Treatment of Myasthenia Gravis Using Zilcoplan

Abstract

The present disclosure provides a method of using zilucoplan as a therapy for AChR-positive gMG patients having gMG refractory to conventional immunosuppressive therapies and / or intravenous (IV) immunoglobulin and plasma exchange (PLEX) therapies.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 338,824, filed May 5, 2022, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Myasthenia gravis (MG) is a rare chronic complement-mediated autoimmune disease characterized by the production of autoantibodies that target proteins critical for the normal transmission of electrical signals from nerves to muscles. The most common target of autoantibodies in MG is the nicotinic acetylcholine receptor (AChR) located on the postsynaptic membrane of the neuromuscular junction (NMJ), where motor neurons transmit chemical signals to skeletal muscle fibers. The prevalence of MG in the United States is estimated to be approximately 60,000 cases. In approximately 15% of patients with MG, the symptoms are limited to the ocular muscles. The remaining patients have MG that affects multiple muscle groups throughout the body, typically referred to as generalized MG (gMG). Patients with gMG characteristically exhibit muscle weakness that worsens with repeated use and recovers with rest. Muscle weakness can be localized to specific muscles but progresses to more diffuse muscle weakness. Systemic myasthenia gravis symptoms can be life-threatening when muscle weakness involves the diaphragm and intercostal muscles in the chest wall involved in breathing. The most dangerous complication of gMG, known as myasthenic crisis, requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG experience myasthenic crisis within 2 years of diagnosis.

[0003] Despite treatment, many patients are unable to achieve control of their gMG symptoms, and the burden of gMG is due to both the disease and conventional treatments. The symptom burden associated with gMG means that many patients require support from caregivers as well as family and friends in their daily activities. Current standard of care (SOC) therapies for gMG include multiple categories of therapeutic agents. However, each therapeutic agent or category of therapeutic agents has its challenges and limitations.

[0004] The approval of eculizumab does not address the needs of all gMG patients. Multiple national MG patient registries have demonstrated that many patients, regardless of current treatment, still experience significant disease burden (e.g., QMG ≥ 12 or MG-ADL ≥ 6).

[0005] Despite standard of care (SOC) therapies, there remains a continuing need for new therapies for patients who continue to have unmet medical needs and disease burden. The goal of gMG treatment is to achieve remission of excessive / chronic muscle fatigue and / or improve their symptoms, reduce the risk of life-threatening acute respiratory failure, and lower the risk of mortality, thereby enabling patients to have an improved quality of life.

Summary of the Invention

[0006] Zilucoplan is a synthetic macrocyclic peptide that binds complement component 5 (C5) with subnanomolar affinity and allosterically inhibits its cleavage to C5a and C5b upon activation of the classical alternative or lectin pathways. Like the C5 inhibitory monoclonal antibody eculizumab, zilucoplan blocks the proteolytic cleavage of C5 to C5a and C5b. Unlike eculizumab, zilucoplan can also block C6 binding, which prevents subsequent assembly of MAC by binding to C5b.

[0007] Zilucoplan has been clinically determined for the treatment of conditions in which C5 activation has been demonstrated to play a role, including generalized myasthenia gravis (gMG). In a Phase 2, 44-patient clinical study of gMG (NCT03315130), both high and low doses of zilucoplan treatment were effective with a favorable safety profile, and higher doses were shown to result in more robust clinical improvement.

[0008] In the RAISE Phase 3 clinical study (NCT04115293) described herein, the efficacy and safety of zilucoplan are studied in patients with gMG, including both patients with refractory gMG to SOC therapy and patients with non-refractory gMG. This disclosure presents the results and analysis of the RAISE study.

[0009] Analysis of the RAISE clinical study results shows that treatment of patients with refractory gMG with zilucoplan at week 12 achieves an improvement in response when compared to the response achieved by eculizumab at week 26 of the corresponding REGAIN Phase 3 study (Howard et al., 2017).

[0010] Accordingly, this disclosure provides a method of using zilucoplan as a therapy for acetylcholine receptor antibody-positive (AChR+) gMG patients with refractory gMG, i.e., gMG refractory to conventional immunosuppressive therapy and / or intravenous (IV) immunoglobulin and plasma exchange (PLEX) therapy (e.g., as described herein).

[0011] The foregoing and other objects, features and advantages will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings. The drawings are not necessarily to scale; instead, emphasis has been placed on illustrating the principles of the various disclosed embodiments.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0023] Complement activity protects the body from foreign pathogens but can lead to self-cell destruction with elevated activity or inadequate regulation. Generalized myasthenia gravis (gMG) is a neurological disorder characterized by self-antibody-mediated nervous system destruction. This disclosure relates to a particular method of treating gMG by administering the complement C5 inhibitor zilucoplan. These and other embodiments of the disclosure are described in detail below.

[0024] I. Zilucoplan Compounds and Compositions Zilucoplan, and compositions containing zilucoplan that function to modulate complement activity (e.g., inhibit complement C5 activation), are useful in the methods of the present disclosure.

[0025] Zilucoplan is a polypeptide. The core amino acid sequence of zilucoplan ([Cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-K; SEQ ID NO: 1) contains 15 amino acids (all L-amino acids) including 4 non-natural amino acids [N-methyl-aspartic acid or "(N-Me)D", tert-butylglycine or "Tbg", 7-azatryptophan or "azaTrp", and cyclohexylglycine or "Chg"]; a lactam bridge between K1 and D6 of the polypeptide sequence; and a C-terminal lysine residue with a modified side chain that forms an N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl) lysine residue (also referred to herein as "B28"). The C-terminal lysine side chain modification includes a polyethylene glycol (PEG) spacer (PEG24), and PEG24 is attached to an L-γ glutamic acid residue derivatized with a palmitoyl group.

[0026] "B28" refers to N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl) lysine.

Chemical formula

[0027] The free acid form of zirconoplan has the molecular formula of C 172 H 278 N 24 O 55 and a molecular weight of 3562.23 Daltons (Da) and a precise mass of 3559.97 amu (see CAS number 1841136-73-9). The tetrasodium form of zirconoplan has the molecular formula of C 172 H 278 N 24 O 55 Na 4 and can be referred to by the following chemical name: acetyl-[L-lysyl 1 -L-valyl 2 -L-glutamyl 3 -L-arginyl 4 -L-phenylalanyl 5 -L-aspartyl 6 -N-methyl-L-aspartyl 7 -L-tert-leucyl 8 -L-tyrosyl 9 -L-7-azatryptophyl 10 -L-glutamyl 11 -L-tyrosyl 12 -L-prolyl 13 -L-cyclohexylglycyl 14 -[L-lysyl 15 , Nε-palmitoyl-γ-L-glutamyl-(1-amino-3,6,9,12,15,18,21,24,27,30, 33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetraoxatetracontapentaheptacontane-75-yl)], cyclic (lactam 1-6), tetrasodium.

[0028] The chemical structure of the sodium salt form of zirconoplan is shown in Structure I:

Chemical formula

[0029] The four sodium ions in the structure are shown in relation to the specified carboxylate, but they can be associated with any of the acidic groups in the molecule. In some embodiments, the zirconoplan drug substance is typically provided in the sodium salt form and lyophilized. In some embodiments, the zirconoplan drug substance is formulated as a sterile preservative-free solution for administration via subcutaneous (SC) injection. In some embodiments, the zirconoplan solution is provided in a single-use injectable passive needle safety device. The free base form of zirconoplan or any pharmaceutically acceptable salt of zirconoplan is encompassed by the term "zirconoplan".

[0030] Isotopic variation The compounds of the present disclosure can contain one or more atoms that are isotopes. The term "isotope" refers to a chemical element having one or more additional neutrons. In some embodiments, the compounds of the present disclosure can be deuterated. The term "being deuterated" refers to a substance in which one or more hydrogen atoms are replaced by deuterium isotopes. Deuterium isotopes are isotopes of hydrogen. The nucleus of hydrogen contains one proton, while the deuterium nucleus contains both a proton and a neutron. The compounds and compositions of the present disclosure can be deuterated to change physical properties such as stability or to enable use in diagnostic and experimental applications.

[0031] II. Methods of treating myasthenia gravis The present disclosure provides methods related to the use of zirconoplan compounds and compositions for the therapeutic treatment of generalized myasthenia gravis.

[0032] Generalized myasthenia gravis (gMG) is a rare complement-mediated autoimmune disease characterized by the production of autoantibodies that target proteins critical for normal transmission of chemical or neurotransmitter signals from nerves to muscles, such as the acetylcholine receptor (AChR) protein. The presence of AChR autoantibodies in patient samples can be used as an indicator of the disease. Approximately 15% of patients have symptoms limited to the ocular muscles, while the majority of patients experience generalized myasthenia gravis.

[0033] In some embodiments, the patients treated according to the methods of this disclosure are adult patients who are anti-acetylcholine receptor (AchR) antibody positive.

[0034] Generalized myasthenia gravis (gMG) refers to MG that affects multiple muscle groups throughout the body. The prognosis of gMG is generally benign, but 10% to 15% of patients have refractory gMG. The clinical classification from the Myasthenia Gravis Foundation of America (MGFA) for the purpose of stratifying patients according to their disease severity is as follows: Class I: Any ocular muscle weakness; may have weakness on closing eyes. All other muscle strength is normal. Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity. IIa. Primarily affects limbs, axial muscles, or both. May have minimal involvement of the pharyngeal muscles. IIb. Primarily affects the pharynx, respiratory muscles, or both. May have minimal or equal involvement of the limbs, axial muscles, or both. Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity. IIIa. Primarily affects limbs, axial muscles, or both. May have minimal involvement of the pharyngeal muscles. IIIb. Primarily affects the pharynx, respiratory muscles, or both. May have minimal or equal involvement of the limbs, axial muscles, or both. Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity. IVa. Affects mainly the limbs, the body axis, or both. There may be minimal involvement of the pharyngeal muscles. IVb. Affects mainly the pharynx, the respiratory muscles, or both. There may be minimal or equal involvement of the limbs, the axial muscles, or both. Class V: Defined as intubation in the presence or absence of mechanical ventilation, except when used during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

[0035] Refractory gMG refers to gMG in which disease control cannot be achieved with conventional therapies and / or which results in severe side effects of immunosuppressive therapy. This severe form of gMG affects approximately 9,000 individuals in the United States. Various criteria are used to characterize treatment-refractory gMG disease (see, e.g., Mantegazza and Antozzi, "When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies," Ther. Adv. Neurol. Disord. January 18, 2018, 1-11, DOI: 10.1177 / 1756285617749134).

[0036] According to the inclusion criteria for the eculizumab Phase 3 study (REGAIN study), the treatment-refractory gMG status of patients treated according to the methods of this disclosure can be defined as follows: a) Failure of treatment for over 1 year using two (2) or more immunosuppressive therapies (ISTs), either in combination or as monotherapy (i.e., continued functional impairment in activities of daily living [persistent weakness, experiencing crises, or inability to tolerate IST], despite IST); and / or b) Failure of at least one IST and the need for long-term plasmapheresis, plasma exchange (PLEX), or IVIg to control symptoms (i.e., study participants who required PLEX and / or IVIg regularly for the management of muscle strength decline at least every 3 months over the previous 12 months).

[0037] In some embodiments of the method, the patient is refractory to treatment with immunosuppressive drug therapy (IST) for more than one year and requires long-term plasma exchange or long-term IVIG to maintain clinical stability.

[0038] Non-refractory gMG refers to gMG in which disease control can be achieved with conventional therapies, i.e., the patient does not meet either of the above inclusion criteria a) or b). In some embodiments, a patient with non-refractory gMG is a patient who has received standard of care (SOC) gMG therapy (e.g., immunosuppressive therapy) for less than one year. In some embodiments, the patient responds to SOC gMG therapy. SOC gMG therapy may be immunosuppressive drug therapy (e.g., steroids and / or non-steroids) that provides maintenance, control, and / or reduction of symptoms to the patient.

[0039] Patients with gMG characteristically exhibit muscle weakness that worsens with repeated use and recovers with rest. Muscle weakness can be localized to specific muscles, such as those involved in eye movement, but often progresses to more generalized muscle weakness. gMG can even become life-threatening when muscle weakness involves the diaphragm and other chest wall muscles involved in breathing. This is the most feared complication known as myasthenic crisis or MG crisis, which requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG experience myasthenic crisis within two years of diagnosis.

[0040] The most common target of autoantibodies in gMG is the acetylcholine receptor or AChR, which is located at the neuromuscular junction, the point where motor neurons signal skeletal muscle fibers. Current therapies for gMG focus on either increasing AChR signaling or nonspecifically suppressing the autoimmune response. First-line therapy for symptomatic gMG is treatment with an acetylcholinesterase inhibitor such as pyridostigmine. Although sometimes appropriate for controlling mild ocular symptoms, pyridostigmine monotherapy is usually insufficient for treating generalized weakness, and the dosing of this therapy can be limited by cholinergic side effects. Therefore, corticosteroids have been shown to be beneficial in patients who remain symptomatic despite pyridostigmine therapy, regardless of the use of systemic immunosuppressants (Sanders DB et al., 2016. Neurology. 87(4):419-25). Immunosuppressive drugs used in gMG include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab. These drugs are associated with well-documented long-term toxicities. In an effort to reduce the production of AChR autoantibodies, surgical thymectomy may be recommended in patients with non-thymomatous gMG and moderate to severe symptoms. Intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) are usually restricted to short-term use in patients with myasthenic crises or life-threatening signs, such as respiratory failure or dysphagia.

[0041] In a phase 2 randomized double-blind placebo-controlled trial, eculizumab was tested in 14 AChR autoantibody-positive patients with refractory gMG who had a quantitative myasthenia gravis (QMG) score ≥12 and had previously failed treatment with at least two immunosuppressive therapies (IST) (Howard, JF. 2013. Myasthenia Gravis Foundation of America. Clinical Overview of MG, which is hereby incorporated by reference in its entirety). Patients were randomized in a 1:1 ratio to receive either eculizumab or placebo. Patients on eculizumab received 600 mg per week for 4 weeks, followed by 900 mg by intravenous infusion every other week for a total of 16 weeks of treatment. After a 5-week drug holiday, patients were crossovered to the opposite arm of the study. Patients who received placebo during the first 16 weeks of the study were treated with eculizumab and vice versa. The primary endpoint was safety and efficacy as measured by the percentage of patients who achieved a ≥3-point reduction in the QMG score. The effect of C5 inhibition by eculizumab on the QMG score occurred rapidly (within 1 week of treatment initiation) and worked to the advantage of eculizumab compared to placebo across all study visits (p = 0.0144). Following the initial 16-week treatment period, 6 out of 7 patients on eculizumab achieved a ≥3-point improvement in the QMG score compared to 4 out of 7 patients in the placebo arm. 4 out of the patients who responded to eculizumab achieved an 8-point reduction in the QMG score compared to only 1 in the placebo arm.

[0042] QMG is a standardized and validated quantitative strength scoring system developed for gMG and is used in clinical trials as an endpoint of interest. The scoring system assesses 13 items related to eye, bulbar, and limb function (Barnet, C. et al., 2015. J Neuromuscul. Dis. 2:301-11). Each item is scored from 0 to 3. The maximum total score is 39. Higher scores represent more severe dysfunction. Recent data suggest that improvements in QMG scores of 2 to 3 points may be clinically meaningful depending on disease severity [Barohn RJ et al., 1998. Ann NY Acad Sci. 841:769-772; Katzberg HD et al., 2014. Muscle Nerve. 49(5):661-665].

[0043] A Phase 3 trial (NCT01997229) that enrolled 125 AChR autoantibody-positive patients with myasthenia gravis - Activities of Daily Living (MG-ADL) score ≥6 who had previously failed two types of IST or failed one type of IST and required long-term plasma exchange or IV immunoglobulin therapy was also completed. MG-ADL is a simple 8-item survey designed to assess the severity of gMG symptoms. Each item is scored from 0 to 3. The maximum total score is 24. Higher scores are associated with more severe symptoms of gMG. MG-ADL has been shown to correlate with other validated gMG prognostic measures (e.g., MG-QOL15r), and a 2-point improvement in the MG-ADL score is considered clinically meaningful [Wolfe GI et al., 1999. (Neurology). 52(7):1487-9; Muppidi S et al., 2011. Muscle Nerve. 44(5):727-31]. MG-QOL15r is a 15-item survey designed to determine the quality of life in patients with gMG based on patient reports. Each item is scored from 0 to 2. The maximum total score is 30. Higher scores indicate a more severe impact of the disease on the patient's lifestyle [Burns, TM et al., 2010. Muscle Nerve. 41(2):219-26; Burns TM et al., 2016. Muscle Nerve. 54(6):1015-22].

[0044] Patients were randomized 1:1 to receive either placebo or eculizumab during a 26-week treatment period, followed by an extension study. Patients receiving eculizumab were treated at 900 mg per week for 4 weeks, followed by 1200 mg by IV infusion every other week. Eculizumab treatment was not associated with a statistically significant benefit relative to placebo at the primary endpoint of change from baseline in MG-ADL in this study (p = 0.0698). However, statistically significant results were observed in 18 of 22 pre-specified analyses, including the secondary endpoint of change from baseline in the QMG score (p = 0.0129).

