Compositions and methods for treating myasthenia gravis

Abstract

Disclosed herein are methods of treating myasthenia gravis (MG), comprising administering (2S)-2-[4-bromo-2-(1, 2-oxazol-3-yl) phenoxy] propionic acid, or a pharmaceutical composition thereof, to a patient suffering from a symptom of MG. Also disclosed are pharmaceutical compositions and multi-component kits comprising (2S)-2-[4-bromo-2-(1, 2-oxazol-3-yl) phenoxy] propionic acid.

Description

Technical Field

[0001] The present disclosure relates to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid for treating myasthenia gravis (MG), a pharmaceutical composition thereof for treating MG, and a method of treating the same. Background Art

[0002] Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) characterized by voluntary skeletal muscle weakness and fatigability, which worsens as the muscles continue to work and improves as the relevant muscles rest (Borges et al., Front. Immunol. 2020, 11: 707). For MG, the distribution of weakness is unique, usually involving the extraocular muscles. MG may initially begin with weakness of the eye muscles that affect eyeball and eyelid movement, known as ocular MG (ocular MG, oMG). In more severe cases (generalized MG), muscles innervated by the pons and medulla oblongata, as well as respiratory muscles, are also usually affected. The least frequently affected are the muscles of the limbs.

[0003] MG can cause life-threatening respiratory failure, called a myasthenic crisis. Approximately 15% to 20% of patients experience a myasthenic crisis during their illness, and 75% of these patients experience a myasthenic crisis within 2 years of diagnosis, requiring hospitalization and ventilatory support.

[0004] In the United States, MG affects approximately 60,000 Americans, with an incidence of 14-20 per 100,000 people. It affects men and women equally, but peak incidence occurs in women in their third decade and in men in their sixth or seventh decade. MG has a mortality rate of approximately 4%, primarily due to respiratory failure.

[0005] MG is typically caused by autoantibodies that target the neuromuscular junction. In generalized MG, approximately 90% of patients have circulating antibodies (Abs) that target the nicotinic acetylcholine receptor (AChR), a postsynaptic neurotransmitter receptor. Loss of AChR function leads to impaired neuromuscular transmission, which results in a failure of muscle fiber activation and ultimately leads to muscle weakness and excessive fatigue. At the neuromuscular junction, the transmission of the nerve action potential to the muscle membrane involves the flow of both excitatory and inhibitory currents. Muscle excitation requires that the excitatory current flow exceeds the inhibitory current flow. In myasthenia gravis, due to the loss of AChRs, the excitatory current is reduced.

[0006] Other commonly detected antibodies in MG patients are those that target the muscle-specific kinase (MuSK) protein. This form of MG is known as MuSK-MG (Borges et al., Front. Immunol. 2020, 11:707). Although MuSK-MG is also an antibody-mediated disease, inflammatory damage to the NMJ does not occur. In fact, most antibodies belong to the IgG4 immunoglobulin subclass, which is characterized in part by the inability to activate complement or bind to Fc receptors. The proposed mode of action of these autoantibodies is to block the normal function of MuSK.

[0007] Although MG cannot be cured, currently available treatments for generalized myasthenia gravis aim to modulate neuromuscular transmission, inhibit the production or action of pathogenic antibodies, inhibit the cleavage of complement component 5, or suppress inflammatory cytokines. Current standard treatment typically combines a cholinesterase inhibitor (most commonly pyridostigmine), a corticosteroid (usually prednisone), and an immunosuppressive drug (most commonly azathioprine, cyclosporine, and mycophenolate mofetil), and most patients with MG have their disease fairly well controlled. Some patients, despite resistance or intolerance to standard therapeutic agents, would benefit from new treatment options.

[0008] Many standard treatments for AChR-MG, including thymectomy and cholinesterase inhibitors, have limited efficacy in MuSK-MG. Therefore, current treatment involves immunosuppression, primarily using corticosteroids or B-cell depleting agents.

[0009] Skeletal muscle-specific ClC-1 chloride channels carry inhibitory currents that counteract neuromuscular transmission. Inhibiting ClC-1 reduces this inhibitory current, thereby increasing muscle membrane excitability and enhancing neuromuscular transmission. This has been shown to restore muscle function in a variety of nonclinical models of neuromuscular disease (Pedersen et al., Acta Physiol. 2021, 1–14).

[0010] Therefore, the ClC-1 ion channel is emerging as a potential drug target, although its potential has not yet been fully realized. US Patent No. 10,385,028 discloses the synthesis of compounds designed to inhibit the action of the ClC-1 ion channel for the treatment of neuromuscular disorders.

[0011] One of the compounds discussed in U.S. Patent No. 10,385,028 is (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, hereinafter referred to as NMD670. The chemical structure of NMD670 is shown below.

[0012]

[0013] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid (NMD670)

[0014] While U.S. Patent No. 10,385,028 discloses a group of compounds that can inhibit the ClC-1 ion channel to treat neuromuscular disorders, it does not discuss how to design treatments so that these compounds can effectively alleviate the wide range of symptoms associated with myasthenia gravis, which fluctuate daily. WO2020 / 254554 (incorporated herein by reference) discloses a method for making NMD670.

[0015] Therefore, due to the limited effectiveness of existing therapies and / or the side effects they cause, there is a need for safe and effective therapies to improve muscle function in patients with all forms of MG. Summary of the Invention

[0016] The present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0017] The present disclosure also relates to a composition formulated into a solid dosage form, comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the composition comprises 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0018] The present disclosure also relates to a method for improving a quantitative myasthenia gravis total score in a subject with myasthenia gravis or improving right hand grip strength in a subject with myasthenia gravis, the method comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0019] The present disclosure also relates to a kit-of-parts or composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor for use in a method of treating myasthenia gravis in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1

[0021] Figure 1 The effects of NMD670 on membrane conductance (G) in the soleus muscle of healthy rats (n=20) and EAMG rats (n=12) are depicted. m ) influence, the G m Expressed as the mean G measured in muscles before (black circles or open squares, respectively) and after (black triangles or open inverted triangles, respectively) addition of 20 μM NMD670. m The black overlay bars are the mean ± SEM of each group. Addition of NMD670 statistically significantly reduced G in healthy and EAMG animals. m。

[0022] Figure 2

[0023] Figure 2 Depicted is the effect of ClC-1 inhibition on skeletal muscle fiber excitability, as assessed by the base current in skeletal muscle fibers of healthy and myasthenia gravis (EAMG) rats. Base current (nA) in soleus muscle fibers of healthy rats (n=20) and EAMG rats (n=12) is expressed as the average base current measured before (black circles or hollow squares, respectively) and after (black triangles or hollow inverted triangles, respectively) the addition of 20 μM NMD670. The black overlay bar shows the mean ± SEM of each group. Adding NMD670 significantly reduced the base current in the muscle fibers of these two groups of rats.

[0024] Figure 3

[0025] Figure 3 Depicted are the endplate potential (EPP) amplitudes of healthy rats (left trace), untreated EAMG rats (middle trace), and EAMG rats after addition of 20 μM NMD670 (right trace). Compared to the EPP of healthy rats, the EPP in EAMG rat muscle fibers was significantly reduced but could be restored after addition of NMD670.

[0026] Figure 4

[0027] Figure 4 Depicted are the mean endplate potential (EPP) amplitudes of 68 myofibers (black diamonds) from EAMG rats without ClC-1 inhibitors and 82 myofibers (open circles) in the presence of 20 μM NMD670 during 30 12 Hz stimulations. Inhibition of ClC-1 by NMD670 increased the EPP by more than 35% during the 12 Hz stimulation train.

[0028] Figure 5

[0029] Figure 5 Depicted are action potentials in muscle fibers stimulated at 30 Hz from healthy rats (left trace), untreated EAMG rats (middle trace), and EAMG rats supplemented with 20 μM NMD670 (right trace). Compared to healthy rats (left trace), sustained action potential firing was impaired in neuromuscular preparations from untreated EAMG rats (middle trace), but the success rate of repetitive action potential firing was significantly improved after supplementation with 20 μM NMD670 (right trace).

[0030] Figure 6

[0031] Figure 6 Depicted are the mean success rate (%) of action potential generation attempts at 30 Hz stimulation before and after treatment with 20 μM NMD670 (n=110 myofibers in both groups). The success rate of repetitive action potential generation was significantly improved after addition of 20 μM NMD670.

[0032] Figure 7

[0033] Figure 7 Depicted are the forces of isolated soleus muscles from healthy rats (left trace), untreated EAMG rats (middle trace), and EAMG rats supplemented with 20 μM NMD670 (right trace) under 60 Hz nerve stimulation. Compared to the forces of healthy rats, the forces of myofibers from EAMG rats were significantly reduced but recovered after the addition of NMD670.

[0034] Figure 8

[0035] Figure 8 Depicted are mean forces of isolated nerve-stimulated soleus (n=14), EDL (n=14), and diaphragm (n=12) muscles from EAMG animals treated with 20 μM NMD670 compared to pre-treatment muscles (values ​​set to 100). Addition of NMD670 restored force production to levels approaching those observed in muscles from healthy animals.

[0036] Figure 9

[0037] Figure 9 Depicted are the nerve stimulation force (bottom panel) and EMG amplitude (top panel) of the triceps surae muscles of age-matched healthy rats (left trace) and myasthenia gravis (EAMG) rats with an EAMG score of 2, which were stimulated via the sciatic nerve at 80 Hz for 1 second before (middle trace) and 20 minutes after (right trace) administration of 40 mg / kg body weight of NMD670. Administration of NMD670 in EAMG animals resulted in rapid recovery of force and EMG amplitude.

[0038] Figure 10

[0039] Figure 10 The muscle strength of EAMG rats (e.g. Figure 8 Figure 1 shows the average muscle strength (mean ± SEM) before (white) and after (grey) oral administration of NMD670 (from 2 to 120 mg / kg). The figure shows that the administration of NMD670 in EAMG rats leads to a rapid and dose-dependent recovery of muscle strength. The numbers in the columns represent the number of rats in each dose group.

[0040] Figure 11

[0041] Figure 11 Depicted are increases in grip strength (45 minutes post-dose) in EAMG rats receiving vehicle (black, n=35), 0.375 mg / kg body weight pyridostigmine bromide (Mestinon) (grid pattern, n=10), 20 mg / kg body weight NMD670 (diagonal line, n=17), or a combination of 0.375 mg / kg body weight pyridostigmine bromide and 20 mg / kg body weight NMD670 (horizontal line, n=5). Grip strength increased significantly after administration of NMD670 or the combination of NMD670 and pyridostigmine bromide. Vehicle treatment did not affect grip strength.

[0042] Figure 12

[0043] Figure 12 Depicted are grip strength relative to body weight in EAMG rats receiving vehicle (solid black circles) or 20 mg / kg NMD670 twice daily (open circles) for 14 days of chronic administration. Throughout the treatment period, rats receiving NMD670 had increased grip strength relative to the vehicle group.

[0044] Figure 13

[0045] Figure 13 Depicted are rotarod performance relative to body weight in EAMG rats receiving vehicle (solid black circles) or 20 mg / kg NMD670 twice daily for 14 days of chronic administration (open circles). Throughout the treatment period, rats receiving NMD670 had greater endurance on the rotarod (longer latency to fall) relative to the vehicle group.

[0046] Figure 14

[0047] Figure 14 Depicted are body weights of EAMG animals receiving vehicle (solid black circles) or 40 mg / kg BID NMD670 (open circles) over 14 days of chronic dosing relative to individual body weight on study day 0. Treated animals experienced reduced weight loss (compared to vehicle) during the study.

[0048] Figure 15

[0049] Figure 15 The number of adverse events recorded during the single ascending dose study is shown. Row 4 describes the total incidence of all adverse events (AEs) for that dose of NMD670, with the number of subjects reporting that AE in parentheses. Row 5 describes the total incidence of serious adverse events (SAEs). The lower half of the table describes the incidence of the most common adverse events (recorded in more than one subject). The number of subjects reporting that AE is in parentheses.

[0050] Figure 16

[0051] Figure 16 The study design of a double-blind, placebo-controlled, three-way crossover comparison of two single oral doses of NMD670 in men and women with stable symptoms of myasthenia gravis is described.

[0052] Figure 17

[0053] Figure 17 Depicted is a timeline of activities during Part C of the Phase IIA clinical trial. QMG: Quantitative Myasthenia Gravis Scale; RNS: Repetitive Nerve Stimulation; MVRC: Muscle Velocity Recovery Cycle; RoVEMP: Repetitive Oculovestibular Myogenic Potential. The time points indicated in the timeline are approximate.

[0054] Figure 18

[0055] Figure 18 Depicted is a study diagram of a prospective Phase 2b clinical trial. BID = twice daily; N = number of participants.

[0056] Figure 19A and 19B

[0057] Figure 19A and 19B Depicts a timeline of activities for a predictive Phase 2b clinical trial. Note: Whenever possible, assessments should be performed at the same time across visits and in the order shown in the table unless otherwise noted.

[0058] Abbreviations: AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EOT = end of treatment; FU = follow-up; HIV = human immunodeficiency virus; IRT = interactive response technology; myasthenia gravis activities of daily living; MGC = myasthenia gravis composite scale; MG-QOL15r = myasthenia gravis quality of life 15-item revised; QMG = quantitative myasthenia gravis score; Neuro-QoL; PK = pharmacokinetics; SAE = serious adverse event; WOCBP = women of childbearing potential.

[0059] definition

[0060] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0061] The nomenclature used in this application is based on IUPAC systematic nomenclature, unless otherwise indicated.

[0062] The term "patient" or "subject" refers to a person (e.g., a male or female human) who has been diagnosed with MG. The Myasthenia Gravis Foundation of America Classification (MGFA) clinical classification (Barnett et al., Neurol Clin. 2018, 36(2):339-353) can be used to diagnose and classify MG patients.

[0063] The term "Quantitative Myasthenia Gravis Total Score" (QMG Total Score) refers to a 13-item standardized test used in clinical trials to measure muscle strength, endurance, or fatigability (Barohn et al., Ann N Y Acad Sci 1998, 841:769–72) (see Table 1). These items measure the following symptoms and signs: ptosis, diplopia, double vision, swallowing, speech (dysarthria episodes), percentage of predicted forced vital capacity, grip strength (2 items), arm muscle endurance (2 items), leg muscle endurance (2 items), and head lift endurance. All items are scored on a scale of 0 to 3, with a total score range of 0 to 39; higher scores indicate greater disease severity.

[0064] The term "improvement" refers to a reduction in myasthenia gravis (MG) symptoms in a patient when a composition described herein is administered to the patient, as compared to the patient's MG symptoms when a placebo is administered to the patient. The term "improvement" may also refer to a reduction in MG symptoms in a group of patients after administration of a composition described herein to the group of patients, for example, as assessed by a comparative test score between the group of patients administered a composition described herein and a control group receiving, for example, a placebo. Improvement in a patient's MG symptoms can be determined, for example, using the following indicators: a quantitative myasthenia gravis (QMG) total score (where a decrease in the QMG total score means that the patient's symptoms have improved); an improvement in hand grip strength (where an increase in the force measured by the dynamometer means that the patient can pull a heavier weight); an increase in compound muscle action potentials; recovery from muscle degeneration; a decrease in the MG activities of daily living profile (MG-ADL) score, an increase in muscle strength, a decrease in the Myasthenia Gravis Composite (MGC) scale, a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score, an increase in health status determined using the EQ-5D scale, a decrease in tremor; a decrease in blockade; a decrease in a personalized neuromuscular quality of life score; a decrease in the Fatigue Severity Scale score, and / or an improvement in lung function. In an exemplary embodiment, improvement in MG symptoms includes a decrease in the QMG total score.

[0065] The term "jitter" refers to the variation in the time it takes for action potentials to arrive at the recording electrode between successive electrical stimuli when measuring neuromuscular function using single-fiber electromyography (sfEMG).

[0066] The term "blocking" refers to the complete failure of action potential transmission to the NMJ of the recording electrode between successive electrical discharges when measuring neuromuscular function using sfEMG.

[0067] The term "placebo" refers to a dosage form that has no therapeutic activity.

[0068] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that possesses a specific biological activity.

[0069] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used to formulate a drug product.

[0070] The term "pharmaceutical composition" refers to a preparation that is in such form that the biological activity of the active ingredient contained therein is effective and that contains no other ingredients that are unacceptably toxic to a subject to which the composition is to be administered.

[0071] The term "pharmaceutically acceptable" refers to the properties of materials that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and have neither biologically nor other adverse effects, and are acceptable for veterinary and human pharmaceutical use.

[0072] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical composition other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers or acidifiers, excipients, stabilizers, or preservatives.

[0073] The term "solid dosage form release" refers to the amount of compound that is released or dissolved into solution after a specified period of time when using a United States Pharmacopeia (USP) Type 2 dissolution apparatus with a paddle speed of 75 rpm and a temperature of 37°C ± 0.5°C in 900 mL of phosphate / citrate buffer, pH 6.8, as described in Example 10.

[0074] The term "C max ” (expressed in ng / mL) refers to the maximum observed plasma concentration of NMD670. The term “mean C max " refers to each C max The arithmetic mean of the values.

[0075] The term "T max ” (expressed in hours, or T max The median number of hours after drug administration is the median number of hours observed to reach C max time; if it occurs at more than one time point, then T max Defined as the first time point with this value.

[0076] The term "dose" refers to the dose of NMD670 free acid administered to a subject. Additionally, the term "dose" may include NMD670 in combination with a pharmaceutically acceptable salt.

[0077] As used herein, the term "therapeutically effective dose" refers to the amount of NMD670 required to elicit a therapeutic response in a subject. The terms "therapeutically effective dose" and "therapeutic dose" are used interchangeably herein.

[0078] The composition comprising a (therapeutic) dose can be administered in one or more unit dosage forms. As used herein, "unit dosage form" refers to a physically discrete unit suitable for human and animal subjects. Each unit dose includes a predetermined amount of therapeutically active compound, combined with a pharmaceutical carrier, vehicle, or diluent if necessary. Examples of unit dosage forms include tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, ampoules and syringes, oral solutions or suspensions, and oil-in-water emulsions. Unit dosage forms can be individually packaged, such as blister packs, as known in the art. Unit dosage forms can be administered in fractions or multiples thereof.

[0079] The term "T 1 / 2 " (expressed in hours) refers to the terminal elimination half-life of NMD670 in plasma.

[0080] The term "AUC 0-无穷 ” (expressed in h·ng / mL) refers to the cumulative area under the plasma time-concentration curve (AUC) calculated from time 0 to infinity using the trapezoidal method after a single dose of NMD670. The term “mean AUC 0-无穷 ” refers to each AUC 0-无穷 The arithmetic mean of the values.

[0081] The term "AUC 0-24小时 " (expressed in h·ng / mL) refers to the cumulative area under the plasma time-concentration curve (AUC) calculated from time 0 to 24 hours using the trapezoidal method after a single dose of NMD670. The term "mean AUC 0-24小时 ” refers to each AUC 0-24小时 The arithmetic mean of the values.

[0082] As used in the following disclosure, the term "NMD670" refers to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and any pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0083] According to the present disclosure, (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid refers to the compound of the following formula (I) with a CAS number of 2354321-33-6.

[0084]

[0085] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Detailed Description of the Invention

[0087] Myasthenia gravis is an autoimmune or congenital neuromuscular disorder that causes episodic muscle weakness and fatigue. Most commonly, muscle weakness is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter ACh on nicotinic ACh receptors at the neuromuscular junction.

[0088] NMD670 is a compound designed to inhibit the ClC-1 ion channel for the treatment of neuromuscular disorders, one of which is myasthenia gravis. Inhibiting the ClC-1 ion channel can reduce the incidence of inhibitory currents flowing through the NMJ region of muscle fibers, thereby prolonging the effects of excitatory currents flowing within the NMJ region. This prolongation may improve muscle contraction and control in patients with myasthenia gravis.

