Compositions and methods for treating myasthenia gravis

Abstract

Disclosed herein is a method for treating myasthenia gravis (MG) comprising administering (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or a pharmaceutical composition thereof to a patient suffering from symptoms of MG. Pharmaceutical compositions and kits of parts containing (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid are also disclosed.

Description

[Technical Field]

[0001] The present disclosure relates to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid for use in the treatment of myasthenia gravis (MG), pharmaceutical compositions thereof for use in the treatment of MG, and methods of treatment. [Background technology]

[0002] Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) characterized by voluntary skeletal muscle weakness and fatigue, which worsens with continued muscle activity and improves with rest of the involved muscle(s) (Borges et al., Front. Immunol. 2020, 11:707). In MG, the distribution of weakness is unique, often involving extraocular muscles. MG may initially begin with ocular muscle weakness affecting eye and eyelid movement, a condition known as ocular MG (oMG). In more severe cases (generalized MG), muscles innervated by pontine and bulbar nerves, as well as respiratory muscles, are also commonly affected. Limb muscles are least frequently involved.

[0003] MG can lead to life-threatening respiratory failure, called myasthenic crisis. Approximately 15% to 20% of subjects will experience a myasthenic crisis during the course of their disease, and 75% will require hospitalization and ventilatory support within 2 years of diagnosis.

[0004] In the United States, MG affects approximately 60,000 Americans, with a prevalence of 14-20 per 100,000. Although men and women are equally affected, incidence peaks in women in their 30s, compared with men in their 60s or 70s. Mortality from MG is approximately 4%, with the majority of deaths due to respiratory failure.

[0005] MG is generally caused by autoantibodies targeting the neuromuscular junction. In systemic MG, approximately 90% of patients have circulating antibodies (Abs) targeting the postsynaptic neurotransmitter receptor, the nicotinic acetylcholine receptor (AChR). Loss of AChR function results in impaired neuromuscular transmission, which can lead to failure of muscle fiber activation and ultimately muscle weakness and excessive fatigue. At the neuromuscular junction, the transmission of a nerve action potential to the muscle membrane involves the flow of both excitatory and inhibitory currents. For muscles to become excited, the excitatory current must exceed the inhibitory current. In myasthenia gravis, loss of AChRs reduces the flow of excitatory currents.

[0006] Another antibody commonly detected in patients with MG is one that targets the muscle-specific kinase (MuSK) protein. This form of MG is known as MuSK-MG (Borges et al., Front. Immunol. 2020, 11:707). MuSK-MG is also an Ab-mediated disease, but does not involve inflammatory damage to the NMJ. In fact, the majority of Abs belong to the IgG4 immunoglobulin subclass, which is characterized by its inability to activate complement or bind to Fc receptors. The proposed mechanism of action of these self-Abs is to inhibit the normal function of MuSK.

[0007] Although there is no cure for MG, currently available treatments for generalized myasthenia gravis aim to modulate neuromuscular transmission, inhibit the production or effects of pathogenic antibodies, inhibit the cleavage of complement component 5, or inhibit inflammatory cytokines. Current standard treatments typically combine cholinesterase inhibitors (most commonly pyridostigmine), corticosteroids (commonly prednisone), and immunosuppressants (most commonly azathioprine, cyclosporine, and mycophenolate mofetil), resulting in fairly good disease control in the majority of patients with MG. However, some patients are refractory to or intolerant of standard treatments and may benefit from new treatment options.

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

[0009] The skeletal muscle-specific ClC-1 chloride ion channel conducts an inhibitory current that opposes neuromuscular transmission. Inhibiting ClC-1 reduces the inhibitory current, thereby increasing muscle membrane excitability and enhancing neuromuscular transmission. This has been shown to lead to recovery of muscle function in preclinical models of several neuromuscular diseases (Pedersen et al., Acta Physiol. 2021, 1-14).

[0010] Thus, the ClC-1 ion channel has emerged as a potential drug target, although its potential has largely unrealized. U.S. Patent No. 10,385,028 discloses the synthesis of compounds designed to inhibit the action of the ClC-1 ion channel to treat 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 NMD670). The chemical structure of NMD670 is shown below. [ka] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid (NMD670)

[0012] U.S. Patent No. 10,385,028 discloses a series of compounds capable of inhibiting the ClC-1 ion channel to treat neuromuscular disorders, but does not discuss how to design a treatment regimen that would allow these compounds to effectively alleviate the wide range of symptoms associated with myasthenia gravis that fluctuate from day to day. WO2020 / 254554, incorporated herein by reference, discloses a method for producing NMD670.

[0013] Therefore, due to the limited efficacy and / or side effects caused by existing treatments, there is a need for safe and effective treatments to improve muscle function in patients with all forms of MG. Summary of the Invention

[0014] 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.