[0045] The present disclosure provides methods of treating gMG by inhibiting C5 activity in a subject. "C5-dependent complement activity" or "C5 activity" refers to the activation of the complement cascade through cleavage of C5, the set of downstream cleavage products of C5, or any other process or event associated with or resulting from the cleavage of C5. In some cases, the percentage of C5 activity inhibited in a subject can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[0046] The C5 inhibitor zilucoplan can be used to treat gMG, where there are few or no adverse effects resulting from the treatment. In some cases, non-adverse cardiovascular, respiratory, and / or central nervous system (CNS) effects occur. In some cases, there are no changes in heart rate and / or arterial blood pressure. In some cases, there are no changes in respiratory rate, tidal volume, and / or minute ventilation.

[0047] The treatment or prophylactic effect is often evident by a significant improvement, often a statistically significant improvement, in one or more parameters of the disease state or by not worsening or developing symptoms that would otherwise be predicted. By way of example, a suitable change of at least 10%, and at least 20%, 30%, 40%, 50% or more in a measurable parameter of the disease can indicate an effective treatment. The efficacy of a given compound or composition can also be determined using an experimental animal model for a given disease, as is known in the art. When using an experimental animal model, the efficacy of the treatment is demonstrated when a statistically significant modulation in a marker or symptom is observed.

[0048] In some embodiments, the present disclosure provides a method of inhibiting C5 activity in a tissue by contacting the tissue with a tissue-permeable C5 inhibitor, such as zilucoplan. The term "tissue-permeable" refers to a property characterized by tissue permeability. An agent having enhanced tissue penetration may demonstrate better distribution in a tissue when compared to an agent having little or no tissue penetration. Tissue penetration can be determined by the ability to cross the basement membrane. The term "basement membrane" refers to an extracellular matrix (ECM) protein layer that separates endothelial cells from underlying tissue. Tissue penetration determination can be performed in vivo or in vitro and can include the use of a basement membrane model. Such models can include measuring the diffusion of a compound across an artificial basement membrane. Such models can include the use of upper and lower reservoirs separated by an artificial basement membrane. The artificial basement membrane can include any of the ECM gel membranes described in Arends, F. et al. 2016. IntechOpen, DOI:10.5772 / 62519, the contents of which are hereby incorporated by reference in their entirety. The ECM gel membrane can be prepared to include matrix components that mimic those found in the basal lamina of the neuromuscular junction. In some models, the compound being tested is introduced into the upper reservoir and compound diffusion is detected in the lower reservoir.

[0049] Tissue penetration determination can include, for example, visual determination via the use of a fluorescent label to visualize the movement of an analyte across a basement membrane. Some determinations can include biochemical analysis of a sample obtained from the penetration side of the basement membrane.

[0050] In some embodiments, compound permeability can be determined using quantitative whole body autoradiography (QWBA). QWBA is a form of analysis that uses autoradiography to determine the distribution of a radiolabeled analyte. In some embodiments, a radiolabeled compound is administered to a subject and the tissue distribution of the compound is analyzed over time.

[0051] Contacting a tissue with a tissue - penetrating C5 inhibitor can include administering zilucoplan to the tissue as part of a formulation. Such formulations can be administered by subcutaneous injection. The tissue - penetrating C5 inhibitor may be able to penetrate the basement membrane. The basement membrane permeability of a polypeptide tissue - penetrating C5 inhibitor can be greater than that of larger proteins such as antibodies. Such advantages can be due to the limitedly large size of proteins and antibodies. The zilucoplan basement membrane permeability can be about 3 - fold to about 5 - fold greater than that of eculizumab and provides advantages over eculizumab with respect to inhibiting C5 activity in tissues and treating related complement - related indications. In some embodiments, the zilucoplan permeability enhances the distribution in one or more of the lung, heart, muscle, small intestine, large intestine, spleen, liver, bone, stomach, lymph node, fat, brain, pancreas, testis, and thymus in comparison to eculizumab.

[0052] Polypeptide - based C5 inhibitors (e.g., zilucoplan) can be used to treat complement - related indications (e.g., myasthenia gravis) that benefit from rapid and / or enhanced inhibitor tissue distribution. The tissue can include muscle and / or the neuromuscular junction (NMJ). Polypeptide inhibitors (e.g., zilucoplan) can provide superior penetration into muscle and / or the NMJ compared to antibodies based on their smaller size and / or favorable charge profile. Such penetration can lead to faster release from overactive complement. Further, polypeptide inhibitor (e.g., zilucoplan) penetration can stabilize and / or improve the NMJ membrane potential by preventing MAC pore formation. Thus, the safety factor at the NMJ can be improved. The term "safety factor" refers to the excess neurotransmitter level released after a nerve impulse that ensures neuromuscular transmission effectiveness under physiological stress. Excess means an amount that exceeds the amount required to trigger a muscle fiber action potential and contributes to membrane potential recovery.

[0053] Combination therapy Zilcoplan, along with additional therapeutic agent(s) and / or therapy(ies), can be administered in combination. Such combinations can be in the same composition, or the additional therapeutic agent or therapy can be administered as part of separate compositions or by another method described herein.

[0054] During administration of zilcoplan according to the methods of this disclosure, a subject can receive standard of care (SOC) therapy for gMG. Standard of care therapy for gMG can include, but is not limited to, plasma exchange (PLEX), intravenous immunoglobulin (IVIg) treatment, biologic agents (e.g., rituximab or eculizumab or ravulizumab), pyridostigmine treatment, corticosteroid treatment, and / or immunosuppressive (e.g., non-steroidal immunosuppressive) drug treatment.

[0055] In some embodiments of the methods of this disclosure, a subject is co-administered zilcoplan and one or more steroids and / or non-steroidal immunosuppressive agents (e.g., as described herein). In some embodiments, zilcoplan is co-administered to a subject identified as having side effects and / or at risk of adverse events caused by immunosuppressive therapy. In some embodiments, zilcoplan is co-administered with a reduced dosage of steroid and / or non-steroidal immunosuppressive therapy to treat gMG with acceptable side effects and adverse events. Reduced dosage means a reduction in dosage as compared to the conventional dosage under standard of care (SOC) immunosuppressive therapy for gMG. In some embodiments, the steroid is a corticosteroid. In some embodiments, the immunosuppressive agent is selected from azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab.

[0056] In some embodiments, a subject receives cholinesterase inhibitor treatment over the course of zilcoplan treatment.

[0057] Cyclosporin A is a known immunosuppressive agent that is an inhibitor of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is a potential concomitant drug therapy in PNH and other complement-related indications. In some embodiments, Cyclosporin A and Zilucoplan can be administered in combination to a subject having myasthenia gravis. Cyclosporin A and Zilucoplan can be administered in overlapping dosing regimens. Other immunosuppressive agents that can be administered in combination with Zilucoplan or in overlapping dosing regimens can include, but are not limited to, azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab.

[0058] In some embodiments, the present disclosure provides a method of treating gMG in a subject by administering Zilucoplan in combination with neonatal Fc receptor (FcRN) inhibitor treatment. FcRN inhibitor treatment can be used to treat autoimmune diseases including autoantibody-mediated tissue destruction. FcRN inhibitor treatment can include intravenous immunoglobulin (IVIG) treatment that reduces the half-life of IgG antibodies by overwhelming the Fc recycling mechanism with high doses of immunoglobulin. Some FcRN inhibitor treatments can include administration of DX-2504 or a functionally equivalent variant thereof, such as DX-2507, which includes modifications to reduce aggregation and improve manufacturability (described in Nixon, A.E. et al., 2015. Front Immunol. 6:176). DX-2504 is an inhibitor of FcRN recycling. By inhibiting FcRN, DX-2504 inhibits Fc-mediated recycling, thereby reducing the half-life of IgG antibodies. Administration of DX-2504 can also be used in models of IVIG treatment. In some embodiments, Zilucoplan can be administered to treat complement-related indications (such as myasthenia gravis) in an overlapping dosing regimen with FcRN inhibitor treatment. FcRN inhibitor treatment can include DX-2504 (or DX-2507) administration and / or IVIG treatment.

[0059] Screening and Diagnosis Patients to be treated with zilcoplan according to the methods of this disclosure can be screened prior to zilcoplan administration. The terms "patient," "subject," and "individual" are used interchangeably herein. The term "screening" refers to an examination or evaluation conducted for purposes of selection or filtration. A patient can be screened to select individuals in need of treatment. In some embodiments, a subject is screened to select the individuals most likely to respond favorably to treatment.

[0060] Screening can include selecting subjects previously diagnosed with gMG. The gMG diagnosis can be made according to the Myasthenia Gravis Foundation of America (MGFA) criteria; Class II-Iva (see Howard, J.F., 2009. Myasthenia Gravis A Manual for the Health Care Provider, Myasthenia Gravis Foundation of America, Inc.).

[0061] In some embodiments of the methods of this disclosure, screening includes determining whether a human patient is positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors.

[0062] In some embodiments of the methods of this disclosure, screening includes determining whether a human patient has refractory gMG.

[0063] In some embodiments of the methods of this disclosure, screening includes determining whether a human patient has non-refractory gMG.

[0064] In some embodiments, screening can be performed to identify subjects having a stage of gMG that occurs before reaching a critical or crisis stage. Such screening can be performed to identify subjects before the onset of gMG or early in a disease process that may benefit from active or preventive treatment.

[0065] In some embodiments, screening is performed to exclude individuals with a greater risk associated with treatment.

[0066] In some embodiments, a patient is identified as having refractory gMG.

[0067] Screening can include determination of one or more quantitative scoring systems for disease severity for gMG. Subjects receiving conventional or SOC gMG therapy before or during screening may be maintained on such therapy during the screening process or may be required to withhold one or more treatments before or during the screening process. In some embodiments, a period of time between previous gMG therapy and screening determination is required. That period may be required to obtain reliable results from a particular screening determination.

[0068] Screening can include selecting subjects based on age. In some embodiments, screening can be performed to select subjects between the ages of 18 and 85. In some embodiments, screening can be performed to select subjects between the ages of 18 and 74.

[0069] Screening can include determination of biomarker levels. In some embodiments, the biomarker includes acetylcholine receptor (AChR) autoantibody levels. AChR autoantibodies can lead to disease by binding to AChR and stimulating complement activation. Thus, AChR autoantibody levels can be a good indicator of complement-mediated disease. In some embodiments, the biomarker includes autoantibodies against muscle-specific tyrosine kinase (MuSK). Subjects with anti-MuSK antibodies are part of a distinct subset of MG associated with a less predictable treatment prognosis (Lavrnic, D. et al., 2005. J Neurol Neurosurg Psychiatry. 76:1099-102). Screening can include excluding subjects with anti-MuSK antibodies from treatment and / or evaluation.

[0070] Screening can include a review of the subject's previous and current treatments. In some embodiments, the subject is screened based on recent changes in treatment. In some embodiments, the subject is screened to confirm no change in corticosteroid dose or immunosuppressive therapy prior to screening. Screening can exclude the subject from treatment if the subject's corticosteroid treatment dose or immunosuppressive therapy regimen has changed within 30 days prior to screening.

[0071] The subject can be screened for pregnancy status. In some embodiments, pregnant subjects can be excluded from treatment. Pregnancy status screening can be performed by a serum pregnancy test. In some embodiments, pregnancy screening can include a urine pregnancy test.

[0072] Zilucoplan treatment Zilucoplan inhibits C5a formation in a dose-dependent manner with activation of the classical pathway and inhibits C5b formation with activation of the classical and alternative complement pathways (as measured by deposition of C5b-9 or MAC on the complement activation surface).

[0073] The methods of the present disclosure include methods of treating gMG by administering zilcoplan to a subject. The zilcoplan administration is subcutaneous (SC) administration. Zilcoplan can be administered at a dose of from about 0.01 mg / kg (mg of zilcoplan per kg of subject body weight) to about 1.0 mg / kg, from about 0.02 mg / kg to about 2.0 mg / kg, or from about 0.05 mg / kg to about 3.0 mg / kg.

[0074] The methods of the present disclosure can include the step of administering zilcoplan at a daily dose of from about 0.1 mg / kg to about 0.3 mg / kg. In some embodiments, zilcoplan is administered at a daily dose of 0.3 mg / kg.

[0075] Zilcoplan administration can be by self-administration. Zilcoplan administration can include the use of a pre-filled syringe. Self-administration can include the use of a self-administration device. The self-administration device can include or be incorporated with a pre-filled syringe.

[0076] Zilcoplan can be provided in solution. Examples of zilcoplan solutions can include aqueous solutions. The zilcoplan solution can include phosphate buffered saline (PBS). The zilcoplan solution can be preservative-free. Zilcoplan can be present in solution at a concentration of from about 1 mg / mL to about 400 mg / mL, for example, from about 4 mg / ml to about 200 mg / ml, from about 1 mg / mL to about 5 mg / mL, from about 2 mg / mL to about 10 mg / mL, or from about 10 mg / mL to about 50 mg / mL. In some embodiments, the solution includes about 40 mg / ml of zilcoplan.

[0077] In some embodiments, the self - administration device contains a zirconium coplan solution. In some embodiments, the self - administration device has a maximum fill volume of at least 1 ml. The self - administration device can contain a volume of zirconium coplan solution from about 0.010 ml to about 0.500 mL, from about 0.050 ml to about 0.600 mL, from about 0.100 ml to about 0.700 mL, from about 0.150 ml to about 0.810 mL, from about 0.200 ml to about 0.900 mL, or from about 0.250 ml to about 1.00 mL. In some embodiments, the self - administration device contains a zirconium coplan solution from about 0.15 ml to about 0.81 mL.

[0078] The zirconium coplan treatment can include the administration of one or more doses. In some embodiments, the treatment occurs at hourly, twice - daily, daily, every - other - day, weekly, every - other - week, monthly, or combinations thereof. The zirconium coplan treatment can include daily consecutive dosing. The subject's zirconium coplan plasma level can reach a maximum concentration (C max ) on the first day of treatment. Serum hemolysis can be inhibited by the zirconium coplan treatment. In some embodiments, at least 90% hemolysis inhibition is achieved in the subject's serum using the zirconium coplan treatment.

[0079] The zirconium coplan treatment for gMG can be performed in various subjects from different demographic backgrounds and disease stages. Refractory subjects can include those who were resistant or non - responsive to previous therapies using eculizumab.

[0080] In some embodiments, subjects having a stage of gMG that occurs before reaching a critical or crisis stage are treated with zirconium coplan. Such treatments can be performed to treat the subject before the onset of gMG or early in the disease process in order to provide the benefits of an active or preventive treatment.

[0081] In some embodiments, the present invention provides zilcoplan for use in a method of treating gMG comprising administering 0.1 mg / kg to 0.3 mg / kg of zilcoplan subcutaneously or intravenously to a subject. In some embodiments, the present invention provides zilcoplan for use in a method of treating gMG comprising administering 0.1 mg / kg or 0.3 mg / kg of zilcoplan subcutaneously or intravenously to a subject. In some embodiments, the present invention provides zilcoplan for use in a method of treating refractory gMG comprising administering 0.3 mg / kg of zilcoplan subcutaneously to a subject.

[0082] Evaluation Subjects receiving zilcoplan treatment for gMG can be evaluated for efficacy during or after treatment. The term "subject being treated" refers to an individual who has received at least one treatment. Zilcoplan treatment subject evaluation can include evaluation of one or more measures of efficacy. In some embodiments, the evaluation may require that the subject treatment be withheld for a period of time prior to evaluation. Some evaluations may require that the subject maintain consistent treatment before, during, and / or after the evaluation. The treatment that is withheld or maintained can be zilcoplan treatment. In some embodiments, the treatment that is withheld or maintained includes other treatments for gMG or for a non-MG state.

[0083] The evaluation can be performed to determine a primary efficacy endpoint. The term "primary endpoint" refers to the result that answers the most important question addressed by a particular study. The term "secondary endpoint" refers to the result that answers other related questions that are subordinate to the main question. The primary efficacy endpoint is the result that addresses whether the treatment is effective or not, while the secondary efficacy endpoint addresses one or more peripheral questions (e.g., impact on quality of life, severity of side effects, etc.).

[0084] The evaluation can be performed to determine the gMG characteristics of interest. The term "gMG characteristic" refers to a physical or mental trait or set of traits related to the presence or severity of gMG in the subject. gMG characteristics can include scores obtained using different disease evaluation methods. gMG characteristics can include, but are not limited to, the quality of life measured by the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, the Myasthenia Gravis score (QMG), the Myasthenia Gravis Composite (MGC) score, or the Revised Myasthenia Gravis Quality of Life (MG-QOL-15r) score. In some embodiments, the subject can be monitored over time for gMG characteristics. Such monitoring can be performed over the course of the gMG disease. Monitoring can be performed over the course of disease treatment. In some embodiments, the subject evaluation or monitoring is performed to determine changes in gMG characteristics during or after treatment of the subject with zilcoplan. Such changes can be determined via comparison to a baseline characteristic or score determined prior to the start of treatment with zilcoplan (e.g., as described herein).