[0089] After conducting various nonclinical and clinical trial experiments, the inventors of this disclosure discovered treatment regimens and compositions that can use NMD670 to treat various symptoms of myasthenia gravis, thereby providing an improved quality of life for myasthenia gravis patients. Various aspects and embodiments of these treatment methods and compositions are described below. However, these various aspects and embodiments can be embodied in a variety of different forms. Therefore, this disclosure should not be construed as limited to these embodiments; rather, these embodiments are provided to make this disclosure comprehensive and complete, and to fully convey the scope of the technology described herein to those skilled in the art. The various nonclinical and clinical trial experiments that led to the discovery of the treatment methods described herein are detailed below.

[0090] To evaluate whether ClC-1 inhibition could enhance neuromuscular transmission and restore muscle function in the setting of disease-mediated NMJ transmission failure, the effects of ClC-1 inhibition were first determined from the synaptic level to the intact skeletal muscle level. This was done by acute and chronic administration in an active immune MG rat model (EAMG), which exhibits severe muscle weakness and excessive fatigue (Losen et al., Exp. Neurol. 2015, 270:18–28). The ability of NMD670 to inhibit ClC-1 was first demonstrated in healthy rat muscle fibers using electrophysiological techniques using three intracellular microelectrodes ( Figure 1 (Riisager et al. J Physiol. 2014, 592(20):4417-29). The same method was used to confirm the inhibition of ClC-1 by NMD670 in EAMG rat muscle. It was confirmed that neuromuscular disease itself does not affect ClC-1 function, nor does it affect the ability of NMD670 to inhibit ClC-1 channels. Inhibition of ClC-1 in MG rat muscle fibers increased the excitability of the muscle fibers, as observed by a decrease in the base strength current required to trigger the action potential of the muscle fiber ( Figure 2 ).

[0091] To determine the effects of ClC-1 inhibition at the monosynaptic level, two series of experiments were performed using isolated neuromuscular preparations from severely affected EAMG rats. In both series, the motor nerve was electrically stimulated, and intracellular electrodes inserted at the NMJ recorded the membrane potential of the muscle fiber in response to nerve stimulation. In the first series of experiments, the effect of ClC-1 inhibition on EPP was determined. In these experiments, the skeletal muscle-specific voltage-gated Na+ was selectively blocked by using μ-conotoxin. + Similar to the findings in MG patients (Elmqvist et al. J. Physiol. 1965, 178: 505–529), the EPP amplitude in muscle fibers of EAMG rats was significantly reduced compared with that in healthy animals ( Figure 3 After inhibition of ClC-1 with NMD670, the EPP amplitude increased by more than 35% during the 12 Hz stimulation train ( Figure 4 ).

[0092] In a second series of experiments at the monosynaptic level, we explored whether the increase in EPP amplitude by inhibition of ClC-1 was associated with the restoration of NMJ transmission in EAMG muscles. In these experiments, action potentials were recorded during short trains of nerve stimulation before and after inhibition of ClC-1. Figure 5 As shown, compared with healthy animals ( Figure 5 , left trace) compared to untreated EAMG animals ( Figure 5 , middle trace) in the neuromuscular preparation. The success rate of repeated action potential firing was significantly improved after the addition of 20 μM NMD670 ( Figure 5 , right trace; and Figure 6 In summary, the recovered EPP amplitude ( Figure 4 ) and improved action potential firing ( Figure 6 ) demonstrated that ClC-1 inhibition enhanced neuromuscular transmission in the EAMG model.

[0093] Subsequently, the researchers used both in vitro and in vivo methods to determine whether the enhanced synaptic strength following ClC-1 inhibition in EAMG rat muscles led to the recovery of muscle function. Isolated neuromuscular preparations were mounted in a tissue bath, and force generation was triggered by nerve stimulation. In contrast to the well-maintained force generation in muscles of age-matched healthy rats, muscles from EAMG animals were unable to maintain force generation during brief nerve stimulation. Figure 7 This excessive fatigue during stimulation was evident in the distal hindlimb muscles but was also observed in the diaphragm. Inhibition of ClC-1 with 20 μM NMD670 restored force production in all muscles ( Figure 8) to levels close to those observed in muscle from healthy animals.

[0094] Next, the effects of ClC-1 inhibition on muscle strength were evaluated in vivo in EAMG rats with overt MG symptoms. The rats were anesthetized, and electromyography (EMG) and force were recorded simultaneously from the triceps surae muscle during sciatic nerve stimulation. Measurements were taken before and after oral administration of NMD670, and blood samples were obtained to measure plasma concentrations of NMD670 and to determine the pharmacokinetic / pharmacodynamic relationship. Similar to the observations in isolated specimens, the effect of ClC-1 inhibition on muscle strength was similar to that in healthy animals ( Figure 9 , left trace), both the EMG amplitude and the muscle force stimulated by the nerve were greatly reduced in EAMG ( Figure 9 , middle trace). Administration of NMD670 in EAMG animals resulted in a rapid and dose-dependent recovery of both EMG and force ( Figure 9 , right trace).

[0095] Figure 10 Depicted are the average muscle strength (mean ± SEM) of rats with myasthenia gravis (EAMG) before (white) and after (grey) oral administration of NMD670 (2 to 120 mg / kg) compared to the muscle strength of healthy age-matched rats. The graph shows that administration of NMD670 in EAMG rats results in a rapid and dose-dependent restoration of muscle strength.

[0096] The next series of experiments were conducted using awake EAMG rats to determine whether the enhanced neuromuscular transmission and restored muscle strength through ClC-1 inhibition would also increase strength during voluntary movement. The effect of a single administration of NMD670 on grip strength in severely affected EAMG rats was first determined. The experiments were performed in a blinded manner and the acetylcholinesterase inhibitor pyridostigmine bromide was used as a positive control. Figure 11 As shown, grip strength increased by 15±5% after NMD670 administration and by 5±4% after pyridostigmine bromide. As expected based on their different mechanisms of action for enhancing neuromuscular transmission, the two approaches were additive (24±12%). Vehicle treatment did not affect grip strength (1±2%). In summary, these data indicate that a single administration of NMD670 enhances neuromuscular transmission and restores skeletal muscle function in EAMG rats.

[0097] MG is a chronic disease that requires lifelong treatment. Given that the therapeutic effects of ClC-1 inhibition in MG have not been previously evaluated, it is unknown how long-term administration of NMD670 and inhibition of ClC-1 function will affect muscle function. To this end, a 14-day efficacy study was conducted in EAMG rats exhibiting severe symptoms. The effects of twice-daily administration of NMD670 (20 mg / kg) or vehicle on body weight, grip strength, and endurance (rotarod) were evaluated. The study was blinded, and all rats had confirmed antibodies to acetylcholine receptors. Blood sampling was performed during the 14 days of the study, and muscle biopsies were performed at the end of the study to confirm the correct dosing between the study groups. Throughout the treatment period, rats receiving NMD670 had an increase in grip strength ( Figure 12 ), and also had higher endurance on the rotating rod ( Figure 13 ).

[0098] Treated animals also experienced slower weight loss (compared to vehicle) during the study period ( Figure 14 In both groups, the study required early termination when body weight dropped below 80% of the maximum body weight before disease induction. In the NMD670-treated group, 6 of 8 treated rats completed the study, compared with only 3 of 8 vehicle-treated rats. Therefore, these findings support the concept that prolonged ClC-1 inhibition can improve muscle function and, consequently, overall health in EAMG rats over the long term.

[0099] The efficacy of ClC-1 inhibition in the treatment of MG was further evaluated in a Phase I / IIA clinical trial. Specifically, a Phase I / IIA clinical trial was conducted to preliminarily determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) and multiple ascending doses (MAD) of NMD670 in healthy male and female subjects, as well as the efficacy of ClC-1 inhibition in the treatment of MG.

[0100] Part A1 tested a single dose of NMD670 in healthy male subjects in a double-blind, randomized, placebo-controlled, partial crossover, dose-escalation design. A total of nine dose levels were studied in three cohorts of subjects. Each cohort consisted of nine subjects, and each subject had three study sessions. Each subject received two escalating doses of NMD670 and one placebo, with the order randomized in a crossover fashion. Each dose level was randomized in a 6:3 ratio (active drug vs placebo).

[0101] Dose escalation was discontinued after a moderate-intensity adverse event of myotonia (which resolved spontaneously and completely within hours) was observed in one subject receiving 1600 mg of NMD670 at dose level 7. Due to a temporary halt and partial unblinding of the study during dose level 7, new randomization was required. After unblinding of the three subjects at dose level 7, the original randomization for doses 8 and 9 was modified to maintain study blinding. Because only two opportunities remained for subjects in cohort 3, the original design (three-way crossover) could not be randomized without affecting the proportion of subjects receiving active drug and placebo, thereby preventing within-subject comparisons that are important for evaluating PD markers. Therefore, for the remaining two doses, a full crossover design was used to study one of the previously tested dose levels. Nine subjects in cohort 3 were randomized to receive study drug at dose level 8 and placebo at dose level 9, or vice versa. To determine the effect of food on exposure to a single oral dose of NMD670, dose level 5 was administered both fasting and fed. Subjects receiving dose level 5 returned for a fourth visit where they received dose level 5 (or matching placebo) under fed conditions at the same randomization as the dose level selected under fasting conditions.

[0102] Part A2 of the study investigated the safety, tolerability, and pharmacokinetics of NMD670 using a single dose of NMD670 in eight healthy, non-fertile female subjects, randomized in a double-blind, placebo-controlled manner. Subjects received 800 mg of NMD670. Subjects were randomized in a 6:2 ratio (active drug vs placebo).

[0103] No serious or severe adverse reactions were reported. There was no meaningful relationship between increasing doses of NMD670 and the incidence of AEs in participants ( Figure 15 ). A total of 70 AEs were reported, of which 47 (67%) were at least possibly related to the drug. The most common AEs reported (>1 subject) are listed in Table 15. There was no relationship between dose escalation and the incidence of these individual AEs after administration of a single dose of NMD670, with the exception of transient myotonia reported at the highest dose levels tested (1200 mg and 1600 mg). Most AEs were mild, with the exception of one myotonia AE (1600 mg) and tooth extraction (unrelated, 50 mg), which were moderate in intensity. No subject discontinued the drug.

[0104] The Phase IIA portion of the clinical trial was a double-blind, placebo-controlled, three-way crossover comparison of two single oral doses of NMD670 in men and women with stable symptomatic myasthenia gravis (class I, II, III, or IVa on the Myasthenia Gravis Foundation classification scale). Twelve patients diagnosed with MG participated in the clinical trial.

[0105] The Myasthenia Gravis Foundation (MGFA) clinical classification is derived from the Osserman score developed in the 1950s (Osserman et al., AMA Arch Intern Med, 1958, 102(1):72–81), which is one of the earliest MG classification systems. The MGFA classification is intended to group patients according to disease severity and symptom localization and does not have an evaluation purpose. The MGFA classification is as follows (Barnett et al., Neurol Clin. 2018, 36(2):339-353):

[0106] Class I: Weakness of any eye muscle; weakness may occur with eye closure. All other muscle strength is normal.

[0107] Class II is mild weakness affecting muscles other than the eyes; ocular weakness of any severity may occur.

[0108] IIa: Affects primarily the limbs, axial muscles, or both. May also affect oropharyngeal muscles to a lesser extent. IIb: Affects primarily the oropharyngeal muscles, respiratory muscles, or both. May also affect limbs, axial muscles, or both to a lesser or equal extent.

[0109] Class III moderate weakness affects muscles other than the eyes; ocular weakness of any severity may occur.

[0110] IIIa: Primarily affects limbs, axial muscles, or both. May also affect oropharyngeal muscles to a lesser extent. IIIb: Primarily affects oropharyngeal muscles, respiratory muscles, or both. May also affect limbs, axial muscles, or both to a lesser or equal extent.

[0111] Class IV is severe weakness affecting muscles other than the eyes; ocular weakness of any severity may occur.

[0112] IVa primarily affects the limbs, axial muscles, or both. It may also affect the oropharyngeal muscles to a lesser extent. IVb primarily affects the oropharyngeal muscles, respiratory muscles, or both. It may also affect the limbs, axial muscles, or both to a lesser or equal extent.

[0113] Category V is defined as intubation, with or without the need for mechanical ventilation, except when used during routine postoperative management. Use of a feeding tube without intubation places the patient in category IVb.

[0114] In the general classification classes II, III, and IV, patients are subdivided into class A if their symptoms are primarily systemic and class B if their symptoms are primarily bulbar (Jaretzki et al., Neurology, 2000, 55(1):16–23). The MGFA also has a system for categorizing patients based on post-intervention outcomes and includes remission, defined as the absence of signs or symptoms for 1 year or more without any symptomatic (pyridostigmine) treatment, which can be categorized as complete remission (completely without medication) or medication remission. A minimal manifestation state is defined as minimal signs or symptoms (without a specific time frame) and can tolerate the use of pyridostigmine. In addition, patients can improve, remain unchanged, worsen, experience an exacerbation of MG, or die from MG (Jaretzki et al., Neurology, 2000, 55(1):16–23). In some studies, MGFA category 0 is also used to represent patients who are asymptomatic (due to stable treatment with, for example, pyridostigmine bromide (Mestinon) or due to remission) (Boldingh et al., Health and Quality of Life Outcomes, 2015, 13:115; Al-Moallem et al., Ann Saudi Med 2008, 28(5):341-345).

[0115] The clinical trial consisted of three study periods during which subjects received a single dose of NMD670 or placebo. The single doses were administered in a randomized order (400 mg of free acid, 1200 mg of free acid, or placebo) with a 7-day washout period between visits. Figure 16 The effect of NMD670 was assessed using the quantitative myasthenia gravis (QMG) score card shown in Table 1.

[0116] The quantitative myasthenia gravis (QMG) test is a standardized quantitative strength scoring system that was developed in the context of MG clinical trials and originally had 8 items (Besinger et al., Neurology 1983, 33(10):1316–21); it was later modified for use in trials of cyclosporine (Tindall et al., N Engl J Med 1987, 316(12):719–24), increasing the number of items to 13. Barohn and colleagues modified the measure again (Barohn et al., Ann NY Acad Sci 1998, 841:769–72), making all 13 items examination-based, and this is the version currently used (see Table 1). The QMG test has several items that measure muscle strength, endurance, or fatigability. These items measure the following symptoms and signs: ptosis, dysphagia, diplopia, swallowing, speech / dysarthria episodes, percentage of predicted forced vital capacity, grip strength (2 items), arm muscle endurance (2 items), leg muscle endurance (2 items), and head-lift endurance. All items are scored on a scale of 0 to 3, with a total score ranging from 0 to 39; higher scores indicate greater disease severity.

[0117] Table 1: Quantitative Myasthenia Gravis Score Card

[0118]

[0119]

[0120] Based on the findings provided by the above studies, the inventors were able to develop the compositions and methods for treating MG described herein. Exemplary embodiments of these compositions and methods are provided below. The compositions and methods described herein are not intended to be limited to the following exemplary embodiments.

[0121] Compositions for Use

[0122] One aspect of the present disclosure relates to compositions for use in methods of treating myasthenia gravis in a subject. Use of these compositions comprises administering to the patient a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid (NMD670), wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0123] Thus, one aspect of the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0124] In exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is less than 1500 mg, less than 1450 mg, less than 1300 mg, less than 1250 mg, less than 1200 mg, less than 1150 mg, less than 1100 mg, less than 1050 mg, less than 1000 mg, less than 950 mg, less than 900 mg, less than 850 mg, less than 800 mg, less than 750 mg, less than 700 mg, less than 650 mg, less than 600 mg, less than 550 mg, less than 500 mg, less than 450 mg, less than 400 mg, less than 350 mg, less than 300 mg, or less than 250 mg.

[0125] In other embodiments, the therapeutically effective dose of NMD670 administered to a patient is at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, at least 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, or at least 1450 mg.

[0126] In some exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is 100 to 600 mg, 200 to 600 mg, 250 to 550 mg, 300 to 500 mg, 350 to 450 mg, 375 to 425 mg, or 400 mg. In other exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is 700 to 1400 mg, 800 to 1350 mg, 900 to 1300 mg, 1000 to 1250 mg, 1100 to 1250 mg, or about 1200 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 100 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 150 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 200 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 250 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 300 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 350 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 400 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 500 mg. In an exemplary embodiment, the therapeutically effective dose of NMD670 administered to a patient is about 600 mg.

[0127] In an exemplary embodiment, the therapeutic dose will be administered at least once daily. In an exemplary embodiment, the therapeutic dose will be administered once daily. In an exemplary embodiment, the therapeutic dose will be administered twice daily. In an exemplary embodiment, the therapeutic dose will be administered three times daily. In an exemplary embodiment, the therapeutic dose will be administered four times daily.

[0128] In an exemplary embodiment, the therapeutic dose is administered once daily, i.e., the therapeutic dose is the total daily dose. In an exemplary embodiment, the therapeutic dose is 100 to 600 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is 200 to 600 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is 300 to 500 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 100 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 150 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 200 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 250 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 300 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 350 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 400 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 500 mg, administered once daily. In an exemplary embodiment, the therapeutic dose is about 600 mg, administered once daily.

[0129] In an exemplary embodiment, the therapeutic dose is administered twice daily, i.e., the total daily dose is twice the therapeutic dose. In an exemplary embodiment, the therapeutic dose is 100 to 600 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is 200 to 600 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is 300 to 500 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 100 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 150 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 200 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 250 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 300 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 350 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 400 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 500 mg, administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 600 mg, administered twice daily.

[0130] In an exemplary embodiment, the therapeutic dose is administered three times daily, i.e., the total daily dose is three times the therapeutic dose. In an exemplary embodiment, the therapeutic dose is 100 to 600 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is 200 to 600 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is 300 to 500 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 100 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 150 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 200 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 250 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 300 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 350 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 400 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 500 mg, administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 600 mg, administered three times daily.

[0131] The composition comprising the therapeutic dose can be administered in one or more unit dosage forms. For example, a 400 mg therapeutic dose can be administered in one unit dosage form comprising 400 mg, or two unit dosage forms comprising 200 mg, or four unit dosage forms comprising 100 mg.

[0132] In an exemplary embodiment, the composition of the purposes is administered orally. In an exemplary embodiment, the composition of the purposes is a solid dosage form. In an exemplary embodiment, the solid dosage form is administered orally. In an exemplary embodiment, the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, sustained-release tablets) and sprinkles. In an exemplary embodiment, the composition is in the form of a liquid, a liquid suspension, an oil, an emulsion or a syrup. In an exemplary embodiment, when measured in a United States Pharmacopoeia (USP) Type 2 dissolution apparatus at a temperature of 37°C ± 0.5°C with a paddle at 75rpm in 900mL pH 6.8 phosphate / citrate buffer, the solid dosage form releases not less than 80% of the compound after 30 minutes.

[0133] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein T is reached within 1 to 5 hours, e.g., within 1.5 to 4 hours, e.g., about 2 hours or about 3 hours after administration.max .

[0134] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the average C max In an exemplary embodiment, the average C max The concentration of the 50mg / mL saturated fatty acid was 21,700 ng / mL, and the standard deviation was 5,970 ng / mL.

[0135] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the average C max From about 80% to about 125%, such as from 80.00% to 125.00%, of 21,700 ng / mL.

[0136] In an exemplary embodiment, the composition for use is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the average C maxIn an exemplary embodiment, the average C max is 77,700 ng / mL with a standard deviation of 30,400 ng / mL. In an exemplary embodiment, the average C max The concentration of the serum creatinine in the serum was 76,700 ng / mL, with a standard deviation of 30,400 ng / mL.

[0137] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the average C max From about 80% to about 125%, such as from 80.00% to 125.00%, of 76,700 ng / mL.

[0138] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the mean AUC 0-无穷大 In an exemplary embodiment, the average AUC is 60,000 to 130,000 h·ng / mL, such as 64,100 to 123,300 h·ng / mL, such as 70,000 to 120,000 h·ng / mL, such as 74,960 to 117,125 h·ng / mL, such as 80,000 to 110,000 h·ng / mL, such as 90,000 to 100,000 h·ng / mL, such as about 93,700 h·ng / mL. 0-无穷大 The concentration of the serum creatinine in the serum was 93,700 ng / mL, with a standard deviation of 29,600 ng / mL.