[0015] The present disclosure further relates to 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, comprising 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0016] The present disclosure further relates to a method of improving a quantitative myasthenia gravis total score or improving right hand grip strength in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0017] The present disclosure further relates to a kit-of-parts 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. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 shows the effect of NMD670 on membrane conductance (Gm) in the soleus muscle of healthy rats (n = 20) and rats with myasthenia gravis (EAMG) (n = 12), as shown by the mean Gm measured in the muscle before (closed circles or open squares, respectively) and after (closed triangles or inverted open triangles, respectively) the addition of 20 μM NMD670. The black overlay bars represent the mean ± SEM for each group. The addition of NMD670 resulted in a statistically significant decrease in Gm in both healthy and EAMG animals. [Figure 2] Figure 2 shows the effect of ClC-1 inhibition on skeletal muscle fiber excitability, as assessed by rheobase in skeletal muscle fibers from healthy and EAMG rats. The rheobase (nA) in soleus muscle fibers from healthy (n = 20) and EAMG rats (n = 12) is shown as the average rheobase measured before (closed circles or open squares, respectively) and after (closed triangles or inverted open triangles, respectively) the addition of 20 μM NMD670. The black overlay bar indicates the group mean ± SEM. The addition of NMD670 significantly reduced the rheobase in muscle fibers from both groups of rats. [Figure 3]Figure 3 shows the end-plate potential (EPP) amplitudes of a healthy rat (left trace), an untreated EAMG rat (middle trace), and an EAMG rat after the addition of 20 μM NMD670 (right trace). Compared to the EPPs of healthy rats, the EPPs of muscle fibers from EAMG rats were significantly reduced but could be restored after the addition of NMD670. [Figure 4] Figure 4 shows the mean end-plate potential (EPP) amplitude in 68 muscle fibers (black diamonds) from myasthenia gravis (EAMG) rats without ClC-1 inhibitors and in 82 muscle fibers (white circles) in the presence of 20 μM NMD670 during 30 12 Hz stimulations. ClC-1 inhibition by NMD670 increased EPPs by more than 35% throughout the 12 Hz stimulation train. [Figure 5] Figure 5 shows action potentials at 30 Hz stimulation in muscle fibers from a healthy rat (left trace), an untreated EAMG rat (middle trace), and an EAMG rat after the addition of 20 μM NMD670 (right trace). In the nerve muscle preparation from the untreated EAMG rat (middle trace), sustained action potential firing was impaired compared to the healthy rat (left trace), but after the addition of 20 μM NMD670, the success of repeated action potential firing was significantly improved (right trace). [Figure 6] Figure 6 shows the average success rate (%) of action potential generation trials at 30 Hz before and after treatment with 20 μM NMD670 (n = 110 muscle fibers in both groups). After the addition of 20 μM NMD670, the success rate of repetitive action potential generation was significantly improved. [Figure 7] Figure 7 shows the force from isolated soleus muscles nerve-stimulated at 60 Hz from a healthy rat (left trace), an untreated EAMG rat (middle trace), and an EAMG rat after the addition of 20 μM NMD670 (right trace). Compared to the force from healthy rats, the force from muscle fibers from EAMG rats was significantly reduced but could be recovered after the addition of NMD670. [Figure 8]Figure 8 shows the average force in isolated, nerve-stimulated soleus (n=14), EDL (n=14), and diaphragm (n=12) muscles from EAMG animals treated with 20 μM NMD670 compared to the muscles before treatment (value set at 100). Addition of NMD670 restored force production to levels close to those observed in muscles from healthy animals. [Figure 9] Figure 9 shows nerve stimulation force (lower panel) and EMG amplitude (upper panel) of the triceps surae muscle from an age-matched healthy rat (left trace) and an EAMG rat with myasthenia gravis (EAMG) score of 2. The muscle was stimulated via the sciatic nerve at 80 Hz for 1 second before (middle trace) and 20 minutes after (right trace) administration of 40 mg of NMD670 per kg of body weight. Administration of NMD670 to EAMG animals resulted in a rapid recovery of force and EMG amplitude. [Figure 10] Figure 10 shows the average muscle strength (mean ± SEM) of EAMG rats (illustrated in Figure 8) before (white) and after (gray) oral administration of NMD670 (2–120 mg / kg), compared to that of age-matched healthy rats. This figure demonstrates that administration of NMD670 in EAMG rats resulted in rapid and dose-dependent recovery of muscle strength. Numbers within columns indicate the number of rats per dose group. [Figure 11] Figure 11 shows the increase in grip strength (45 minutes after administration) in EAMG rats receiving vehicle (black, n = 35), 0.375 mg mestinon per kg body weight (checkered pattern, n = 10), 20 mg NMD670 per kg body weight (diagonal line, n = 17), or a combination of 0.375 mg mestinon per kg body weight and 20 mg NMD670 per kg body weight (horizontal line, n = 5). Grip strength increased significantly after administration of NMD670 or the combination of NMD670 and mestinon. Vehicle treatment did not affect grip strength. [Figure 12]Figure 12 shows grip strength versus body weight during 14 days of chronic treatment in EAMG rats receiving vehicle (filled circles) or 20 mg / kg NMD670 twice daily (open circles). Rats receiving NMD670 showed increased grip strength compared to the vehicle group throughout the treatment period. [Figure 13] Figure 13 shows rotarod performance versus body weight during 14 days of chronic dosing in EAMG rats receiving either 20 mg / kg NMD670 (filled circles) or 20 mg / kg NMD670 twice daily (open circles). Rats receiving NMD670 had greater endurance on the rotarod (longer latency to fall) than the vehicle group throughout the treatment period. [Figure 14] Figure 14 shows body weights in EAMG animals receiving vehicle (filled circles) or 40 mg / kg NMD670 (open circles) twice daily during 14 days of chronic dosing compared to individual body weights at study day 0. Treated animals showed attenuated weight loss (vs. vehicle) over the course of the study. [Figure 15] Figure 15 shows the number of adverse events recorded during the single ascending dose study. Line 4 lists the total incidence of all adverse events (AEs) at that dose of NMD670, with the number of subjects reporting that AE in parentheses. Line 5 lists the total incidence of serious adverse events (SAEs). The bottom of the table lists the incidence of the most common adverse events (recorded in >1 subject). The number of subjects reporting an AE is shown in parentheses. [Figure 16] Figure 16 shows the study design for 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. [Figure 17] Figure 17 shows the behavioral schedule for Part C of the early Phase II clinical trial. QMG: Quantitative Myasthenia Gravis Scale, RNS: Repetitive Nerve Stimulation, MVRC: Muscle Velocity Recovery Cycle, RoVEMP: Repetitive Ocular Vestibular Myoelectric Potential. Time points indicated on the schedule are approximate. [Figure 18]Figure 18 shows a study diagram from a prospective Phase II clinical trial. BID = twice daily, N = number of participants. [Figure 19A] Figure 19A shows the behavioral schedule for a prospective Phase II clinical trial. Note: If possible, assessments should be performed simultaneously at different visits and in the order shown in the table, unless otherwise specified. [Figure 19B] Figure 19B shows the behavioral schedule for a prospective Phase II clinical trial. Note: If possible, assessments should be performed simultaneously at different visits and in the order shown in the table, unless otherwise specified.

[0019] 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 automated response technology, MG-ADL: Myasthenia Gravis Activities of Daily Living, MGC = Myasthenia Gravis Composite, 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

[0020] definition All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0021] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0022] The term "patient" or "subject" refers to a human (e.g., a male or female human) diagnosed with MG. Patients with MG may be diagnosed and graded using the Myasthenia Gravis Foundation of America (MGFA) clinical classification (Barnett et al., Neurol Clin. 2018, 36(2):339-353).

[0023] The term "Quantitative Myasthenia Gravis Total Score" (QMG Total Score) refers to a 13-item (see Table 1) standardized test used in clinical trial settings to measure muscle strength, endurance, or fatigability (Barohn et al., Ann NY Acad Sci 1998, 841:769-72). The items measure the following symptoms and signs: ptosis, diplopia, double vision, swallowing, speech (including dysarthria), percent 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 0-3 scale, with a total score ranging from 0 to 39. Higher scores indicate greater disease severity.