[0085] In some embodiments, subjects treated with zilcoplan are evaluated or monitored for MG-ADL scores. A change in the MG-ADL score from baseline can be a primary efficacy endpoint. MG-ADL is a simple 8-item survey designed to assess gMG symptom severity. Each item is scored from 0 to 3. The maximum total score is 24. Higher scores are associated with more severe symptoms of gMG. MG-ADL has been shown to correlate with other validated gMG prognostic measures (e.g., MG-QOL15r), and a 2-point improvement in the MG-ADL score is considered clinically meaningful [Wolfe GI et al., 1999. Neurology. 52(7):1487-9; Muppidi S et al., 2011. Muscle Nerve. 44(5):727-31, the contents of which are incorporated herein by reference in their entirety].

[0086] In some embodiments, the subject of the zilcoplan treatment is evaluated or monitored for the QMG score. QMG is a standardized and validated quantitative intensity scoring system specifically developed for gMG and has been previously used in clinical trials. The scoring system determines 13 items related to the functions of the eyes, medulla oblongata, and limbs (Barnet, C. et al., 2015. J Neuromuscul.Dis. 2:301-11). Each item is scored from 0 to 3. The maximum total score is 39. A higher score represents more severe dysfunction. Recent data suggest that an improvement in the QMG score of 2 to 3 points may be considered clinically significant depending on the disease severity [Barohn RJ et al., 1998. Ann NY Acad Sci. 841:769-772; Katzberg HD et al., 2014. Muscle Nerve. 49(5):661-665, the entire content of which is incorporated herein by reference]. The subject being determined for the QMG score may be withdrawn from gMG therapy for at least 10 hours prior to the QMG score determination. The gMG therapy can include acetylcholinesterase inhibitor therapy (e.g., pyridostigmine treatment) for at least 10 hours prior to the QMG score determination.

[0087] The change in the QMG score from baseline can be a primary or secondary efficacy endpoint. The subject QMG score can be reduced. The QMG score can be reduced by at least 3 points. The QMG score can be reduced after completion of 12 weeks of zilcoplan treatment. The QMG score can be reduced during or before 12 weeks of zilcoplan treatment. The subject QMG score can be monitored over the course of zilcoplan treatment.

[0088] In some embodiments, the evaluation of the treatment target of zilcoplan can include testing and / or monitoring one or more of the MG-ADL score, QMG score, MG-QOL15r score, and MG composite score. Such scores can be evaluated as primary or secondary efficacy endpoints. MG-QOL15r is a 15-item survey designed to determine the quality of life in patients with gMG based on patient reports. Each item is scored from 0 to 2. The maximum total score is 30. A higher score indicates a more severe impact of the disease on the patient's lifestyle [Burns, TM et al., 2010. Muscle Nerve. 41(2):219-26; Burns TM et al., 2016. Muscle Nerve. 54(6):1015-22, the contents of which are incorporated herein by reference in their entirety]. The MG composite is a 10-item scale that has been used to measure the clinical status of patients with gMG in both practice settings and clinical trials to evaluate treatment response (Burns, T.M. et al., 2008. Muscle Nerve. 38:1553-62). Ten items related to the function of the eyes, medulla, respiratory system, neck, and limbs are judged. The items are weighted and the scores range from 0 to 9. The maximum total score is 50. A higher score in the MG composite indicates more severe dysfunction due to the disease. A 3-point change in this instrument is considered clinically significant [Burns, T.M. et al., 2010. Neurology. 74(18):1434-40; Sadjadi, DB et al., 2012. Neurology. 2016;87(4):419-425, the contents of which are incorporated herein by reference in their entirety].

[0089] Tests or monitoring for MG-ADL, QMG, MG-QOL15r, and / or MG composite scores can be used to identify changes from baseline scores. The term "baseline score" refers to the score obtained prior to initial treatment. The baseline score may be the score obtained during a switch from one treatment to another. The switch can be from a placebo to an active pharmaceutical compound. In some embodiments, the zilcoplan treatment can be evaluated for a reduction in the MG-ADL score of at least 2 points. The reduction can occur at or before 12 weeks of zilcoplan treatment. In some embodiments, the zilcoplan treatment can be evaluated for a reduction in the MG composite score of at least 3 points. The reduction can occur at or before 12 weeks of zilcoplan treatment.

[0090] In some embodiments, the zilcoplan treatment results in a reduction in the target symptom manifestation. The reduction in the target symptom manifestation can exceed the reduction in the target symptom manifestation associated with eculizumab administration.

[0091] Evaluation Method In some embodiments, the present disclosure provides a method for evaluating a treatment for gMG. Such methods can include screening evaluation candidates for at least one evaluation participation criterion. The term "evaluation candidate" refers to any individual being considered for participation in an evaluation (e.g., a clinical study). The "evaluation participation criterion" refers to a measurement criterion or factor used to select individuals for inclusion in the evaluation. Evaluation candidates selected for participation in the evaluation are referred to herein as "evaluation participants". In some embodiments, a method for evaluating a treatment for gMG can include screening evaluation candidates for at least one evaluation participation criterion; selecting evaluation participants; administering a treatment for gMG to the evaluation participants; and determining at least one efficacy endpoint.

[0092] In some embodiments, the evaluation participation criteria include a gMG diagnosis. The diagnosis of gMG can be performed according to the MGFA criteria. In some embodiments, the evaluation participation criteria include a QMG score. Evaluation participant selection may require an evaluation candidate QMG score of ≧12. Some evaluation candidates may have received at least one alternative gMG treatment (i.e., an alternative to the treatment for the gMG being tested, e.g., a standard care treatment) prior to screening. In some embodiments, such candidates can be determined for the QMG score at least 10 hours after the most recent alternative gMG treatment. Alternative gMG treatments can include standard care gMG treatments including, but not limited to, cholinesterase inhibitor treatment, acetylcholinesterase inhibitor treatment, pyridostigmine treatment, corticosteroid treatment, and immunosuppressive drug treatment. Evaluation participant selection may require a score of ≧2 for ≧4 QMG test items.

[0093] In some embodiments, the evaluation participation criteria include the evaluation candidate age. In some embodiments, the evaluation candidate must be between 18 and 85 years old. In some embodiments, the evaluation candidate must be between 18 and 74 years old.

[0094] The evaluation participation criteria can include candidate biomarker levels. In some embodiments, the biomarker includes the acetylcholine receptor (AChR) autoantibody level. AChR autoantibodies can lead to disease by binding to AChR and by stimulating complement activation. Thus, the AChR autoantibody level can be a good indicator of susceptibility to complement-mediated disease.

[0095] The evaluation participation criteria can include the previous and current alternative gMG treatment status of the candidate. In some embodiments, the evaluation participants are selected based on the consistency of the current or previous alternative gMG treatment. In some embodiments, candidates without recent changes in corticosteroid dosage or immunosuppressive therapy are selected. Candidates with changes in corticosteroid treatment dosage or immunosuppressive therapy regimen within the past 30 days may be excluded from evaluation participation.

[0096] The evaluation participation criteria can include pregnancy status. In some embodiments, subjects who are pregnant may be excluded from evaluation participation. Pregnancy status screening can be performed by a serum pregnancy test. In some embodiments, pregnancy screening can include a urine pregnancy test.

[0097] A method for evaluating a treatment for gMG can include administering a treatment for gMG to an evaluation participant over an evaluation period. As used herein, the term "evaluation period" refers to the time frame during which a particular study is conducted. The treatment can be administered over an evaluation period of from about 1 day to about 24 weeks. Some evaluation periods are 12 weeks or more. The evaluation participant may continue to receive standard care gMG therapy over the evaluation period. Such therapies can include, but are not limited to, cholinesterase inhibitor treatment, acetylcholinesterase inhibitor treatment, pyridostigmine treatment, corticosteroid treatment, and / or immunosuppressive drug treatment.

[0098] The efficacy endpoint can include certain scores or changes in scores related to the determination for individuals with gMG. Such determinations can include, but are not limited to, the QMG score, the MG-ADL score, the MG-QOL15r score, and the MG composite score. In some embodiments, the efficacy endpoint includes a reduction in the QMG score. The efficacy endpoint can include at least a 3-point reduction in the QMG score. For evaluation participants who receive an alternative gMG treatment (e.g., acetylcholinesterase inhibitor treatment) during the evaluation period, one or more of those treatments may be withheld for at least 10 hours prior to the QMG score determination. In some embodiments, the efficacy endpoint includes a reduction in one or more of the MG-ADL score, the MG-QOL15r score, and the MG composite score with respect to the baseline score. The efficacy endpoint can include a 2-point reduction in the MG-ADL score relative to the baseline score. The reduction in the MG-ADL score can occur at or before 12 weeks of treatment for gMG.

[0099] In some embodiments, determining the efficacy endpoint includes a series of determinations. The series of determinations can be performed in a particular order. In some embodiments, the series of determinations are performed in the following order: (1) determining the evaluation participant's MG-QOL15r score; (2) determining the evaluation participant's MG-ADL score; (3) determining the evaluation participant's QMG score; and (4) determining the evaluation participant's MG composite score.

[0100] The determination for the efficacy endpoint can be performed in one or more instances after administering the treatment for gMG. Such determinations can be performed at specific times and / or days, or can be performed repeatedly (e.g., hourly, daily, weekly, monthly, or combinations thereof). In some embodiments, the determination is performed 1 week, 2 weeks, 4 weeks, 8 weeks, and / or 12 weeks after starting the administration of the treatment for gMG.

[0101] In some embodiments of the methods of this disclosure, a patient is identified as having refractory gMG and experiences a clinically significant improvement (reduction) in quality of life as measured by the Quantitative Myasthenia Gravis (QMG) score, the Myasthenia Gravis Composite (MGC) score, or the Revised Myasthenia Gravis Quality of Life (MG-QOL-15r) score 12 weeks after treatment. In some embodiments, a clinically significant improvement is experienced at or before 12 weeks of zilucoplan treatment. In some embodiments, a clinically significant improvement is experienced at or before 8 weeks of zilucoplan treatment.

[0102] In some embodiments, a patient identified as having refractory gMG experiences a reduction of at least 3 points from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score 12 weeks after zilucoplan treatment (e.g., a reduction of at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline). In some embodiments, a reduction of at least 3 points from baseline in the MG-ADL score is achieved or experienced at or before 12 weeks of zilucoplan treatment. In some embodiments, a reduction of at least 3 points from baseline in the MG-ADL score is achieved or experienced 8 weeks after zilucoplan treatment.

[0103] In some embodiments, a patient identified as having refractory gMG experiences a reduction of at least 3 points from baseline in the QMG score 12 weeks after zilucoplan treatment (e.g., a reduction of at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline). In some embodiments, a reduction of at least 3 points from baseline in the QMG score is achieved or experienced at or before 12 weeks of zilucoplan treatment. In some embodiments, a reduction of at least 3 points from baseline in the QMG score is achieved or experienced 8 weeks after zilucoplan treatment.

[0104] In some embodiments, patients identified as having refractory gMG experience a reduction of at least 3 points from baseline in the MGC score 12 weeks after the zilucoplan treatment (e.g., a reduction of at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline). In some embodiments, a reduction of at least 3 points from baseline in the MGC score is achieved or experienced at 12 weeks of the zilucoplan treatment or before.

[0105] In some embodiments, patients identified as having refractory gMG experience a reduction of at least 2 points from baseline in the MG-QOL-15r score 12 weeks after the zilucoplan treatment (e.g., a reduction of at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline). In some embodiments, a reduction of at least 2 points from baseline in the MG-QOL-15r score is achieved or experienced at 12 weeks of the zilucoplan treatment or before.

[0106] Pharmaceutical composition In some embodiments, the C5 inhibitor zilucoplan composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises at least one of a salt and a buffer. The salt may be sodium chloride. The buffer may be sodium phosphate. Sodium chloride is present at a concentration of about 0.1 mM to about 1000 mM. In some cases, sodium chloride is present at a concentration of about 25 mM to about 100 mM. Sodium phosphate is present at a concentration of about 0.1 mM to about 1000 mM. In some cases, sodium phosphate is present at a concentration of about 10 mM to about 100 mM.

[0107] In some embodiments, the zirconium plan composition comprises a solution containing zirconium plan at a concentration of from about 0.01 mg / mL to about 4000 mg / mL. In some cases, zirconium plan is present at a concentration of from about 1 mg / mL to about 400 mg / mL, such as from about 4 mg / ml to about 200 mg / mL. In some embodiments, the zirconium plan composition comprises a solution of zirconium plan at about 40 mg / mL.

[0108] The compositions of the present disclosure can contain zirconium plan at a concentration of approximately, about, or precisely any of the following values: 0.001 mg / mL, 0.2 mg / mL, 0.01 mg / mL, 2 mg / mL, 0.1 mg / mL, 10 mg / mL, 0.5 mg / mL, 5 mg / mL, 1 mg / mL, 20 mg / mL, 15 mg / mL, 40 mg / mL, 25 mg / mL, 75 mg / mL, 50 mg / mL, 200 mg / mL, 100 mg / mL, or 400 mg / mL. In some cases, the composition contains zirconium plan at a concentration of at least 40 mg / mL.

[0109] In some embodiments, the compounds or compositions of the present disclosure, such as pharmaceutical compositions, are formulated in an aqueous solution. In some cases, the aqueous solution further contains one or more salts and / or one or more buffers. Examples of salts that can be included at a concentration of from about 0.05 mM to about 50 mM, from about 1 mM to about 100 mM, from about 20 mM to about 200 mM, or from about 50 mM to about 500 mM include sodium chloride. Further solutions can contain at least 500 mM of sodium chloride. In some cases, the aqueous solution contains sodium phosphate. Sodium phosphate can be included in the aqueous solution at a concentration of from about 0.005 mM to about 5 mM, from about 0.01 mM to about 10 mM, from about 0.1 mM to about 50 mM, from about 1 mM to about 100 mM, from about 5 mM to about 150 mM, or from about 10 mM to about 250 mM. In some cases, a sodium phosphate concentration of at least 250 mM is used.

[0110] The aqueous zilcoplan formulation can have a pH level of from about 2.0 to about 3.0, from about 2.5 to about 3.5, from about 3.0 to about 4.0, from about 3.5 to about 4.5, from about 4.0 to about 5.0, from about 4.5 to about 5.5, from about 5.0 to about 6.0, from about 5.5 to about 6.5, from about 6.0 to about 7.0, from about 6.5 to about 7.5, from about 7.0 to about 8.0, from about 7.5 to about 8.5, from about 8.0 to about 9.0, from about 8.5 to about 9.5, or from about 9.0 to about 10.0.

[0111] Dosage and Administration For the treatment of human subjects, it can be formulated as a C5 inhibitor (e.g., zilcoplan) pharmaceutical composition. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prophylaxis, prevention, or therapy), the C5 inhibitor (e.g., zilcoplan) can be formulated in a manner consistent with these parameters. A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0112] The C5 inhibitor (e.g., zilcoplan) can be provided in a therapeutically effective amount. In some cases, the therapeutically effective amount of the C5 inhibitor (e.g., zilcoplan) can be achieved by administration of a dosage of from about 0.1 mg to about 1 mg, from about 0.5 mg to about 5 mg, from about 1 mg to about 20 mg, from about 5 mg to about 50 mg, from about 10 mg to about 100 mg, from about 20 mg to about 200 mg, or at least 200 mg of one or more C5 inhibitors (e.g., zilcoplan).

[0113] In some embodiments, a subject can be administered a therapeutic amount of a C5 inhibitor (e.g., zilucoplan) based on the weight of such subject. In some cases, zilucoplan is administered at a dose of from about 0.1 mg / kg to about 3 mg / kg. Such ranges can include ranges suitable for administration to human subjects. The dosage levels can be highly dependent on the nature of the condition; the efficacy of the drug; the condition of the patient; the judgment of the practitioner; and the frequency and mode of administration.

[0114] In some cases, a C5 inhibitor (e.g., zilucoplan) is provided at a concentration adjusted to achieve a desired level of the C5 inhibitor in a sample, biological system, or subject (e.g., plasma levels in a subject). In other embodiments, the C5 inhibitor is administered at a dose sufficient to achieve a maximum serum concentration (C max ) of at least 0.1 μg / mL, at least 0.5 μg / mL, at least 1 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 50 μg / mL, at least 100 μg / mL, or at least 1000 μg / mL.

[0115] In some embodiments, a C5 inhibitor (e.g., zilucoplan and / or its active metabolite or variant) is administered daily at a dose sufficient to deliver from about 0.1 mg / day to about 60 mg / day per kg of the subject's body weight. In some cases, the C max achieved at each dose is from about 0.1 μg / mL to about 1000 μg / mL. In such cases, the area under the curve (AUC) between doses can be from about 200 μg * hr / mL to about 10,000 μg * hr / mL.

[0116] According to some methods of the present disclosure, zilucoplan is provided at a concentration required to achieve the desired effect. In some cases, the compounds and compositions of the present disclosure are provided in an amount necessary to reduce a given reaction or process by half. The concentration required to achieve such reduction is herein referred to as the half-maximal inhibitory concentration or "IC 50is referred to as. Alternatively, the compounds and compositions of the present disclosure can be provided in an amount that increases a given reaction, activity, or process by half. The concentration required for such an increase is herein referred to as the half-maximal effective concentration or "EC 50 " is referred to as.

