investigator should follow up on participants, including those whose trial intervention has been interrupted, to determine whether there is a medical indication or to conduct or arrange for additional investigations requested by the sponsor to fully elucidate the nature and causality of the device defect, if possible.

[0284] 8.5.5.3. Prompt Reporting of Defects in Medical Devices to the Sponsor ● The principal investigator and participants must record all defects in medical devices observed during the trial using the eCRF (see Section 10.5). Further details of the reporting process and reporting timeframes for defects in medical devices are specified in the pharmacy manual. ● For example, devices with reported malfunctions that involve safety devices or needles must be collected in accordance with the pharmacy manual procedures for further investigation and sent to the sponsor or designated testing laboratory. The sponsor may request the collection and further investigation of defects in other types of devices during the trial.

[0285] 8.6. Treatment of Overdose Any blinded dose of a trial intervention that exceeds the dose specified in the protocol is considered a suspected overdose. However, for example, alternative doses to supplement incomplete or missed delivery of the trial intervention after user error or malfunction of PFS-SD, or supplementary doses administered as necessary after PP / PE (Section 6.5.3.1) do not constitute an overdose.

[0286] Overdose is a medication error that is not considered an AE or ADE unless there are troublesome medical events resulting from the overdose. The sponsor of the clinical trial recommends measures directed at systemic symptoms after overdose with the fusion polypeptide described in this specification. For example, specific treatment related to the mechanism of action is not required.

[0287] In case of overdose or suspected overdose, the responsible investigator of the clinical trial should do the following. ● Immediately contact the medical monitor. ● Thoroughly monitor the participants for any AE / SAE. ● If required by the medical monitor (determined on a case-by-case basis), obtain plasma samples for PK analysis. ● Document the amount of the overdose and the frequency of the overdose in the eCRF.

[0288] 8.7. Pharmacokinetics ● Whole blood samples are collected for the measurement of the serum concentration of the fusion polypeptide as specified in the SoA. Samples may be collected at additional time points during the trial if justified and agreed upon between the responsible investigator of the clinical trial and the sponsor of the clinical trial. ● Instructions for sample collection and handling are provided by the sponsor of the clinical trial. The actual date and time (24-hour clock) of each sample must be recorded. ● Every effort is made to obtain PK samples at the exact nominal time relative to dosing. Samples collected for the analysis of the fusion polypeptide serum concentration may also be used to evaluate aspects of safety or efficacy related to concerns that arise during or after the trial.

[0289] 8.8. Pharmacodynamics ● Whole blood samples are collected for the measurement of the serum concentration of free C5 and total C5 as specified in the SoA. Samples may be collected at additional time points during the trial if justified and agreed upon between the responsible investigator of the clinical trial and the sponsor of the clinical trial. ●Instructions for the collection and handling of PD samples are provided in the laboratory manual. The actual date and time (24-hour clock) of each sample must be recorded. ●Every effort is made to obtain PD samples at the exact nominal time for dosing. PD samples collected outside the window are recorded as protocol deviations. ●Samples collected for PD analysis may also be used for research purposes, or to evaluate aspects of safety or efficacy during or after the trial.

[0290] 8.9. Biomarkers Samples are collected for analysis that may include, but are not limited to, the evaluation of complement components, functional assays, anti-AChR antibody functional assays, markers of inflammation, and other non-genetic preliminary biomarkers in adults with gMG.

[0291] Blood samples for biomarker research are collected from all participants in this trial as specified in the SoA. Additional details regarding the methods by which biomarkers are collected and analyzed are provided in Section 10.7.

[0292] 8.10. Immunogenicity Assessment Serum samples for ADA analysis are collected according to the SoA. Every effort is made to obtain immunogenicity samples at the designated nominal time for dosing. ADA samples collected outside the window are recorded as protocol deviations.

[0293] 8.10.1. ADA Variables ADA variables include, as follows, the incidence rates and titers of ADA response categories over the duration of the trial. ADA response category definitions and titer thresholds are provided in the SAP.