[0024] The term "improvement" refers to a reduction in the patient's myasthenia gravis (MG) symptoms when the patient is administered a composition described herein, compared to the patient's MG symptoms when the patient is administered a placebo. The term "improvement" can also refer to a reduction in the MG symptoms of a patient group after administering a composition as described herein to the patient group, such as assessed based on comparative test scores between a patient group administered a composition as described herein and a control group that received, for example, a placebo. Improvement in a patient's MG symptoms can be determined using, for example, the Quantitative Myasthenia Gravis (QMG) total score (a decrease in the QMG total score indicates an improvement in the patient's symptoms), an improvement in hand grip strength (an increase in force measured with a dynamometer indicates that the patient can pull a heavier weight), an increase in compound muscle action potential, reversal of muscle wasting, a decrease in the MG Profile of Activities of Daily Living (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 (MG-QOL15) score, improved health status as determined using the EQ-5D scale, a decrease in jitter, a decrease in blockages, a decrease in individual neuromuscular quality of life scores, a decrease in fatigue severity scale scores, and / or an improvement in pulmonary function. In an exemplary embodiment, improvement in MG symptoms includes a decrease in the QMG total score.

[0025] The term "jitter" refers to the variability in the arrival time of action potentials at the recording electrode between successive discharges when measuring neuromuscular function using single fiber electromyography (sfEMG).

[0026] The term "block" refers to the complete failure of NMJ transmission of action potentials to the recording electrode between successive discharges when measuring neuromuscular function using sfEMG.

[0027] The term "placebo" refers to a dosage form that has no therapeutic activity.

[0028] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0029] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to the subject to which it is administered, examples of which include disintegrants, binders, fillers, solvents, buffers, isotonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in pharmaceutical formulations.

[0030] The term "pharmaceutical composition" refers to a preparation in a form such that the biological activity of the active ingredient contained therein is effective and which does not contain additional ingredients that are unacceptably toxic to the subject to which the composition is administered.

[0031] The term "pharmaceutically acceptable" refers to the attributes of a material that is generally safe, non-toxic, biologically or otherwise undesirable, and useful in preparing pharmaceutical compositions that are acceptable for veterinary, as well as human, pharmaceutical use.

[0032] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers or acidifying agents, excipients, stabilizers, or preservatives.

[0033] The term "solid dosage form release" refers to the amount of compound released or dissolved into solution after a specified period of time when used in a United States Pharmacopeia (USP) Type 2 dissolution apparatus in 900 mL of pH 6.8 phosphate / citrate buffer at a temperature of 37°C ± 0.5°C with a paddle speed of 75 rpm, as described in Example 10.

[0034] "C max The term "mean C" (expressed in ng / mL) refers to the maximum observed plasma concentration of NMD670. max The term " max means the arithmetic mean of the values.

[0035] "T max ” (expressed in units of time, or T max The term "C" refers to the time after drug administration that max If this occurs at more than one time point, T max is defined as the first time point with this value.

[0036] The term "dose" refers to the dose of NMD670 as the free acid given to a subject. Additionally, the term "dose" may include NMD670 in combination with a pharmaceutically acceptable salt.

[0037] As used herein, the term "therapeutically effective dose" refers to the amount of NMD670 required to elicit a therapeutic response in a subject. As used herein, the terms "therapeutically effective dose" and "therapeutic dose" are used interchangeably.

[0038] A composition containing a (therapeutic) dose may 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 dosage contains a predetermined amount of a therapeutically active compound, optionally together with a pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, ampoules and syringes, and oral solutions or suspensions, and oil-water emulsions. Unit dosage forms can be individually packaged, such as in a blister pack, as is known in the art. Unit dosage forms can be administered in fractions or multiples thereof.

[0039] "T 1 / 2 The term "(expressed in units of time)" refers to the terminal elimination half-life of NMD670 in plasma.

[0040] "AUC 0-infinity The term "mean AUC" (expressed in units of h ng / mL) refers to the cumulative area under the plasma time-concentration curve (AUC) calculated using the trapezoidal method from time 0 to infinity after a single dose of NMD670. 0-infinity The term "AUC" refers to the individual 0-infinity means the arithmetic mean of the values.

[0041] "AUC 0-24hours The term "mean AUC" (expressed in units of h ng / mL) refers to the cumulative area under the plasma time-concentration curve (AUC) calculated using the trapezoidal method from time 0 to 24 hours after a single dose of NMD670. 0-24hours The term "AUC" refers to the individual 0-24hours means the arithmetic mean of the values.

[0042] As used within the following disclosure, the term "NMD670" refers to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, as well as any pharmaceutically acceptable salts, hydrates, polymorphs, tautomers, or solvates thereof.

[0043] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid according to the present disclosure refers to the compound of formula (I) below (CAS number 2354321-33-6): [ka]

[0044] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION

[0045] Myasthenia gravis is a neuromuscular disorder, either autoimmune or congenital, that causes fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effect of the neurotransmitter ACh on nicotinic ACh receptors at the neuromuscular junction.

[0046] NMD670 is a compound designed to treat neuromuscular disorders, one of which is myasthenia gravis, by inhibiting the ClC-1 ion channel. Inhibiting the ClC-1 ion channel reduces the generation of inhibitory currents flowing through the NMJ region of muscle fibers, thereby prolonging the effect of excitatory currents flowing through the NMJ region. This prolongation may lead to improved muscle contraction and control in patients with myasthenia gravis.

[0047] After conducting various non-clinical and clinical pilot experiments, the inventors of the present disclosure have discovered treatment regimens and compositions that enable NMD670 to treat various symptoms of myasthenia gravis and thereby provide patients suffering from myasthenia gravis with improved quality of life. Various aspects and embodiments of these treatment methods and compositions are described below. However, these various aspects and embodiments may be embodied in many different forms. Accordingly, this disclosure should not be construed as limited to these embodiments; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the technology described herein to those skilled in the art. Various non-clinical and clinical trial experiments that led to the discovery of the treatment methods described herein are described in detail below.

[0048] To assess whether ClC-1 inhibition can enhance neuromuscular transmission and restore muscle function in disease-mediated NMJ dysfunction, we first assessed the effects of ClC-1 inhibition from the synapse level to intact skeletal muscle. This was performed acutely and chronically in an actively immunized rat model of muscle atrophy (EAMG), which exhibits severe symptoms of muscle weakness and excessive fatigue (Losen et al., Exp. Neurol. 2015, 270:18-28). NMD670's ability to inhibit ClC-1 was first confirmed in healthy rat muscle fibers using electrophysiological techniques with three intracellular microelectrodes (Figure 1) (Riisager et al. J Physiol. 2014, 592(20):4417-29). Using the same approach, we confirmed ClC-1 inhibition by NMD670 in EAMG rat muscle. We confirmed that neuromuscular disease does not affect ClC-1 function itself or the ability of NMD670 to inhibit the ClC-1 channel. Inhibition of ClC-1 in muscle fibers from MG rats increased muscle fiber excitability, as observed by a decrease in the rheobase required to trigger muscle fiber action potentials (Fig. 2).