[0117] The C5 inhibitor (e.g., zilucoplan) can be present in an amount that totals from 0.1% to 95% by weight of the total weight of the composition. In some cases, the C5 inhibitor is provided by intravenous (IV) administration. In some cases, the C5 inhibitor is provided by subcutaneous (SC) administration.

[0118] SC administration of a C5 inhibitor (e.g., zilucoplan) can, in some cases, provide advantages over IV administration. SC administration can include self-administration by use of an administration device such as a self-administration device. As used herein, the term "self-administration" refers to any form of therapeutic delivery that is performed, in whole or in part, by the recipient of the therapeutic treatment. The self-administration device can include a self-injection device. The self-administration procedure can be advantageous in that the patient can provide treatment to themselves in their own home and avoid the need to travel to a provider or medical facility. Further, the SC procedure can enable the patient to avoid the long-term complications associated with IV administration, such as infections, loss of venous access, local thrombosis, and hematomas. In some embodiments, self-administration using a self-injection device can increase patient compliance, patient satisfaction, quality of life, reduce treatment costs, and / or increase drug requirements.

[0119] In some cases, daily SC administration provides a steady-state C5 inhibitor concentration that is achieved within 1 to 3 doses, 2 to 3 doses, 3 to 5 doses, or 5 to 10 doses. In some cases, an SC daily dose of from about 0.1 mg / kg to about 0.3 mg / kg can achieve a sustained C5 inhibitor level of 2.5 μg / mL or greater and / or inhibition of complement activity of greater than 90%.

[0120] C5 inhibitors (e.g., zirconium coplanar) exhibit slow absorption kinetics (time to maximum observed concentration exceeding 4 to 8 hours) and high bioavailability (from about 75% to about 100%) after SC administration.

[0121] In some embodiments, the dosage and / or administration is changed to modulate the half-life (t 1 / 2 ) of the C5 inhibitor (e.g., zirconium coplanar) in the subject or in the subject's fluid (e.g., plasma).

[0122] In some embodiments, the C5 inhibitor (e.g., zirconium coplanar) may exhibit a long terminal t 1 / 2 . The extended terminal t 1 / 2 may be due to extensive target binding and / or additional plasma protein binding. In some cases, the C5 inhibitor exhibits a t 1 / 2 value exceeding 24 hours in both plasma and whole blood. In some cases, the C5 inhibitor does not lose its functional activity after incubation for 16 hours at 37°C in human whole blood.

[0123] In some embodiments, the dosage and / or administration is changed to modulate the steady-state volume of distribution of the C5 inhibitor. In some cases, the dosage and / or administration of the C5 inhibitor is adjusted to ensure that the steady-state volume of distribution is equal to at least 50% of the total blood volume. In some embodiments, the C5 inhibitor distribution may be restricted to the plasma compartment.

[0124] The period (T max value) during which the maximum concentration of the C5 inhibitor in the subject (e.g., in the subject's serum) is maintained can be adjusted by changing the dosage and / or administration (e.g., subcutaneous administration).

[0125] In some embodiments, a C5 inhibitor (e.g., zilucoplan) can be administered without off-target effects. In some cases, the C5 inhibitor does not inhibit hERG (human ether-a-go-go related gene) even at concentrations of 300 μM or less. SC injection of a C5 inhibitor using a dose level of up to 10 mg / kg can exhibit good tolerance and may not result in any adverse effects on the cardiovascular system (e.g., increased risk of ventricular repolarization prolongation) and / or the respiratory system.

[0126] In some embodiments, the C5 inhibitors of the present disclosure enable rapid drug withdrawal periods in cases of infectious diseases where prolonged inhibition of the complement system has been found to be harmful.

[0127] Administration of a C5 inhibitor according to the present disclosure can be modified to reduce potential clinical risks to a subject. Infection with Neisseria meningitides is a known risk of C5 inhibitors, including eculizumab. In some cases, the risk of infection with Neisseria meningitides is minimized by initiating one or more prophylactic steps. Such steps can include exclusion of subjects who may already be colonized by these bacteria. In some cases, the prophylactic steps can include co-administration with one or more antibiotics. In some cases, ciprofloxacin can be co-administered. In some cases, ciprofloxacin can be co-administered orally at a dose of about 100 mg to about 1000 mg (e.g., 500 mg).

[0128] In some embodiments, the C5 inhibitor (e.g., zilucoplan) is administered hourly, every 2 hours, every 4 hours, every 6 hours, every 12 hours, every 18 hours, every 24 hours, every 36 hours, every 72 hours, every 84 hours, every 96 hours, every 5 days, every 7 days, every 10 days, every 14 days, weekly, every 2 weeks, every 3 weeks, every 4 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, annually, or at least annually. In some cases, the C5 inhibitor is administered once daily, or in two, three, or more sub-doses at appropriate intervals throughout the day.

[0129] In some embodiments, the C5 inhibitor is administered in multiple daily doses. In some cases, the C5 inhibitor is administered daily for 7 days. In some cases, the C5 inhibitor is administered daily for between 7 and 100 days. In some cases, the C5 inhibitor is administered daily for at least 100 days. In some cases, the C5 inhibitor is administered daily for an indefinite period.

[0130] The methods of the present disclosure can include administering a C5 inhibitor (e.g., zilucoplan) at a daily dose of from about 0.1 mg / kg to about 0.3 mg / kg. In some embodiments, the C5 inhibitor (e.g., zilucoplan) is administered at a daily dose of 0.3 mg / kg.

[0131] The C5 inhibitor delivered intravenously can be delivered over a period such as over a period of 5, 10, 15, 20, or 25 minutes by infusion. Administration can be repeated periodically, e.g., hourly, daily, weekly, every other week (i.e., every 2 weeks), etc., for a period of 1 month, 2 months, 3 months, 4 months, or more than 4 months. After an initial treatment regimen, the treatment can be administered on a less frequent basis. For example, after 3 months of administration every other week, the administration can be repeated once a month for 6 months or more than 1 year.

[0132] Prior to administration of the total dose of the C5 inhibitor and / or C5 inhibitor composition, the patient can be administered a smaller dose, e.g., 5% of the total dose, and monitored for adverse effects such as allergic or infusion reactions or for increases in lipid levels or blood pressure. In another example, the patient can be monitored for unwanted immunostimulatory effects, e.g., increases in cytokine (e.g., TNF-alpha, IL-1, IL-6, or IL-10) levels.

[0133] Genetic factors play a role in the development of some diseases or disorders. Thus, patients in need of a C5 inhibitor can be identified by family history analysis or by screening, for example, for one or more genetic markers or variants. A healthcare provider (e.g., a physician or nurse) or family member can analyze family history information prior to prescribing or administering the therapeutic compositions of the present disclosure.

[0134] III. Kits and Devices In some embodiments, the present disclosure provides kits and devices. Such kits and devices can include any of the compounds or compositions described herein. By way of non-limiting example, zirconoplan can be included.

[0135] The devices of the present disclosure can include an administration device. As used herein, the term "administration device" refers to any tool for providing a substance to a recipient. The administration device can include a self - administration device. As used herein, the term "self - administration device" refers to any tool used to provide a substance to a recipient, where the use of the tool is performed, in whole or in part, by the recipient. The self - administration device can include a self - injection device. A "self - injection device" is a self - administration device that enables an individual to subcutaneously administer a substance to their own body. The self - injection device can include a pre - filled syringe. As used herein, the term "pre - filled syringe" refers to a syringe that has a substance or cargo loaded prior to access or use by an operator of the syringe. For example, a pre - filled syringe (also referred to herein as a "pre - loaded syringe") can be filled with a therapeutic composition before being packaged in a kit, before being shipped to a vendor, administrator, or operator of the syringe, or before access by the subject for whom the syringe is to be used for self - administration. Due to the cyclic peptide stability, cyclic peptide inhibitors (e.g., zilucoplan) are particularly well - suited for manufacture, storage, and distribution in pre - loaded syringes. Further, pre - loaded syringes are particularly well - suited for self - administration (i.e., administration by the subject without the assistance of a medical professional). Self - administration is a convenient way for a subject to obtain treatment without relying on a medical professional who may be far away or otherwise difficult to access. This makes self - administration options very suitable for treatments that require frequent injections (e.g., daily injections).

[0136] The pre-filled syringe can be of any material (e.g., glass, plastic, or metal). In some embodiments, the pre-filled syringe is a glass syringe. The pre-filled syringe can include a maximum fill volume of at least 0.1 ml, at least 0.2 ml, at least 0.3 ml, at least 0.4 ml, at least 0.5 ml, at least 0.75 ml, at least 1.0 ml, at least 1.5 ml, at least 2.0 ml, at least 5.0 ml, at least 10 ml, or more than 10 ml (meaning the maximum amount of liquid that can be contained). The syringe can include a needle. The needle can be of any gauge. In some embodiments, the syringe includes a 29-gauge needle. The needle may be assembled with the syringe or may be attached prior to use of the syringe. The self-injection device can include the BD ULTRASAFE PLUS™ self-administration device (BD, Franklin Lakes, NJ).

[0137] The administration device can include a self-injection device that includes a syringe and a needle and a predetermined volume of a zilcoplan composition. The zilcoplan composition can be a pharmaceutical composition. The composition can include a zilcoplan concentration of from about 1 mg / mL to about 200 mg / mL. In some embodiments, the zilcoplan concentration is about 40 mg / mL. The predetermined volume is pre-determined based on the subject's weight. In some embodiments, the predetermined zilcoplan composition volume is modified to facilitate zilcoplan administration to the subject at a dose of from about 0.1 mg / kg to about 0.6 mg / kg. The volume can be modified to facilitate a 0.3 mg / kg zilcoplan dosage. The self-injection device can include the BD ULTRASAFE PLUS™ self-administration device. In some embodiments, the administration device is prepared for storage at a specific temperature or temperature range. Some administration devices can be prepared for storage at room temperature. Some administration devices can be prepared for storage between about 2°C and about 8°C.

[0138] The pre-filled syringe can include the ULTRASAFE PLUS™ passive needle guard (Becton Dickenson, Franklin Lakes, NJ). Other pre-filled syringes can include an injection pen. The injection pen can be a multi-dose pen. Some pre-filled syringes can include a needle. In some embodiments, the needle gauge is from about 20 to about 34. The needle gauge can be from about 29 to about 31.

[0139] In some embodiments, the kits of the disclosure include kits for practicing a method of treating MG as described herein. Such kits can include one or more of the dosing devices described herein and instructions for use of the kit.

[0140] The kit components can be packaged in a liquid (e.g., aqueous or organic) medium or in a dry (e.g., lyophilized) form. The kit can include a container, including but not limited to, a vial, test tube, flask, bottle, syringe, or bag. The kit container can be used to aliquot, store, preserve, insulate, and / or protect the kit components. The kit components can be packaged together or separately. Some kits can include a container of a sterile pharmaceutically acceptable buffer and / or other diluent (e.g., phosphate buffered saline). In some embodiments, the kit includes a container of the kit components in dry form, together with a separate container of a solution for dissolving the dried components. In some embodiments, the kit includes a syringe for administering one or more of the kit components.

[0141] When the polypeptide is provided as a dried powder, between 10 micrograms and 1000 milligrams of the polypeptide, or at least or at most those amounts are contemplated to be provided in the kit.

[0142] The container can include at least one vial, test tube, flask, bottle, syringe and / or other receptacle, into which the polypeptide formulation can be placed and preferably can be appropriately assigned. The kit can also include a container for a sterile pharmaceutically acceptable buffer and / or other diluent.

[0143] The kit can include instructions for using the kit components and, similarly, for using any other reagents not included in the kit. The instructions can include variations that can be practiced.

[0144] The kit can include one or more articles for dealing with syringe wounds. Such articles can include, but are not limited to, alcohol wipes and wound dressings (such as cotton balls, mesh pads, band-aids, tape, gauze, etc.). The kit can further include a waste container for the disposal of the used kit components. The waste container can be designed for the disposal of sharp objects such as needles and syringes. Some kits can include instructions for the disposal of sharp objects.

[0145] In some embodiments, the kits of the present disclosure include zilcoplan in powdered form or in solution (e.g., as a pharmaceutical composition). The solution can be an aqueous solution. The solution can include PBS. The zilcoplan solution can include from about 4 mg / ml to about 200 mg / ml of zilcoplan. In some embodiments, the zilcoplan solution includes about 40 mg / ml of zilcoplan. The zilcoplan solution can include a preservative. In some embodiments, the zilcoplan solution is preservative-free.

[0146] In some embodiments, the kit is prepared for storage at a specific temperature or temperature range. Some kits can be prepared for storage at room temperature. Some kits can be prepared for storage between about 2°C and about 8°C.

[0147] IV. Definitions Biological availability: As used herein, the term "biological availability" refers to the systemic availability of a given amount of a compound (e.g., a C5 inhibitor) administered to a subject. Biological availability can be determined by measuring the area under the curve (AUC) of the unchanged form of the compound or the maximum serum or plasma concentration (C max ) following administration of the compound to the subject. AUC is the determination of the area under the curve when the serum or plasma concentration of the compound is plotted against time along the x-axis (horizontal axis) and the y-axis (vertical axis). In general, the AUC for a particular compound can be calculated using methods known to those of skill in the art and / or as described in G.S. Banker, Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, Volume 72, Marcel Dekker, New York, Inc., 1996, the contents of which are hereby incorporated by reference in their entirety.

[0148] Biological system: As used herein, the term "biological system" refers to cells, cell populations, tissues, organs, organ populations, organelles, biological fluids, biological signaling pathways (e.g., receptor activation signaling pathways, charge activation signaling pathways, metabolic pathways, cell signaling pathways, etc.), protein groups, nucleic acid groups, or groups of molecules (including, but not limited to, biomolecules) that perform at least one biological function or biological task within a cell membrane, cell compartment, cell, cell culture, tissue, organ, organ system, organism, multicellular organism, biological fluid, or any biological entity. In some embodiments, the biological system is a cell signaling pathway that includes intracellular and / or extracellular signaling biomolecules. In some embodiments, the biological system includes a proteolytic cascade (e.g., the complement cascade).

[0149] Buffer: The term "buffer" refers to a compound used in solution for the purpose of resisting changes in pH. Such compounds can include, but are not limited to, acetic acid, adipic acid, sodium acetate, benzoic acid, citric acid, sodium benzoate, maleic acid, sodium phosphate, tartaric acid, lactic acid, potassium metaphosphate, glycine, sodium bicarbonate, potassium phosphate, sodium citrate, and sodium tartrate.

[0150] Clearance rate: The term "clearance rate" refers to the rate at which a particular compound is eliminated from a biological system or fluid.

[0151] Complement activity includes the activation of the complement cascade, the formation of cleavage products from complement components such as C3 or C5, cleavage events, or the assembly of downstream complexes subsequent to or resulting from any process or event associated with or caused by the cleavage of a complement component, for example, C3 or C5. Complement inhibitors can include C5 inhibitors that block complement activation at the level of the complement component C5. A C5 inhibitor can bind C5 and prevent its cleavage by C5 convertase into the cleavage products C5a and C5b.

[0152] Complement component C5 or C5 is defined as a complex that is cleaved by C5 convertase into at least the cleavage products, C5a and C5b.

[0153] C5 inhibitors include any compound or composition that inhibits the processing or cleavage of the complement component C5 complex prior to cleavage or the cleavage products of the complement component C5. Inhibition of C5 cleavage is understood to prevent the assembly and activity of the cell-lytic membrane attack complex (MAC) against glycosylphosphatidylinositol (GPI)-anchored protein-deficient erythrocytes. In some cases, the C5 inhibitors described herein can also bind C5b and prevent C6 binding and subsequent assembly of C5b-9 MAC.

[0154] Compound: The term "compound" refers to a characteristic chemical entity. In some embodiments, a particular compound can exist in one or more isomeric or isotopic forms (including, but not limited to, stereoisomers, geometric isomers, and isotopes). In some embodiments, a compound is provided or utilized in only a single such form. In some embodiments, a compound is provided or utilized as a mixture of two or more such forms (including, but not limited to, a racemic mixture of stereoisomers). One of ordinary skill in the art will understand that some compounds exist in different forms and exhibit different properties and / or activities (including, but not limited to, biological activity). In such cases, it is within the ordinary skill of one of ordinary skill in the art to select or avoid a particular form of a compound for use according to the present disclosure. For example, a compound containing an asymmetrically substituted carbon atom can be isolated in an optically active or racemic form.

[0155] Cyclic or cyclized: As used herein, the term "cyclic" refers to the presence of a continuous loop. A cyclic molecule need not be cyclic in the sense of being joined to form an unbroken chain of subunits. A cyclic polypeptide can include a "cyclic loop" formed when two amino acids are connected by a crosslinking moiety. The cyclic loop includes the amino acids along the polypeptide that are present between the crosslinked amino acids. The cyclic loop can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids.

[0156] Downstream event: As used herein, the term "downstream" or "downstream event" refers to any event that occurs after and / or as a result of another event. In some cases, a downstream event is an event that occurs after and / or as a result of C5 cleavage and / or complement activation. Such events can include, but are not limited to, the generation of C5 cleavage products, activation of MAC, hemolysis, and hemolysis-related diseases (e.g., PNH).