[0294] ADA Response Categories ●ADA Negative ●ADA Positive Participants who are ADA positive are classified as follows. ● Existing immunoreactivity ● ADA response expressed after treatment Response expressed after continuous treatment Uncertain response expressed after treatment Transient response expressed after treatment ● ADA response enhanced by treatment ADA maximum titer category: ● Lower titer ● Moderate titer ● Higher titer

[0295] 8.11. Healthcare economics data and / or healthcare resource utilization Healthcare economics data and / or healthcare resource utilization parameters are not evaluated in this trial.

[0296] 8.12. Other evaluations and procedures 8.12.1. Informed consent Participants or their legally authorized representatives must give consent in accordance with the informed consent process outlined in Section 10.1.3.

[0297] 8.12.2. Inclusion / exclusion criteria All inclusion (Section 5.1) and exclusion (Section 5.2) criteria must be reviewed by the principal investigator or a qualified designee to ensure that participants are eligible to participate in the trial.

[0298] 8.12.3. Medical history The relevant medical and surgical history of the participant, including previous and concurrent conditions or disorders, is evaluated by the principal investigator or a qualified designee at the time of screening. Specific aspects of the MG history are required, including the following. ● Date of symptom onset ● Date of diagnosis ● Initial clinical findings (ocular or systemic MG) ● If the initial clinical findings are limited to the extraocular muscles, time to systemic symptoms and signs ● Maximum MGFA classification since diagnosis ● Ventilatory support since diagnosis ●Worsening or crisis day of MG ●Hospitalizations related to MG in the 2 years before screening ●Agents or other forms of treatment related to MG within 2 years before screening, and additional information on such agents or treatments in the initial few years, if available The data collected are documented in the source documents and eCRF. Any changes to the medical history occurring before Day 1 are documented before the administration of the study intervention.

[0299] 8.12.4. Demographics If permitted by country-specific regulations, scrutiny of demographic parameters, including age, gender, race, and ethnicity, is performed at screening and documented in the eCRF.

[0300] 10. Supplementary Documents and Operational Considerations 10.1. Regulatory, Ethical, and Trial Monitoring Considerations 10.1.1. Regulatory and Ethical Considerations This trial is conducted in accordance with the protocol and the following. Consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and CIOMS International Ethical Guidelines Applicable ICH Good Clinical Practice (GCP) guidelines for the conduct of clinical trials of medicinal products Applicable laws and regulations

[0301] The protocol, substantial protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) are submitted by the principal investigator / sponsor to the IRB / IEC and must be reviewed and approved by the IRB / IEC before the start of the trial.

[0302] If any of these documents require approval from the regulatory / health authorities in accordance with local regulations, the sponsor must also obtain such approval before the start of the trial.

[0303] Any significant amendment to the protocol requires approval from the IRB / IEC and the regulatory / health authorities before implementation of changes added to the clinical trial design, except for changes necessary to eliminate an immediate risk to the trial participants.

[0304] The principal investigator of the clinical trial notifies the IRB / IEC of any deviation from the protocol or GCP as defined by the Clinical Trials Regulation EU No 536 / 2014 as a significant breach or as required by the IRB / IEC procedures.

[0305] The principal investigator of the clinical trial is responsible for the following. Providing the IRB / IEC with a written summary of the status of the trial annually or at more frequent intervals, in accordance with the requirements, guidelines and procedures established by the IRB / IEC Notifying the IRB / IEC of SAEs or other important safety findings required by the IRB / IEC procedures Overseeing the conduct of the trial at the trial site and ensuring compliance with the requirements of Title 21 of the Code of Federal Regulations (CFR), ICH guidelines, the IRB / IEC, Directive 2001 / 20 / EC, the European Regulation 536 / 2014 on clinical trials (where applicable), and all other applicable local regulations

[0306] 10.1.3. Informed consent process It is the responsibility of the principal investigator of the clinical trial or the designee to obtain an informed consent (signed, either in writing or electronically) from all trial participants or the legally authorized representatives of the participants before conducting any trial-related procedures, including screening evaluations.