[0139] In an exemplary embodiment, the composition for use is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the mean AUC 0-无穷大 From about 80% to about 125%, such as from 80.00% to 125.00%, of 93,700 h·ng / mL.

[0140] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the mean AUC 0-无穷大 250,000 to 500,000 h·ng / mL, for example 265,000 to 491,000 h·ng / mL, for example 280,000 to 480,000 h·ng / mL, for example 302,400 to 472,500 h·ng / mL, for example 320,000 to 450,000 h·ng / mL, for example 340,000 to 425,000, for example 360,000 to 400,000 h·ng / mL, for example about 378,300 h·ng / mL. In exemplary embodiments, the average AUC 0-无穷大 The concentration of the serum creatinine in the serum of the patient was 378,000 ng / mL, and the standard deviation was 113,000 ng / mL.

[0141] In an exemplary embodiment, the composition for use is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the mean AUC 0-无穷大 From about 80% to about 125%, such as from 80.00% to 125.00%, of 378,300 h·ng / mL.

[0142] In an exemplary embodiment, the composition or use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein T is reached within 1 to 6 hours after administration. max , for example, reaching T about 2 hours after administration max .

[0143] In an exemplary embodiment, the composition or use is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein T is reached within 3 to 7 hours after administration. max .

[0144] In an exemplary embodiment, the AUC is measured after administration of a single dose to a human subject with myasthenia gravis. 0-24无穷大 、C max or T max .

[0145] The compositions for use described herein can be formulated for oral, parenteral, intravenous, inhalation, topically, enteral, rectal, buccal or as an aerosol administration.

[0146] In an exemplary embodiment, the composition for use further comprises at least one pharmaceutically acceptable excipient and / or excipient. In an exemplary embodiment, the composition for use comprises at least one pharmaceutically acceptable excipient and / or excipient, and the pharmaceutically acceptable excipient and / or excipient is selected from the group consisting of fillers, binders, lubricants and disintegrants. In an exemplary embodiment, the composition for use comprises at least one pharmaceutically acceptable excipient and / or excipient, and the pharmaceutically acceptable excipient and / or excipient is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate and croscarmellose sodium.

[0147] In an exemplary embodiment, the composition for use comprises 10 to 80 wt %, e.g., 40 to 65 wt %, e.g., 50 to 55 wt %, e.g., about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0148] In an exemplary embodiment, the composition for use comprises 10 to 80 wt %, e.g., 40 to 65 wt %, e.g., 50 to 60 wt %, e.g., 50 to 55 wt %, e.g., 55 to 60 wt %, e.g., about 53 wt %, e.g., about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0149] In an exemplary embodiment, the composition for use is in the form of one or more solid dosage forms comprising:

[0150] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0151] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0152] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0153] d. 0.25 to 3 wt%, for example 0.4 to 2.0 wt%, of a lubricant; and

[0154] e. 0.25 to 5 wt %, e.g. 0.3 to 2.5 wt % of a disintegrant;

[0155] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0156] In an exemplary embodiment, the composition for use is in the form of one or more solid dosage forms comprising:

[0157] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0158] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0159] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0160] d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant;

[0161] e. 0.25 to 5 wt%, e.g. 0.3 to 2.5 wt% of a disintegrant; and

[0162] f. 1 to 10 wt% film coating;

[0163] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0164] In an exemplary embodiment, the composition for use is in the form of one or more solid dosage forms comprising:

[0165] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0166] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0167] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0168] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0169] e. 0.25 to 3 wt%, e.g. 0.4 to 2.0 wt% of magnesium stearate; and

[0170] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0171] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0172] In an exemplary embodiment, the composition for use is in the form of a solid dosage form and comprises:

[0173] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0174] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0175] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0176] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0177] e. 0.25 to 3 wt%, for example 0.4 to 2.0 wt% of magnesium stearate; and

[0178] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0179] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0180] In an exemplary embodiment, the composition for use is in the form of one or more solid dosage forms comprising or consisting of:

[0181] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 55 wt %, for example about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0182] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0183] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0184] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0185] e. 0.25 to 3 wt%, e.g. 0.4 to 2.0 wt% of magnesium stearate; and

[0186] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0187] g. 1 to 10 wt% of a film coating composition, such as Opadry white,

[0188] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0189] In an exemplary embodiment, the composition for use is in the form of a solid dosage form and comprises or consists of:

[0190] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 55 wt %, for example about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0191] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0192] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0193] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0194] e. 0.25 to 3 wt %, e.g. 0.4 to 2.0 wt % of magnesium stearate;

[0195] f. 0.25 to 5 wt%, e.g., 0.3 to 2.5 wt% of croscarmellose sodium; and

[0196] g. 1 to 10 wt% of a film coating composition, such as Opadry white,

[0197] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0198] In an exemplary embodiment, the subject's serum uric acid level is less than 6.5 mg / dL.

[0199] In an exemplary embodiment, the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification prior to treatment is I, IIa, IIb, IIIa, IIIb, IVa, IVb, or V. In an exemplary embodiment, the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification prior to treatment is I, IIa, IIb, IIIa, IIIb, IVa, IVb, or V. In an exemplary embodiment, the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification prior to treatment is I, IIa, IIb, or IIIb.

[0200] In an exemplary embodiment, the subject experiences a reduction in the quantitative myasthenia gravis total score after treatment. In an exemplary embodiment, the subject experiences a reduction in the quantitative myasthenia gravis total score after treatment, wherein the reduction in the QMG total score after treatment is at least 0.9 points, e.g., at least 1.0 points, e.g., at least 1.5 points, e.g., at least 2.0 points, e.g., at least 3.0 points between 2 and 5 hours after treatment, e.g., 2 hours after treatment, e.g., 3 hours after treatment, e.g., 4 hours after treatment, or e.g., 5 hours after treatment.

[0201] In an exemplary embodiment, at the same time point after treatment, the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo. In an exemplary embodiment, at the same time point after treatment, the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo, and between 2 and 5 hours after treatment, for example, 2 hours after treatment, for example, 3 hours after treatment, for example, 4 hours after treatment, or for example, 5 hours after treatment, the reduction in the QMG total score after treatment is at least 0.9 points, for example, at least 1.0 points, for example, at least 1.5 points, for example, at least 2.0 points, for example, at least 3.0 points.

[0202] In an exemplary embodiment, the subject experiences a decrease in the QMG total score after treatment with NMD670. In an exemplary embodiment, the decrease in the QMG total score can be determined by comparing the change in the QMG total score relative to baseline after a defined period of time (e.g., 21 days) with the change in the QMG total score relative to baseline after a defined period of time (e.g., 21 days) with a placebo. In an exemplary embodiment, the subject experiences a decrease in the QMG total score after treatment with NMD670, wherein the score decreases by at least 0.9 points, e.g., at least 1.0 points, e.g., at least 1.5 points, e.g., at least 2.0 points, e.g., at least 3.0 points. In an exemplary embodiment, the subject experiences a decrease in the QMG total score after 2 to 5 hours after treatment with NMD670, e.g., 2 hours after treatment, e.g., 3 hours after treatment, e.g., 4 hours after treatment, or e.g., 5 hours after treatment.

[0203] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0204] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0205] The composition will be administered twice daily;

[0206] The composition is in the form of a solid dosage form and is to be administered orally; and

[0207] Subjects experienced a decrease in the quantitative myasthenia gravis (QMG) total score.

[0208] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0209] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0210] The composition will be administered twice daily;

[0211] The composition is in the form of a solid dosage form and is to be administered orally; and

[0212] Subjects experienced a decrease in the quantitative myasthenia gravis (QMG) total score.

[0213] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0214] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0215] The composition will be administered once daily.

[0216] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0217] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0218] The composition will be administered once daily.

[0219] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0220] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0221] The composition will be administered twice daily.

[0222] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0223] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0224] The composition will be administered twice daily.

[0225] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0226] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0227] The composition will be administered three times daily.

[0228] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0229] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0230] The composition will be administered three times daily.

[0231] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0232] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0233] The composition will be administered four times daily.

[0234] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0235] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; and

[0236] The composition will be administered four times daily.

[0237] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0238] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0239] The composition is to be administered once daily; and

[0240] The composition is in the form of a solid dosage form and is to be administered orally.

[0241] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0242] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0243] The composition is to be administered once daily; and

[0244] The composition is in the form of a solid dosage form and is to be administered orally.

[0245] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0246] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0247] The composition is to be administered twice daily; and

[0248] The composition is in the form of a solid dosage form and is to be administered orally.

[0249] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0250] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0251] The composition is to be administered twice daily; and

[0252] The composition is in the form of a solid dosage form and is to be administered orally.

[0253] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0254] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0255] The composition is to be administered three times daily; and

[0256] The composition is in the form of a solid dosage form and is to be administered orally.

[0257] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0258] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0259] The composition is to be administered three times daily; and

[0260] The composition is in the form of a solid dosage form and is to be administered orally.

[0261] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0262] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0263] The composition is to be administered four times daily; and

[0264] The composition is in the form of a solid dosage form and is to be administered orally.

[0265] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0266] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0267] The composition is to be administered four times daily; and

[0268] The composition is in the form of a solid dosage form and is to be administered orally.

[0269] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0270] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0271] The composition will be administered twice daily;

[0272] The composition is in the form of a solid dosage form and is to be administered orally;

[0273] The subject experienced a reduction in the quantitative myasthenia gravis total score following treatment, wherein the reduction in the QMG total score following treatment was at least 0.9 points.

[0274] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0275] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0276] The composition will be administered twice daily;

[0277] The composition is in the form of a solid dosage form and is to be administered orally;

[0278] The subject experienced a reduction in the quantitative myasthenia gravis total score following treatment, wherein the reduction in the QMG total score following treatment was at least 0.9 points.

[0279] In an exemplary embodiment, a subject experiences a decrease in MG-ADL scores after treatment with NMD670 (Wolfe et al., Neurology 1999, 52(7):1487-9; Muppidi et al., Muscle Nerve, 2022, 65(6):630-639). In an exemplary embodiment, the decrease in MG-ADL scores can be determined by comparing the change in MG-ADL scores relative to baseline after treatment with NMD670 for a defined period of time (e.g., 21 days) with the change in MG-ADL scores relative to baseline after treatment with a placebo for a defined period of time (e.g., 21 days). In an exemplary embodiment, the subject experiences a decrease in MG-ADL score following treatment with NMD670, wherein the score decreases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., between 0.3 and 10 points, e.g., between 0.5 and 6 points, e.g., between 0.3 and 5 points.

[0280] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0281] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0282] The composition will be administered twice daily;

[0283] The composition is in the form of a solid dosage form and is to be administered orally; and

[0284] Subjects experienced a decrease in MG activities of daily living scores.

[0285] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0286] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0287] The composition will be administered twice daily;

[0288] The composition is in the form of a solid dosage form and is to be administered orally; and

[0289] Subjects experienced a decrease in MG activities of daily living scores.

[0290] In an exemplary embodiment, the subject or subject group experiences an increase in muscle strength after treatment with NMD670. Grip strength is a measure of muscle strength or the maximum force / tension generated by the forearm muscles. It can be used as a screening tool for measuring upper body strength and overall strength. In an exemplary embodiment, the increase in muscle strength can also be determined by measuring the power of the thigh (knee flexor), upper arm (elbow flexor and extension) and / or shoulder (shoulder abduction). In an exemplary embodiment, when the grip strength is determined by using a handheld dynamometer, the subject or subject group experiences an increase in muscle strength after treatment with NMD670 (see Example 13 and Besinger et al., Neurology 1983, 33 (10): 1316–21; Tindall et al., N Engl J Med 1987, 316 (12): 719–24; and Barohn et al., Ann N Y Acad Sci 1998, 841: 769–72). In an exemplary embodiment, the increase in muscle strength can be determined by comparing the change in muscle strength relative to baseline after treatment with NMD670 for a defined period of time (e.g., 21 days) with the change in muscle strength relative to baseline after treatment with a placebo for a defined period of time (e.g., 21 days). In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, as determined by measuring grip strength using a handheld dynamometer, wherein muscle strength increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 10% to 400%, such as from 15% to 200%, such as from 20% to 100%.

[0291] In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, when determined by measuring hand grip strength using a handheld dynamometer, wherein hand grip strength is increased by at least 0.25 kg, e.g., at least 0.50 kg, e.g., at least 0.75 kg, e.g., at least 1.0 kg, e.g., at least 1.25 kg, e.g., at least 1.5 kg, e.g., at least 1.75 kg, e.g., at least 2.0 kg, e.g., at least 2.5 kg, e.g., at least 3.0 kg, e.g., 0.25 to 5.0 kg, e.g., 0.25 to 4.0 kg, e.g., 0.5 to 4.0 kg.

[0292] In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength following treatment with NMD670, as determined by measuring knee flexor muscle strength using a handheld dynamometer, wherein knee flexor muscle strength is increased by at least 0.25 kg, e.g., at least 0.50 kg, e.g., at least 0.75 kg, e.g., at least 1.0 kg, e.g., at least 1.25 kg, e.g., at least 1.5 kg, e.g., at least 1.75 kg, e.g., at least 2.0 kg, e.g., at least 2.5 kg, e.g., at least 3.0 kg, e.g., at least 5.0 kg, e.g., at least 7.5 kg, e.g., 0.25 to 15.0 kg, e.g., 0.25 to 10.0 kg, e.g., 0.5 to 15.0 kg.

[0293] In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength following treatment with NMD670, as determined by measuring elbow flexor muscle strength using a handheld dynamometer, wherein elbow flexor muscle strength is increased by at least 0.25 kg, e.g., at least 0.50 kg, e.g., at least 0.75 kg, e.g., at least 1.0 kg, e.g., at least 1.25 kg, e.g., at least 1.5 kg, e.g., at least 1.75 kg, e.g., at least 2.0 kg, e.g., at least 2.5 kg, e.g., at least 3.0 kg, e.g., 0.25 to 5.0 kg, e.g., 0.25 to 4.0 kg, e.g., 0.5 to 4.0 kg.

[0294] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0295] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0296] The composition will be administered twice daily;

[0297] The composition is in the form of a solid dosage form and is to be administered orally; and

[0298] Subjects experienced increased muscle strength.

[0299] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0300] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0301] The composition will be administered twice daily;

[0302] The composition is in the form of a solid dosage form and is to be administered orally; and

[0303] Subjects experienced increased muscle strength.

[0304] In an exemplary embodiment, the subject, after being treated with NMD670, experiences a decline in myasthenia gravis composite (MGC) scale score (Burns et al., Neurology 2010, 74 (18): 1434-40). In an exemplary embodiment, the decline in the MGC scale can be determined by comparing the change of the MGC scale relative to baseline after the NMD670 treatment limit time period (e.g., 21 days) and the placebo treatment limit time period (e.g., 21 days). In an exemplary embodiment, the subject, after being treated with NMD670, experiences a decline in the MGC scale, wherein scoring has declined by at least 0.3 points, for example, at least 0.5 points, for example, at least 0.75 points, for example, at least 1 point, for example, at least 2 points, for example, at least 3 points, for example, at least 4 points, for example, at least 5 points, for example, at least 6 points, for example, at least 8 points, for example, at least 10 points, for example, 0.3 to 10 points, for example, 0.5 to 6 points, for example, 0.3 to 5 points.

[0305] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0306] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0307] The composition will be administered twice daily;

[0308] The composition is in the form of a solid dosage form and is to be administered orally; and

[0309] Subjects experienced a decrease in their Myasthenia Gravis Composite Scale score.

[0310] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein

[0311] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0312] The composition will be administered twice daily;

[0313] The composition is in the form of a solid dosage form and is to be administered orally; and

[0314] Participants experienced a decrease in their Myasthenia Gravis Composite Scale score.

[0315] In an exemplary embodiment, a subject experiences a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score after treatment with NMD670 (Burns et al., Muscle Nerve, 2008, 38(2):957-63; Diez Porras et al., J Clin Med. 2022, 11(8):2189). In an exemplary embodiment, the decrease in the MG-QOL15 score can be determined by comparing the change from baseline in the MG-QOL15 score after treatment with NMD670 for a defined period of time (e.g., 21 days) with the change from baseline in the MG-QOL15 score after treatment with a placebo for a defined period of time (e.g., 21 days). In an exemplary embodiment, the subject experiences a decrease in MG-QOL15 score following treatment with NMD670, wherein the score decreases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0316] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0317] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0318] The composition will be administered twice daily;

[0319] The composition is in the form of a solid dosage form and is to be administered orally; and

[0320] Participants experienced a decrease in the 15-item Myasthenia Gravis Quality of Life score.

[0321] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0322] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0323] The composition will be administered twice daily;

[0324] The composition is in the form of a solid dosage form and is to be administered orally; and

[0325] Participants experienced a decrease in the 15-item score on the myasthenia gravis quality of life.

[0326] In an exemplary embodiment, after treatment with NMD670, when the subject experiences improved health status using the EQ-5D scale, the subject experiences improved health status (Rabin and Charro, Ann Med. 2001, 33 (5): 337-43). In an exemplary embodiment, the EQ-5D scale can be determined by comparing the change of the EQ-5D scale relative to baseline after a limited time period (e.g., 21 days) for NMD670 treatment and the change of the EQ-5D scale relative to baseline after a limited time period (e.g., 21 days) for placebo treatment. In an exemplary embodiment, the subject experiences an increase in the EQ-5D scale after treatment with NMD670, wherein the score increases by at least 0.3 points, for example, at least 0.5 points, for example, at least 0.75 points, for example, at least 1 point, for example, at least 2 points, for example, at least 3 points, for example, at least 4 points, for example, at least 5 points, for example, at least 6 points, for example, at least 8 points, for example, at least 10 points, for example, 0.3 to 10 points, for example, 0.5 to 6 points, for example, 0.3 to 5 points.

[0327] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0328] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0329] The composition will be administered twice daily;

[0330] The composition is in the form of a solid dosage form and is to be administered orally; and

[0331] The subjects experienced improved health status as measured using the EQ-5D scale.

[0332] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0333] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0334] The composition will be administered twice daily;

[0335] The composition is in the form of a solid dosage form and is to be administered orally; and

[0336] The subjects experienced improved health status as measured using the EQ-5D scale.

[0337] In an exemplary embodiment, the subject experiences a reduction in jitter after treatment with NMD670. In an exemplary embodiment, when determined using single fiber electromyography, the subject experiences a reduction in jitter after treatment with NMD670 (Sanders et al., Clin Neurophysiol. 2019, 130(8): 1417-1439). In an exemplary embodiment, the reduction in jitter can be determined by comparing the change in jitter relative to baseline after a defined time period (e.g., 21 days) of NMD670 treatment with a placebo treatment defined time period (e.g., 21 days). In an exemplary embodiment, when determined using single fiber electromyography, the subject experiences a reduction in jitter after treatment with NMD670, wherein the jitter is reduced by at least 10%, for example, at least 15%, for example, at least 20%, for example, at least 25%, for example, at least 30%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, 5% to 95%, for example, 5% to 80%, for example, 10% to 50%. In an exemplary embodiment, the subject experiences a reduction in jitter following treatment with NMD670, as determined using single-fiber electromyography, wherein jitter is reduced by at least 5 μs, e.g., at least 10 μs, e.g., at least 15 μs, e.g., at least 20 μs, e.g., at least 25 μs, e.g., at least 30 μs, e.g., at least 40 μs, e.g., at least 50 μs, e.g., at least 75 μs, e.g., at least 100 μs, e.g., 5 to 200 μs, e.g., 5 to 100 μs, e.g., 10 to 50 μs.

[0338] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0339] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0340] The composition will be administered twice daily;

[0341] The composition is in the form of a solid dosage form and is to be administered orally; and

[0342] The subjects experienced a reduction in jitters as measured using single-fiber electromyography.