[0049] To determine the effects of ClC-1 inhibition at the single synapse level, two series of experiments were performed using nerve-muscle preparations isolated from severely EAMG rats. In both series, motor nerves were electrically stimulated, and intracellular electrodes inserted at the NMJ recorded the membrane potential of muscle fibers in response to nerve stimulation. In the first series of experiments, the effect of ClC-1 inhibition on EPPs was determined. These experiments demonstrated that μ-conotoxin inhibited skeletal muscle-specific voltage-dependent Na+ release. + Selective blockade of the channel prevented action potential firing in muscle fibers. Similar to findings in MG patients (Elmqvist, et al. J. Physiol. 1965, 178:505-529), EPP amplitude was significantly reduced in muscle fibers from EAMG rats compared with healthy animals (Figure 3). ClC-1 inhibition with NMD670 increased EPP amplitude by more than 35% throughout the entire 12 Hz stimulation train (Figure 4).

[0050] A second series of experiments at the single synapse level explored whether the increase in EPP amplitude due to ClC-1 inhibition 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 ClC-1 inhibition. As shown in Figure 5, sustained action potential firing was impaired in nerve muscle preparations derived from untreated EAMG animals (Figure 5, middle trace) compared with healthy animals (Figure 5, left trace). After the addition of 20 μM NMD670, the success rate of repeated action potential firing significantly improved (Figure 5, right trace, and Figure 6). Taken together, the restored EPP amplitude (Figure 4) and improved action potential firing (Figure 6) confirmed that ClC-1 inhibition enhances neuromuscular transmission in the EAMG model.

[0051] We next used both ex vivo and in vivo approaches to determine whether enhanced synaptic strength in EAMG rat muscles following ClC-1 inhibition resulted in recovery of muscle function. Isolated nerve-muscle preparations were placed in tissue baths, and force generation was evoked by nerve stimulation. In contrast to well-maintained force generation in muscles from age-matched healthy rats, muscles from EAMG animals were unable to sustain force generation during short-term nerve stimulation (Figure 7). This excessive fatigue during stimulation was most pronounced in distal hindlimb muscles, but was also observed in diaphragm muscles. In all muscles, ClC-1 inhibition using 20 μM NMD670 restored force generation to levels similar to those observed in muscles from healthy animals (Figure 8).

[0052] Next, the effect of ClC-1 inhibition on muscle force was evaluated in vivo in EAMG rats, which exhibit clear symptoms of MG. Rats were anesthetized, and simultaneous electromyogram (EMG) and force recordings were obtained from the triceps surae muscle during sciatic nerve stimulation. Measurements were performed before and after oral administration of NMD670, and blood samples were collected to measure NMD670 plasma concentrations and to allow for the determination of pharmacokinetic / pharmacodynamic relationships. Similar to observations in isolated preparations, both EMG amplitude and nerve-stimulated muscle force were significantly reduced in EAMG rats (Figure 9, center trace) compared with healthy animals (Figure 9, left trace). Administration of NMD670 to EAMG rats resulted in a rapid and dose-dependent recovery of both EMG and force (Figure 9, right trace).

[0053] Figure 10 shows the average muscle strength (mean ± SEM) of EAMG rats before (white) and after (gray) oral administration of NMD670 (2–120 mg / kg) compared with that of age-matched healthy rats. This figure demonstrates that administration of NMD670 in EAMG rats resulted in rapid and dose-dependent recovery of muscle strength.

[0054] The next series of experiments was performed in conscious EAMG rats to determine whether ClC-1 inhibition could enhance neuromuscular transmission and restore muscle strength, thereby increasing strength during voluntary movement. First, we determined the effect of a single dose of NMD670 on grip strength in severe EAMG rats. Experiments were performed in a blinded fashion, and the acetylcholinesterase inhibitor mestinon was used as a positive control. As shown in Figure 11, grip strength increased by 15 ± 5% after NMD670 administration and 5 ± 4% after mestinon administration. As expected from different mechanisms of action for enhancing neuromuscular transmission, the two approaches were additive (24 ± 12%). Vehicle treatment had no effect on grip strength (1 ± 2%). Collectively, these data demonstrate that a single dose of NMD670 enhanced neuromuscular transmission and restored skeletal muscle function in EAMG rats.

[0055] MG is a chronic disease requiring lifelong treatment. Given that ClC-1 inhibition has not previously been evaluated for the treatment of MG, it was unclear how chronic administration of NMD670 and its suppression of ClC-1 function would affect muscle function. For this reason, we performed a 14-day efficacy study in severely symptomatic EAMG rats. We assessed the effects of twice-daily administration of NMD670 (20 mg / kg) or vehicle on body weight, grip strength, and endurance (rotarod). The study was blinded, and all rats were tested for the presence of antibodies against acetylcholine receptors. Blood sampling was performed throughout the 14-day study period, and muscle biopsies were performed at the end of the study to confirm dose adequacy between study groups. Rats receiving NMD670 demonstrated improved grip strength (Figure 12) throughout the treatment period and improved endurance on the rotarod (Figure 13).

[0056] Treated animals also showed attenuated weight loss (vs. vehicle) throughout the study (Figure 14). In both groups, early termination was necessary when body weight decreased to less than 80% of the maximum pre-disease weight. In the NMD670-treated group, six of eight treated rats completed the study, whereas only three of eight vehicle-treated rats completed the study. Thus, these findings support the notion that long-term ClC-1 inhibition chronically improves muscle function in EAMG rats, thereby improving overall health.

[0057] The effect of ClC-1 inhibition on the treatment of MG was further evaluated in clinical trials. Specifically, a Phase I / early Phase II clinical trial was conducted to initially 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 effect of ClC-1 inhibition on the treatment of MG.

[0058] Part A1 examined 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 investigated in three cohorts of subjects. Each cohort consisted of nine subjects, and each subject underwent three study sessions. Each subject received two ascending 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).

[0059] Dose escalation was stopped after a moderate-intensity myotonic adverse event was observed in one subject receiving 1600 mg of NMD670 at dose level 7 (which resolved spontaneously and completely within a few hours). Because of this temporary halt and the partial unblinding of the study during dose level 7, a new randomization was necessary. After unblinding three subjects at dose level 7, the original randomization at doses 8 and 9 was modified to maintain the blinding of the study. Because only two subjects remained in Cohort 3, randomization according to the original design (three-way crossover) was not possible without compromising the ratio of active-treated to placebo-treated subjects and therefore the within-subject comparisons important for the assessment of PD markers. Therefore, for the remaining two doses, a complete crossover design investigating one previously tested dose level was used. Nine subjects in Cohort 3 were randomized to receive the investigational drug at level 8 and placebo at level 9 (or vice versa).