[0307] The principal investigator of the clinical trial or the designee explains the nature of the trial (including, but not limited to, the purpose, potential benefits and risks, inconveniences, and the rights and responsibilities of the participants) to the participants or their legally authorized representatives as defined by the regulations of the region and country where the trial is being conducted and answers all questions regarding the trial.

[0308] Participants must be informed that their participation is voluntary. The participant or legally authorized representative must, where applicable, sign an informed consent or certified translation statement that complies with 21 CFR 50, local regulations, the European Union (EU) General Data Protection Regulation (GDPR), ICH GCP guidelines, the Health Insurance Portability and Accountability Act (HIPAA) (where applicable), and the requirements of the IRB / IEC or the test center.

[0309] The participant's medical records must include a statement that signed (written or electronic) informed consent was obtained before screening procedures were performed on the participant, and the date on which written consent was obtained. The person authorized to obtain informed consent must also sign the ICF.

[0310] Participants must, where applicable, re-consent to the most current version of the ICF during their participation in the study.

[0311] A copy of the signed (written or electronic) informed consent documents (i.e., the complete set of the participant information sheet and fully signed signature pages) must, where applicable, be provided to the participant or the participant's legally authorized representative. This document may require translation into the local language. The original signed (written or electronic) consent form must remain in each participant's study file and be available for verification at all times.

[0312] Participants who are re-screened outside of the screening window must sign a new ICF (Section 5.4).

[0313] 10.1.9. Opening and Closing of the Study and the Study Sites The study start date is the date on which the first participant consents.

[0314] The sponsor reserves the right, at its sole discretion, to close the trial site or terminate the trial for any reason at any time. The trial site will be closed after the trial is completed or after a decision is made to complete or terminate the trial. The trial site is considered closed when all participants have completed their EoS or ET visits, all data have been collected, entered into the electronic data capture (EDC) system, all required documents and trial supplies have been collected and reconciled, and a trial site closure visit has been conducted.

[0315] The principal investigator of the trial may initiate the closure of the trial site at any time, provided that there are reasonable grounds and sufficient notice has been given prior to the intended end.

[0316] Reasons for early closure of the trial site by the sponsor or the principal investigator of the trial may include, but are not limited to, the following. The principal investigator of the trial is unable to comply with the protocol, requirements of the IRB / IEC or local health authorities, procedures of the sponsor, or ICH GCP guidelines Inappropriate recruitment of participants by the principal investigator of the trial Interruption of further development of the trial intervention

[0317] The sponsor or the health authorities may terminate the trial for reasonable reasons. Conditions that may justify the termination of the trial may include, but are not limited to, the following. Discovery of unexpected, serious, or unacceptable risks of the trial intervention to participants enrolled in or continuing the trial Decision by the sponsor to temporarily interrupt or discontinue the development of the trial, evaluation, or trial intervention

[0318] If the trial is terminated early or suspended initially, the sponsor shall promptly notify the sponsor, the IRB / IEC, the regulatory authority, and any contract research organization used in the trial of the reason for the termination or suspension, as specified by the applicable regulatory requirements. The principal investigator of the trial shall promptly notify the participants and shall ensure appropriate treatment and / or follow-up of the participants.

[0319] 10.2. Clinical Tests The tests detailed in the table shall be conducted by the central laboratory, unless otherwise specified. Local test results are required only if the central laboratory results are not available in time for response evaluation. If local samples are required, it is important that samples for central analysis are obtained simultaneously. In addition, if local laboratory results are used to make either a trial intervention decision or a response evaluation, the results must be available in the participant's source documents.

[0320] Protocol-specific requirements for participant inclusion or exclusion are detailed in Section 5. Additional tests may be conducted at any time during the trial if determined necessary by the principal investigator of the trial or required by local regulations.