[0343] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0344] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0345] The composition will be administered twice daily;

[0346] The composition is in the form of a solid dosage form and is to be administered orally; and

[0347] The subjects experienced a reduction in jitters as measured using single-fiber electromyography.

[0348] In an exemplary embodiment, the subject experiences block reduction after being treated with NMD670. In an exemplary embodiment, when determined using single fiber electromyography, the subject experiences block reduction after being treated with NMD670 (Sanders et al., Clin Neurophysiol. 2019, 130 (8): 1417-1439). In an exemplary embodiment, the reduction of block can be determined by comparing the change of block relative to baseline after the NMD670 treatment limit time period (for example, 21 days) and the placebo treatment limit time period (for example, 21 days). In an exemplary embodiment, when measured using single fiber electromyography, the subject experiences block reduction after being treated with NMD670, wherein block reduction is at least 5%, for example, at least 10%, for example, at least 15%, for example, at least 20%, for example, at least 25%, for example, at least 30%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, 5% to 95%, for example, 5% to 80%, for example, 10% to 50%.

[0349] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0350] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0351] The composition will be administered twice daily;

[0352] The composition is in the form of a solid dosage form and is to be administered orally; and

[0353] The subjects experienced a reduction in blockade as measured using single-fiber electromyography.

[0354] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0355] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0356] The composition will be administered twice daily;

[0357] The composition is in the form of a solid dosage form and is to be administered orally; and

[0358] The subjects experienced a reduction in blockade as measured using single-fiber electromyography.

[0359] In an exemplary embodiment, the subject is treated with NMD670 after personalized neuromuscular quality of life score declines (Vincent et al., Neurology, 2007, 68 (13): 1051-7). In an exemplary embodiment, the decline of individualized neuromuscular quality of life score can be determined by comparing the change of individualized neuromuscular quality of life score relative to baseline after NMD670 treatment limited time period (e.g., 21 days) and the change of individualized neuromuscular quality of life score relative to baseline after placebo treatment limited time period (e.g., 21 days). In an exemplary embodiment, the subject experiences individualized neuromuscular quality of life score declines after treatment with NMD670, wherein score declines by 0.5 point, for example, at least 1 point, for example, at least 2 points, for example, at least 3 points, for example, at least 4 points, for example, at least 5 points, for example, at least 6 points, for example, at least 8 points, for example, at least 10 points, for example, at least 15 points, for example, at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0360] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0361] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0362] The composition will be administered twice daily;

[0363] The composition is in the form of a solid dosage form and is to be administered orally; and

[0364] Participants experienced a decrease in personalized neuromuscular quality of life scores.

[0365] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0366] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0367] The composition will be administered twice daily;

[0368] The composition is in the form of a solid dosage form and is to be administered orally; and

[0369] Participants experienced a decrease in personalized neuromuscular quality of life scores.

[0370] In an exemplary embodiment, a subject or group of subjects experiences a decrease in fatigue severity scale score after treatment with NMD670 (Werlauff et al., Qual Life Res., 2014, 23: 1479-1488). In an exemplary embodiment, the decrease in fatigue severity scale score can be determined by comparing the change in fatigue severity scale score relative to baseline after treatment with NMD670 for a defined period of time (e.g., 21 days) with the change in fatigue severity scale score relative to baseline after treatment with a placebo for a defined period of time (e.g., 21 days). In an exemplary embodiment, the subject or group of subjects experiences a decrease in fatigue severity scale score following treatment with NMD670, wherein the score is decreased by 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 1.5 points, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., at least 15 points, e.g., at least 20 points, e.g., 0.5 to 30 points, e.g., 1 to 20 points, e.g., 0.5 to 10 points.

[0371] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0372] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0373] The composition will be administered twice daily;

[0374] The composition is in the form of a solid dosage form and is to be administered orally; and

[0375] Participants experienced a decrease in fatigue severity scale scores.

[0376] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0377] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0378] The composition will be administered twice daily;

[0379] The composition is in the form of a solid dosage form and is to be administered orally; and

[0380] Participants experienced a decrease in fatigue severity scale scores.

[0381] In an exemplary embodiment, a subject or group of subjects experiences an improvement in lung function after treatment with NMD670 (Oliveira et al., Neuromuscul Disord. 2017, 27(2):120-127; Neder et al., Braz J Med Biol Res. 1999, 32(6):719-27). In an exemplary embodiment, the improvement in lung function can be determined by comparing the change in lung function relative to baseline after treatment with NMD670 for a defined period of time (e.g., 21 days) with the change in lung function relative to baseline after treatment with a placebo for a defined period of time (e.g., 21 days). In an exemplary embodiment, a subject or group of subjects experiences an improvement in lung function after treatment with NMD670, as determined by measuring forced vital capacity (FVC), wherein FVC increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%. In an exemplary embodiment, a subject or group of subjects experiences an improvement in lung function after treatment with NMD670, as determined by measuring forced expiratory volume in 1 second (FEV1), wherein FEV1 increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%. In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function after treatment with NMD670, as determined by measuring maximum inspiratory pressure (MIP), wherein the MIP increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%. In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function after treatment with NMD670, as determined by measuring maximum expiratory pressure (MEP), wherein the MEP increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%.

[0382] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0383] The composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0384] The composition will be administered twice daily;

[0385] The composition is in the form of a solid dosage form and is to be administered orally; and

[0386] The subjects experienced improvements in lung function.

[0387] In an exemplary embodiment, the present disclosure is directed to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein:

[0388] The composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid;

[0389] The composition will be administered twice daily;

[0390] The composition is in the form of a solid dosage form and is to be administered orally; and

[0391] The subjects experienced improvements in lung function.

[0392] In an exemplary embodiment, the present disclosure relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in a method of treating myasthenia gravis in a subject, wherein the subject has a serum uric acid level of less than 6.5 mg / dL. In an exemplary embodiment, the composition for use is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0393] In an exemplary embodiment, the composition for use is for administration in a therapeutic dose as defined herein.

[0394] In one aspect, the present disclosure relates to the use of a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof in the manufacture of a medicament for treating myasthenia gravis in a subject, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0395] Pharmaceutical composition

[0396] Another aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 for treating or ameliorating symptoms of myasthenia gravis in a patient with myasthenia gravis. Another aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 for treating or ameliorating symptoms of myasthenia gravis in a patient with myasthenia gravis. All of the following exemplary composition embodiments can be used in the methods of treatment described herein.

[0397] In one aspect, the present invention relates to a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In one embodiment, the composition comprises 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In one aspect, the present invention relates to a composition formulated as a solid dosage form, comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the composition comprises 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid. In an exemplary embodiment, the composition further comprises at least one pharmaceutically acceptable excipient and / or vehicle. In an exemplary embodiment, the composition is for oral administration. In an exemplary embodiment, the composition further comprises a pharmaceutically acceptable excipient and / or vehicle selected from the group consisting of a filler, a binder, a lubricant, and a disintegrant. In an exemplary embodiment, the composition comprises a pharmaceutically acceptable excipient and / or vehicle selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate, and croscarmellose sodium.

[0398] In an exemplary embodiment, the composition comprises 50 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0399] In an exemplary embodiment, the composition comprises 10% to 80% by weight, for example, 40 to 65% by weight, for example, 50 to 55% by weight, for example, about 53% by weight of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof. In an exemplary embodiment, the composition comprises 10% to 80% by weight, for example, 40 to 65% by weight, for example, 50 to 60% by weight, for example, 50 to 55% by weight, for example, 55 to 60% by weight, for example, about 53% by weight, for example, about 56% by weight of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0400] In an exemplary embodiment, the composition comprises:

[0401] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0402] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0403] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0404] d. 0.25 to 3 wt%, for example 0.4 to 2.0 wt%, of a lubricant; and

[0405] e. 0.25 to 5 wt %, e.g. 0.3 to 2.5 wt % of a disintegrant;

[0406] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0407] In an exemplary embodiment, the composition comprises:

[0408] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0409] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0410] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0411] d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant;

[0412] e. 0.25 to 5 wt%, e.g. 0.3 to 2.5 wt% of a disintegrant; and

[0413] f. 1 to 10 wt% film coating;

[0414] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0415] In an exemplary embodiment, the composition comprises:

[0416] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0417] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0418] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0419] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0420] e. 0.25 to 3 wt%, e.g. 0.4 to 2.0 wt% of magnesium stearate; and

[0421] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0422] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0423] In an exemplary embodiment, the composition comprises or consists of:

[0424] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 55 wt %, for example about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0425] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0426] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0427] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0428] e. 0.25 to 3 wt %, e.g. 0.4 to 2.0 wt % of magnesium stearate;

[0429] f. 0.25 to 5 wt%, e.g., 0.3 to 2.5 wt% of croscarmellose sodium; and

[0430] g. 1 to 10 wt% of a film coating composition, such as Opadry white,

[0431] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0432] In an exemplary embodiment, the present disclosure is directed to a composition comprising a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg.

[0433] In an exemplary embodiment, the present disclosure is directed to a composition formulated as a solid dosage form comprising a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 50 mg to 400 mg. In an exemplary embodiment, the therapeutically effective dose is 100 mg. In an exemplary embodiment, the therapeutically effective dose is 150 mg. In an exemplary embodiment, the therapeutically effective dose is 200 mg. In an exemplary embodiment, the therapeutically effective dose is 250 mg. In an exemplary embodiment, the therapeutically effective dose is 300 mg. In an exemplary embodiment, the therapeutically effective dose is 350 mg. In an exemplary embodiment, the therapeutically effective dose is 400 mg. In an exemplary embodiment, the therapeutically effective dose is administered once daily. In an exemplary embodiment, the therapeutically effective dose is administered twice daily. In an exemplary embodiment, the therapeutically effective dose is administered three times daily.

[0434] In an exemplary embodiment, the present disclosure is directed to a composition formulated as a solid dosage form comprising 50 mg to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the solid dosage form comprises 100 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 150 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 200 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 250 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 300 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 350 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 400 mg of NMD670.

[0435] In an exemplary embodiment, the composition is a solid dosage form. In an exemplary embodiment, the solid dosage form is selected from the group consisting of capsules (e.g., dusting capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, sustained-release tablets), and dusters. In an exemplary embodiment, the composition is in the form of a liquid, a liquid suspension, an oil, an emulsion, or a syrup. In an exemplary embodiment, the solid dosage form releases not less than 80% of the compound after 30 minutes when measured using a United States Pharmacopoeia (USP) Type 2 dissolution apparatus with a paddle at 75 rpm at a temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate / citrate buffer.

[0436] method

[0437] In an exemplary embodiment, the method of treating a patient suffering from symptoms of myasthenia gravis can result in an improvement in the patient's quantitative myasthenia gravis total score, hand grip strength, compound muscle action potential, and / or muscle attenuation. In an exemplary embodiment, the method of treating a patient suffering from symptoms of myasthenia gravis can result in a decrease in the quantitative myasthenia gravis total score; a decrease in the MG Activities of Daily Living Scale (MG-ADL) score; an increase in muscle strength; a decrease in the Myasthenia Gravis Composite (MGC) scale score; a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score; an improvement in health status as determined using the EQ-5D scale; a decrease in tremors; a decrease in blockades; a decrease in a personalized neuromuscular quality of life score; a decrease in the Fatigue Severity Scale score, and / or an improvement in lung function.

[0438] Thus, one aspect of the present disclosure relates to methods of treating myasthenia gravis resulting in an improvement in a patient's quantitative myasthenia gravis total score, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0439] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a subject in need thereof, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

[0440] In one aspect, the present disclosure relates to a method of improving a quantitative myasthenia gravis total score in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof. In an exemplary embodiment, the reduction in QMG total score after treatment is at least 0.9 points, e.g., at least 1.0 points, e.g., at least 1.5 points, e.g., at least 2.0 points, e.g., at least 3.0 points. In an exemplary embodiment, the reduction in QMG total score after treatment is at least 0.9 points, e.g., at least 1.0 points, e.g., at least 1.5 points, e.g., at least 2.0 points, e.g., at least 3.0 points, compared to a placebo at the same time point. In an exemplary embodiment, the reduction in QMG total score after treatment is between 2 and 5 hours after treatment, e.g., 2 hours after treatment, e.g., 3 hours after treatment, e.g., 4 hours after treatment, or e.g., 5 hours after treatment.

[0441] Another aspect of the present disclosure relates to a method for treating myasthenia gravis, which results in an improvement in the patient's hand grip strength, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. In an exemplary embodiment, the patient's hand grip strength is improved by at least 10%, at least 20%, at least 30%, or at least 40% compared to the patient's hand grip strength before administering the therapeutically effective dose of NMD670. The measurement of hand grip strength is part of the QMG test (see Example 13; and Besinger et al., Neurology 1983, 33(10): 1316–21; Tindall et al., N Engl J Med 1987, 316(12): 719–24 and Barohn et al., Ann N Y Acad Sci 1998, 841: 769–72).

[0442] In one aspect, the present disclosure relates to a method for improving right hand grip strength in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In exemplary embodiments, the improvement in right hand grip strength after treatment is at least 2.0 kg, e.g., at least 2.5 kg. In exemplary embodiments, the improvement in right hand grip strength is at least 2.0 kg, e.g., at least 2.5 kg, compared to a placebo at the same time point.

[0443] Another aspect of the present disclosure relates to methods for treating myasthenia gravis in a patient resulting in an improvement in compound muscle action potential, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. In an exemplary embodiment, the patient's compound muscle action potential is improved by at least 10%, at least 20%, at least 30%, or at least 40% compared to the patient's compound muscle action potential before administering the therapeutically effective dose of NMD670. The improvement in compound muscle action potential can be determined by repetitive nerve stimulation (see Example 13; and Niks et al., Muscle & Nerve, 2003, 28(2):236-238; Ruys-Van Oeyen et al., Muscle & Nerve, 2002, 26(2):279-282; Schumm et al., Muscle & Nerve, 1984, 7(2):147-151).

[0444] Another aspect of the present disclosure relates to methods for treating myasthenia gravis in a patient to result in restoration of muscle attenuation, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. In exemplary embodiments, the patient's muscle attenuation is improved by at least 10%, at least 20%, at least 30%, or at least 40% compared to the patient's muscle attenuation before administration of the therapeutically effective dose of NMD670.

[0445] In one aspect, the present disclosure relates to a method for reducing EMG attenuation during repetitive nerve stimulation in a subject with myasthenia gravis, comprising administering to the patient a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. Recovery of muscle attenuation can be determined by repetitive nerve stimulation (see Example 13; and Niks et al., Muscle & Nerve, 2003, 28(2):236-238; Ruys-Van Oeyen et al., Muscle & Nerve, 2002, 26(2):279-282; Schumm et al., Muscle & Nerve, 1984, 7(2):147-151).

[0446] In one aspect, the present disclosure relates to a method of improving diplopia in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. Diplopia measurement is part of the QMG test (see Example 13; and Besinger et al., Neurology 1983, 33(10):1316–21; Tindall et al., N Engl J Med 1987, 316(12):719–24 and Barohn et al., Ann N Y Acad Sci 1998, 841:769–72).

[0447] In one aspect, the present disclosure relates to a method of improving ptosis in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. Ptosis is measured as part of the QMG test (see Example 13; and Besinger et al., Neurology 1983, 33(10):1316–21; Tindall et al., N Engl J Med 1987, 316(12):719–24 and Barohn et al., Ann N Y Acad Sci 1998, 841:769–72).

[0448] In one aspect, the present disclosure relates to a method of improving dysarthria symptoms in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. Measurement of dysarthria is part of the QMG test (see Example 13; and Besinger et al., Neurology 1983, 33(10):1316–21; Tindall et al., N Engl J Med 1987, 316(12):719–24 and Barohn et al., Ann N Y Acad Sci 1998, 841:769–72).

[0449] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a decrease in MG-ADL scores, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The improvement in MG-ADL scores is a decrease in scores (Wolfe et al., Neurology 1999, 52(7):1487-9; Muppidi et al., Muscle Nerve, 2022, 65(6):630-639).

[0450] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in increased muscle strength, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. Improvements in muscle strength can be determined by measuring grip strength using a handheld dynamometer (see Example 13; and Besinger et al., Neurology 1983, 33(10):1316–21; Tindall et al., N Engl J Med 1987, 316(12):719–24 and Barohn et al., Ann N Y Acad Sci 1998, 841:769–72).

[0451] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a decrease in myasthenia gravis composite (MGC) scale score, comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. An improvement in the myasthenia gravis composite (MGC) scale refers to a decrease in score (Burns et al., Neurology 2010, 74(18):1434-40).

[0452] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a decrease in myasthenia gravis quality of life 15-item (MG-QOL15) score, comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. An improvement in the myasthenia gravis quality of life 15-item (MG-QOL15) score refers to a decrease in the score (Burns et al., Muscle Nerve, 2008, 38(2):957-63; Diez Porras et al., J Clin Med. 2022, 11(8):2189).

[0453] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in an improvement in health status as determined using the EQ-5D scale, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. Improvement in health status can be determined using the EQ-5D scale and is an increase in score (Rabin and Charro, Ann Med. 2001, 33(5):337-43).

[0454] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in reduced tremor, comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The reduction in tremor can be determined using single-fiber electromyography (Sanders et al., Clin Neurophysiol. 2019, 130(8):1417-1439).

[0455] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a reduction in blockade, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The reduction in blockade can be determined using single-fiber electromyography (Sanders et al., Clin Neurophysiol. 2019, 130(8):1417-1439).

[0456] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a decrease in an individualized neuromuscular quality of life score, the methods comprising administering to the patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is within the range of 100 mg to 1500 mg. The improvement in the individualized neuromuscular quality of life score is a decrease in the score (Vincent et al., Neurology, 2007, 68(13):1051-7).

[0457] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in a decrease in fatigue severity scale scores, comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The improvement in fatigue severity scale scores is a decrease in scores (Werlauff et al., Qual Life Res., 2014, 23: 1479–1488).

[0458] One aspect of the present disclosure relates to methods for treating myasthenia gravis resulting in improved lung function, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The improvement in lung function can be determined by measuring forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum inspiratory pressure (MIP) and / or maximum expiratory pressure (MEP) (Oliveira et al., Neuromuscul Disord. 2017, 27(2):120-127; Neder et al., Braz J Med Biol Res. 1999, 32(6):719-27).

[0459] In one aspect, the present disclosure relates to a method for enhancing neuromuscular transmission and / or restoring skeletal muscle function, comprising administering to a subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0460] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0461] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered once daily.

[0462] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0463] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0464] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered four times per day.

[0465] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered once daily.

[0466] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0467] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0468] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered four times per day.

[0469] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0470] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0471] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times per day.

[0472] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0473] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0474] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered four times per day.

[0475] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered once daily.

[0476] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0477] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0478] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times per day.

[0479] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0480] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0481] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0482] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times per day.

[0483] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0484] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0485] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0486] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered four times per day.

[0487] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0488] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0489] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0490] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times per day.

[0491] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0492] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0493] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0494] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times per day.

[0495] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered once daily.

[0496] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered twice daily.

[0497] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0498] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered once daily.

[0499] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0500] In an exemplary embodiment, the composition is administered at a therapeutic dose of about 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, and the composition is administered three times daily.

[0501] Restoration of a patient's muscle attenuation may include, but is not limited to, enhancement of their neuromuscular transmission and / or restoration of their skeletal muscle function.

[0502] The therapeutic methods disclosed herein may also include administering other active agents known to treat, prevent, and / or improve neuromuscular disorders. These active agents may be acetylcholinesterase inhibitors, such as neostigmine or pyridostigmine, immunosuppressive drugs, compounds for anti-myotonic treatment, for increasing the Ca2+ of the contractile filaments in the muscle, 2+ Sensitivity compounds and / or for blocking voltage-gated K + Compounds that increase ACh release through the channels.

[0503] In one aspect, the present disclosure relates to a method of treating myasthenia gravis, comprising administering to a subject in need thereof (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor.