[0060] To determine the effect of food on the exposure of a single oral dose of NMD670, dose level 5 was administered under both fasted and fed conditions. Subjects who received dose level 5 returned for a fourth visit where they received dose level 5 (or matching placebo) under the fed condition, with the same randomization as the dose level selected under the fasted condition.

[0061] Part A2 of the study investigated the safety, tolerability, and pharmacokinetics of NMD670 in eight healthy female subjects of non-childbearing potential in a randomized, double-blind, placebo-controlled, single-dose study. Subjects received 800 mg of NMD670. Subjects were randomized in a 6:2 ratio (active drug vs. placebo).

[0062] No serious or severe adverse events were reported. There was no meaningful relationship between increasing dose of NMD670 and the number of AEs experienced by participants (Figure 15). A total of 70 AEs were reported, of which 47 (67%) were at least possibly drug-related. The most common AEs reported (>1 subject) are listed in Table 15. With the exception of transient myotonia reported at the highest dose levels tested (1200 mg and 1600 mg), there was no relationship between increasing dose after single dose administration of NMD670 and the number of these individual AEs. Most AEs were mild, with the exception of one AE: myotonia (1600 mg) and tooth extraction (unrelated, 50 mg), which was of moderate intensity. There were no subject discontinuations.

[0063] The early Phase II portion of the clinical trial was double-blind, placebo-controlled, and involved a 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 were enrolled in the trial.

[0064] The Myasthenia Gravis Foundation of America (MGFA) clinical classification, derived from the Osserman score developed in the 1950s (Osserman et al., AMA Arch Intern Med, 1958, 102(1):72-81), was one of the first classification systems for MG. The MGFA classification is intended to separate patients into groups based on disease severity and symptom localization, and is not intended for evaluation purposes. The MGFA classes are as follows (Barnett et al., Neurol Clin. 2018, 36(2):339-353):

[0065] Class I Weakness of all eye muscles. Eye closure may be weak. All other muscle strength is normal.

[0066] Class II Mild weakness affecting muscles other than the eyes. Eye muscle weakness of any severity may also be present.

[0067] IIa It primarily affects limb muscles, axial muscles, or both, and may involve oropharyngeal muscles to a lesser extent.

[0068] IIb It primarily affects the oropharyngeal muscles, respiratory muscles, or both, with lesser or equal involvement of limb muscles, axial muscles, or both.

[0069] Class III Moderate weakness affecting muscles other than the eyes. Eye muscle weakness of any severity may also be present.

[0070] IIIa It primarily affects limb muscles, axial muscles, or both, and may involve oropharyngeal muscles to a lesser extent.

[0071] IIIb It primarily affects the oropharyngeal muscles, respiratory muscles, or both, with lesser or equal involvement of limb muscles, axial muscles, or both.

[0072] Class IV Severe weakness affecting muscles other than the eyes, and may involve eye muscle weakness of any severity.

[0073] IVa It primarily affects limb muscles, axial muscles, or both, and may involve oropharyngeal muscles to a lesser extent.

[0074] IVb It primarily affects the oropharyngeal muscles, respiratory muscles, or both, with lesser or equal involvement of limb muscles, axial muscles, or both.

[0075] Class V Intubation is defined as the use of mechanical ventilation with or without mechanical ventilation, unless employed during routine postoperative care. Use of a feeding tube without intubation places the patient in class IVb.

[0076] Within the generalized categories II, III, and IV, patients are subclassified into Class A if their symptoms are primarily generalized or Class B if their symptoms are primarily bulbar (Jaretzki et al., Neurology, 2000, 55(1):16-23). ​​The MGFA has a system for classifying patients based on post-intervention outcomes, including remission. This remission is defined as a period of at least one year without signs or symptoms and without any symptomatic treatment (pyridostigmine) and can be divided into complete remission (no pharmacological treatment) or pharmacological remission. Minimal symptomatic status is defined as minimal signs or symptoms (no specific time frame defined) and may allow the use of pyridostigmine. Furthermore, patients may improve, remain unchanged, worsen, experience an MG exacerbation, or die from MG (Jaretzki et al., Neurology, 2000, 55(1):16-23). In some studies, MGFA class 0 is also used to describe patients who are asymptomatic (either due to stable treatment with, for example, 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).

[0077] The clinical trial consisted of three study periods, during which subjects received either a single dose of NMD670 or a placebo. The single doses were administered in a randomized order (oral 400 mg free acid, 1200 mg free acid, or placebo) with a 7-day washout period between visits (Figure 16). The efficacy of NMD670 was assessed using the Quantitative Myasthenia Gravis (QMG) scorecard, as shown in Table 1.

[0078] The Quantitative Myasthenia Gravis (QMG) test is a standardized quantitative muscle strength scoring system developed for clinical trials of MG, initially consisting of eight items (Besinger et al., Neurology 1983, 33(10):1316-21). It was later modified for cyclosporine testing (Tindall et al., N Engl J Med 1987, 316(12):719-24), increasing the number of items to 13. This measure was again modified by Barohn et al. (Barohn et al., Ann NY Acad Sci 1998, 841:769-72), resulting in the current version being based on all 13 items (see Table 1). The QMG test includes several items measuring muscle strength, endurance, or fatigability. Items measure the following symptoms and signs: These are ptosis, diplopia, double vision, swallowing, speech / dysarthria onset, percent 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. [Table 1]

[0079] The discoveries made in the above studies have led the inventors to develop compositions for use in 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.

[0080] Composition to be used One aspect of the present disclosure relates to compositions for use in methods for treating myasthenia gravis in a subject, comprising administering to the patient a therapeutically effective dose of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid (NMD670), wherein the therapeutic dose is in the range of 100 mg to 1500 mg.

[0081] Accordingly, 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.

[0082] 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.

[0083] In other embodiments, the therapeutically effective dose of NMD670 administered to the 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.

[0084] In some exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is 100-600 mg, 200-600 mg, 250-550 mg, 300-500 mg, 350-450 mg, 375-425 mg, or 400 mg. In other exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is 700-1400 mg, 800-1350 mg, 900-1300 mg, 1000-1250 mg, 1100-1250 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.