[0157] Equilibrium dissociation constant: As used herein, the term "equilibrium dissociation constant" or "K DThe term "___" refers to a value that represents the tendency for two or more agents (e.g., two proteins) to reversibly dissociate. In some cases, K D indicates the concentration of the primary agent associated with the primary agent at which half of the total level of the secondary agent is present.

[0158] Half-life: As used herein, the term "half-life" or "t 1 / 2 " refers to the time it takes for a given process or compound concentration to reach half of its final value. "Terminal half-life" or "terminal t 1 / 2 " refers to the time required for the plasma concentration of a factor to be reduced by half after the concentration of the factor has reached pseudo-equilibrium.

[0159] Identity: As used herein, the term "identity" when referring to a polypeptide or nucleic acid refers to the relationship of comparison between sequences. The term is used to describe the degree of sequence relatedness between polymer sequences and can include the percentage of monomeric components that match a gap alignment (if any) that is addressed by a particular mathematical model or computer program (i.e., "algorithm"). The identity of related polypeptides can be readily calculated by known methods. Such methods include, but are not limited to, those previously described by others (Lesk, A.M., ed., Computational Molecular Biology, Oxford University Press, New York, 1988; Smith, D.W., ed., Biocomputing: Informatics and Genome Projects, Academic Press, New York, 1993; Griffin, A.M., et al., eds., Computer Analysis of Sequence Data, Part 1, Humana Press, New Jersey, 1994; von Heinje, G., Sequence Analysis in Molecular Biology, Academic Press, 1987; Gribskov, M., et al., eds., Sequence Analysis Primer, M. Stockton Press, New York, 1991; and Carillo, et al., Applied Math, SIAM J, 1988, 48, 1073).

[0160] Inhibitor: As used herein, the term "inhibitor" refers to any agent that blocks or causes a reduction in the occurrence of a particular event; a cellular signal; a chemical pathway; an enzymatic reaction; a cellular process; an interaction between two or more entities; a biological event; a disease; a disorder; or a condition.

[0161] Initial loading dose: As used herein, an "initial loading dose" refers to the first dose of a therapeutic agent that may differ from one or more subsequent doses. An initial loading dose can be used to achieve an initial concentration or level of activity of the therapeutic agent before subsequent doses are administered.

[0162] Intravenous: As used herein, the term "intravenous" refers to an area within a blood vessel. Intravenous administration typically refers to the delivery of a compound into the bloodstream via injection into a blood vessel (e.g., a vein).

[0163] In vitro: As used herein, the term "in vitro" refers to events that occur in an artificial environment (e.g., in a test tube, reaction vessel, cell culture, Petri dish, etc.) rather than within an organism (e.g., an animal, plant, or microorganism).

[0164] In vivo: As used herein, the term "in vivo" refers to events that occur within an organism (e.g., an animal, plant, microorganism, or their cells or tissues).

[0165] Lactam bridge: As used herein, the term "lactam bridge" refers to an amide bond that forms a bridge between chemical groups in a molecule. In some cases, lactam bridges are formed between amino acids in a polypeptide.

[0166] Linker: The term "linker", as used herein, refers to a group of atoms (e.g., 10 to 1,000 atoms), molecule(s), or other compound used to join two or more entities. A linker can join such entities via covalent or non-covalent (e.g., ionic or hydrophobic) interactions. A linker can include a chain of two or more polyethylene glycol (PEG) units. In some cases, a linker can be cleavable.

[0167] "Lower" or "reduce" in the context of a disease marker or symptom often means a statistically significant, significant decrease at such levels. The decrease may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and drops to a level that is acceptable as within the normal range for individuals without such disorders.

[0168] "Increase" or "raise" in the context of a disease marker or symptom often means a statistically significant, significant increase at such levels. The increase may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and may be up to a level that is acceptable as within the normal range for individuals without such disorders.

[0169] Minute ventilation: As used herein, the term "minute ventilation" refers to the volume of air inhaled or exhaled from the lungs of a subject per minute.

[0170] Non-proteinogenic: As used herein, the term "non-proteinogenic" refers to any non-natural protein, e.g., one having non-natural components, e.g., non-natural amino acids.

[0171] Patient: As used herein, "patient" refers to a subject seeking, in need of, undergoing, or about to undergo treatment, or a subject under the care of a trained professional for a particular disease or condition.

[0172] Any amino acid-based molecule (natural or non-natural) can be named a polypeptide, and this term encompasses peptides, peptidomimetics, and proteins. Peptides are traditionally thought to range in size from about 4 to about 50 amino acids. Polypeptides larger than about 50 amino acids are generally named proteins. The C5 inhibitor polypeptides of the present disclosure may be peptidomimetics. A peptidomimetic or polypeptide mimetic is a polypeptide in which the molecule contains structural elements not found in natural polypeptides (i.e., polypeptides containing only the 20 proteinogenic amino acids).

[0173] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition having at least one active ingredient (e.g., a C5 inhibitor) in a form and amount that enables the active ingredient to be therapeutically effective.

[0174] Pharmaceutically acceptable: The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0175] Pharmaceutically acceptable excipients: As used herein, the phrase "pharmaceutically acceptable excipients" refers to any component other than the active agent (e.g., the active agent zilcoplan and / or its active metabolites or variants thereof) present in a pharmaceutical composition and having the property of being substantially non-toxic and non-inflammatory in a patient. In some embodiments, the pharmaceutically acceptable excipient is a vehicle capable of suspending or dissolving the active agent. Excipients can include, for example: anti-adhesion agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorants, fragrances, glidants (flow promoters), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and water of hydration. Illustrative excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0176] Plasma compartment: As used herein, the term "plasma compartment" refers to the intravascular space occupied by blood plasma in the blood.

[0177] Salt: As used herein, the term "salt" refers to a compound composed of a cation together with an associated anion. Such compounds can include sodium chloride (NaCl), or other classes of salts including, but not limited to, acetates, chlorides, carbonates, cyanides, nitrites, nitrates, sulfates, and phosphates.

[0178] Sample: As used herein, the term "sample" refers to an aliquot or portion taken from a source and / or provided for analysis or processing. In some embodiments, a sample is a biological source such as tissue, cells, or a component part (e.g., a body fluid including, but not limited to, blood, mucus, lymph, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, umbilical cord blood of amniotic fluid, urine, vaginal fluid, and semen). In some embodiments, a sample can be a whole organism, or a subset, fraction, or part of its tissue, cells, or component parts, including, but not limited to, for example, plasma, serum, cerebrospinal fluid, lymph, skin, external sections of the respiratory, intestinal, and urogenital tracts, tears, saliva, milk, blood cells, tumors, or organs, or a homogenate, solubilized material, or extract prepared from or containing such. In some embodiments, a sample is a medium such as a nutrient broth or gel containing cellular components such as proteins or includes such. In some embodiments, a "primary" sample is an aliquot of the source. In some embodiments, a primary sample is subjected to one or more processing (e.g., separation, purification, etc.) steps to prepare a sample for analysis or other use.

[0179] Subcutaneous: As used herein, the term "subcutaneous" refers to the space under the skin. Subcutaneous administration is the delivery of a compound under the skin.

[0180] Subject: As used herein, the term "subject" refers to any organism to which a compound or method according to the disclosure can be administered or applied for purposes such as experimentation, diagnosis, prevention, and / or treatment. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, porcine subjects, non-human primates, and humans). In some applications, the subject is a human.

[0181] Substantially: As used herein, the term "substantially" refers to a qualitative state that exhibits a degree or extent that is total or nearly total of the characteristics or properties of interest. One of ordinary skill in the biological arts will appreciate that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection, or achieve or avoid absolute results. The term "substantially" is thus used herein to capture the potential lack of perfection inherent in many biological and chemical phenomena.

[0182] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means an amount of an agent (e.g., a C5 inhibitor) to be delivered that is sufficient to treat, ameliorate the symptoms of, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition.

[0183] Tidal volume: As used herein, the term "tidal volume" refers to the normal lung volume of air that is replaced between breaths (in the absence of any extra effort).

[0184] T max : As used herein, the term "t max " refers to the period during which the maximum concentration of a compound in a subject or fluid is maintained.

[0185] Treatment: As used herein, the term "treatment" refers to partially or completely alleviating, remitting, improving, relieving, delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or characteristics of a particular disease, disorder and / or condition. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder and / or condition, and / or to a subject who exhibits only early signs of a disease, disorder and / or condition, for the purpose of reducing the risk of developing a pathological condition associated with the disease, disorder and / or condition.

[0186] Treatment dosage: As used herein, the term "treatment dosage" refers to one or more dosages of a therapeutic agent administered in the process of addressing or alleviating a therapeutic indication. The treatment dosage can be adjusted to maintain a desired concentration or level of the therapeutic agent in a body fluid or biological system.

[0187] Volume of distribution: As used herein, the term "volume of distribution" or "V dist " refers to the fluid volume required to contain the total amount of a compound in the body at the same concentration as in blood or plasma. The volume of distribution can reflect the degree to which a compound is present in extravascular tissues. A large volume of distribution reflects a tendency of the compound to bind to tissue components as compared to plasma protein components. In a clinical setting, V dist can be used to determine the loading dose of a compound to achieve a steady-state concentration of the compound.

[0188] V. Equivalents and scope While various embodiments of the invention have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

[0189] One of ordinary skill in the art will recognize or be able to ascertain many equivalents to the specific embodiments of the invention described herein using nothing more than routine experimentation. The scope of the invention is not intended to be limited to the above description, but rather is as set forth in the appended claims.

[0190] In the claims, the articles “a,” “an,” and “the” may mean one or more than one, unless the contrary is indicated or is otherwise clear from the context. A claim or description that includes “or” between one or more members of a group, unless the contrary is indicated or is otherwise clear from the context, is considered satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The invention includes embodiments where exactly one member of the group is present in, used in, or otherwise related to a given product or process. The invention includes embodiments where more than one or all of the group members are present in, used in, or otherwise related to a given product or process.

[0191] It is noted that the term “comprising,” which is intended to be open-ended, allows for the inclusion of additional elements or steps, but does not require them. When the term “comprising” is used herein, the terms “consisting of” and “including or” are also, therefore, included and disclosed.

[0192] When ranges are indicated, endpoints are included. Further, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values expressed as ranges are to be assumed to cover any and all subranges within the stated range, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0193] In addition, it should be understood that any particular embodiments of the invention that fall within the prior art may be explicitly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art, so they can be excluded even if the exclusion is not explicitly described herein. Any particular embodiments of the compositions of the invention (e.g., any nucleic acid, or protein encoded thereby; any production method; any method of use; etc.) may be excluded from any one or more of the claims for any reason, regardless of whether they are related to the existence of the prior art.

[0194] All cited sources of information, such as references, publications, databases, database entries, and techniques cited herein, are incorporated by reference into this application even if not explicitly stated in the citation. In the event of a conflict between the cited sources of information and the description of the application, the description of the application shall prevail.

[0195] The headings of sections and tables are not intended to be limiting.

[0196] VI. Additional Embodiments Notwithstanding the appended claims, this disclosure provides embodiments defined by the following clauses:

[0197] Clause 1. A method of treating refractory generalized myasthenia gravis in a human patient in need thereof, comprising administering to a human patient who is positive for autoantibodies (anti - AChR) that bind to nicotinic acetylcholine receptors and (ii) identified as having refractory gMG, a therapeutically effective amount of zilcoplan.

[0198] Clause 2. The method of Clause 1, wherein prior to administration, the patient is refractory to treatment with immunosuppressive drug therapy (IST) for more than one year and requires long - term plasma exchange or long - term IVIG to maintain clinical stability.

[0199] Article 3. The method of Article 1 or 2, wherein the patient experiences a reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 points from baseline (e.g., at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline) 12 weeks after treatment.

[0200] Article 4. The method of any one of Articles 1 to 3, wherein the patient experiences a reduction in the MG-ADL score of at least 2 points from baseline (e.g., at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline) 8 weeks after treatment.

[0201] Article 5. The method of any one of Articles 1 to 4, wherein the patient experiences a clinically significant improvement (reduction) in quality of life as measured by the Quantitative Myasthenia Gravis (QMG) score, the Myasthenia Gravis Composite (MGC) score, or the Revised Myasthenia Gravis Quality of Life (MG-QOL-15r) score 12 weeks after treatment with zilcoplan.

[0202] Article 6. The method of Article 5, wherein the patient experiences a reduction in the QMG score of at least 3 points from baseline (e.g., at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline) 12 weeks after treatment.

[0203] Article 7. The method of Article 6, wherein the patient experiences a reduction in the QMG score of at least 3 points from baseline (e.g., at least 4 points, at least 5 points, at least 6 points, at least 8, at least 10, or at least 12 points from baseline) 8 weeks after treatment.

[0204] Clause 8. Any one of the methods of Clauses 3 to 7, wherein the patient experiences a reduction in the MGC score of at least 3 points (e.g., at least 4 points, at least 5 points, at least 6 points, at least 8 points, at least 10 points, or at least 12 points) from the baseline 12 weeks after the treatment.

[0205] Clause 9. Any one of the methods of Clauses 3 to 8, wherein the patient experiences a reduction in the MG-QOL-15r score of at least 2 points (e.g., at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 8 points, at least 10 points, or at least 12 points) from the baseline 12 weeks after the zirconoplan treatment.

[0206] Clause 10. Any one of the methods of Clauses 1 to 9, wherein the zirconoplan administration is subcutaneous (SC).

[0207] Clause 11. Any one of the methods of Clauses 1 to 10, wherein the zirconoplan is administered daily.

[0208] Clause 12. Any one of the methods of Clauses 1 to 11, wherein the zirconoplan is administered to the patient for 12 weeks or more.

[0209] Clause 13. The method of Clause 11 or 12, wherein the zirconoplan is administered at a daily dose of about 0.1 mg / kg (mg of zirconoplan per kg of the subject's body weight) to about 0.6 mg / kg.

[0210] Clause 14. The method of Clause 13, wherein the zirconoplan is administered at a daily dose of about 0.1 mg / kg to about 0.3 mg / kg.

[0211] Clause 15. The method of Clause 14, wherein the zirconoplan is administered at a daily dose of 0.3 mg / kg.

[0212] Clause 16. Any one of the methods of Clauses 1 to 15, wherein the zirconoplan is administered using a self-administration device.

[0213] Clause 17. The method of clause 16, wherein the self - administration device comprises a pre - filled syringe.

[0214] Clause 18. The method of clause 17, wherein the syringe is a glass syringe and includes a 29 - gauge needle.

[0215] Clause 19. The method of any one of clauses 16 to 18, wherein the self - administration device has a maximum fill volume of at least 1 mL.

[0216] Clause 20. The method of clause 19, wherein the self - administration device contains a zilcoplan solution having a volume from about 0.15 mL to about 0.81 mL.

[0217] Clause 21. The method of clause 20, wherein the solution contains zilcoplan from about 4 mg / mL to about 200 mg / mL.

[0218] Clause 22. The method of clause 21, wherein the solution contains about 40 mg / mL of zilcoplan.

[0219] Clause 23. The method of any one of clauses 16 to 22, wherein the self - administration device contains an aqueous solution of zilcoplan or its sodium salt form.

[0220] Clause 24. The method of clause 23, wherein the solution contains phosphate - buffered saline (PBS).

[0221] Clause 25. The method of clause 23 or 24, wherein the solution is preservative - free.

[0222] Clause 26. The method of any one of clauses 1 to 25, wherein the patient is between 18 and 85 years old.

[0223] Clause 27. The method of any one of clauses 1 to 26, wherein the patient does not require or receive rescue therapy during zilcoplan administration.

[0224] The method of any one of clauses 1 to 27, wherein zirconoplan administration is carried out at an MG disease stage before the critical or crisis stage of MG.

[0225] The method of any one of clauses 1 to 28, wherein the patient receives standard care gMG therapy simultaneously throughout the zirconoplan treatment process.

[0226] The method of clause 29, wherein the standard care gMG therapy includes one or more of cholinesterase inhibitor treatment, pyridostigmine treatment, corticosteroid treatment, and IST.

[0227] The method of clause 29 or 30, wherein the subject receives cholinesterase inhibitor treatment throughout the zirconoplan treatment process.

[0228] The method of any one of clauses 1 to 31, further comprising the step of co-administering to the patient a therapeutically effective amount of an additional therapeutic agent.

[0229] The method of clause 32, wherein the additional therapeutic agent is an immunosuppressant.

[0230] The method of clause 33, wherein the immunosuppressant is selected from azathioprine, cyclosporine, cyclosporine A, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab.

[0231] The method of clause 32, wherein the additional therapeutic agent includes an inhibitor of autoantibody-mediated tissue destruction.

[0232] The method of clause 35, wherein the inhibitor of autoantibody-mediated tissue destruction includes a neonatal Fc receptor (FcRN) inhibitor.

[0233] The method of clause 36, wherein the FcRN inhibitor includes intravenous immunoglobulin (IVIG) treatment.

[0234] Zilcoplan for use in treating refractory generalized myasthenia gravis (gMG) in human patients in need thereof, wherein the human patient is (i) positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors, and (ii) identified as having refractory gMG, zilcoplan.