[0321] Pregnancy test: Female participants of childbearing potential should be randomized only after a negative serum pregnancy test at screening visit and a negative urine pregnancy test on Day 1. Additional urine pregnancy tests should be performed according to the protocol standard and at each time point specified in the SoA, unless the serum test is required by the trial site policy, local regulations, or the IRB / IEC.

[0322] The principal investigator of the trial shall document the review of each laboratory report. Clinically significant findings leading to the evaluation of TEAE should be recorded in the AE eCRF.

[0323] Laboratory / analyte results that could unblind the trial shall not be reported to the trial site or other blinded personnel until the trial is unblinded.

Table 15-1

Table 15-2

[0324] 10.3. Adverse Events: Definitions and Procedures for Recording, Evaluation, Follow-up, and Reporting 10.3.1 Definition of AE

Table 16

Table 17

Table 18

[0325] 10.3.2 Definition of SAE If the event is not an AE according to the above definition, it cannot be an SAE even if a serious condition (e.g., hospitalization due to signs / symptoms of a disease during the test, death due to progression of the disease) is met.

Table 19

Table 20

[0326] 10.3.3 Recording and Follow-up of AE and / or SAE

Table 21

Table 22

Table 23

[0327] 10.3.4 Reporting of SAE

Table 24

[0328] 10.4 Adverse effects due to devices, adverse effects due to serious devices, and defects in medical devices: Definitions and procedures for recording, evaluation, follow-up, and reporting The definitions and procedures detailed in this section are in accordance with ISO 14155. Both the principal investigator and the sponsor of the clinical trial comply with all local medical device reporting requirements.

[0329] The detection and documentation procedures described in this protocol apply to the PFS-SD medical devices provided for use in this trial (Section 6.1.2).

[0330] 10.4.1 Definition of adverse effects due to devices

Table 25

[0331] 10.4.2 Definitions of adverse effects due to serious devices and unexpected adverse effects due to serious devices If an event is not an ADE according to the above definitions, it cannot be a SADE even if a serious condition (e.g., hospitalization due to signs / symptoms of a disease during the trial, death due to progression of a disease) is met.

Table 26

[0332] 10.4.3 Definition of defects in medical devices

Table 27

[0333] 10.4.4 Recording and follow-up of adverse effects due to devices and / or adverse effects due to serious devices, and defects in medical devices

Table 28

Table 29

Table 30

[0334] 10.4.5. Report on Adverse Effects Caused by Serious Devices

Table 31

[0335] 10.4.6. Regulatory Reporting Requirements for Adverse Effects Caused by Devices, Adverse Effects Caused by Serious Devices, and Unexpected Serious Adverse Effects Caused by Devices Reporting Requirements for Unexpected Adverse Effects Caused by Devices An unexpected ADE means any serious adverse effect, or its impact, problem, or death, on health or safety, or any life-threatening problem or death caused by or related to the device, or any other unexpected serious problem related to the device with respect to the rights, safety, or welfare of the participant, where such adverse effect, problem, or death was not previously identified in terms of the nature, severity, or degree of occurrence of the clinical trial plan or application (including supplementary plans or applications).

[0336] The sponsor of the clinical trial is required to transmit individual USADE safety reports in the form of a MedWatch 3500A or CIOMS II form, or a series of similar USADEs in conversation form, to the health authority / national competent authority (NCA) and the responsible investigator of the clinical trial as necessary.

[0337] For blinded phase 3 trials, MedWatch 3500A or CIOMS II forms submitted to the responsible investigator are blinded to treatment assignment. In limited circumstances, blinding may be broken in the case of an urgent safety issue that could compromise the safety of the participant.

[0338] 10.4.6.2. Reporting Requirements for Adverse Effects Caused by Critical Equipment in Other Jurisdictions The following events shall be considered events subject to reporting obligations in accordance with other jurisdictions. Any SAE Defects of any medical device that have led to an SAE in the following cases: Appropriate measures have not been taken. Intervention has not been carried out. The situation has not been favorable. New findings / updates related to events that have already been reported.