[0085] In an exemplary embodiment, the therapeutic dose is administered at least once daily. In an exemplary embodiment, the therapeutic dose is administered once daily. In an exemplary embodiment, the therapeutic dose is administered twice daily. In an exemplary embodiment, the therapeutic dose is administered three times daily. In an exemplary embodiment, the therapeutic dose is administered four times daily.

[0086] In an exemplary embodiment, the therapeutic dose is administered once daily. That is, the therapeutic dose is the total daily dosage. In an exemplary embodiment, the therapeutic dose is 100-600 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is 200-600 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is 300-500 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 100 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 150 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 200 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 250 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 300 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 350 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 400 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is approximately 500 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 600 mg administered once daily.

[0087] In an exemplary embodiment, the therapeutic dose is administered twice daily. That is, the total daily dosage is twice the therapeutic dose. In an exemplary embodiment, the therapeutic dose is 100-600 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is 200-600 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is 300-500 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 100 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 150 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 200 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 250 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 300 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 350 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is approximately 400 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 500 mg administered twice daily. In an exemplary embodiment, the therapeutic dose is about 600 mg administered twice daily.

[0088] In an exemplary embodiment, the therapeutic dose is administered three times daily. That is, the total daily dosage is three times the therapeutic dose. In an exemplary embodiment, the therapeutic dose is 100-600 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is 200-600 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is 300-500 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 100 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 150 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 200 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 250 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 300 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 350 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is approximately 400 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 500 mg administered three times daily. In an exemplary embodiment, the therapeutic dose is about 600 mg administered three times daily.

[0089] The composition containing the therapeutic dose may be administered in one or more unit dosage forms. For example, a 400 mg therapeutic dose may be administered as one unit dosage form containing 400 mg, or two unit dosage forms containing 200 mg, or four unit dosage forms containing 100 mg.

[0090] In an exemplary embodiment, the composition used is taken orally. In an exemplary embodiment, the composition used is a solid dosage form. In an exemplary embodiment, the solid dosage form is taken orally. In an exemplary embodiment, the solid dosage form is selected from the group consisting of capsules (such as sprinkle capsules and gelatin capsules), tablets (such as plain tablets, coated tablets, and sustained-release tablets), and sprinkles. In an exemplary embodiment, the composition is in the form of a liquid, liquid suspension, oil, emulsion, or syrup. In an exemplary embodiment, the solid dosage form releases 80% or more of the compound after 30 minutes as measured in a United States Pharmacopeia (USP) Type 2 dissolution apparatus in 900 mL of pH 6.8 phosphate / citrate buffer at a temperature of 37°C ± 0.5°C and a paddle speed of 75 rpm.

[0091] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, that achieves a T within 1 to 5 hours, e.g., within 1.5 to 4 hours, e.g., within about 2 hours or about 3 hours, after administration. max reaches.

[0092] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C after administration of a single dose of 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. maxis 13,000 to 32,000 ng / mL, for example 15,000 to 30,000 ng / mL, for example 15,730 to 27,670 ng / mL, for example 16,000 to 27,000 ng / mL, for example 17,360 to 27,125 ng / mL, for example 18,000 to 25,000 ng / mL, for example 20,000 to 23,000 ng / mL, for example about 21,700 ng / mL. max is 21,700 ng / mL with a standard deviation of 5,970 ng / mL.

[0093] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C after administration of a single dose of 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. max is about 80% to about 125% of 21,700 ng / mL, for example, 80.00% to 125.00%.

[0094] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, showing a mean C after administration of a single dose of 1200 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. maxis 40,000 to 110,000 ng / mL, for example 46,300 to 107,100 ng / mL, for example 50,000 to 100,000 ng / mL, for example 60,000 to 90,000 ng / mL, for example 61,360 to 95,875 ng / mL, for example 70,000 to 80,000 ng / mL, for example about 76,700 ng / mL. max is 77,700 ng / mL with a standard deviation of 30,400 ng / mL. max is 76,700 ng / mL with a standard deviation of 30,400 ng / mL.

[0095] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, showing a mean C after administration of a single dose of 1200 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. max is about 80% to about 125% of 76,700 ng / mL, for example, 80.00% to 125.00%.

[0096] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean AUC 0.01 after administration of a single dose of 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. 0-infinityis between 60,000 and 130,000 h·ng / mL, for example between 64,100 and 123,300 h·ng / mL, for example between 70,000 and 120,000 h·ng / mL, for example between 74,960 and 117,125 h·ng / mL, for example between 80,000 and 110,000 h·ng / mL, for example between 90,000 and 100,000 h·ng / mL, for example about 93,700 h·ng / mL. 0-infinity is 93,700 ng / mL with a standard deviation of 29,600 ng / mL.

[0097] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean AUC 0.01 after administration of a single dose of 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. 0-infinity is about 80% to about 125% of 93,700 h·ng / mL, for example, 80.00% to 125.00%.

[0098] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean AUC 0.01 after administration of a single dose of 1200 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. 0-infinityis between 250,000 and 500,000 h·ng / mL, for example, between 265,000 and 491,000 h·ng / mL, for example, between 280,000 and 480,000 h·ng / mL, for example, between 302,400 and 472,500 h·ng / mL, for example, between 320,000 and 450,000 h·ng / mL, for example, between 340,000 and 425,000 h·ng / mL, for example, between 360,000 and 400,000 h·ng / mL, for example, about 378,300 h·ng / mL. 0-infinity is 378,000 ng / mL with a standard deviation of 113,000 ng / mL.

[0099] In an exemplary embodiment, the composition used is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean AUC 0.01 after administration of a single dose of 1200 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. 0-infinity is about 80% to about 125%, for example, 80.00% to 125.00%, of 378,300 h·ng / mL.

[0100] In an exemplary embodiment, the composition used is orally administered using a solid dosage form and provides a plasma concentration-time profile 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, that achieves a Tmax of 100 / 2000 within 1 to 6 hours after administration, for example, about 2 hours after administration. max reaches.

[0101] In an exemplary embodiment, the composition used 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, that achieves a T within 3 to 7 hours after administration. max reaches.

[0102] In an exemplary embodiment, the AUC 0-24 infinity , C max or T max is measured after administration of a single dose to human subjects suffering from myasthenia gravis.

[0103] The compositions for use as described herein can be formulated and administered either orally, parenterally, intravenously, by inhalation, topically, enterally, rectally, buccally, or as an aerosol.

[0104] In an exemplary embodiment, the composition used further comprises at least one pharmaceutically acceptable adjuvant and / or excipient. In an exemplary embodiment, the composition used comprises at least one pharmaceutically acceptable adjuvant and / or excipient selected from the group consisting of fillers, binders, lubricants, and disintegrants. In an exemplary embodiment, the composition used comprises at least one pharmaceutically acceptable adjuvant and / or excipient selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate, and croscarmellose sodium.