[0504] In some exemplary embodiments, the method of treatment comprises administering a therapeutically effective dose of NMD670 and one or more of the following compounds: amifampridine, prednisolone, prednisone, azathioprine, Soliris, Rituximab, Efgartigimod alfa, Zilucoplan, Rozanolixizumab, cholecalciferol, and immune globulin.

[0505] In an exemplary embodiment, the method of treatment comprises administering a therapeutically effective dose of NMD670 and an active agent to the patient simultaneously. In other exemplary embodiments, the therapeutically effective dose of NMD670 and the active agent are administered to the patient at different times. In some embodiments, the therapeutically effective dose of NMD670 and the active agent are administered sequentially.

[0506] In one aspect, the present disclosure relates to a method of treating myasthenia gravis resulting in an improvement in a quantitative myasthenia gravis total score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid compound, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a Cmax in the patient in the range of 5,000 ng / mL to 14,000 ng / mL, wherein after administration of the therapeutically effective dose of the compound, the patient's quantitative myasthenia gravis score is reduced by at least 0.9 points compared to placebo at the same time point.

[0507] In an exemplary embodiment, the therapeutically effective dose of the compound further provides an AUC in the range of 15,000 ng / mL to 500,000 ng / mL in the patient. inf In an exemplary embodiment, the therapeutically effective dose of the compound is at a T in a patient max In the range of 1 to 5 hours. In an exemplary embodiment, the half-life of a therapeutically effective dose of the compound in a patient is in the range of 3 hours to 7 hours. In an exemplary embodiment, the therapeutically effective dose of the compound is administered orally to the patient. In an exemplary embodiment, the patient's quantitative myasthenia gravis score is reduced by at least 1.0 points, for example, by at least 1.5 points, for example, by at least 2.0 points. In an exemplary embodiment, the patient's Myasthenia Gravis Foundation of America (MGFA) clinical classification before treatment is I, IIa, IIb, IIIa, IIIb, IVa, IVb or V.

[0508] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof, resulting in improved right hand grip strength, the method comprising administering a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 5,000 ng / mL to 14,000 ng / mL. max , wherein after administration of a therapeutically effective dose of the compound, the patient experiences an improvement of at least 1 kg in handgrip strength compared to the patient's handgrip strength before administration.

[0509] In an exemplary embodiment, the improvement in hand grip strength of a patient weighing at least 1 kg occurs at least 3 hours after administration of the therapeutically effective dose of the compound. In an exemplary embodiment, the therapeutically effective dose of the compound also provides an AUC in the patient in the range of 15,000 h·ng / mL to 500,000 h·ng / mL. inf In an exemplary embodiment, a therapeutically effective dose of the compound is administered to a patient at a T max In an exemplary embodiment, the half-life of a therapeutically effective dose of the compound in a patient is in the range of 3 hours to 7 hours.

[0510] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in a decrease in a quantitative myasthenia gravis (QMG) total score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein the patient experiences a decrease in quantitative myasthenia gravis (QMG) total score following administration of a therapeutically effective dose of the compound.

[0511] In an exemplary embodiment, the subject or group of subjects experiences a decrease in the quantitative myasthenia gravis (QMG) total score following treatment with NMD670, wherein the score is decreased by at least 0.9 points, e.g., at least 1.0 points, e.g., at least 1.5 points, e.g., at least 2.0 points, e.g., at least 3.0 points.

[0512] In one aspect, the present disclosure relates to a method for treating myasthenia gravis resulting in decreased MG activities of daily living (MG-ADL) scores in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein the patient experiences a decrease in MG-Activities of Daily Living (MG-ADL) score after administration of a therapeutically effective dose of the compound.

[0513] In an exemplary embodiment, the subject experiences a decrease in MG-ADL score following treatment with NMD670, wherein the score decreases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0514] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof, resulting in increased muscle strength, comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength.

[0515] In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength following treatment with NMD670, as determined by measuring grip strength using a handheld dynamometer, wherein muscle strength is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 10% to 400%, such as from 15% to 200%, such as from 20% to 100%.

[0516] In an exemplary embodiment, the subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, when determined by measuring hand grip strength using a handheld dynamometer, wherein hand grip strength is increased by at least 0.25 kg, e.g., at least 0.50 kg, e.g., at least 0.75 kg, e.g., at least 1.0 kg, e.g., at least 1.25 kg, e.g., at least 1.5 kg, e.g., at least 1.75 kg, e.g., at least 2.0 kg, e.g., at least 2.5 kg, e.g., at least 3.0 kg, e.g., 0.25 to 5.0 kg, e.g., 0.25 to 4.0 kg, e.g., 0.5 to 4.0 kg.

[0517] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in a decrease in Myasthenia Gravis Composite (MGC) scale score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein the patient experiences a decrease in the Myasthenia Gravis Composite (MGC) scale score following administration of a therapeutically effective dose of the compound.

[0518] In an exemplary embodiment, the subject experiences a decrease in MGC scale score following treatment with NMD670, wherein the score decreases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0519] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein the patient experiences a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score after administration of a therapeutically effective dose of the compound.

[0520] In an exemplary embodiment, the subject experiences a decrease in MG-QOL15 score following treatment with NMD670, wherein the score decreases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0521] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in an improvement in health status as determined using the EQ-5D scale, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein following administration of a therapeutically effective dose of the compound, the patient experiences an improvement in well-being as determined using the EQ-5D scale.

[0522] In an exemplary embodiment, the subject experiences an increase in EQ-5D scale score following treatment with NMD670, wherein the score increases by at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0523] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof, resulting in reduced tremor, comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in jitter.

[0524] In an exemplary embodiment, the subject experiences a reduction in jitter after treatment with NMD670, as determined using single-fiber electromyography, wherein jitter is reduced by at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%. In an exemplary embodiment, the subject experiences a reduction in jitter after treatment with NMD670, as determined using single-fiber electromyography, wherein jitter is reduced by at least 5 μs, such as at least 10 μs, such as at least 15 μs, such as at least 20 μs, such as at least 25 μs, such as at least 30 μs, such as at least 40 μs, such as at least 50 μs, such as at least 75 μs, such as at least 100 μs, such as from 5 μs to 200 μs, such as from 5 μs to 100 μs, such as from 10 μs to 50 μs.

[0525] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof, resulting in reduced blockade, comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max, wherein the patient experiences a reduction in retardation following administration of a therapeutically effective dose of the compound.

[0526] In an exemplary embodiment, the subject experiences a reduction in blockade following treatment with NMD670, as measured using single fiber electromyography, wherein the blockade is reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%.

[0527] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in a decrease in a personalized neuromuscular quality of life score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein following administration of a therapeutically effective dose of the compound, the patient experiences a decrease in an individualized neuromuscular quality of life score.

[0528] In an exemplary embodiment, the subject experiences a decrease in a personalized neuromuscular quality of life score following treatment with NMD670, wherein the score decreases by 0.5 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., at least 15 points, e.g., at least 20 points, e.g., 0.5 to 30 points, e.g., 1 to 20 points, e.g., 0.5 to 10 points.

[0529] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof, resulting in a decrease in fatigue severity scale score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in a fatigue severity scale score.

[0530] In an exemplary embodiment, the subject or group of subjects experiences a decrease in fatigue severity scale score following treatment with NMD670, wherein the score decreases by 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 1.5 points, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., at least 15 points, e.g., at least 20 points, e.g., 0.5 to 30 points, e.g., 1 to 20 points, e.g., 0.5 to 10 points.

[0531] In one aspect, the present disclosure relates to a method of treating myasthenia gravis in a patient in need thereof resulting in improved lung function, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 2,790 ng / mL to 76,700 ng / mL. max , wherein after administration of a therapeutically effective dose of the compound, the patient experiences an improvement in lung function.

[0532] In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function following treatment with NMD670 as determined by measuring forced vital capacity (FVC), wherein FVC is increased by at least 5%, e.g., at least 10%, e.g., at least 15%, e.g., at least 20%, e.g., at least 25%, e.g., at least 30%, e.g., at least 50%, e.g., at least 75%, e.g., at least 100%, e.g., at least 150%, e.g., at least 200%, e.g., 5% to 95%, e.g., 5% to 80%, e.g., 10% to 50%.

[0533] In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function following treatment with NMD670, as determined by measuring forced expiratory volume in 1 second (FEV1), wherein FEV1 is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%.

[0534] In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function following treatment with NMD670 as determined by measuring maximum inspiratory pressure (MIP), wherein the MIP increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%.

[0535] In an exemplary embodiment, the subject or group of subjects experiences an improvement in lung function following treatment with NMD670 as determined by measuring maximum expiratory pressure (MEP), wherein MEP is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as from 5% to 95%, such as from 5% to 80%, such as from 10% to 50%.

[0536] In an exemplary embodiment, a therapeutically effective dose of the compound is administered orally to a patient. In an exemplary embodiment, the therapeutically effective dose is in the range of 100 mg to 600 mg. In an exemplary embodiment, the therapeutically effective dose is in the range of 200 mg to 600 mg. In an exemplary embodiment, the therapeutically effective dose is 100 mg. In an exemplary embodiment, the therapeutically effective dose is 150 mg. In an exemplary embodiment, the therapeutically effective dose is 200 mg. In an exemplary embodiment, the therapeutically effective dose is 250 mg. In an exemplary embodiment, the therapeutically effective dose is 300 mg. In an exemplary embodiment, the therapeutically effective dose is 350 mg. In an exemplary embodiment, the therapeutically effective dose is 400 mg. In an exemplary embodiment, the therapeutically effective dose is 500 mg. In an exemplary embodiment, the therapeutically effective dose is 600 mg. In an exemplary embodiment, the therapeutically effective dose is administered once, twice, three times, or four times daily.

[0537] In one aspect, the present disclosure relates to a method of treating a patient suffering from symptoms of myasthenia gravis, comprising administering a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg.

[0538] In one aspect, the present disclosure relates to the use of a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof in the preparation of a medicament for treating myasthenia gravis in a subject, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0539] The methods of the present disclosure may also include administering to the patient a second therapeutically effective dose of NMD670 one, two, three, four, five, six, or at least seven days after the first therapeutically effective dose. The second therapeutically effective dose of NMD670 may range from 100 mg to about 1500 mg. In exemplary embodiments, the second therapeutically effective dose of NMD670 is any dose disclosed herein. In other embodiments, the second therapeutically effective dose of NMD670 is the same as the first therapeutically effective dose administered to the patient.

[0540] In other exemplary embodiments, the methods of the present disclosure further comprise administering to the patient a third therapeutically effective dose of NMD670 one, two, three, four, five, six, or at least seven days after the second therapeutically effective dose. The third therapeutically effective dose of NMD670 can range from 100 mg to about 1500 mg. In exemplary embodiments, the third therapeutically effective dose of NMD670 is any dose disclosed herein. In other embodiments, the third therapeutically effective dose of NMD670 is the same as the first therapeutically effective dose and / or the second therapeutically effective dose administered to the patient.

[0541] In some exemplary embodiments, the therapeutically effective dose of NMD670 is repeated at least 1, 2, 3, 4, 5, or 6 times per week. In other exemplary embodiments, the administration is repeated at least 1-3 times per week, 2-5 times per week, or 3-6 times per week.

[0542] In some exemplary embodiments, a therapeutically effective dose of NMD670 is administered repeatedly daily. For example, a therapeutically effective dose of NMD670 is administered 1, 2, 3, 4, 5, 6, 7, or 8 times daily. In other embodiments, the administration is repeated 1 to 8 times daily or 2 to 5 times daily.

[0543] In some embodiments, a therapeutically effective dose of NMD670 is administered at least once daily. In an exemplary embodiment, a therapeutically effective dose of NMD670 is administered once daily.

[0544] In other embodiments, a therapeutically effective dose of NMD670 is administered twice a day, three times a day, or four times a day.

[0545] In an exemplary embodiment, the therapeutically effective dose of NMD670 is 100 to 600 mg, 300 to 500 mg, or about 400 mg, administered once daily. In an exemplary embodiment, the therapeutically effective dose of NMD670 is 200 to 600 mg, 300 to 500 mg, or about 400 mg, administered once daily.

[0546] In other exemplary embodiments, the therapeutically effective dose of NMD670 is 100 to 600 mg, 300 to 500 mg, or about 400 mg, administered twice daily. In other exemplary embodiments, the therapeutically effective dose of NMD670 is 200 to 600 mg, 300 to 500 mg, or about 400 mg, administered twice daily.

[0547] In some exemplary embodiments, the therapeutically effective dose of NMD670 is a daily dose of NMD670. In these embodiments, the daily dose of NMD670 can be administered as a single dose or in smaller doses throughout the day. That is, in some embodiments, the daily dose of NMD670 can be administered once a day or at least once a day, twice a day or at least at two different time points throughout the day, or three times a day or at least at three different time points throughout the day.

[0548] In other exemplary embodiments, the patient administered a therapeutically effective dose of NMD670 has ocular myasthenia gravis, early-onset generalized myasthenia gravis, late-onset generalized myasthenia gravis, generalized myasthenia gravis, seropositive myasthenia gravis, seronegative myasthenia gravis, AChR antibody positive myasthenia gravis, or muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG).

[0549] In some exemplary embodiments, the patient administered a therapeutically effective dose of NMD670 suffers from Myasthenia Gravis Foundation of America (MGFA) class I, IIa, IIb, IIIa, IIIb, IVa, IVb, V symptoms, or any combination thereof prior to treatment.

[0550] In other exemplary embodiments, the patient to whom a therapeutically effective dose of NMD670 is administered does not suffer from hyperuricemia. For example, the serum uric acid level of the patient to whom a therapeutically effective dose of NMD670 is administered is less than 6.5 mg / dL. Patients whose serum uric acid level is higher than 6.5 mg / dL may not be suitable for receiving the therapeutically effective dose. In exemplary embodiments where the patient's serum uric acid level is higher than 6.5 mg / dL, the treatment method may further include administering a low dose of NMD670 until the patient's serum uric acid level drops to less than 6.5 mg / dL. The low dose of NMD670 may be 20 mg to 150 mg, for example 25 mg to 100 mg, for example 25 mg to 50 mg. Once the patient's serum uric acid level drops to less than 6.5 mg / dL, they can begin receiving a therapeutically effective dose of NMD670.

[0551] Multi-component kits

[0552] In one aspect, the present invention relates to a kit of parts comprising:

[0553] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and

[0554] Acetylcholinesterase inhibitors.

[0555] In an exemplary embodiment, the multi-component kit comprises 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof. In one embodiment, the acetylcholinesterase inhibitor is pyridostigmine.

[0556] In one aspect, the present invention relates to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and acetylcholinesterase for use in treating myasthenia gravis.

[0557] In one aspect, the present invention relates to a method for treating myasthenia gravis, comprising administering to a subject in need thereof (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor.

[0558] In one aspect, the kit of parts is for use in a method of treating myasthenia gravis in a subject.

[0559] In one aspect, the present invention relates to the use of a kit of parts or a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof and an acetylcholinesterase inhibitor for the preparation of a medicament for the treatment of myasthenia gravis.

[0560] In an exemplary embodiment, the active agent is an acetylcholinesterase inhibitor. The acetylcholinesterase inhibitor can be, for example, delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, caffeine-noncompetitive, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine, lactucorin, or any combination thereof.

[0561] In other exemplary embodiments, the activating agent can be an immunosuppressive drug. Immunosuppressive drugs are drugs that suppress or reduce the strength of the body's immune system. They are also referred to as anti-rejection drugs. The immunosuppressive drugs that can be used for patients include but are not limited to glucocorticoids, corticosteroids, cytostatics, antibodies, drugs that act on immunophilins (immunophilins) or any combination thereof. In exemplary embodiments, the activating agent is prednisone.

[0562] In some exemplary embodiments, the active agent is an agent used for anti-myotonic therapy. Such an agent can be, for example, a voltage-gated Na + Channel blockers and aminoglycosides.

[0563] In some exemplary embodiments, the active agent is a Ca2+-containing agent for increasing the Ca2+-containing contractile filaments in the muscle. 2+ Such an agent may be, for example, tirasemtiv.

[0564] In other exemplary embodiments, the active agent is an agent for increasing ACh release that blocks voltage-gated K + Such an agent may be, for example, 3,4-aminopyridine.

[0565] In some exemplary embodiments, a therapeutically effective dose of NMD670 may be administered to a patient to treat or alleviate the following symptoms of myasthenia gravis: diplopia, ptosis, dysarthria, or any combination.

[0566] item

[0567] 1. A composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein the composition is administered at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

[0568] 2. The composition for use according to claim 1, wherein the therapeutic dose is less than 1500 mg, for example, less than 1450 mg, for example, less than 1300 mg, for example, less than 1250 mg, for example, less than 1200 mg, for example, less than 1150 mg, for example, less than 1100 mg, for example, less than 1050 mg, for example, less than 1000 mg, for example, less than 950 mg, for example, less than 900 mg, for example, less than 850 mg, for example, less than 800 mg, for example, less than 750 mg, for example, less than 700 mg, for example, less than 650 mg, for example, less than 600 mg, for example, less than 550 mg, for example, less than 500 mg, for example, less than 450 mg, for example, less than 400 mg, for example, less than 350 mg, for example, less than 300 mg, for example, less than 250 mg.

[0569] 3. The composition according to any of the preceding items, wherein the therapeutic dose is at least 100 mg, such as at least 150 mg, such as at least 200 mg, such as at least 250 mg, such as at least 300 mg, such as at least 350 mg, such as at least 400 mg, such as at least 450 mg, such as at least 500 mg, such as at least 550 mg, such as at least 600 mg, such as at least 650 mg, such as at least 700 mg, such as at least 750 mg, such as at least 800 mg, such as at least 850 mg, such as at least 900 mg, such as at least 950 mg, such as at least 1000 mg, such as at least 1050 mg, such as at least 1100 mg, such as at least 1150 mg, such as at least 1200 mg, such as at least 1250 mg, such as at least 1300 mg, such as at least 1350 mg, such as at least 1400 mg, such as at least 1450 mg.

[0570] 4. A composition for use according to claim 1, wherein the therapeutic dose is 200 to 600 mg, such as 250 to 550 mg, such as 300 to 500 mg, such as 350 to 450 mg, such as 375 to 425 mg, such as 400 mg.

[0571] 5. A composition for use according to claim 1, wherein the therapeutic dose is 700 to 1400 mg, such as 800 to 1350 mg, such as 900 to 1300 mg, such as 1000 to 1250 mg, such as 1100 to 1250 mg, such as about 1200 mg.

[0572] 6. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg.

[0573] 7. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg.

[0574] 8. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg.

[0575] 9. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg.

[0576] 10. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg.

[0577] 11. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg.

[0578] 12. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg.

[0579] 13. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg.

[0580] 14. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg.

[0581] 15. A composition for use according to any preceding claim, wherein the therapeutic dose is to be administered at least once daily.

[0582] 16. A composition for use according to any preceding claim, wherein the therapeutic dose is to be administered once daily.

[0583] 17. The composition for use according to any one of items 1 to 14, wherein the therapeutic dose is to be administered twice daily.

[0584] 18. The composition for use according to any one of items 1 to 14, wherein the therapeutic dose is to be administered three times daily.

[0585] 19. The composition for use according to any one of items 1 to 14, wherein the therapeutic dose is to be administered four times a day.

[0586] 20. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is to be administered once daily.

[0587] 21. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is to be administered once daily.

[0588] 22. The composition for use according to item 1, wherein the therapeutic dose is 300 to 500 mg and the composition is to be administered once daily.

[0589] 23. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is to be administered once daily.

[0590] 24. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is to be administered once daily.

[0591] 25. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is to be administered once daily.

[0592] 26. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg and the composition is to be administered once daily.

[0593] 27. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is to be administered once daily.

[0594] 28. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is to be administered once daily.

[0595] 29. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is to be administered once daily.

[0596] 30. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is to be administered once daily.

[0597] 31. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg and the composition is to be administered once daily.

[0598] 32. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is to be administered twice daily.

[0599] 33. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is to be administered twice daily.