[0235] Use of zilcoplan for the preparation of a medicament for treating refractory generalized myasthenia gravis (gMG) in human patients in need thereof, wherein the human patient is (i) positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors, and (ii) identified as having refractory gMG, use.

Example

[0236] (Example 1) Preparation of zilcoplan Zilcoplan is produced via a 3-step process: linear sequence synthesis via amino acid coupling, cyclization by linking the lysine side chain to the aspartic acid side chain, and finally, coupling of the glutamic acid-ethylene glycol 24 -palmitoyl moiety to the second lysine side chain.

[0237] The zirconoplan polypeptide is synthesized using the standard solid-phase Fmoc / tBu method. The synthesis is carried out on a Liberty automated microwave peptide synthesizer (CEM, Matthews NC) using a standard protocol with Rink amide resin, although other automated synthesizers without microwave capabilities can also be used. All amino acids were obtained from commercial sources. The coupling reagent used is 2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3,-tetramethylaminium hexafluorophosphate (HCTU), and the base is diisopropylethylamine (DIEA). The polypeptide is cleaved from the resin with 95% TFA, 2.5% TIS, and 2.5% water for 3 hours and isolated by precipitation with ether. The crude polypeptide is purified using reverse-phase preparative HPLC on a C18 column with a 20% - 50% acetonitrile / water 0.1% TFA elution gradient over 30 minutes. The elution fractions containing the pure polypeptide are collected and lyophilized, and the polypeptide is analyzed by LC-MS.

[0238] Zirconoplan (SEQ ID NO: 1; CAS No: 1841136-73-9) was prepared as a cyclic peptide containing 15 amino acids (4 of which are non-natural amino acids) together with an acetylated N-terminus and a C-terminal carboxylic acid. The C-terminal lysine of the core peptide has a modified side chain that forms an N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl) lysine residue. This modified side chain contains a polyethylene glycol spacer (PEG24) attached to an L-γ-glutamic acid residue derivatized with a palmitoyl group. Zirconoplan contains an intramolecular cyclization via a lactam bridge between the side chains of L-Lys1 and L-Asp6. All of the amino acids in zirconoplan are L-amino acids. Zirconoplan has a molecular weight of 3562.23 g / mol and a chemical formula of C 172 H 278 N 24 O 55 having.

[0239] The final molecule is purified by reverse-phase chromatography, exchanged into its sodium salt form, and subsequently dried. The drug substance is supplied as a lyophilized powder and stored at -20°C.

[0240] Zilcoplan is prepared as an aqueous solution for injection containing 40 mg / mL of zilcoplan in a sterile preservative-free formulation of 50 mM sodium phosphate and 76 mM sodium chloride at a pH of 7.0. Using the resulting composition, a pharmaceutical product is prepared according to Good Manufacturing Practice (cGMP) standards, and the pharmaceutical product included a pre-filled 1 mL glass syringe with a 29-gauge 1 / 2-inch stacked needle placed within a BD ULTRASAFE PLUS (trademark) (BD, Franklin Lakes, NJ) self-administration device.

[0241] Dose strength variation is thus achieved by varying the syringe fill volume.

[0242] (Example 2) Administration and Storage of Zilcoplan Zilcoplan is administered by subcutaneous (SC) injection, and the dose administered (dose volume) can be adjusted based on the subject body weight on a mg / kg basis. This is achieved using a series of fixed dose presentations adjusted to a series of body weight strata. For the Phase 3 clinical study, three pre-tested strengths are used (16.6 mg, 23.0 mg, and 32.4 mg). Overall, human dosing supports a wide range of body weights from 43 kg to 109 kg. Subjects showing heavier body weights (>109 kg) are addressed on a case-by-case basis with reference to medical monitoring.

[0243] Zilcoplan is stored at 2°C to 8°C. Once dispensed to a subject, zilcoplan is stored at controlled room temperature (20°C to 25°C) for up to 30 days and protected from sources of excessive temperature variation such as heat or exposure to light. Storage of zilcoplan outside of room temperature is preferably avoided. Zilcoplan can be stored for up to 4 months under these conditions.

[0244] (Example 3) Efficacy of Zilucoplan in the Treatment of Myasthenia Gravis in a Phase 2 Clinical Study In a Phase 2 clinical study of gMG (NCT03315130), both high-dose and low-dose zilucoplan treatments were shown to be effective. See, for example, PCT Publication No. WO2020 / 086506 ("Neurological Disease Treatment with Zilucoplan"), the disclosure of which is incorporated herein by reference in its entirety.

[0245] For convenience, the details of the clinical study are reproduced below.

[0246] To evaluate the safety, tolerability, and preliminary efficacy of zilucoplan in treating subjects with gMG, a multi-site, randomized, double-blind, placebo-controlled study was conducted. In the study, subjects were randomized in a 1:1:1 ratio to receive a daily SC dose of 0.1 mg / kg zilucoplan, 0.3 mg / kg zilucoplan, or matching placebo. Randomization was stratified based on the screening Quantitative Myasthenia Gravis (QMG) score (≤17 vs. ≥18).

[0247] The main part of the study included a screening period of up to 4 weeks and a treatment period of 12 weeks. During the treatment period, subjects returned to the clinic weekly for the first two visits (days 8 and 15) after the first visit on day 1, and then visited on weeks 4 (day 29), 8 (day 57), and 12 (day 84) to evaluate safety, tolerability, and preliminary efficacy. Additional assessments included Quality of Life (QOL) questionnaires, biomarker samples, pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety assessments included physical examinations, vital signs, ECG, clinical laboratory tests, AEs, and immunogenicity.

[0248] Zilcoplan and the matching placebo were supplied as a sterile preservative-free aqueous solution pre-filled in a 1 mL glass syringe with a 29-gauge 1 / 2-inch stacked needle placed within a self-administration device. The fill volume was adjusted based on the target body weight range to achieve the exact mg / kg dose range. Subjects were instructed to self-administer the SC daily dose.

[0249] The dose of zilcoplan was determined by the target dose and body weight and achieved using fixed doses by body weight strata. These strata were grouped by body weight category so that each subject received above the target minimum dose to avoid sub-therapeutic dosing. For the 0.1 mg / kg dose, subjects received a fixed dose of at least 0.1 mg / kg (range: 0.10 mg / kg to 0.14 mg / kg). For the 0.3 mg / kg dose, subjects received a minimum dose of 0.3 mg / kg (range: 0.30 mg / kg to 0.42 mg / kg). Table 1 summarizes the dose presentation for zilcoplan 0.1 mg / kg and 0.3 mg / kg doses. Subjects showing a heavier body weight (>150 kg) were addressed on a case-by-case basis. The matching placebo was provided at 0.220 mL for the 0.1 mg / kg dose and 0.574 mL for the 0.3 mg / kg dose in both presentations.

Table 1

[0250] Screening Screening was conducted to determine eligibility for the study. Screening included determination of the QMG score. The patient population most appropriate for zilcoplan treatment was expected to have a QMG score ≥ 12 and ≥ 2 test items scored ≥ 4 when determined by screening and baseline (off acetylcholinesterase inhibitor therapy, e.g., pyridostigmine, for at least 10 hours). Other eligibility criteria determined during screening included age between 18 and 85 years; gMG diagnosis at screening [Myasthenia Gravis Foundation of America (MGFA) criteria; by class II-IVa]; positive serology for AChR autoantibodies; no change in corticosteroid dose for at least 30 days prior to baseline or no change expected to occur during the 12-week treatment period; and no change in immunosuppressive therapy, including dose, for at least 30 days prior to baseline or no change expected to occur during the 12-week treatment period. Female subjects of childbearing potential were required to have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of study drug. Female subjects of childbearing potential who were sexually active (i.e., women who were not postmenopausal or who had not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and all male subjects (not surgically sterilized by vasectomy) consented to use effective contraception during the study.

[0251] During screening, determinations were made including review of medical history and demographics, including collection of disease history with diagnosis of gMG by MGFA criteria (class II-IVa), serology for AChR autoantibodies, determination of the QMG score, height and weight measurements, determination of vital signs [heart rate (HR), body temperature, and blood pressure in the sitting position], 12-lead ECG, determination of previous meningococcal (Neisseria meningitidis) vaccine inoculation, collection of blood samples for laboratory tests [hematology, chemistry, coagulation, adenosine deaminase (ADA) test, and pharmacogenomic analysis], collection of urine samples for urinalysis, and serum pregnancy test for female subjects of childbearing potential.

[0252] Subjects meeting any of the following criteria were excluded from the study: (1) thymectomy occurring within 6 months before baseline or scheduled to occur during the 12-week treatment period; (2) abnormal thyroid function as determined by local criteria; (3) known positive serology for muscle-specific kinase (MuSK) or lipoprotein receptor-related peptide 4 (LRP4); (4) mild symptom state of myasthenia gravis based on clinical evaluation; (5) change in diet therapy in renal disease at screening calculated by the Modification of Diet in Renal Disease (MDRD) formula <60 mL / min / 1.73m 2 Calculation of glomerular filtration rate:

Number

[0253] Treatment period The randomized subjects received 0.1 mg / kg of zilcoplan, 0.3 mg / kg of zilcoplan, or a matching placebo administered subcutaneously (SC) at the first visit on Day 1. Following in-clinic education and training, all subjects self-injected the SC daily dose of the blinded study drug according to the randomized treatment assignment for the subsequent 12 weeks. An injection device was provided for use during the study. Subjects were expected to continue on a stable dose of standard of care (SOC) therapy for generalized myasthenia gravis (gMG) throughout the study, including pyridostigmine, corticosteroids, or immunosuppressive medications. Medication on study visit days was withheld until completion of Quantitative Myasthenia Gravis (QMG) scoring and blood sampling [for pharmacokinetic (PK) and pharmacodynamic (PD) analyses]. On days when rescue therapy was administered concomitantly, study drug dosing was held until after administration of the rescue therapy and PK / PD sample collection. Rescue therapy was accompanied by an escalation of gMG therapy due to worsening of the subject's clinical condition. During rescue therapy, subjects received intravenous immunoglobulin (IVIG) or plasmapheresis procedures.

[0254] During the main part of the study, the total duration of study participation for all subjects was up to approximately 16 weeks, including a screening period of up to 4 weeks and a treatment period of 12 weeks. An extension of the study was made available for continuation of zilcoplan administration.

[0255] Subjects received treatment with 0.1 mg / kg of zilcoplan, 0.3 mg / kg of zilcoplan, or a matching placebo according to randomization from Day 1 to Day 84 during the treatment period of the main part of the study. Subjects who completed the visit on Day 84 (including those randomized to the placebo arm) had the option to continue treatment with zilcoplan in the extension part of the study.

[0256] The end of the study and the final study procedures included weight measurement; review and documentation of concomitant drug therapy; symptom-targeted physical examinations; determination of vital signs (e.g., heart rate, body temperature, and blood pressure in the sitting position); 12-lead ECG; collection of blood samples for laboratory tests (hematology, chemistry, coagulation, ADA test, pharmacokinetic analysis, pharmacodynamic analysis, and biomarker analysis); collection of urine for urinalysis; urine pregnancy test for women of childbearing potential; QMG score determination; and determination of MG-ADL, MG-QOL15r, and MG composite (MGC).

[0257] Sample analysis During the main part of the study, blood samples for PK and PD analysis were collected from all subjects at the time points presented in Table 2. The extended part blood sample collection for PK and PD analysis was designed to be the same under the rescue therapy scenario. Additionally, the blood collected at week 36 of the extension part was planned to follow the "Day 1" schedule described for the main part blood collection.

Table 2

[0258] On all other study visits, a single PK and PD sample was collected before the administration of the study drug. Plasma concentrations of zilcoplan and its metabolites were measured in all blood samples.

[0259] Blood samples for safety analysis were collected on Day 1 at the following time points: (i) pre-dose (within 1 hour before the first dose administration of the study drug) and (ii) 6 hours (±90 minutes) post-dose. On all other study visits, samples for safety analysis were collected before the administration of the study drug. Additional blood samples for the study were collected at 6 hours (±90 minutes) post-dose on Day 84 from subjects who intended to participate in the study extension part. The blood sample analytes to be determined included those listed in Table 3.

Table 3

[0260] Myasthenia gravis pathophysiological biomarker analysis [e.g., complement fixation, complement function, complement pathway proteins, autoantibody characterization (titer and immunoglobulin class), and inflammatory markers] was available to provide further insight into the clinical efficacy and safety of zilucoplan in subjects with gMG. Determination of complement protein levels and complement activity can be used to evaluate response to zilucoplan and to understand subject characteristics associated with variability in drug response. Inflammatory marker testing can be used to determine correlation with complement function and clinical response to zilucoplan. The list of analytes can be created through review of the literature, ongoing clinical studies, and ongoing exploratory work and finalized after completion of the study.

[0261] The primary efficacy endpoint was the change from baseline at week 12 (day 84) in the QMG score. The QMG score is a standardized and validated quantitative strength scoring system developed specifically for gMG and previously used in clinical trials. Higher scores represent more severe dysfunction. Recent data suggest that an improvement in the QMG score of 2 to 3 points may be considered clinically meaningful depending on disease severity [Barohn, RJ et al., 1998, Ann N Y Acad Sci. 841:769-72; Katzberg, HD et al., 2014, (Muscle Nerve), 49(5):661-5]. QMG assessments were performed at each study visit and at screening to determine subject eligibility. QMG assessments were performed at approximately the same time (preferably, in the morning) on each visit day throughout the study. If the subject was receiving a cholinesterase inhibitor (e.g., pyridostigmine), the dose was withheld for at least 10 hours prior to the QMG test. The 0.3 mg / kg and 0.1 mg / kg dose groups were compared to the placebo dose group, and a linear trend was determined based on all three treatment groups.

[0262] The secondary efficacy endpoints included the changes from baseline at week 12 in MG-ADL, MG-QOL15r, and MG composite. Each of the active doses was compared to the placebo group. For subjects with a ≥3-point reduction in the QMG score at week 12 and subjects who required rescue therapy over the 12-week treatment period, the rate of subjects meeting the endpoint for each of the active treatment groups was compared to the placebo group.

[0263] To reduce subject fatigue and enhance the reliability of the results, a specific order of efficacy endpoint analysis was arranged. The MG-QOL15r analysis was performed first, followed by the MG-ADL analysis, QMG score determination, and MG composite. To reduce judgment variability, the same evaluator was used throughout the study.

[0264] Results Study results were obtained from participants in a broad, demographically well-balanced population. The pre-study baseline characteristics for the study participants are presented in Table 4. In the table, "SD" refers to "standard deviation" and "SOC" refers to "standard care".

[0265]

Table 4

[0266] The population included subjects with baseline disease characteristics indicating refractory as well as non-refractory disease states. The baseline disease characteristics, including MGFA classification and efficacy outcome measures, were also well-balanced among the study participants. In the study, 15 subjects received placebo, while 15 subjects received low-dose zilcoplan (0.1 mg / kg) and 14 subjects received high-dose zilcoplan (3 mg / kg). The significance test was pre-specified with a one-sided alpha of 0.1.

[0267] The baseline demographic characteristics were similar across the groups with respect to mean age (from 48.4 to 54.6 years), race representation (from 78.6% to 86.7% white), mean weight (from 85.27 kg to 110.9 kg), and mean BMI (from 30.856 to 36.000). There was an imbalance between the groups with respect to sex, with 71.4%, 46.7%, and 26.7% male in the 0.3 mg / kg zilcoplan, 0.1 mg / kg zilcoplan, and placebo groups, respectively. However, sex is not known to play a significant role in treatment response in gMG.

[0268] The medical histories, including disease duration, previous MG crises, previous thymectomy, and previous treatments with pyridostigmine, corticosteroids, immunosuppressants, or rescue therapy with IVIG or PLEX, were well balanced across the treatment groups. Over 90% of the subjects in each group had received acetylcholinesterase inhibitors; over 85% had received corticosteroids; 64.3% to 80% had received immunosuppressive therapy; 53.3% to 71.4% had received IVIG; and 46.7% to 60.0% had received plasma exchange.

[0269] The MG disease severity as measured by MGFA classification was similar across the treatment groups using all subjects in the 0.1 mg / kg zilcoplan and placebo groups who were in MGFA class II (mild disease severity) and III (moderate disease severity), although the 0.3 mg / kg zilcoplan group also included four subjects in MGFA class IV (severe disease).

[0270] The MG-specific baseline characteristics were well balanced across the primary (QMG) and first secondary (MG-ADL) endpoint scores, with mean baseline QMG scores of 19.1, 18.7, and 18.7 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively; and mean MG-ADL scores of 7.6, 6.9, and 8.8. MG-QOL15r was approximately 3 points higher in the 0.1 mg / kg zilucoplan group than in the 0.3 mg / kg zilucoplan group, with mean MG-QOL15r scores of 16.5, 19.1, and 15.9 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively. MGC was >4 points higher in the placebo group than in the other two groups, with mean MGC scores of 14.6, 14.5, and 18.7 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively.

[0271] Clinical efficacy outcomes are provided in Table 5. In the table, P-values are one-sided based on analysis of the analysis of covariance (ANCOVA) model, using baseline values as covariates and last observation carried forward (LOCF) for subjects who received rescue therapy. "LS" refers to "least squares", "CFB" refers to change from baseline, and "se" refers to "standard error".