[0105] In an exemplary embodiment, the composition used comprises 10 to 80% by weight, such as 40 to 65% by weight, such as 50 to 55% by weight, for example about 53% by weight, 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.

[0106] In an exemplary embodiment, the composition used comprises 10 to 80% by weight, such as 40 to 65% by weight, for example 50 to 60% by weight, such as 50 to 55% by weight, for example 55 to 60% by weight, such as about 53% by weight, for example about 56% by weight 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.

[0107] In an exemplary embodiment, the composition employed is in the form of one or more solid dosage forms, comprising: a. 10 to 80% by weight, such as 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, such as about 53% by weight, for example about 56% by weight, 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. 20 to 80% by weight, for example 25 to 50% by weight, of a filler; c. 2 to 20% by weight, for example 3 to 16% by weight, of a binder; d. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight of a lubricant; and e. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of a disintegrant, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0108] In an exemplary embodiment, the composition employed is in the form of one or more solid dosage forms, comprising: a. 10 to 80% by weight, such as 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, such as about 53% by weight, for example about 56% by weight, 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. 20 to 80% by weight, for example 25 to 50% by weight, of a filler; c. 2 to 20% by weight, for example 3 to 16% by weight, of a binder; d. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight, of a lubricant; e. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of a disintegrant; and f. 1-10% by weight of film coating, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0109] In an exemplary embodiment, the composition used is in the form of one or more solid dosage forms, comprising: a. 10 to 80% by weight, such as 40 to 65% by weight, for example 50 to 60% by weight, such as 50 to 55% by weight, for example 55 to 60% by weight, such as about 53% by weight, for example about 56% by weight, 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% by weight, such as 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, such as 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, such as 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. f. 0.25-3% by weight, for example 0.4-2.0% by weight, of magnesium stearate; and f. 0.25-5% by weight, for example 0.3-2.5% by weight, of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0110] In an exemplary embodiment, the composition used is in the form of a solid dosage form and comprises: a. 10 to 80% by weight, such as 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, such as about 53% by weight, for example about 56% by weight, 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% by weight, such as 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, such as 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. f. 0.25-3% by weight, for example 0.4-2.0% by weight, of magnesium stearate; and f. 0.25-5% by weight, for example 0.3-2.5% by weight, of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0111] In an exemplary embodiment, the composition used is in the form of one or more solid dosage forms, comprising: a. 10 to 80% by weight, such as 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, such as 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; e. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight of magnesium stearate; and f. It comprises or consists of 0.25-5 wt. % of croscarmellose sodium, e.g., 0.3-2.5 wt. % of croscarmellose sodium, and 1-10 wt. % of a film coating composition such as g. Opadry White, with the proviso that the sum of the wt. % of the ingredients does not exceed 100 wt. %.

[0112] In an exemplary embodiment, the composition used is in the form of a solid dosage form and comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; e. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight of magnesium stearate; and f. It comprises or consists of 0.25-5 wt. % of croscarmellose sodium, e.g., 0.3-2.5 wt. % of croscarmellose sodium, and 1-10 wt. % of a film coating composition such as g. Opadry White, with the proviso that the sum of the wt. % of the ingredients does not exceed 100 wt. %.

[0113] In an exemplary embodiment, the subject has a serum uric acid level of less than 6.5 mg / dL.

[0114] In an exemplary embodiment, the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification prior to treatment is class 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 class 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 class I, IIa, IIb, or IIIb.

[0115] In an exemplary embodiment, the subject experiences a decrease in quantitative myasthenia gravis total score following treatment. In an exemplary embodiment, the subject experiences a decrease in quantitative myasthenia gravis total score following treatment, wherein the decrease in QMG total score following treatment is at least 0.9 points, such as at least 1.0 point, such as at least 1.5 points, such as at least 2.0 points, for example at least 3.0 points between 2 and 5 hours following treatment, such as at 2 hours following treatment, such as at 3 hours following treatment, such as at 4 hours following treatment, or such as at 5 hours following treatment.

[0116] In an exemplary embodiment, the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo at the same time point after treatment. In an exemplary embodiment, the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo at the same time point after treatment, and the reduction in QMG total score after treatment is at least 0.9 points, such as at least 1.0 point, such as at least 1.5 points, such as at least 2 points, for example at least 3 points between 2 and 5 hours after treatment, such as at 2.0 hours after treatment, such as at 3.0 hours after treatment, such as at 4 hours after treatment, or such as at 5 hours after treatment.

[0117] In an exemplary embodiment, the subject experiences a decrease in QMG total score after treatment with NMD670. In an exemplary embodiment, the decrease in QMG total score can be determined by comparing the change from baseline in QMG total score after a specified period of NMD670 treatment (e.g., 21 days) with the change from baseline in QMG total score after a specified period of placebo treatment (e.g., 21 days). In an exemplary embodiment, the subject experiences a decrease in QMG total score after treatment with NMD670, the score decreasing by at least 0.9 points, e.g., at least 1.0 point, 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 QMG total score 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.

[0118] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a reduction in Quantitative Myasthenia Gravis (QMG) total score.

[0119] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a reduction in Quantitative Myasthenia Gravis (QMG) total score.

[0120] In an exemplary embodiment, the 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 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered once daily.

[0121] In an exemplary embodiment, the 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 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered once daily.

[0122] In an exemplary embodiment, the 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 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered twice daily.

[0123] In an exemplary embodiment, the 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 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered twice daily.

[0124] In an exemplary embodiment, the 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 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered three times daily.

[0125] In an exemplary embodiment, the 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 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered three times daily.

[0126] In an exemplary embodiment, the 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 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered four times daily.

[0127] In an exemplary embodiment, the 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 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, wherein the composition is administered four times daily.

[0128] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered once daily, the composition being in the form of a solid dosage form, and being taken orally.

[0129] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered once daily, the composition being in the form of a solid dosage form, and being taken orally.

[0130] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered twice daily, and the composition being in the form of a solid dosage form and being taken orally.

[0131] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, and the composition being in the form of a solid dosage form and being taken orally.

[0132] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered three times daily, and the composition being in the form of a solid dosage form and being taken orally.

[0133] In an exemplary embodiment, the 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, the composition being 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 being administered three times daily, and the composition being in the form of a solid dosage form and being taken orally.

[0134] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered four times daily, and the composition being in the form of a solid dosage form and being taken orally.

[0135] In an exemplary embodiment, the 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 for treating myasthenia gravis in a subject, the composition being 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 being administered four times daily, and the composition being in the form of a solid dosage form and being taken orally.