[0600] 34. A composition for use according to any preceding claim, wherein the therapeutic dose is 300 to 500 mg and the composition is to be administered twice daily.

[0601] 35. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is to be administered twice daily.

[0602] 36. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is to be administered twice daily.

[0603] 37. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is to be administered twice daily.

[0604] 38. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg and the composition is to be administered twice daily.

[0605] 39. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is to be administered twice daily.

[0606] 40. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is to be administered twice daily.

[0607] 41. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is to be administered twice daily.

[0608] 42. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is to be administered twice daily.

[0609] 43. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg and the composition is to be administered twice daily.

[0610] 44. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is to be administered three times a day.

[0611] 45. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is to be administered three times a day.

[0612] 46. ​​The composition for use according to item 1, wherein the therapeutic dose is 300 to 500 mg and the composition is to be administered three times a day.

[0613] 47. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is to be administered three times a day.

[0614] 48. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is to be administered three times a day.

[0615] 49. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is to be administered three times a day.

[0616] 50. The composition for use according to claim 1, wherein the therapeutic dose is about 250 mg and the composition is to be administered three times a day.

[0617] 51. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is to be administered three times a day.

[0618] 52. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is to be administered three times a day.

[0619] 53. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is to be administered three times a day.

[0620] 54. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is to be administered three times a day.

[0621] 55. The composition for use according to claim 1, wherein the therapeutic dose is about 600 mg and the composition is to be administered three times a day.

[0622] 56. A composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is to be administered four times a day.

[0623] 57. A composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is to be administered four times a day.

[0624] 58. A composition for use according to any preceding claim, wherein the therapeutic dose is the total daily dose.

[0625] 59. A composition for use according to any preceding claim, wherein the composition is administered orally, parenterally, intravenously, by inhalation, topically, enterally, rectally, buccally or as an aerosol.

[0626] 60. A composition for use according to any one of items 1 to 59, wherein the composition is in the form of a liquid, a liquid suspension, an oil, an emulsion or a syrup.

[0627] 61. A composition for use according to any one of items 1 to 59, wherein the composition is a solid dosage form.

[0628] 62. The composition for use according to item 61, wherein the solid dosage form is administered orally.

[0629] 63. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 100 to 600 mg, and the composition is to be administered once daily.

[0630] 64. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 200 to 600 mg, and the composition is to be administered once daily.

[0631] 65. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 100 to 600 mg, and the composition is to be administered twice daily.

[0632] 66. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 200 to 600 mg, and the composition is to be administered twice daily.

[0633] 67. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 100 to 600 mg, and is to be administered three times a day.

[0634] 68. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 200 to 600 mg, and the composition is to be administered three times a day.

[0635] 69. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 100 to 600 mg, and is to be administered four times a day.

[0636] 70. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is to be administered orally, the therapeutic dose is 200 to 600 mg, and is to be administered four times a day.

[0637] 71. A composition for use according to any one of items 61 to 70, wherein the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, sustained-release tablets) and sprinkles.

[0638] 72. A composition for use according to any one of items 61 to 71, wherein the solid dosage form releases not less than 80% of the compound after 30 minutes when measured in a United States Pharmacopoeia (USP) Type 2 dissolution apparatus with a paddle at 75 rpm at a temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate / citrate buffer.

[0639] 73. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein T is reached within 1 to 5 hours, e.g., within 1.5 to 4 hours, e.g., about 2 hours or about 3 hours after administration. max .

[0640] 74. A composition for use according to any one of items 1 to 72, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein T is reached within 1 to 6 hours after administration. max .

[0641] 75. A composition for use according to any one of items 1 to 72, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein T is reached within 3 to 7 hours after administration. max .

[0642] 76. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average C max 13,000 to 32,000 ng / mL, such as 15,000 to 30,000 ng / mL, such as 15,730 to 27,670 ng / mL, such as 16,000 to 27,000 ng / mL, such as 17,360 to 27,125 ng / mL, such as 18,000 to 25,000 ng / mL, such as 20,000 to 23,000 ng / mL, such as about 21,700 ng / mL.

[0643] 77. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average C max From about 80% to about 125%, such as from 80.00% to 125.00%, of 21,700 ng / mL.

[0644] 78. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, the average C max 40,000 to 110,000 ng / mL, such as 46,300 to 107,100 ng / mL, such as 50,000 to 100,000 ng / mL, such as 60,000 to 90,000 ng / mL, such as 61,360 to 95,875 ng / mL, such as 70,000 to 80,000 ng / mL, such as about 76,700 ng / mL.

[0645] 79. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average C max From about 80% to about 125%, e.g., from 80.00% to 125.00%, of 76,700 ng / mL.

[0646] 80. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the mean AUC 0-无穷大60,000 to 130,000 h·ng / mL, for example 64,100 to 123,300 h·ng / mL, for example 70,000 to 120,000 h·ng / mL, for example 74,960 to 117,125 h·ng / mL, for example 80,000 to 110,000 h·ng / mL, for example 90,000 to 100,000 h·ng / mL, for example about 93,700 h·ng / mL.

[0647] 81. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average AUC 0-无穷大 From about 80% to about 125%, such as from 80.00% to 125.00%, of 93,700 h·ng / mL.

[0648] 82. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the mean AUC 0-无穷大 250,000 to 500,000 h·ng / mL, for example 265,000 to 491,000 h·ng / mL, for example 280,000 to 480,000 h·ng / mL, for example 302,400 to 472,500 h·ng / mL, for example 320,000 to 450,000 h·ng / mL, for example 340,000 to 425,000 h·ng / mL, for example 360,000 to 400,000 h·ng / mL, for example about 378,300 h·ng / mL.

[0649] 83. A composition for use according to any preceding claim, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 1200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average AUC 0-无穷大 From about 80% to about 125%, such as from 80.00% to 125.00%, of 378,300 h·ng / mL.

[0650] 84. A composition for use according to any one of the preceding claims, wherein the AUC 0-24无穷大 、C max or T max It was measured after a single dose was administered to human subjects with myasthenia gravis.

[0651] 85. A composition for use according to any preceding claim, wherein the composition further comprises at least one pharmaceutically acceptable adjuvant and / or excipient.

[0652] 86. The composition for use according to item 85, wherein the pharmaceutically acceptable adjuvant and / or excipient is selected from the group consisting of fillers, binders, lubricants and disintegrants.

[0653] 87. The composition for use according to item 85, wherein the pharmaceutically acceptable excipients and / or vehicles are selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate and croscarmellose sodium.

[0654] 88. A composition for use according to any one of items 61 to 87, wherein the composition comprises 10 to 80 wt%, such as 40 to 65 wt%, such as 50 to 55 wt%, such as about 53 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0655] 89. A composition for use according to any one of items 61 to 87, wherein the composition comprises 10 to 80 wt%, for example 40 to 65 wt%, for example 50 to 60 wt%, for example 50 to 55 wt%, for example 55 to 60 wt%, for example about 53 wt%, for example 56 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0656] 90. A composition for use according to any one of items 61 to 87, wherein the composition comprises:

[0657] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0658] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0659] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0660] d. 0.25 to 3 wt%, for example 0.4 to 2.0 wt%, of a lubricant; and

[0661] e. 0.25 to 5 wt %, e.g. 0.3 to 2.5 wt % of a disintegrant;

[0662] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0663] 91. A composition for use according to any one of items 61 to 87, wherein the composition comprises:

[0664] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0665] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0666] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0667] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0668] e. 0.25 to 3 wt%, e.g. 0.4 to 2.0 wt% of magnesium stearate; and

[0669] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0670] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0671] 92. A composition for use according to any one of items 61 to 87, wherein the composition comprises:

[0672] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0673] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0674] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0675] d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant;

[0676] e. 0.25 to 5 wt%, e.g. 0.3 to 2.5 wt% of a disintegrant; and

[0677] f. 1 to 10 wt% film coating;

[0678] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0679] 93. A composition for use according to any one of items 61 to 87, wherein the composition comprises or consists of:

[0680] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 55 wt %, for example about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0681] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0682] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0683] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0684] e. 0.25 to 3 wt %, e.g. 0.4 to 2.0 wt % of magnesium stearate;

[0685] f. 0.25 to 5 wt%, e.g., 0.3 to 2.5 wt% of croscarmellose sodium; and

[0686] g. 1 to 10 wt% of a film coating composition, such as Opadry white,

[0687] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0688] 94. A composition for use according to any preceding claim, wherein the composition is administered in one or more unit dosage forms.

[0689] 95. A composition for use according to any preceding claim, wherein the subject has a serum uric acid level below 6.5 mg / dL.

[0690] 96. The composition for use according to any preceding claim, wherein the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification before treatment is I, IIa, IIb, IIIa, IIIb, IVa, IVb or V class.

[0691] 97. A composition for use according to item 96, wherein the MGFA clinical classification before treatment is I, IIa, IIb or IIIb.

[0692] 98. A composition for use according to any preceding claim, wherein the subject experiences a reduction in the quantitative myasthenia gravis (QMG) total score following treatment.

[0693] 99. A composition for use according to claim 98, wherein the reduction in QMG total score after treatment is at least 0.9 points between 2 and 5 hours after treatment, such as 2 hours after treatment, such as 3 hours after treatment, such as 4 hours after treatment or such as 5 hours after treatment.

[0694] 100. The composition for use according to any preceding claim, wherein the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo at the same time point after treatment.

[0695] 101. A composition for use according to claim 100, wherein the reduction in QMG total score is at least 0.9 points between 2 and 5 hours after treatment, e.g., 2 hours after treatment, e.g., 3 hours after treatment, e.g., 4 hours after treatment, or e.g., 5 hours after treatment, compared to placebo at the same time point after treatment.

[0696] 102. A composition for use according to claim 98, wherein the QMG total score is determined by comparing the change in QMG total score relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in QMG total score relative to baseline after treatment with a placebo for a defined period of time.

[0697] 103. The composition for use according to item 102, wherein the time period is 21 days.

[0698] 104. The composition for use according to any one of items 98 to 103, wherein the reduction in QMG total score is at least 1.0 point, such as at least 1.5 points, such as at least 2.0 points, such as at least 3.0 points.

[0699] 105. The composition for use according to any preceding claim, wherein the subject or group of subjects experiences a decrease in MG-Activities of Daily Living (MG-ADL) score after treatment with the composition.

[0700] 106. A composition for use according to claim 105, wherein the MG-ADL score is determined by comparing the change from baseline in the MG-ADL score after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change from baseline in the MG-ADL score after treatment with a placebo for a defined period of time.

[0701] 107. The composition for use according to item 106, wherein the time period is 21 days.

[0702] 108. The composition for use according to any of the preceding claims, wherein the MG-ADL score is decreased by at least 0.3 points, such as at least 0.5 points, such as at least 0.75 points, such as at least 1 point, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points.

[0703] 109. The composition for use according to any preceding claim, wherein the MG-ADL score is reduced by 0.3 to 10 points, such as 0.5 to 6 points, such as 0.3 to 5 points.

[0704] 110. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in MG activities of daily living score.

[0705] 111. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in MG activities of daily living score.

[0706] 112. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences an increase in muscle strength after treatment with the composition.

[0707] 113. The composition for use according to item 112, wherein the force is measured using a handheld dynamometer.

[0708] 114. The composition for use according to any one of items 112 or 113, wherein muscle strength is measured as grip strength.

[0709] 115. A composition for use according to any one of items 112 or 113, wherein muscle strength is measured as strength of the thigh (knee flexors), upper arm (elbow flexors and extension) and / or shoulder (shoulder abduction).

[0710] 116. A composition for use according to any one of items 112 to 115, wherein the increase in muscle strength is determined by comparing the change in muscle strength relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in muscle strength relative to baseline after treatment with a placebo for a defined period of time.

[0711] 117. The composition for use according to item 116, wherein the time period is 21 days.

[0712] 118. A composition for use according to any one of items 112 to 117, wherein muscle strength is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0713] 119. The composition for use according to any one of items 112 to 118, wherein muscle strength is increased by 10% to 400%, such as 15% to 200%, such as 20% to 100%.

[0714] 120. A composition for use according to any one of items 112 to 119, wherein muscle strength as determined by measuring grip strength using a handheld dynamometer is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0715] 121. A composition for use according to any one of items 112 to 120, wherein muscle strength as determined by measuring grip strength using a handheld dynamometer is increased by 10% to 400%, such as 15% to 200%, such as 20% to 100%.

[0716] 122. A composition for use according to any one of items 112 to 121, wherein muscle strength as determined by measuring grip strength using a handheld dynamometer is increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0717] 123. A composition for use according to any one of items 112 to 122, wherein muscle strength as determined by measuring grip strength using a handheld dynamometer is increased by 0.25 to 5.0 kg, such as 0.25 to 4.0 kg, such as 0.5 to 4.0 kg.

[0718] 124. A composition for use according to any one of items 112 to 123, wherein the muscle strength determined by measuring the strength of the knee flexor muscle using a handheld dynamometer is increased by at least 0.25 kg, for example at least 0.50 kg, for example at least 0.75 kg, for example at least 1.0 kg, for example at least 1.25 kg, for example at least 1.5 kg, for example at least 1.75 kg, for example at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg.

[0719] 125. A composition for use according to any one of items 112 to 124, wherein muscle strength as determined by measuring knee flexor strength using a handheld dynamometer is increased by 0.25 to 5.0 kg, such as 0.25 to 4.0 kg, such as 0.5 to 4.0 kg.

[0720] 126. A composition for use according to any one of items 112 to 125, wherein the muscle strength determined by measuring elbow flexor strength using a handheld dynamometer is increased by at least 0.25 kg, for example at least 0.50 kg, for example at least 0.75 kg, for example at least 1.0 kg, for example at least 1.25 kg, for example at least 1.5 kg, for example at least 1.75 kg, for example at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg.

[0721] 127. A composition for use according to any one of items 112 to 126, wherein muscle strength as determined by measuring elbow flexor strength using a handheld dynamometer is increased by 0.25 to 5.0 kg, such as 0.25 to 4.0 kg, such as 0.5 to 4.0 kg.

[0722] 128. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences an increase in muscle strength.

[0723] 129. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences an increase in muscle strength.

[0724] 130. The composition for use according to any preceding claim, wherein the subject or group of subjects experiences a decrease in the Myasthenia Gravis Composite (MGC) scale following treatment with the composition.

[0725] 131. A composition for use according to item 130, wherein the decrease in the MGC scale is determined by comparing the change in the MGC scale relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in the MGC scale relative to baseline after treatment with a placebo for a defined period of time.

[0726] 132. A composition for use according to item 131, wherein the time period is 21 days.

[0727] 133. A composition for use according to any one of items 130 to 132, wherein the MGC scale is decreased by at least 0.3 points, such as at least 0.5 points, such as at least 0.75 points, such as at least 1 point, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points.

[0728] 134. The composition for use according to any one of items 130 to 133, wherein the MGC scale is decreased by 0.3 to 10 points, such as 0.5 to 6 points, such as 0.3 to 5 points.

[0729] 135. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease on the Myasthenia Gravis Composite Scale.

[0730] 136. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease on the Myasthenia Gravis Composite Scale.

[0731] 137. The composition for use according to any preceding claim, wherein the subject or group of subjects experiences a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score after treatment with the composition.

[0732] 138. A composition for use according to claim 137, wherein the decrease in MG-QCL15 score is determined by comparing the change from baseline in the decrease in MG-QCL15 score after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change from baseline in the decrease in MG-QCL15 score after treatment with a placebo for a defined period of time.

[0733] 139. The composition for use according to item 138, wherein the time period is 21 days.

[0734] 140. The composition for use according to any one of items 137 to 139, wherein the MG-QCL15 score is decreased by at least 0.3 points, such as at least 0.5 points, such as at least 0.75 points, such as at least 1 point, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points.

[0735] 141. The composition for use according to any one of items 137 to 140, wherein the MG-QCL15 score is reduced by 0.3 to 10 points, such as 0.5 to 6 points, such as 0.3 to 5 points.

[0736] 142. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in a 15-item myasthenia gravis quality of life score.

[0737] 143. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in a 15-item myasthenia gravis quality of life score.

[0738] 144. The composition for use according to any preceding claim, wherein following treatment with the composition, the subject or group of subjects experiences an improvement in health status as measured using the EQ-5D scale.

[0739] 145. The composition for use according to item 144, wherein the increase in the EQ-5D scale is determined by comparing the change from baseline in the EQ-5D scale after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change from baseline in the EQ-5D scale after treatment with a placebo for a defined period of time.

[0740] 146. The composition for use according to item 145, wherein the time period is 21 days.

[0741] 147. The composition for use according to any one of items 144 to 146, wherein the EQ-5D scale is increased by at least 0.3 points, such as at least 0.5 points, such as at least 0.75 points, such as at least 1 point, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points.

[0742] 148. The composition for use according to any one of items 144 to 147, wherein the EQ-5D scale is increased by 0.3 to 10 points, such as 0.5 to 6 points, such as 0.3 to 5 points.

[0743] 149. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences an improvement in health status as determined using the EQ-5D scale.

[0744] 150. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences an improvement in health status as determined using the EQ-5D scale.

[0745] 151. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences a reduction in jitteriness following treatment with the composition.

[0746] 152. A composition for use according to item 151, wherein tremor is determined using single fiber electromyography.

[0747] 153. A composition for use according to any one of items 151 or 152, wherein the reduction in jitter is determined by comparing the change in jitter relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in jitter relative to baseline after treatment with a placebo for a defined period of time.

[0748] 154. A composition for use according to item 153, wherein the time period is 21 days.

[0749] 155. A composition for use according to any one of items 151 to 154, wherein jitter is reduced by at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0750] 156. A composition for use according to any one of items 151 to 154, wherein jitter is reduced by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0751] 157. A composition for use according to any one of items 151 to 154, wherein jitter as determined using single fiber electromyography is reduced by at least 5 μs, such as at least 10 μs, such as at least 15 μs, such as at least 20 μs, such as at least 25 μs, such as at least 30 μs, such as at least 40 μs, such as at least 50 μs, such as at least 75 μs, such as at least 100 μs.

[0752] 158. A composition for use according to any one of items 151 to 154, wherein jitter as determined using single fiber electromyography is reduced by 5 to 200 μs, such as 5 to 100 μs, such as 10 to 50 μs.

[0753] 159. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a reduction in tremor as measured using single-fiber electromyography.

[0754] 160. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a reduction in tremor as determined using single-fiber electromyography.

[0755] 161. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences a reduction in retardation following treatment with the composition.

[0756] 162. A composition for use according to item 161, wherein blockade is determined using single fiber electromyography.

[0757] 163. A composition for use according to any one of items 161 or 162, wherein the reduction in retardation is determined by comparing the change in retardation relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in retardation relative to baseline after treatment with a placebo for a defined period of time.

[0758] 164. A composition for use according to item 163, wherein the time period is 21 days.

[0759] 165. A composition for use according to any one of items 161 to 164, wherein the retardation is reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0760] 166. The composition for use according to any one of items 161 to 165, wherein the retardation is reduced by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0761] 167. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a reduction in blockade as measured using single-fiber electromyography.

[0762] 168. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a reduction in blockade as measured using single-fiber electromyography.

[0763] 169. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences a decrease in an individualized neuromuscular quality of life score following treatment with the composition.

[0764] 170. A composition for use according to claim 169, wherein the reduction in the personalized neuromuscular quality of life score is determined by comparing the change from baseline in the personalized neuromuscular quality of life score after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change from baseline in the personalized neuromuscular quality of life score after treatment with a placebo for a defined period of time.

[0765] 171. A composition for use according to item 170, wherein the time period is 21 days.

[0766] 172. A composition for use according to any one of items 169 to 171, wherein the individualized neuromuscular quality of life score decreases by 0.5 points, such as at least 0.75 points, such as at least 1 point, such as at least 1.5 points, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points, such as at least 15 points, such as at least 20 points.

[0767] 173. The composition for use according to any preceding claim, wherein the individualized neuromuscular quality of life score is decreased by 0.5 to 30 points, such as 1 to 20 points, such as 0.5 to 10 points.