[0272]

Table 5

[0273] The 0.3 mg / kg treatment group showed clinically and statistically significant improvement (≥ 3 points) in QMG score relative to baseline at 12 weeks, with a mean difference of -2.8 (p = 0.05) relative to placebo. Clinically and statistically significant improvement (≥ 2 points) in MG-ADL score relative to baseline was also observed at 12 weeks with this treatment, with a mean difference of -2.3 (p = 0.04) relative to placebo. Clinically and statistically significant improvement was also observed in the low-dose treatment group, demonstrating a slightly lower change from baseline than that observed in the higher-dose group. With the lower-dose treatment (0.1 mg / kg), clinically and statistically significant improvement in QMG score was observed, with a mean difference of -2.3 points relative to placebo at 12 weeks (p = 0.09). Clinically and statistically significant change in MG-ADL score at 12 weeks was also observed in this group (mean difference of -2.2 relative to placebo; p = 0.05). The change from baseline in MG-ADL relative to placebo for the pooled low-dose and high-dose zilcoplan treatment groups (n = 29) showed a statistically significant advantage for zilcoplan treatment relative to placebo (mean difference of -2.2 relative to placebo; p = 0.047, two-sided). When comparing placebo responders and treatment responders in the high-dose group relative to placebo at 12 weeks, the highest levels of improvement in QMG score and MG-ADL were in all zilcoplan treatment groups, and most patients were in zilcoplan, which improved at each cutoff level compared to placebo.

[0274] Zilcoplan reduced the need for rescue treatment, with only 1 subject (7%) in the low-dose treatment group and 0 subjects in the high-dose treatment group requiring rescue (compared to 3 subjects (20%) in the placebo group requiring rescue therapy). No significant endpoint differences were observed between treatment groups based on previous therapy co-variates (immunosuppressive therapy, IVIG, or PLEX), with all P-values greater than 0.20.

[0275] Responder analysis was performed for QMG and MG-ADL endpoints. Clinically meaningful responses regarding the QMG total score were defined as improvements of 3 points or more that coincided with the upper end of the established minimal clinically important difference (MCID) for QMG (Barohn et al., 1998; Katzberg et al., 2014). The responder rate at week 12 using a cutoff of ≥3 points for QMG was higher for subjects receiving 0.3 mg / kg zilcoplan (n = 10 / 14) and 0.1 mg / kg zilcoplan (n = 10 / 15) compared to the placebo group (n = 8 / 15). Additional pre-planned analyses showed advantages for the zilcoplan treatment group at all cutoffs for QMG, including that there were no subjects with worsening in the 0.3 mg / kg zilcoplan group compared to 3 and 2 subjects in the 0.1 mg / kg zilcoplan and placebo groups, respectively. None of these differences were statistically significant (Table 6) except for the 0.1 mg / kg zilcoplan group vs. placebo at ≥7-point and ≥11-point improvement cutoffs, and no correction for multiple tests was performed. Overall, the data were consistent with the primary analysis and generally showed higher clinical responses in the zilcoplan treatment arms compared to the placebo group.

Table 6

[0276] The generally accepted MCID for the MG-ADL total score is an improvement of 2 points or more (Wolfe et al., 1999; Muppidi et al., 2011). The analysis also included higher cutoffs up to a maximum difference of at least 11 points. The responder rate at week 12 using a cutoff of ≥2 points for MG-ADL was higher for subjects receiving zilcoplan at 0.3 mg / kg (n = 10 / 14, 71.4%) and 0.1 mg / kg (n = 10 / 15) compared to the placebo group (n = 8 / 15) (Table 7).

Table 7

[0277] The minimal symptom expression (MSE) endpoint was determined to identify which subjects become, or substantially become, free of gMG symptoms (based on achieving a MG-ADL total score of 0 or 1) with zilucoplan therapy. In this study, 35.7% (5 / 14) of subjects in the 0.3 mg / kg zilucoplan group achieved a MG-ADL of 0 or 1, compared to 26.7% (4 / 15) in the 0.1 mg / kg zilucoplan and 13.3% (2 / 15) in the placebo group. Further, the percent achievement for the high-dose treatment group was greater than that observed with 26 weeks of eculizumab treatment (based on eculizumab study results presented in Vissing, J. et al., 2018. AANEM Abstract 193). This analysis highlighted the large degree to which improvement in the subjective perception of disease burden can be achieved within a short period using zilucoplan. The dose response at a higher rate of patients achieving MSE in the 0.3 mg / kg zilucoplan group was again evident in this analysis.

[0278] For determination of pharmacokinetic and pharmacodynamic data, minimal sampling was performed. Steady-state zilucoplan plasma concentrations were achieved within the first 2 weeks of treatment and no further accumulation was observed. Steady-state (after 2 weeks) trough levels of zilucoplan in the 0.3 mg / kg zilucoplan dose group ranged between 7,168 ng / mL and 13,710 ng / mL, while they were between 2,364 ng / mL and 7,290 ng / mL in the 0.1 mg / kg zilucoplan dose group. The 0.3 mg / kg zilucoplan dose consistently achieved complete terminal complement pathway inhibition as measured by the sheep red blood cell (sRBC) lysis assay (≥95% inhibition at trough). In contrast, the 0.1 mg / kg dose of zilucoplan did not consistently achieve complete lysis inhibition. Pharmacokinetic and pharmacodynamic results were closely correlated in patients with gMG, showing complete inhibition of the terminal complement pathway at zilucoplan plasma concentrations exceeding approximately 9,000 ng / ml.

[0279] Overall, both high-dose and low-dose zilcoplan treatments were effective with a favorable safety profile, and the higher dose resulted in more robust clinical improvement.

[0280] Extension At the end of the treatment period in the main part of the Phase 2 study described in the above example, all subjects were given the option to receive zilcoplan in the extension of the study, provided they met the extension selection criteria. Subjects assigned to the zilcoplan treatment arm during the main part of the study continued to receive the same dose of the study drug during the extension. Subjects assigned to the placebo arm during the main part of the study were randomized at a 1:1 ratio to receive a daily SC dose of either 0.1 mg / kg zilcoplan or 0.3 mg / kg zilcoplan. Assessments and visits during the first 12 weeks of the extension were the same as in the main part of the study for all subjects to ensure appropriate monitoring of subjects who had moved from placebo to active treatment and to maintain the blinding of treatment assignment.

[0281] Selection criteria for inclusion in the extension included the following: (1) positive serology for AChR autoantibodies; (2) negative serum pregnancy test at screening for female subjects of childbearing potential and negative urine pregnancy test within 24 hours prior to the first dose of the study drug; (3) consent to use effective contraception during the study for female subjects of childbearing potential who were sexually active (i.e., women who were not postmenopausal or who had not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and for all male subjects (who had not been surgically sterilized by vasectomy); (4) use of any non-permitted drug therapy or change in dosing of any other concomitant drug therapy according to the exclusion criteria from the main part of the study, unless medically indicated; and (5) no new medical conditions since entry into the main part of the study.

[0282] During the extension of the study, biopsy specimens obtained from subjects who had undergone thymectomy, lymph node resection, or other surgical resection were sent for exploratory immunohistochemical and biomarker analysis.

[0283] Forty-one patients completed the 12-week extension of the study (total treatment period of 24 weeks). Sustained responses were observed for each of the following: (1) QMG, 8.7-point reduction from baseline, p < 0.0001; (2) MG-ADL, 4.5-point reduction from baseline, p < 0.0001; (3) MG composite, 10.2-point reduction from baseline, p < 0.0001; and MG-QOL15r, 7.5-point reduction from baseline, p = 0.0006.

[0284] Placebo subjects who switched to active drug after 12 weeks also experienced rapid, clinically meaningful, and statistically significant improvements for each endpoint: (1) QMG, 3.1-point reduction from the pretreatment level (level associated with 12-week placebo treatment), p = 0.01; (2) MG-ADL, 3.6-point reduction from the pretreatment level, p = 0.0004; (3) MG composite, 5.5-point reduction from the pretreatment level, p = 0.004; and MG-QOL15r, 4.0-point reduction from the pretreatment level, p = 0.04.

[0285] (Example 4) Efficacy of Zilucoplan in the RAISE Phase 3 Clinical Study RAISE (also known as MG0010) (NCT04115293) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. The study involved daily subcutaneous treatment with zilucoplan compared to placebo over 12 weeks to evaluate the efficacy of zilucoplan in subjects with gMG, including both patients with refractory gMG and patients with non-refractory gMG.

[0286] Dosing regimen: 0.3 mg / kg of zilucoplan daily by subcutaneous injection for 12 weeks with options for extension.

[0287] Study description:

[0288] Study participants were randomized in a 1:1 ratio to receive either ZLP at a SC daily dose of 0.3 mg / kg or placebo. Randomization was stratified based on baseline MG-ADL score (≤9 vs. ≥10), baseline QMG score (≤17 vs. ≥18), and geographic region (North America, Europe, and East Asia).

[0289] The schematic of this Phase 3 study design is presented in Figure 1. The study included a screening period of up to 4 weeks and a 12-week double-blind treatment period. During the double-blind treatment period, study participants returned to the clinic at week 1, week 2, week 4, week 8, and week 12 to evaluate efficacy, safety, and tolerability.

[0290] After the 12-week double-blind placebo-controlled period, all subjects will have the option to receive zilcoplan in an open-label study extension. Subjects will be evaluated for changes in MG-ADL (primary endpoint), QMG, MG composite, and MG-QOL15r (key secondary endpoints). The primary and secondary endpoints are at week 12 (end of the double-blind period), but subjects were judged during the primary study and extension study treatments and thereafter.

[0291] Safety assessments included physical examinations, vital signs, ECG, clinical laboratory tests, AE monitoring, immunogenicity, and the Columbia Suicide Severity Rating Scale.

[0292] For all SOC therapies for gMG, drug therapies, including corticosteroids and immunosuppressive drug therapies, were maintained at the same dose throughout the 12-week study. If an escalation of gMG therapy (i.e., "rescue therapy") became necessary due to a major worsening of the study participant's clinical condition or the risk of MG crisis as determined by the investigator, the study participant could receive IVIG or PLEX treatment as "rescue therapy".

[0293] Selected inclusion criteria: Males or females aged ≥18 years and <75 years old; Diagnosis of gMG at Screening [Myasthenia Gravis Foundation of America (MGFA) Classes II-IV]; Positive serology for acetylcholine receptor (AChR) autoantibodies; MG-ADL score of ≥6 at screening and baseline; Four or more QMG test items scored ≥2 at screening and baseline, with a QMG score ≥12 at screening and baseline (acetylcholinesterase inhibitor therapy off for at least 10 hours); No change in corticosteroid dose expected to occur within at least 30 days prior to baseline or during the 12-week treatment period; No change in immunosuppressive therapy, including dose, expected to occur within at least 30 days prior to baseline or during the 12-week treatment period; and Patients immunized with meningococcal vaccine at least 2 weeks prior to administration of the first dose.

[0294] Exclusion criteria: Thymectomy within 12 months prior to baseline or scheduled to occur during the 12-week treatment period. History of meningococcal disease. Current or recent systemic infection within 2 weeks prior to baseline or an injection requiring intravenous (IV) antibiotics within 4 weeks prior to baseline.

[0295] Patient demographics and baseline disease characteristics were generally well balanced across the study treatment arms (Table 8).

[0296]

Table 8

[0297] mITT population unless otherwise specified. The mITT population includes all randomized subjects who received at least one dose of study drug and had at least one post-dose MG-ADL score. *Participants are considered "MG refractory" if they have had a treatment with at least two of the following therapies for at least 1 year: prednisone, azathioprine, mycophenolate, cyclosporine, cyclophosphamide, methotrexate, tacrolimus, rituximab, eculizumab, or other corticosteroids; or a treatment with at least one of the above therapies for more than 1 year, and a history of long-term PLEX, IVIg, or SCIg required at least every 3 months for 12 months prior to enrollment. † Safety Set. Includes all subjects who received at least one dose of the study drug, together with subjects analyzed based on the actual study treatment received.

[0298] Primary Outcome Measure:

[0299] Change from baseline to week 12 in the MG-ADL score (CFB) [Time Frame: from baseline (day 1) to week 12]. The MG-ADL profile provides a determination of the severity of MG symptoms, measuring 8 items on a 0-3 scale, with 0 being the least severe. The total sum of the 8 items represents the MG-ADL score. The MG-ADL score can range from 0 (least severe) to 24 (most severe).

[0300] Secondary Outcome Measures:

[0301] Change from baseline to week 12 in the Quantitative Myasthenia Gravis (QMG) score [Time Frame: from baseline (day 1) to week 12]. The QMG test is a standardized quantitative strength scoring system, measuring 13 items on a 0-3 scale, with 0 being the least severe. The total sum of the 13 items represents the QMG score. The QMG score can range from 0 (least severe) to 39 (most severe).

[0302] Change from baseline to week 12 in the Myasthenia Gravis Composite (MGC) score [Time frame: from baseline (day 1) to week 12]. The MGC is a 10-item scale used to measure the clinical status of patients with myasthenia gravis (MG) to assess treatment response. The MGC has 4-point Likert-type response options (weighted response options) ranging from 0 to 2, 3, 4, 5, 6, or 9 according to the item. The total score is the sum of all items (range 0-50), where a higher score indicates more severe dysfunction due to the disease.

[0303] Change from baseline to week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QOL15r) score [Time frame: from baseline (day 1) to week 12]. The MG-QOL15r is a 15-item survey designed to determine the quality of life in patients with MG. The MG-QOL has 3-point Likert scale response options ranging from 0 to 2. The MG-QOL15r score can range from 0 to 30, where a higher score indicates a more severe impact of the disease on aspects of the patient's life.

[0304] Time to first rescue therapy during the 12-week treatment period until receipt [Time frame: treatment period (day 1 to week 12)]. For patients who require rescue treatment, the time from the first investigational medicinal product (IMP) to the first dose of rescue treatment is calculated.

[0305] Percentage of participants who achieved minimal symptom expression (MSE) at week 12 [Time frame: week 12]. MSE is defined as MG-ADL of 0 or 1 at week 12 without rescue therapy. The MG-ADL profile provides a determination of MG symptom severity, measuring 8 items on a 0-3 scale, with 0 being the least severe. The overall total of 13 items represents the MG-ADL score. The MG-ADL score can range from 0 (least severe) to 24 (most severe).

[0306] Percentage of participants who achieved a 3-point reduction in the MG-ADL score at week 12 without rescue therapy [time frame: week 12]. The MG-ADL profile provides an assessment of gMG symptom severity, measuring 8 items on a 0-3 scale, with 0 being the least severe. The total of 13 items represents the MG-ADL score. The MG-ADL score can range from 0 (least severe) to 24 (most severe). A 3-point change in this assessment is considered clinically meaningful.

[0307] Percentage of participants who achieved a ≥5-point reduction in the QMG score at week 12 without rescue therapy [time frame: week 12]. The QMG test is a standardized quantitative intensity scoring system, measuring 13 items on a 0-3 scale, with 0 being the least severe. The total of 13 items represents the QMG score. The QMG score can range from 0 (least severe) to 39 (most severe). A change in the QMG score of 3 points or more can be considered clinically meaningful in a typical clinical trial population of gMG patients.

[0308] Incidence of treatment-emergent adverse events (TEAEs) [time frame: from baseline (day 1) to safety follow-up visit (up to week 19)]. Treatment-emergent adverse events are any adverse medical occurrences in patients or clinical study participants that are temporally associated with the use of the study drug therapy, whether considered related or not related to the study drug therapy.

[0309] Of the 174 study participants who were dosed in this study, 166 completed the study. Overall, zilucoplan demonstrated a favorable safety profile and good tolerability.

[0310] Efficacy of zilucoplan in the patient population

[0311] This series of data demonstrates the efficacy of zilucoplan in a broader patient population, including non-refractory and / or refractory gMG patients.

[0312] To evaluate efficacy in a broad patient population, the following clinical determinations were made: The MG-ADL score was the primary outcome measure, and the key secondary outcome measures were the QMG scale, MGC, and MG-QOL15r. The secondary outcome measures were as follows: time to first administration of rescue therapy over a 12-week treatment period, achieving minimal symptom expression (MSE) defined as MG-ADL of 0 or 1 at week 12 without rescue therapy, achieving a ≥3-point reduction in the MG-ADL score at week 12 without rescue therapy, and achieving a ≥5-point reduction in the QMG score at week 12 without rescue therapy. The exploratory outcome measure included responder analysis for changes in the MG-ADL and QMG composite scores from baseline without rescue therapy. The results are presented below. There were clinically meaningful and statistically significant improvements in the zilcoplan treatment group compared to placebo in the primary and key secondary variables. The efficacy results in all other efficacy determinations were consistent with the above results, demonstrating robust and consistent efficacy of zilcoplan in different aspects of gMG.

[0313] Efficacy of zilcoplan in all study participants with generalized myasthenia gravis: MG-ADL score

[0314] Clinically meaningful improvement (defined as ≥2-point reduction) and statistically significant improvement from baseline in the MG-ADL score were observed at week 12 in the zilcoplan (ZLP) treatment group compared to placebo (Table 9). The jump-to-reference sensitivity analysis (as required by the European Medicines Agency) was consistent with the primary analysis.