[0339] To meet regulatory reporting requirements, defects of medical devices and SAEs shall be documented during the course of clinical trials and reported to the relevant authorities.

[0340] Device events subject to reporting obligations shall be reported simultaneously by the sponsor of the clinical trial to all NCAs where the clinical trial has been initiated.

[0341] All reportable events indicating imminent risk of death, serious injury, or serious illness and requiring prompt corrective measures or new findings for other trial participants, users, or other persons: Immediately, but within 2 calendar days after the sponsor of the clinical trial becomes aware of a new reportable event or new information related to an event that has already been reported.

[0342] Other reportable events or new findings / updates thereto: Immediately, but within 7 calendar days after the date the sponsor of the clinical trial becomes aware of a new reportable event or new information related to an event that has already been reported.

[0343] 10.5 Complaints about Investigational Medicinal Products or Devices If the use of an investigational medicinal product or device has led to an AE or ADE as defined in Sections 10.3 and 10.4 respectively, the event shall be evaluated by the sponsor's GDS and the recording and reporting procedures shall be followed as described.

[0344] An adverse event is a written, electronic, or oral communication that alleges a defect in the identity, quality, durability, reliability, safety, or performance of an investigational medical device. When identifying an adverse event for the PFS-SD, the study site or participant must contact the sponsor or designee using the local telephone number in the IFU document. The study site or participant must complete a Product Quality Adverse Event Form (see Pharmacy Manual for details).

[0345] The following include potential problems that may justify an adverse event report. ● Malfunction of the medical device: The PFS-SD is used in accordance with the IFU but does not function as described (e.g., incomplete dosing or no dosing delivered). ● Labeling irregularities (e.g., missing or illegible information on the package or any part of the IFU). ● Appearance changes of the investigational intervention (e.g., discoloration or presence of particulate matter in the cartridge). ● Evidence of tampering or infringement of the PFS-SD kit packaging ● User error: The PFS-SD is not used in accordance with the IFU. Additional details are provided in the IFU.

[0346] The Investigator is responsible for ensuring that all product adverse events occurring after the signing of the ICF are reported within 30 days after the last dose of the investigational intervention or at the end of the study, whichever is later.

[0347] 10.7 Biomarkers Blood matrix (serum / plasma) samples are collected for biomarker analysis and the data are used in studies related to the investigational intervention or gMG (e.g., pilot). Samples may also be used to develop tests / assays including diagnostic tests related to the investigational intervention and gMG.

[0348] Samples can be analyzed as part of the multi-test evaluation of biomarkers in response to a test intervention to understand the test disease or related conditions. The results of biomarker analysis can be reported in the clinical study report (CSR) or a separate study summary. ● The sponsor or nominee shall store the samples obtained for biomarker analysis in a secure storage space using appropriate measures to protect confidentiality. ● Samples are retained during the continuation of the study of the test intervention, but for no more than 25 years after the end of the trial, or for another period / time point in accordance with local requirements.

[0349] 10.8. Participant or Clinician Reported Outcome Instruments Participant-reported outcomes or clinician-reported outcomes (clinical outcome assessments) can be collected on paper or electronically.

[0350] 10.11 Abbreviations The following abbreviations and terms are used in this test protocol in Table 18.

Table 1-2-1

Table 1-2-2

Table 1-2-3

Table 1-2-4

[0351] 10.12 Glossary

Table 2-2-1

Table 2-2-2

[0352] Other embodiments The above invention has been described in some detail as an illustration and example for the sake of clear understanding, but these explanations and examples should not be construed as limiting the scope of the present invention. The disclosures of all patents and scientific documents cited herein are hereby incorporated by reference in their entirety expressly.

Claims

1. A composition for treating myasthenia gravis (MG) in a human subject in need thereof, comprising a fusion protein, the fusion protein comprising an engineered polypeptide that specifically binds to human complement component C5, which is fused to an engineered polypeptide that specifically binds to human serum albumin, the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, the engineered polypeptide that specifically binds to human complement component C5 comprises three complementation-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences shown in SEQ ID NOs. 5, 6, and 7, respectively, the composition comprising the engineered polypeptide that specifically binds to human serum albumin comprising three complementation-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences shown in SEQ ID NOs. 1, 2, and 3, respectively.