[0768] 174. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in an individualized neuromuscular quality of life score.

[0769] 175. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in an individualized neuromuscular quality of life score.

[0770] 176. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences a decrease in fatigue severity scale score after treatment with the composition.

[0771] 177. A composition for use according to claim 176, wherein the reduction in fatigue severity scale score is determined by comparing the change in fatigue severity scale score relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in fatigue severity scale score relative to baseline after treatment with a placebo for a defined period of time.

[0772] 178. A composition for use according to item 177, wherein the time period is 21 days.

[0773] 179. A composition for use according to any one of items 176 to 178, wherein the fatigue severity scale score is reduced by 0.5 points, for example, at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, for example, at least 2 points, for example, at least 3 points, for example, at least 4 points, for example, at least 5 points, for example, at least 6 points, for example, at least 8 points, for example, at least 10 points, for example, at least 15 points, for example, at least 20 points.

[0774] 180. The composition for use according to any one of items 176 to 179, wherein the fatigue severity scale score is reduced by 1 to 20 points, such as 0.5 to 10 points.

[0775] 181. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in fatigue severity scale score.

[0776] 182. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences a decrease in fatigue severity scale score.

[0777] 183. A composition for use according to any preceding claim, wherein a subject or group of subjects experiences an improvement in lung function following treatment with the composition.

[0778] 184. A composition for use according to claim 183, wherein the improvement in lung function is determined by comparing the change in lung function relative to baseline after treatment with a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for a defined period of time with the change in lung function relative to baseline after treatment with a placebo for a defined period of time.

[0779] 185. A composition for use according to item 184, wherein the time period is 21 days.

[0780] 186. A composition for use according to any one of items 183 to 185, wherein lung function is determined by measuring forced vital capacity (FVC).

[0781] 187. A composition for use according to claim 186, wherein FVC is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0782] 188. A composition for use according to item 186, wherein FVC is increased by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0783] 189. A composition for use according to any one of items 183 to 185, wherein lung function is determined by measuring the forced expiratory volume in 1 second (FEV1).

[0784] 190. A composition for use according to claim 189, wherein FEV1 is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0785] 191. A composition for use according to item 189, wherein FEV1 is increased by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0786] 192. A composition for use according to any one of items 183 to 185, wherein lung function is determined by measuring maximum inspiratory pressure (MIP).

[0787] 193. A composition for use according to claim 192, wherein the MIP is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0788] 194. A composition for use according to item 192, wherein the MIP is increased by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0789] 195. A composition for use according to any one of items 183 to 185, wherein lung function is determined by measuring maximum expiratory pressure (MEP).

[0790] 196. A composition for use according to claim 195, wherein MEP is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0791] 197. A composition for use according to item 195, wherein the MEP is increased by 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0792] 198. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences improvement in lung function.

[0793] 199. A composition for use according to any preceding claim, wherein the composition is for administration at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; the composition is to be administered twice daily; the composition is in the form of a solid dosage form and is to be administered orally; and the subject experiences improvement in lung function.

[0794] 200. A composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein the subject has a serum uric acid level of less than 6.5 mg / dL.

[0795] 201. A composition for use according to item 200, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

[0796] 202. The composition for use according to any one of items 200 to 201, wherein the therapeutic dose is as defined in any one of items 2 to 57.

[0797] 203. A composition formulated into a solid dosage form comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the composition comprises 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0798] 204. A composition according to claim 203, wherein the solid dosage form comprises 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0799] 205. A composition according to claim 203, wherein the solid dosage form comprises 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0800] 206. A composition according to claim 203, wherein the solid dosage form comprises 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0801] 207. A composition according to claim 203, wherein the solid dosage form comprises 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0802] 208. A composition according to claim 203, wherein the solid dosage form comprises 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0803] 209. A composition according to claim 203, wherein the solid dosage form comprises 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0804] 210. A composition according to claim 203, wherein the solid dosage form comprises 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0805] 211. The composition of any one of items 203 to 209, wherein the composition further comprises at least one pharmaceutically acceptable adjuvant and / or excipient.

[0806] 212. The composition of any one of items 203 to 211, wherein the composition is administered orally.

[0807] 213. A composition according to any one of items 203 to 212, wherein the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, sustained-release tablets) and sprinkles.

[0808] 214. The composition according to any one of items 211 to 213, wherein the pharmaceutically acceptable adjuvant and / or excipient is selected from the group consisting of fillers, binders, lubricants and disintegrants.

[0809] 215. The composition of any one of items 211 to 213, wherein the pharmaceutically acceptable excipients and / or excipients are selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate and croscarmellose sodium.

[0810] 216. A composition according to any one of items 203 to 215, wherein the composition comprises 10 to 80 wt%, for example 40 to 65 wt%, for example 50 to 55 wt%, for example about 53 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0811] 217. A composition according to any one of items 203 to 215, wherein the composition comprises 10 to 80 wt%, for example 40 to 65 wt%, for example 50 to 60 wt%, for example 50 to 55 wt%, for example 55 to 60 wt%, for example about 53 wt%, for example about 56 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0812] 218. The composition of any one of items 203 to 215, wherein the composition comprises:

[0813] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0814] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0815] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0816] d. 0.25 to 3 wt%, for example 0.4 to 2.0 wt%, of a lubricant; and

[0817] e. 0.25 to 5 wt %, e.g. 0.3 to 2.5 wt % of a disintegrant;

[0818] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0819] 219. The composition of any one of items 203 to 215, wherein the composition comprises:

[0820] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0821] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0822] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0823] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0824] e. 0.25 to 3 wt%, e.g. 0.4 to 2.0 wt% of magnesium stearate; and

[0825] f. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt % croscarmellose sodium;

[0826] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0827] 220. The composition of any one of items 203 to 215, wherein the composition comprises:

[0828] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0829] b. 20 to 80 wt%, for example 25 to 50 wt% of a filler;

[0830] c. 2 to 20 wt%, for example 3 to 16 wt% of a binder;

[0831] d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant;

[0832] e. 0.25 to 5 wt%, e.g. 0.3 to 2.5 wt% of a disintegrant; and

[0833] f. 1 to 10 wt% film coating;

[0834] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0835] 221. The composition of any one of items 203 to 215, wherein the composition comprises or consists of:

[0836] a. 10 to 80 wt %, for example 40 to 65 wt %, for example 50 to 60 wt %, for example 50 to 55 wt %, for example 55 to 60 wt %, for example about 53 wt %, for example about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof;

[0837] b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose;

[0838] c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose;

[0839] d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% of maltodextrin;

[0840] e. 0.25 to 3 wt %, e.g. 0.4 to 2.0 wt % of magnesium stearate;

[0841] f. 0.25 to 5 wt%, e.g., 0.3 to 2.5 wt% of croscarmellose sodium; and

[0842] g. 1 to 10 wt% of a film coating composition, such as Opadry white,

[0843] Provided that the sum of the wt% of the components does not exceed 100 wt%.

[0844] 222. A composition formulated as a solid dosage form comprising a therapeutically effective amount of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof,

[0845] The therapeutically effective dose is in the range of 50 mg to 400 mg.

[0846] 223. A composition according to item 222, wherein the therapeutically effective dose is 400 mg.

[0847] 224. The composition of claim 222, wherein the therapeutically effective dose is 350 mg.

[0848] 225. The composition of claim 222, wherein the therapeutically effective dose is 300 mg.

[0849] 226. A composition according to item 222, wherein the therapeutically effective dose is 250 mg.

[0850] 227. The composition of claim 222, wherein the therapeutically effective dose is 200 mg.

[0851] 228. The composition of claim 222, wherein the therapeutically effective dose is 150 mg.

[0852] 229. The composition of claim 222, wherein the therapeutically effective dose is 100 mg.

[0853] 230. The composition of claim 222, wherein the therapeutically effective dose is administered once daily.

[0854] 231. A composition according to item 222, wherein the therapeutically effective dose is administered twice daily.

[0855] 232. A composition according to item 222, wherein the therapeutically effective dose is administered three times daily.

[0856] 233. A composition according to any one of items 203 to 232, wherein the composition is for oral administration.

[0857] 234. A method of treating myasthenia gravis in a subject in need thereof, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

[0858] 235. The method of clause 234, wherein the method results in:

[0859] a. Reduction in the quantitative myasthenia gravis total score;

[0860] b. Decrease in MG-ADL score;

[0861] c. Increased muscle strength;

[0862] d. Decrease in the Myasthenia Gravis Composite (MGC) scale;

[0863] e. Decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score;

[0864] f. Improvement in health status as determined using the EQ-5D scale;

[0865] g. Reduction of jitter;

[0866] h. Reduction of blockage;

[0867] i. Decrease in individualized neuromuscular quality of life scores;

[0868] j. A decrease in the Fatigue Severity Scale score; and / or

[0869] k. Improvement of lung function.

[0870] 236. A method for treating myasthenia gravis resulting in decreased MG activities of daily living (MG-ADL) scores in a subject, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0871] 237. The method of claim 236, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0872] 238. The method of one of items 236 or 237, wherein the subject experiences a decrease in MG-ADL score of at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0873] 239. A method of treating myasthenia gravis in a subject resulting in increased muscle strength, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0874] 240. The method of claim 239, wherein improvement in muscle strength is determined by measuring grip strength using a handheld dynamometer.

[0875] 241. The method of one of items 239 or 240, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0876] 242. A method according to one of items 239 to 241, wherein muscle strength is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as 10% to 400%, such as 15% to 200%, such as 20% to 100%.

[0877] 243. A method according to one of items 239 to 241, wherein grip strength is increased by at least 0.25 kg, for example at least 0.50 kg, for example at least 0.75 kg, for example at least 1.0 kg, for example at least 1.25 kg, for example at least 1.5 kg, for example at least 1.75 kg, for example at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg, for example 0.25 to 5.0 kg, for example 0.25 to 4.0 kg, for example 0.5 to 4.0 kg.

[0878] 244. A method of treating myasthenia gravis in a subject resulting in a decrease in the Myasthenia Gravis Composite (MGC) scale, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0879] 245. The method of claim 244, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0880] 246. A method according to one of items 244 or 245, wherein the subject experiences a decrease on the MGC scale of at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0881] 247. A method of treating myasthenia gravis in a subject resulting in a decrease in the Myasthenia Gravis Quality of Life 15-item (MG-QOL15) score, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0882] 248. The method of claim 247, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0883] 249. The method of one of items 247 or 248, wherein the subject experiences a decrease in MG-QOL15 score of at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points.

[0884] 250. A method of treating myasthenia gravis in a subject resulting in an improvement in health status as determined using the EQ-5D scale, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0885] 251. The method of claim 250, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0886] 252. The method of one of items 250 or 251, wherein the subject experiences an increase of at least 0.3 points, e.g., at least 0.5 points, e.g., at least 0.75 points, e.g., at least 1 point, e.g., at least 2 points, e.g., at least 3 points, e.g., at least 4 points, e.g., at least 5 points, e.g., at least 6 points, e.g., at least 8 points, e.g., at least 10 points, e.g., 0.3 to 10 points, e.g., 0.5 to 6 points, e.g., 0.3 to 5 points on the EQ-5D scale.

[0887] 253. A method of treating myasthenia gravis in a subject resulting in reduced tremor, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0888] 254. A method according to claim 253, wherein the reduction in tremor is determined using single fiber electromyography.

[0889] 255. The method of one of items 253 or 254, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0890] 256. A method according to one of items 253 to 255, wherein the jitter is reduced by at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%, for example 5% to 95%, for example 5% to 80%, for example 10% to 50%.

[0891] 257. A method according to one of items 253 to 256, wherein the jitter is reduced by at least 5μs, for example at least 10μs, for example at least 15μs, for example at least 20μs, for example at least 25μs, for example at least 30μs, for example at least 40μs, for example at least 50μs, for example at least 75μs, for example at least 100μs, for example 5μs to 200μs, for example 5μs to 100μs, for example 10μs to 50μs.

[0892] 258. A method of treating myasthenia gravis in a subject resulting in reduced blockade, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0893] 259. A method according to claim 258, wherein the reduction of blockade is determined using single fiber electromyography.

[0894] 260. The method of one of items 258 or 259, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0895] 261. A method according to one of items 258 to 260, wherein the retardation is reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0896] 262. A method for treating myasthenia gravis in a subject resulting in a decrease in an individualized neuromuscular quality of life score, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0897] 263. The method of claim 262, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0898] 264. A method according to one of items 262 or 263, wherein the individualized neuromuscular quality of life score is reduced by at least 0.5 points, such as at least 1 point, such as at least 2 points, such as at least 3 points, such as at least 4 points, such as at least 5 points, such as at least 6 points, such as at least 8 points, such as at least 10 points, such as at least 15 points, such as at least 20 points, such as 0.5 to 30 points, such as 1 to 20 points, such as 0.5 to 10 points.

[0899] 265. A method for treating myasthenia gravis in a subject resulting in a decrease in fatigue severity scale score, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0900] 266. The method of claim 265, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0901] 267. A method according to one of items 265 or 266, wherein the fatigue severity scale score is reduced by at least 0.5 points, for example, at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, for example, at least 2 points, for example, at least 3 points, for example, at least 4 points, for example, at least 5 points, for example, at least 6 points, for example, at least 8 points, for example, at least 10 points, for example, at least 15 points, for example, at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0902] 268. A method of treating myasthenia gravis in a subject resulting in improved lung function, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0903] 269. A method according to claim 268, wherein the improvement in lung function is determined by measuring forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximal inspiratory pressure (MIP) and / or maximal expiratory pressure (MEP).

[0904] 270. The method of one of items 268 or 269, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0905] 271. The method of one of items 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring forced vital capacity (FVC), wherein the FVC is increased by at least 5%, e.g., at least 10%, e.g., at least 15%, e.g., at least 20%, e.g., at least 25%, e.g., at least 30%, e.g., at least 50%, e.g., at least 75%, e.g., at least 100%, e.g., at least 150%, e.g., at least 200%, e.g., 5% to 95%, e.g., 5% to 80%, e.g., 10% to 50%.

[0906] 272. A method according to one of items 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring forced expiratory volume in 1 second (FEV1), wherein FEV1 is increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0907] 273. A method according to one of items 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring maximum inspiratory pressure (MIP), wherein the MIP increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0908] 274. A method according to one of items 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring maximum expiratory pressure (MEP), wherein MEP increases by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as 5% to 95%, such as 5% to 80%, such as 10% to 50%.

[0909] 275. A method of treating myasthenia gravis in a subject resulting in a decrease in a quantitative myasthenia gravis (QMG) total score, comprising administering to the subject a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0910] 276. The method of claim 275, wherein the therapeutically effective dose provides a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max .

[0911] 277. The method of one of items 275 to 276, wherein the subject experiences a decrease in QMG total score of at least 0.9 points, such as at least 1.0 points, such as at least 1.5 points, such as at least 2.0 points, such as at least 3.0 points.

[0912] 278. A method of improving a quantitative myasthenia gravis total score in a subject having myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0913] 279. A method according to claim 278, wherein the reduction in QMG total score after treatment is at least 0.9 points, such as at least 1.0 points, such as at least 1.5 points, such as at least 2.0 points, such as at least 3.0 points.

[0914] 280. A method according to claim 278, wherein the reduction in QMG total score after treatment is at least 0.9 points, such as at least 1.0 points, such as at least 1.5 points, such as at least 2.0 points, such as at least 3.0 points compared to placebo at the same time point.

[0915] 281. The method of claim 278, wherein the reduction in QMG total score after treatment is between 2 and 5 hours after treatment, e.g., 2 hours after treatment, e.g., 3 hours after treatment, e.g., 4 hours after treatment, or e.g., 5 hours after treatment.

[0916] 282. A method for improving right hand grip strength in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0917] 283. A method according to item 282, wherein the improvement in right hand grip strength is at least 2.0 kg, such as at least 2.5 kg.

[0918] 284. A method according to claim 282, wherein the improvement in right hand grip strength is at least 2.0 kg, such as at least 2.5 kg, compared to placebo at the same time point.

[0919] 285. A method of reducing EMG decrements during repetitive neural stimulation in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0920] 286. A method of improving diplopia symptoms in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0921] 287. A method for improving ptosis symptoms in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0922] 288. A method of improving dysarthria symptoms in a subject with myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0923] 289. A method for enhancing neuromuscular transmission and / or restoring skeletal muscle function, comprising administering to a subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0924] 290. A method for treating myasthenia gravis comprising administering to a subject in need thereof (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor.

[0925] 291. A method of treating myasthenia gravis in a patient in need thereof resulting in an improvement in a quantitative myasthenia gravis total score, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof,

[0926] wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 5,000 ng / mL to 14,000 ng / mL. max ,

[0927] Therein, following administration of a therapeutically effective dose of the compound, the patient experiences a reduction in a quantitative myasthenia gravis score of at least 0.9 points when compared to placebo at the same time point.

[0928] 292. The method of claim 291, wherein the therapeutically effective dose of the compound further provides an AUC in the patient in the range of 15,000 ng / mL to 500,000 ng / mL. inf .

[0929] 293. A method according to claim 291, wherein the therapeutically effective dose of the compound is in the patient's T max In the range of 1 to 5 hours.

[0930] 294. A method according to claim 291, wherein the half-life of the compound in the patient at a therapeutically effective dose is in the range of 3 hours to 7 hours.

[0931] 295. A method according to claim 291, wherein a therapeutically effective dose of the compound is administered orally to the patient.

[0932] 296. The method of claim 291, wherein the patient experiences a reduction in a quantitative myasthenia gravis score of at least 1.0 points, such as at least 1.5 points, such as at least 2.0 points.

[0933] 297. A method according to claim 291, wherein the patient's Myasthenia Gravis Foundation of America (MGFA) clinical classification before treatment is I, IIa, IIb, IIIa, IIIb, IVa, IVb or V class.

[0934] 298. A method of treating myasthenia gravis in a patient in need thereof resulting in improved right hand grip strength, the method comprising administering a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof,

[0935] wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg and provides a C in the patient in the range of 5,000 ng / mL to 14,000 ng / mL. max ,

[0936] wherein after administration of a therapeutically effective dose of the compound, the patient experiences an improvement in handgrip strength of at least 1 kg compared to the patient's handgrip strength prior to administration.

[0937] 299. A method according to claim 298, wherein the improvement in hand grip strength of a patient of at least 1 kg occurs at least 3 hours after administration of a therapeutically effective dose of the compound.

[0938] 300. The method of claim 298, wherein the therapeutically effective dose of the compound further provides an AUC in the patient in the range of 15,000 h·ng / mL to 500,000 h·ng / mL. inf .

[0939] 301. The method of claim 298, wherein the therapeutically effective amount of the compound is in the patient's T max In the range of 1 to 5 hours.

[0940] 302. A method according to claim 298, wherein the half-life of the compound in the patient at a therapeutically effective dose is in the range of 3 hours to 7 hours.

[0941] 303. A method according to claim 298, wherein a therapeutically effective dose of the compound is administered orally to the patient.

[0942] 304. The method of claim 298, wherein the therapeutically effective dose is in the range of 100 mg to 600 mg.

[0943] 305. The method of claim 298, wherein the therapeutically effective dose is in the range of 200 mg to 600 mg.

[0944] 306. The method of claim 298, wherein the therapeutically effective dose is 400 mg.

[0945] 307. The method of claim 298, wherein the therapeutically effective dose is 350 mg.

[0946] 308. The method of claim 298, wherein the therapeutically effective dose is 300 mg.

[0947] 309. The method of claim 298, wherein the therapeutically effective dose is 250 mg.

[0948] 310. The method of claim 298, wherein the therapeutically effective dose is 200 mg.

[0949] 311. The method of claim 298, wherein the therapeutically effective dose is 150 mg.

[0950] 312. The method of claim 298, wherein the therapeutically effective dose is 100 mg.

[0951] 313. The method of claim 298, wherein the therapeutically effective dose is administered once, twice or three times daily.