[0315]

Table 9

[0316] The changes from baseline over time in the MG-ADL score are presented in Figure 2 for the modified intention-to-treat (mITT) population. The rapid separation of the curves started at week 1 and then steadily increased until week 4. This effect was maintained up to week 12 (nominal p < 0.05 for the LS mean difference for all post-baseline visits). Figure 2 illustrates that zilcpuran very significantly and clinically significantly reduced MG-ADL from baseline to week 12, with the least squares (LS) mean difference (95% CI) being -2.12 (-3.26, -0.97) compared to placebo (p < 0.001).

[0317] As detailed below, the least squares (LS) mean difference for zilcpuran compared to placebo at week 12 for the key secondary efficacy endpoints was also very statistically significant and clinically meaningful: -3.07 (-4.48, -1.66; p < 0.001) for QMG, -3.20 (-5.54, -1.16; p = 0.0023) for MGC, and -2.51 (-4.46, -0.55; p < 0.02) for MG-QoL15r. The rapid separation of the zilcpuran and placebo curves for the key primary and secondary efficacy endpoints started at week 1, increased until week 4, and then steadily increased up to week 12 (nominal p < 0.05 for the LS mean difference for all post-baseline visits; Figures 2 - 5).

[0318] Efficacy of zilcpuran in all study participants with generalized myasthenia gravis: QMG score

[0319] Clinically meaningful improvement (defined as a reduction of ≥ 3 points) and statistically significant improvement from baseline in the QMG score were observed in the ZLP treatment group at week 12 compared to placebo (Table 10).

[0320]

Table 10

[0321] The change from baseline over time in the QMG score is presented for the mITT population in (Figure 3). The rapid separation of the curves started at week 1 and then increased steadily until week 4. This effect was maintained up to week 12 (nominal p < 0.05 for the LS mean difference for all visits after baseline).

[0322] Efficacy of zilcpuran for all study participants with generalized myasthenia gravis: MGC score

[0323] Clinically meaningful improvement from baseline (defined as a reduction of ≥ 3 points) and statistically significant improvement in the MGC score were observed for the ZLP treatment group at week 12 compared to placebo (Table 11).

[0324]

Table 11

[0325] The change from baseline over time in the MGC score is presented for the mITT population in (Figure 4). The rapid separation of the curves started at week 1 and then increased steadily until week 4. This effect was maintained up to week 12 (nominal p < 0.05 for the LS mean difference for all visits after baseline).

[0326] Efficacy of zilcpuran for all study participants with generalized myasthenia gravis: MG QOL15r score.

[0327] Statistically significant improvement from baseline in the MG QOL15r score was observed for the ZLP treatment group at week 12 compared to placebo (Table 12). The threshold for the minimal clinically important difference (MCID) has not yet been defined for MG QOL15r.

[0328]

Table 12

[0329] Changes from baseline over time in the MG-QOL15r score are presented for the mITT population in (Figure 5). The rapid separation of the curves started at week 1 and then steadily increased until week 4. This effect was maintained up to week 12 (nominal p < 0.05 for the LS mean difference for all visits after baseline). Notably, no threshold or minimally clinically important difference has been established for this scale.

[0330] Secondary endpoint: Time to first rescue therapy

[0331] Substantially fewer participants received rescue therapy by week 12 in the ZLP treatment group compared to placebo (Tables 13 and Figure 6).

[0332]

Table 13

[0333] Secondary endpoint: Response rate

[0334] Figures 7A - 7C illustrate the response rates for MG-ADL without rescue therapy (Figure 7A), QMG score (Figure 7B), and minimal manifestation of symptoms (MSE) (Figure 7C) at week 12 for placebo vs. zilcoplan (ZLP). Significantly more participants treated with ZLP achieved a reduction of ≥3 points in the MG-ADL score (73.1% vs. 46.1%, p < 0.001) (Figure 7A) and a reduction of ≥5 points in the QMG score (58.1% vs. 33.1%, p = 0.0012) (Figure 7B) at week 12 compared to placebo. Substantially more participants in the ZLP arm achieved MSE (MG-ADL score of 0 or 1) compared to placebo (14.0% vs. 5.8% respectively) (Figure 7C). Numerically higher rates are observed at week 12 with ZLP compared to dupilumab at week 26 (phase 3 study REGAIN, Howard et al., 2017).

[0335] Exploratory endpoint: Responder analysis for changes in MG-ADL

[0336] Figure 8 shows the responder analysis for changes in MG-ADL scores at week 12 in the modified intention-to-treat (mITT) population of the RAISE clinical study. The graph in Figure 8 shows the minimal point improvement in the MG-ADL score; that is, the negative value scale represents a greater score decrease from baseline. A greater proportion of participants who received ZLP showed improvement in the MG-ADL score response at week 12 compared to placebo (Figure 8). Participants who received rescue medication therapy were classified as non-responders after the first administration of rescue medication therapy.

[0337] Exploratory endpoint: Responder analysis for changes in QMG

[0338] Figure 9 shows the responder analysis for changes in QMG scores at week 12 in the modified intention-to-treat (mITT) population of the RAISE clinical study. Participants who received rescue medication therapy were classified as non-responders after the first administration of rescue medication therapy. A greater proportion of participants who received ZLP showed improvement in the QMG response at week 12 compared to placebo (Figure 9).

[0339] The MG-ADL and QMG response rates for each level of improvement are shown in Figures 8 - 9. Logistic regression analysis showed that 76.5% of zirconoplan patients achieved a 3-point improvement in MG-ADL compared to 46.1% in the placebo arm (OR [95%CI] = 3.182 [1.660, 6.098]; p < 0.001). A ≥5-point improvement in QMG was seen in 58.0% of patients who received zirconoplan compared to 33.1% in the placebo arm (OR [95%CI] = 2.869 [1.520, 5.418]; p = 0.0012).

[0340] The MG-ADL results in subgroups based on baseline demographics or disease characteristics resembled those seen in the overall population. CFB in MG-ADL at week 12 using zilcoplan versus placebo for the following: age (<65 years: -4.56 vs -2.75; ≥65 years: -5.14 vs -3.08), sex (male: -5.12 vs -2.85; female: -4.43 vs -2.84), baseline MG-ADL (≤9: -3.88 vs -2.48; ≥10: -5.24 vs -3.06) and region (North America: -4.67 vs -3.61; Europe: -4.74 vs -2.31; Asia: -4.71 vs -1.00).

[0341] Further analysis

[0342] Adults with AChR-positive gMG (MGFA disease classes II-IV) were randomized 1:1 to receive daily subcutaneous zilcoplan (ZLP) 0.3 mg / kg (n = 86) or placebo (PBO; n = 88) for 12 weeks. MG-ADL and QMG responders (≥3- and ≥5-point improvements, respectively) were determined and a post-hoc analysis of baseline disease characteristics for treatment response was performed. The responder rate at week 12 was higher for ZLP compared to PBO (MG-ADL: 73% vs 46%, p < 0.001; QMG: 58% vs 33%, p = 0.0012). ZLP showed rapid onset of efficacy: at week 1, 45% and 32% of ZLP patients were MG-ADL and QMG responders, respectively (PBO: 30% and 8%). There were no significant differences in baseline disease characteristics between MG-ADL responders and non-responders at week 12, and the MG-ADL responder rate continued to increase up to week 12 at most.

[0343] Figures 10A-10D and 11A-11C illustrate baseline characteristics for MG-ADL responders and non-responders at week 12 (zilucoplan responders n = 63, zilucoplan non-responders n = 23, placebo responders n = 43, placebo non-responders n = 45). Figures 10A-10D, continuous characteristics. Figure 10A, age at baseline. Figure 10B, age at diagnosis. Figure 10C, disease duration at baseline. Figure 10D, MG-ADL score at baseline. CI, confidence interval. Figures 11A-11C, categorical characteristics. Figure 11A, gender (male). Figure 11B, refractory status (yes). Figure 11C, at least two previous MG therapies excluding acetylcholinesterase inhibitor (AChEI). CI is not adjusted for covariates or multiple testing. CI, confidence interval.

[0344] Extension study

[0345] MG0011 is a multicenter, open-label extension study to evaluate the long-term efficacy, safety, and tolerability of zilucoplan in study participants with gMG who have previously participated in a qualifying ZLP study. Study participants receive zilucoplan 0.3 mg / kg SC until zilucoplan is approved and available in the territory or until UCB discontinues the development of zilucoplan for gMG. All study participants who completed Study MG0010 decided to enter Study MG0011. The good rollover rate indicates the preference of patients and clinicians to continue long-term treatment.

[0346] Summary

[0347] The approval of eculizumab was a major advance but does not address the needs of all gMG patients. Many patients still experience significant disease burden (QMG ≥ 12 or MG-ADL ≥ 6) despite current treatments.

[0348] Retrospective analysis of MG-ADL and QMG scores recorded during the Eculizumab REGAIN study and its open-label extension (OLE) showed that there remained a non-negligible proportion of participants who did not respond to the drug and / or were long responders (Howard et al., 2017), thus indicating the need for alternative therapies as eculizumab may not be the best option. For example, between week 12 of eculizumab treatment and the end of OLE, MG-ADL response was achieved by 17% of participants (MG-ADL late responders), and 15% of participants did not achieve the defined MG-ADL response during eculizumab treatment (MG-ADL non-responders). For QMG, 15% of participants achieved QMG response between week 12 and the end of OLE (QMG late responders); 29% of participants did not achieve the defined QMG response during eculizumab treatment (QMG non-responders).

[0349] In the double-blind part of the REGAIN study, approximately 40% to 55% of randomized participants were classified as non-responders at week 26 (<3-point reduction in MG-ADL or <5-point reduction in QMG [Howard, 2017]).

[0350] The Zilucoplan Phase 3 study described above studied a broad population of moderate to severe participants with gMG regardless of previous treatment history.

[0351] Zilucoplan demonstrated consistent statistically significant and clinically meaningful benefits across all clinical endpoints (MG-ADL, QMG, MG-QOL15r, and MGC) and a favorable safety and tolerability profile in a wide range of study participants living with gMG. This reinforces the role of the terminal complement cascade in gMG pathogenesis in all AChR-positive participants, not just those considered "refractory" to SOC therapy.

[0352] The primary endpoint of the trial was met; a clinically significant (MCID = 2) and statistically significant improvement from baseline in the MG-ADL score at week 12 was observed in the zilcoplan treatment group compared to placebo. All key secondary endpoints of the trial were met; a statistically significant improvement from baseline in the QMG, MGC, and MG-QoL15r scores was observed in the zilcoplan treatment group at week 12 compared to placebo.

[0353] Overall, zilcoplan demonstrated a favorable safety profile and good tolerability; there were no major safety findings. The incidence of serious TEAEs in the zilcoplan and placebo treatment arms was also similar.

[0354] The data and analyses presented herein clearly demonstrate the efficacy of zilcoplan in a broad patient population, including patients with non-refractory and / or refractory gMG.

[0355] Efficacy of zilcoplan in non-refractory gMG compared to refractory gMG

[0356] In this Phase 3 gMG randomized study, the ZLP 0.3 mg / kg dose demonstrated significant benefit in a broad gMG study participant population, including approximately 50% of non-refractory study participants (compared to the refractory population as defined herein). By the inclusion criteria for the Eculizumab Phase 3 study (REGAIN study), treatment-refractory status was defined as follows: (clintrials.gov) a. Failure of treatment for over 1 year using two or more immunosuppressive therapies (ISTs), either in combination or as monotherapy (i.e., continuing to have functional impairment in activities of daily living [persistent fatigue, experience of crises, or inability to tolerate IST]); or b. Failure of at least 1 type of IST and the need for long-term plasmapheresis, plasma exchange (PLEX), or IVIg to control symptoms (i.e., study participants who required PLEX and / or IVIg regularly for the management of muscle strength decline every 3 months for at least 3 months over the previous 12 months)

[0357] Immunosuppressive therapy includes, but is not limited to, corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.

[0358] The ZLP Phase 3 study defines its refractory and non-refractory populations according to the same entry criteria.

[0359] A pre-specified subgroup analysis was performed to understand whether the treatment response differed significantly between people considered "refractory" (by the definition in the eculizumab program) and those considered non-refractory. This analysis showed variation in the observed effect sizes at some endpoints; however, the overall data demonstrated the efficacy of ZLP in both subpopulations (Table 14). For QMG in particular, it is considered a more objective physician-reported scale compared to MG-ADL, which is a patient-reported outcome.

[0360]

Table 14

[0361]

Table 15

[0362] These data suggest that zilucoplan can provide additional clinical benefit to a broad population of patients.

[0363] Improvement in the efficacy of zilucoplan compared to eculizumab in patients with refractory gMG

[0364] Analysis of the clinical outcome data of this study demonstrates the efficacy of zilucoplan in treating patients with refractory gMG. In addition, these clinical outcomes were compared with the results obtained using eculizumab in the REGAIN study for the treatment of refractory gMG.

[0365] While cross-study comparisons should be made with caution, it is notable that the clinical effect of zilucoplan administered at 0.3 mg / kg daily SC, as measured by MG-ADL and QMG at week 12 in the refractory population, was numerically higher when compared to the effect observed with eculizumab at week 26 in the REGAIN study (Table 16).

[0366]

Table 16

[0367] These results indicate that consistent and greater clinical benefit is achieved with zilucoplan compared to eculizumab in a shorter period, even in patients with refractory gMG.

[0368] Incorporation by Equivalents and Reference Although the present invention has been shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.

[0369] All references, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

**Claim 1** A method of treating refractory generalized myasthenia gravis (gMG) in a human patient in need thereof, comprising: (i) being positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors, and (ii) administering to a human patient identified as having refractory gMG a therapeutically effective amount of zilucoplan. The method as described above. **Claim 2** The method according to claim 1, wherein prior to administration, the patient is refractory to treatment with immunosuppressive drug therapy (IST) for more than one year and requires long-term plasma exchange or long-term IVIG to maintain clinical stability. **Claim 3** The method according to claim 1 or 2, wherein the patient experiences a reduction in the myasthenia gravis activities of daily living (MG-ADL) score of at least 3 points from baseline 12 weeks after treatment. **Claim 4** The method according to any one of claims 1 to 3, wherein the patient experiences a reduction in the MG-ADL score of at least 2 points from baseline 8 weeks after treatment. **Claim 5** The method according to any one of claims 1 to 4, wherein the patient experiences a clinically significant improvement (reduction) in the quality of life as measured by the quantitative myasthenia gravis (QMG) score, the myasthenia gravis composite (MGC) score, or the myasthenia gravis quality of life revised (MG-QOL-15r) score 12 weeks after treatment. **Claim 6** The method according to claim 5, wherein the patient experiences a reduction in the QMG score of at least 3 points from baseline 12 weeks after treatment. **Claim 7** The method according to claim 6, wherein the patient experiences a reduction in the QMG score of at least 3 points from baseline 8 weeks after treatment. **Claim 8** The method according to any one of claims 5 to 7, wherein the patient experiences a reduction in the MGC score of at least 3 points from baseline 12 weeks after treatment. **Claim 9** The method according to any one of claims 5 to 8, wherein the patient experiences a reduction in the MG-QOL-15r score of at least 2 points from baseline 12 weeks after treatment. **Claim 10** The method according to any one of claims 1 to 9, wherein zilucoplan is administered subcutaneously daily to the patient for 12 weeks or more. **Claim 11** The method according to claim 10, wherein zilcoplan is administered at a daily dose of from about 0.1 mg / kg (mg of zilcoplan per kg of the subject body weight) to about 0.6 mg / kg.

12. The method according to claim 11, wherein zilcoplan is administered at a daily dose of 0.3 mg / kg.

13. The method according to any one of claims 1 to 12, wherein zilcoplan is administered using a self - administration device comprising a pre - filled syringe containing a zilcoplan - free - preservative 40 mg / mL aqueous solution or its sodium salt form having a volume of from about 0.15 mL to about 0.81 mL.

14. The method according to any one of claims 1 to 13, wherein the patient is between 18 and 85 years old.

15. The method according to any one of claims 1 to 14, wherein the patient does not require or receive rescue therapy during zilcoplan administration.

16. The method according to any one of claims 1 to 15, wherein zilcoplan administration is carried out at an MG disease stage that is before the severe or crisis stage of MG.

17. The method according to any one of claims 1 to 16, wherein the patient simultaneously receives standard care gMG therapy throughout the course of zilcoplan treatment, and the standard care gMG therapy comprises one or more of cholinesterase inhibitor treatment, pyridostigmine treatment, corticosteroid treatment, and IST.

18. The method according to any one of claims 1 to 17, further comprising the step of co - administering to the patient a therapeutically effective amount of an additional therapeutic agent.

19. The additional therapeutic agent is an immunosuppressant selected from azathioprine, cyclosporine, cyclosporine A, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab; and selected from inhibitors of self - antibody - mediated tissue destruction comprising a neonatal Fc receptor (FcRn) inhibitor, and administration of the FcRn inhibitor comprises intravenous immunoglobulin (IVIG) treatment, the method according to claim 18.

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