2. The polypeptide that specifically binds to human serum albumin contains an amino acid sequence that is at least 95% identical to SEQ ID NO: 4, or contains the amino acid sequence of SEQ ID NO:

4. The polypeptide that specifically binds to human complement component C5 contains an amino acid sequence that is at least 95% identical to SEQ ID NO: 8, or contains the amino acid sequence of SEQ ID NO: 8, and / or The peptide linker contains the amino acid sequence of SEQ ID NO: 10, The composition according to claim 1.

3. The composition according to claim 1, wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9, or comprises the amino acid sequence of SEQ ID NO:

9.

4. The subject is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR), and / or The aforementioned MG is generalized myasthenia gravis (gMG). The composition according to claim 1.

5. The subject has been diagnosed with MG for at least three months, Whether the subject is 18 years of age or older, The subject has a clinical classification of II to IV by the American Myasthenia Gravis Foundation (MGFA), or The aforementioned patient has a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 5 or higher, The composition according to claim 1.

6. The composition according to claim 1, further comprising one or more additional pharmaceutical compositions, wherein the pharmaceutical composition is an acetylcholinesterase inhibitor, an immunosuppressive therapy (IST), or an immunoglobulin.

7. The composition according to claim 6, wherein IST is selected from the group consisting of corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).

8. The subject is characterized in that it has not been administered B-cell depletion therapy in the past six months. The subject has not been administered an FcRn inhibitor within five half-lives of FcRn prior to the administration of the fusion protein, and / or The subject has not been administered a complement inhibitor within five half-lives of the complement inhibitor prior to the administration of the fusion protein. The composition according to claim 1.

9. The composition according to claim 8, wherein the B-cell depletion therapy is rituximab or ocrelizumab.

10. The subject in question has a body weight of at least 40 kg. The subjects mentioned above have a body mass index of 18.5 kg / m² or more and less than 40 kg / m², and / or The effective therapeutic dose is determined based on the subject's body weight. The composition according to claim 1.

11. (1) The composition is used in patients weighing less than 80 kg, (a) Once on day 1 of the administration cycle, with a loading dose of 600 mg of the fusion protein, (b) A maintenance dose of 300 mg of the fusion protein is administered on day 8 of the administration cycle and weekly thereafter, or (2) The composition is used in patients weighing 80 kg or more. (a) Once on day 1 of the administration cycle, with a loading dose of 900 mg of the fusion protein, (b) The fusion protein is administered at a maintenance dose of 600 mg on the 8th day of the administration cycle and weekly thereafter. The composition according to claim 1.

12. To a patient weighing less than 80 kg, the composition is administered weekly at a dose of 300 mg of the fusion protein for a maximum of two years after the administration cycle, or The composition is characterized in that, for patients weighing 80 kg or more, the composition is administered weekly at a dose of 600 mg of the fusion protein for a maximum of two years after the administration cycle. The composition according to claim 11.

13. The composition is administered subcutaneously to the subject, and / or The composition is characterized in that it is administered to the subject using a pre-filled syringe. The composition according to claim 1.

14. The composition according to claim 13, wherein the pre-filled syringe includes a passive needle safety device.

15. As a result of the aforementioned treatment, the patient experiences a change from baseline in their MG-ADL score. As a result of the treatment, the patient will experience a change from baseline in the MG-ADL score after 26 weeks, and / or As a result of the aforementioned treatment, the patient experiences a decrease in the MG-ADL score after 26 weeks. The composition according to claim 1.

16. The composition according to claim 15, wherein the reduction is at least 3.0 points, or the reduction is at least 4.0 points.