[0952] 314. A method of treating a subject suffering from symptoms of myasthenia gravis, the method comprising administering a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the therapeutically effective dose is in the range of 100 mg to 1500 mg.

[0953] 315. The method of claim 314, wherein the therapeutically effective dose is in the range of 100 mg to 600 mg.

[0954] 316. The method of claim 314, wherein the therapeutically effective dose is in the range of 200 mg to 600 mg.

[0955] 317. The method of claim 314, wherein the therapeutically effective dose is 100 mg.

[0956] 318. The method of claim 314, wherein the therapeutically effective dose is 150 mg.

[0957] 319. The method of claim 314, wherein the therapeutically effective dose is 200 mg.

[0958] 320. The method of claim 314, wherein the therapeutically effective dose is 250 mg.

[0959] 321. The method of claim 314, wherein the therapeutically effective dose is 300 mg.

[0960] 322. The method of claim 314, wherein the therapeutically effective dose is 350 mg.

[0961] 323. The method of claim 314, wherein the therapeutically effective dose is 400 mg.

[0962] 324. The method of claim 314, wherein the therapeutically effective dose is 500 mg.

[0963] 325. The method of claim 314, wherein the therapeutically effective dose is 600 mg.

[0964] 326. The method of claim 314, wherein the therapeutically effective dose is administered once, twice, three times or four times daily.

[0965] 327. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0966] 328. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered once daily.

[0967] 329. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered once daily.

[0968] 330. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered twice daily.

[0969] 331. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered twice daily.

[0970] 332. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[0971] 333. A method according to any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[0972] 334. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0973] 335. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0974] 336. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0975] 337. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered twice daily.

[0976] 338. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[0977] 339. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 100 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[0978] 340. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0979] 341. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is to be administered twice daily.

[0980] 342. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered three times daily.

[0981] 343. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 150 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid and the composition is administered four times daily.

[0982] 344. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0983] 345. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered twice daily.

[0984] 346. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered three times daily.

[0985] 347. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 200 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[0986] 348. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0987] 349. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered twice daily.

[0988] 350. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered three times daily.

[0989] 351. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 250 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[0990] 352. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered once daily.

[0991] 353. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered twice daily.

[0992] 354. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[0993] 355. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 300 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[0994] 356. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0995] 357. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered twice daily.

[0996] 358. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[0997] 359. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 350 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[0998] 360. The method of one of items 234 to 314, wherein the composition is administered at a therapeutic dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is to be administered once daily.

[0999] 361. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[1000] 362. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[1001] 363. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered four times daily.

[1002] 364. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered twice daily.

[1003] 365. A method according to any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[1004] 366. A method according to any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered twice daily.

[1005] 367. The method of any one of items 234 to 314, wherein the composition is administered at a therapeutic dose of about 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid and the composition is administered three times daily.

[1006] 368. Use of a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof in the preparation of a medicament for treating myasthenia gravis in a subject, wherein the composition is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[1007] 369. A kit or composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor for use in a method of treating myasthenia gravis in a subject.

[1008] 370. A kit of parts or composition for use according to claim 369, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof is used for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

[1009] 371. A kit of parts or a composition for use according to any one of items 369 to 370, wherein the therapeutic dose is as defined in any one of items 2 to 57.

[1010] 372. A kit of parts or composition for use according to any one of items 369 to 371, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof and an acetylcholinesterase inhibitor are administered simultaneously.

[1011] 373. A kit of parts or composition for use according to any one of items 369 to 371, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof and an acetylcholinesterase inhibitor are administered sequentially.

[1012] 374. A kit of parts or composition for use according to any one of items 369 to 373, wherein the acetylcholinesterase inhibitor is pyridostigmine.

[1013] 375. Use of a multi-component kit or composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof and an acetylcholinesterase inhibitor in the preparation of a medicament for treating myasthenia gravis.

[1014] 376. A composition for use, a method or a combination of uses according to any preceding claim, wherein the subject is a human.

[1015] 377. The composition for use, the method, or the combination for use according to any preceding claim, wherein the subject suffers from myasthenia gravis.

[1016] 378. The composition of any preceding use, the method, or the combination of uses, wherein the subject suffers from ocular myasthenia gravis, early-onset generalized myasthenia gravis, late-onset generalized myasthenia gravis, generalized myasthenia gravis, seropositive myasthenia gravis, seronegative myasthenia gravis, AChR antibody-positive myasthenia gravis, or muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG).

[1017] 379. The composition for use, the method or the combination for use according to any preceding claim, wherein the subject is further administered one or more compounds selected from the following list: amipridine, eculizumab, prednisolone, prednisone, azathioprine, Soliris, rituximab, agamod alfa, zetacapine, lorixizumab, cholecalciferol and immunoglobulin. Example

[1018] Example 1: EAMG model

[1019] All animal handling, use, and maintenance were in compliance with European and Danish animal welfare regulations, including euthanasia. To test the efficacy of ClC-1 inhibition under conditions of impaired neuromuscular transmission, rat experimental autoimmune MG (EAMG) was selected as a model of neuromuscular transmission disorders, which is a well-established model for determining the efficacy of drug treatments for MG (Losen et al., Exp. Neurol. 2015, 270: 18–28). All activities related to handling, disease induction, and novel compound testing were covered by licenses numbered 2018-15-0201-01408 and 2018-15-0201-01420.

[1020] To induce EAMG, 250 μL of complete Freund's adjuvant emulsion (composed of heat-killed Mycobacterium tuberculosis H37Ra in nonmetabolizable oil, along with phosphate-buffered saline (PBS) and 80 μg of a peptide fragment of the extracellular α-domain of the human nicotinic acetylcholine receptor (antigen)) was injected subcutaneously into seven-week-old anesthetized Lewis rats. The disease-inducing antigen was provided by the Hellenic Pasteur Institute 3. The emulsion was deposited at the base of the tail, left hind leg, and right foreleg. After injection, the animals were allowed to recover and returned to their home cages, which were maintained on a ventilated rack at a temperature controlled between 20 and 22°C, humidity controlled between 55%, and a 12-h light / 12-h dark cycle. Food and water were provided ad libitum. The animals were kept pathogen-free, and the housing and feeding system was designed to ensure this condition during the study. EAMG rats were observed, weighed, and scored for MG symptoms weekly until MG symptoms developed, after which the animals were observed daily.

[1021] Scoring of MG symptoms involves visual inspection of the animals, as described elsewhere (Losen et al., Exp. Neurol. 2015, 270:18–28). If there are obvious signs of fatigue, the animal is not examined further. However, if no obvious signs of fatigue are observed, a forced exercise is performed in which the animal pulls on a grid on the device to measure grip strength for 30 seconds, at least 10 times. This is done to detect any muscle fatigue. After the exercise, the animal is observed again, and if clinical signs of fatigue are present, the animal is scored as 1 according to the following scoring system:

[1022] 0; no observed clinical signs.

[1023] 1. Fatigue: No clinical signs were observed before exercise, but fatigue / weakness symptoms occurred after exercise.

[1024] 2. Clinical signs of fatigue are observed before exercise. Symptoms may include hunched back, head drooping, fatigue, and / or tremors.

[1025] 3; hind leg paralysis, labored breathing, restricted movement, lack of grip and / or noticeable fatigue (humane endpoint).

[1026] 4; Dying (humane end).

[1027] The disease is expected to break out within five to seven weeks after immunization. When the animal shows symptoms equivalent to EAMG score 1, the frequency of weighing and disease scoring is increased to 3 times a week, and softened breeding feed and / or diet gel are supplemented in standard feeding to reduce possible accelerated weight loss. When the animal shows symptoms equivalent to EAMG score 2, the animal is weighed and scored once a day and checked at least once a day in the morning and afternoon. Animals with small wounds at the site of injection of the immune emulsion are treated with antibacterial ointment until the wound heals. Animals that show clinical signs of moderate pain, moderate distress or any degree of discomfort are appropriately treated, i.e., the application is stopped or the animal is euthanized.

[1028] No animals had to discontinue treatment with any of the ClC-1 inhibitors. In accordance with European and Danish laws on experimental animals, the severity of disease requiring humane euthanasia of animals was limited. Specifically, this included animals showing disease progression to an EAMG score of 3 or weight loss exceeding 20% ​​compared to their maximum weight before disease induction. Trained personnel handled animals under veterinary supervision. Health monitoring of the animal facility was performed according to standard operating procedures. Decisions regarding animal welfare were recorded and made daily.

[1029] Experiments involving isolated neuromuscular preparations from healthy and EAMG rats

[1030] In order to measure electrophysiological properties at the cellular level and to measure force, neuromuscular preparations must be isolated from rats. To this end, the animals are sacrificed and the muscles with 1 to 3 cm of intact nerves are excised. The neuromuscular preparations are then transferred to an organ bath for the specific experiment (see below) and perfused with normal Krebs-Ringer (NKR) solution, which consists of the following (in mM): 122 NaCl, 25 NaHCO3, 2.8 KCl, 1.2 KH2PO4, 1.2 MgSO 4、 1.27CaCl2 and 5D-glucose. The NKR solution was continuously aerated with a mixture of 95% oxygen and 5% CO2 to maintain a pH of approximately 7.4. In some experiments, methyl sulfate was used instead of Cl in the solution. - All chemicals used were of analytical grade.

[1031] Example 2: Membrane Conductivity and Basal Strength in Myofibers of Isolated Neuromuscular Preparations

[1032] The effects of compounds on the resting membrane conductance (G) of single myofibers in freshly dissected intact muscles from adult rats were measured. m ) to evaluate the ability of compounds to inhibit ClC-1 in native tissues. m It is an electrical measure of the flow of ions across the surface membrane through ion channels that are open at the resting membrane potential. ClC-1 is known to account for the majority of G m It is the only known skeletal muscle surface membrane Cl - channel (Pedersen et al., J. Gen. Physiol. 2016, 147: 291–308). m Any changes in can mainly reflect changes in the function of ClC-1. - In the experiment G m The records can be used to separate the effects of compounds on ClC-1.

[1033] The experiments used soleus or diaphragm muscles from healthy rats and EAMG rats with scores of 0, 1, or 2. After dissection, the muscles were mounted in organ baths perfused with NKR solution at 30-31°C and a pH of 7.4-7.5. To select the fibers to be measured, the bath was placed on the XY stage of a Nikon upright microscope (Eclipse FN1, DFA, Glostrup, Denmark) to allow movement of the bath and visual inspection of the fibers and electrodes. The muscles were allowed to rest in the solution for 30 minutes before starting the experiments.

[1034] Measuring resting G using electrophysiological techniques mThis technique involves inserting three intracellular microelectrodes into a single myofiber, as explained in detail elsewhere (Riisager, A., Aarhus University, 2015). Briefly, three electrodes (E1-E3) were placed into the same myofiber so that three different inter-electrode distances could be identified (E1→E2=X1; E2→E3=X2; E1→E3=X3), where X2 is approximately twice the distance from X1. All electrodes recorded membrane potential, and a two-electrode current injection protocol was used: first, a 50ms steady-state current (I) of -30-50nA was injected by E1, while the steady-state membrane potential response (ΔV) was measured with E2 and E3, resulting in recordings at X1 and X3, respectively. Subsequently, a current of the same duration and magnitude was injected through E3, while ΔV was measured with E1 and E2, resulting in another recording at X3 and one at X2. Overall, this leads to the measurement of ΔV at three different distances along the fiber (X1, X2, X3), where X3 is recorded twice by E1 and E3. From these recordings, the transfer resistance (ΔV / I) at the three distances can be calculated and G can be determined using the linear cable theory described previously. m。

[1035] Once the G in the fiber is determined m A series of 25ms positive currents were injected through E1, with amplitudes increasing from 5 to 70 nA in 5nA increments. This was done to determine the current required to elicit APs in impaled fibers. This current, called the base strength current, is a measure of fiber excitability. It was included to explore the hypothesis that ClC-1 inhibition would increase myofiber excitability following the addition of ClC-1 inhibitor compounds, as reflected by a decrease in the base strength current.

[1036] To test the effect of compounds on G m To investigate the effects of NMD670 on ClC-1 binding, recordings were first obtained from a series of muscle fibers before compound addition and then after compound addition at varying concentrations. Muscle specimens were incubated with each compound concentration for 20–30 min before starting the measurement, and recordings were obtained from approximately 10 fibers per muscle at each concentration. The affinity of NMD670 for inhibiting ClC-1 was determined based on the G values ​​before compound addition and at varying compound concentrations. m The binding affinity was determined by fitting a four-parameter Hill function with a variable slope to extract the apparent affinity.

[1037] To demonstrate the effects of NMD670 on ClC-1 inhibition and excitability in muscle fibers of EAMG animals, G in intact EAMG soleus muscle fibers was measured before and after addition of 20 μM NMD670 to the experimental solution. m and base current ( Figure 1 ). Figure 1The effect of NMD670 on the membrane conductance (G) of rat soleus muscle from healthy animals (n=20) and EAMG animals (n=12) is shown. m ) influence, the G m are the average G values ​​measured in muscles before (black circles or open squares, respectively) and after (black triangles or open inverted triangles, respectively) addition of 20 μM NMD670. m The addition of NMD670 statistically significantly reduced G in both healthy and EAMG animals. m .

[1038] Figure 2 The effect of NMD670 on skeletal muscle fiber excitability is shown, as assessed by basal current in the soleus muscle of healthy (n=20) and EAMG (n=12) rats before (black circles or hollow squares, respectively) and after (black triangles or hollow inverted triangles, respectively) addition of 20 μM NMD670. Addition of NMD670 significantly reduced basal current in myofibers of both groups of rats.

[1039] To confirm that NMD670 exerts its G-lowering effect by inhibiting ClC-1 channels, m The effect of NMD670 with increasing concentrations and without Cl - Under these conditions, NMD670 did not reduce G m .

[1040] Example 3: Endplate Potential

[1041] The effects of ClC-1 inhibition on neuromuscular transmission were investigated at the cellular level by recording end-plate potentials (EPPs) using intracellular electrodes in isolated neuromuscular preparations from healthy and EAMG rats (scores 0-2). The muscle preparations used in the experiments were either the diaphragm or the levator auris (LAL) muscle, which offers the advantage of dissecting out intact motor nerves of 1-3 cm. Immediately after dissection, the preparations were fixed in a chamber perfused with NKR at a temperature of 30-31°C and a pH of 7.4-7.5. The preparations were allowed to rest in the solution for 30 minutes before starting the experiment.

[1042] To establish stable and reliable motor nerve stimulation, a field stimulation electrode was developed to selectively stimulate motor nerves. The electrode consisted of two silver wires, insulated except for their tips, positioned so that the nerve was located between the uninsulated ends of the wires. The wires were connected to a glass pipette in a pipette holder, which was placed on a micromanipulator, which was then placed on the XY stage of a microscope. The electrode allowed for continuous stimulation of the nerve while avoiding the degradation observed with suction electrodes (data not shown). To avoid direct muscle fiber stimulation and minimize stimulation artifacts in the recordings, the electrode was placed as far away from the muscle itself as possible. Trigger pulses for nerve stimulation were provided by an external constant current stimulator (DS3 Isolated Constant Current Stimulator; Digitimer, USA) and controlled by recording software (Signal version 6.4, Cambridge Electronics Design Ltd, Cambridge, UK). Before starting the experimental protocol, the external stimulator was adjusted to provide the minimum current magnitude and duration required to elicit EPPs in the muscle. This was done to avoid nerve damage and, again, to minimize the risk of directly stimulating the muscle through the bath rather than the nerve.

[1043] To record EPPs evoked by nerve stimulation, glass microelectrodes were inserted into individual muscle fibers immediately adjacent to the neuromuscular junction. The relatively thin muscle fiber layer and the transparent nature of the diaphragm and LAL allowed for visual localization of the endplates using a microscope. To further verify the position of the microelectrode on the endplate, recordings were included only when a small endplate potential was observed during initial electrode insertion. 0.5–1 μM voltage-gated Na + The channel blocker μ-conotoxin GIIIB (Alamone Labs, IL) was used to prevent the firing of action potentials in response to nerve stimulation.

[1044] The stimulation protocol for eliciting EPPs consisted of two different trigger pulse trains: the first at 12 Hz, 30 pulses, and the second at 30 Hz, 30 pulses. A 10-second pause separated the two trains. This allowed for the recording of two EPP trains per fiber, and their EPP amplitudes were analyzed. For each muscle, a control set of measurements was first obtained from approximately 20 fibers before compound addition, followed by a set of measurements from approximately 20 fibers starting after 20-30 minutes of incubation with 20 μM NMD670.

[1045] To account for subtle variations in resting membrane potential between fibers, EPP amplitudes were corrected using the following expression:

[1046] Among them, EPP amp and EPP amp,corr Refers to the EPP amplitude before and after correction respectively. V m,0is the membrane potential to which all fibers are calibrated (set to -80 mV), V m is the actual recorded membrane potential. E Rev is the reversal potential of the acetylcholine receptor, set at -15 mV (del Castillo et al., J. Physiol. 1954, 124:560-573).

[1047] Figure 3 showed that EPP was significantly reduced in the myofibers of EAMG rats compared with healthy animals, but after the addition of NMD670, EPP in the myofibers of EAMG rats was ...

Claims

1. A composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof for use in a method of treating myasthenia gravis in a subject, wherein the composition is administered at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

2. The composition for use according to claim 1, wherein the therapeutic dose is 200 to 600 mg.

3. A composition for use according to any one of the preceding claims, wherein the therapeutic dose is to be administered twice daily.

4. A composition for use according to any one of the preceding claims, wherein the composition is administered orally.

5. A composition for use according to any one of the preceding claims, wherein the composition is a solid dosage form.

6. A composition for use according to any one of the preceding claims, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein T is reached within 1 to 5 hours after administration. max .

7. A composition for use according to any one of the preceding claims, wherein the composition is to be administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein after administration of a single dose of 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, the average C max 13,000 to 32,000 ng / mL.

8. A composition for use according to any one of the preceding claims, wherein the quantitative myasthenia gravis (QMG) total score is reduced after treatment compared to placebo at the same time point, and the reduction in the QMG total score after treatment is at least 0.9 points.

9. A composition for use according to any one of the preceding claims, wherein the subject suffers from ocular myasthenia gravis, early-onset generalized myasthenia gravis, late-onset generalized myasthenia gravis, generalized myasthenia gravis, seropositive myasthenia gravis, seronegative myasthenia gravis, AChR antibody-positive myasthenia gravis, or muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG).

10. A composition formulated as a solid dosage form, comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, wherein the composition comprises 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

11. The composition according to claim 10, wherein the composition comprises 10 to 80 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

12. The composition according to any one of claims 10 to 11, wherein the composition further comprises at least one pharmaceutically acceptable auxiliary material and / or excipient selected from the group consisting of a filler, a binder, a lubricant and a disintegrant.

13. A composition according to any one of claims 10 to 12, wherein the composition comprises: a. 10 to 80 wt%, for example 40 to 65 wt%, for example 50 to 60 wt%, for example 50 to 55 wt%, for example 55 to 60 wt%, for example about 53 wt%, for example about 56 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof; b. 5 to 60 wt%, such as 20 to 40 wt%, such as 21 to 37 wt% of silicified microcrystalline cellulose; c. 2 to 60 wt%, for example 5 to 16 wt% of microcrystalline cellulose; d. 1 to 15 wt%, such as 1.5 to 7 wt%, such as 1.8 to 6.0 wt% maltodextrin; e. 0.25 to 3 wt%, for example 0.4 to 2.0 wt% of magnesium stearate; and f. 0.25 to 5 wt %, e.g. 0.3 to 2.5 wt % of cross-linked sodium carboxymethyl cellulose; Provided that the sum of the wt% of the components does not exceed 100 wt%.

14. A kit or composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, and an acetylcholinesterase inhibitor for use in a method of treating myasthenia gravis in a subject.

15. The kit for use according to claim 14, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof is used for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propionic acid.

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