17. As a result of the aforementioned treatment, the patient experiences a change from baseline in their quantitative myasthenia gravis (QMG) score. As a result of the treatment, the patient will experience a change from baseline in their QMG score after 26 weeks, and / or As a result of the aforementioned treatment, the patient experiences a decrease in QMG score after 26 weeks. The composition according to claim 1.

18. The composition according to claim 17, wherein the reduction is at least 2.0 points, or the reduction is at least 5.0 points.

19. As a result of the aforementioned treatment, the patient experiences a change from baseline in the quantitative myasthenia gravis composite (MGC) score. As a result of the aforementioned treatment, the patient will experience a change from baseline in their MGC score after 26 weeks. As a result of the aforementioned treatment, the patient experiences a decrease in MGC score after 26 weeks. As a result of the aforementioned treatment, the subject experiences a change from baseline in blood free or total C5 concentration. As a result of the aforementioned treatment, the patient will experience a change from baseline in the MG Quality of Life 15 (MG-QoL15r) score after 26 weeks. As a result of the aforementioned treatment, the patient will experience a change from baseline in the EQ-5D-5L score after 26 weeks. As a result of the aforementioned treatment, the patient will experience a change from baseline in the SF-36 score after 26 weeks. As a result of the aforementioned treatment, the patient will experience a change from baseline in the Neuro-QoL Fatigue (Quality of Life in Neurological Disorders Fatigue Short Form) score after 26 weeks. As a result of the aforementioned treatment, the patient will experience an MG-ADL score of 1 or less after 26 weeks. As a result of the aforementioned treatment, the patient experiences a change in their post-MGFA intervention state after 26 weeks. As a result of the aforementioned treatment, the patient experiences a reduced incidence of clinical exacerbation after 26 weeks. As a result of the aforementioned treatment, the patient experiences a reduction in the incidence of hospitalization after 26 weeks. As a result of the aforementioned treatment, the patient experiences a reduced incidence of needing salvage treatment after 26 weeks. The aforementioned treatment alters the concentration of one or more inflammatory biomarkers. The aforementioned treatment alters the concentration of complement proteins or complement pathway regulators. The therapeutic effect is maintained up to 26 weeks after the start of treatment, and / or The aforementioned therapeutic effect is maintained up to 96 weeks after the start of treatment. The composition according to claim 1.

20. The composition according to claim 19, wherein the one or more inflammatory biomarkers include MMP-10 or IL-6.

21. A composition for administering gMG to a human subject in need thereof, comprising a fusion protein, the fusion protein comprising an engineered polypeptide that specifically binds to human complement component C5, which is fused to an engineered polypeptide that specifically binds to human serum albumin, the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, the engineered polypeptide that specifically binds to human complement component C5 comprises three complementation-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences shown in SEQ ID NOs. 5, 6, and 7, respectively, the engineered polypeptide that specifically binds to human serum albumin comprises three complementation-determining regions CDR1, CDR2, and CDR3, each comprising the amino acid sequences shown in SEQ ID NOs. 1, 2, and 3, respectively. The subject is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR), The aforementioned subjects are 18 years of age or older. (a) The composition is used in patients weighing less than 80 kg. (i) once on day 1 of the administration cycle with a loading dose of 600 mg of the fusion protein, (ii) The fusion protein is administered at a maintenance dose of 300 mg on day 8 of the administration cycle and thereafter weekly, and the composition is administered at a dose of 300 mg of the fusion protein weekly for up to two years after the administration cycle, or (b) The composition is used in patients weighing 80 kg or more. (i) once on day 1 of the administration cycle with a loading dose of 900 mg of the fusion protein, and (ii) The composition is administered at a maintenance dose of 600 mg of the fusion protein on day 8 of the administration cycle and thereafter weekly, characterized in that the composition is administered at a dose of 600 mg of the fusion protein weekly for up to two years after the administration cycle. The composition wherein the subject has an improvement from baseline in at least one measurement of gMG severity selected from the group consisting of MG-ADL, QMG, MGC, MG-QoL15r, EQ-5D-5L, SF-36, and nerve-QoL fatigue.

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