[0136] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a reduction in quantitative myasthenia gravis total score following treatment, wherein the reduction in QMG total score following treatment is at least 0.9 points.

[0137] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a reduction in quantitative myasthenia gravis total score following treatment, wherein the reduction in QMG total score following treatment is at least 0.9 points.

[0138] In exemplary embodiments, subjects experience a decrease in MG Activities of Daily Living Profile (MG-ADL) score after treatment with NMD670 (Wolfe et al., Neurology 1999, 52(7):1487-9; Muppidi et al., Muscle Nerve, 2022, 65(6):630-639). In exemplary embodiments, the decrease in MG-ADL score can be determined by comparing the change from baseline in MG-ADL score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in MG-ADL score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, the subject experiences a decrease in MG-ADL score following treatment with NMD670, wherein the score is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0139] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in MG Activities of Daily Living Profile score.

[0140] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in MG Activities of Daily Living Profile score.

[0141] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670. Grip strength is a measure of muscle strength, i.e., the maximum force / tension generated by the muscles of the forearm. It can be used as a screening tool to measure upper body strength and overall strength. In an exemplary embodiment, the increase in muscle strength can also be determined by measuring the muscle strength of the thigh (knee flexors), upper arm (elbow flexors and elbow extensors) and / or shoulder (shoulder abductors). In an exemplary embodiment, a 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 (see Example 13, as well as 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 NY Acad Sci 1998, 841:769-72). In an exemplary embodiment, the increase in muscle strength can be determined by comparing the change from baseline in muscle strength after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in muscle strength after a defined period (e.g., 21 days) of placebo treatment. In exemplary embodiments, a 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 the muscle strength is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 10% and 400%, such as between 15% and 200%, for example between 20% and 100%.

[0142] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength following treatment with NMD670 as determined by measuring hand grip strength using a handheld dynamometer, wherein the hand grip strength increases by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, such as at least 3.0 kg, for example between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, for example between 0.5 and 4.0 kg.

[0143] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength following treatment with NMD670 as determined by measuring knee flexion muscle strength using a handheld dynamometer, wherein the knee flexion muscle strength increases by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, such as at least 3.0 kg, for example at least 5.0 kg, such as at least 7.5 kg, for example between 0.25 and 15.0 kg, for example between 0.25 and 10.0 kg, for example between 0.5 and 15.0 kg.

[0144] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength following treatment with NMD670 as determined by measuring elbow flexion muscle strength using a handheld dynamometer, wherein the elbow flexion muscle strength increases by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, such as at least 3.0 kg, for example between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, for example between 0.5 and 4.0 kg.

[0145] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing an increase in muscle strength.

[0146] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing an increase in muscle strength.

[0147] In an exemplary embodiment, the subject experiences a reduction in the Myasthenia Gravis Composite (MGC) score after treatment with NMD670 (Burns et al, Neurology 2010, 74(18):1434-40). In an exemplary embodiment, the reduction in the MGC score can be determined by comparing the change from baseline in the MGC score after a defined period of NMD670 treatment (e.g., 21 days) with the change from baseline in the MGC score after a defined period of placebo treatment (e.g., 21 days). In an exemplary embodiment, the subject experiences a reduction in the MGC score after treatment with NMD670, the score being reduced by at least 0.3 points, such as at least 0.5 points, for example, at least 0.75 points, such as at least 1 point, for example, at least 2 points, such as 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, such as 0.3 to 10 points, for example, 0.5 to 6 points, for example, 0.3 to 5 points.

[0148] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing a reduction in Myasthenia Gravis Composite Scale.

[0149] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a reduction in Myasthenia Gravis Composite Scale.

[0150] In an exemplary embodiment, a subject experiences a decrease in Myasthenia Gravis Quality of Life 15 (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 MG-QOL15 score can be determined by comparing the change from baseline in MG-QOL15 score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in MG-QOL15 score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, the subject experiences a decrease in MG-QOL15 score following treatment with NMD670, the score being reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0151] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing a decreased Myasthenia Gravis Quality of Life 15 score.

[0152] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing a decreased Myasthenia Gravis Quality of Life 15 score.

[0153] In an exemplary embodiment, the subject experiences an improvement in health status as determined using the EQ-5D scale after treatment with NMD670 (Rabin and Charro, Ann Med. 2001, 33(5):337-43). In an exemplary embodiment, the improvement in the EQ-5D scale can be determined by comparing the change from baseline in the EQ-5D scale after a defined period of NMD670 treatment (e.g., 21 days) with the change from baseline in the EQ-5D scale after a defined period of placebo treatment (e.g., 21 days). In an exemplary embodiment, the subject experiences an improvement in the EQ-5D scale after treatment with NMD670, the score increasing by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, for example at least 1 point, such as at least 2 points, for example at least 3 points, such as 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.

[0154] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences an improvement in well-being as measured using the EQ-5D scale.

[0155] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences an improvement in well-being as measured using the EQ-5D scale.

[0156] In an exemplary embodiment, a subject experiences a reduction in jitter after treatment with NMD670. In an exemplary embodiment, a subject experiences a reduction in jitter after treatment with NMD670 as determined using single-fiber electromyography (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 from baseline in jitter after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in jitter after a defined period (e.g., 21 days) of placebo treatment. In exemplary embodiments, the subject experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein the jitter is reduced by at least 10%, such as at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%. In an exemplary embodiment, the subject experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein the jitter is reduced by at least 5 μs, such as at least 10 μs, for example at least 15 μs, such as at least 20 μs, for example at least 25 μs, such as at least 30 μs, for example at least 40 μs, such as at least 50 μs, for example at least 75 μs, such as at least 100 μs, for example between 5 μs and 200 μs, for example between 5 μs and 100 μs, such as between 10 μs and 50 μs.

[0157] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in jitter as determined using single fiber electromyography.

[0158] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in jitter as determined using single fiber electromyography.

[0159] In an exemplary embodiment, the subject experiences a reduction in block after treatment with NMD670. In an exemplary embodiment, the subject experiences a reduction in block after treatment with NMD670 as determined using single-fiber electromyography (Sanders et al, Clin Neurophysiol. 2019, 130(8):1417-1439). In an exemplary embodiment, the reduction in block can be determined by comparing the change from baseline in block after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in block after a defined period (e.g., 21 days) of placebo treatment. In exemplary embodiments, the subject experiences a reduction in block following treatment with NMD670 as determined using single fiber electromyography, wherein the block is reduced by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%, such as between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0160] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in block as determined using single fiber electromyography.

[0161] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and wherein the subject experiences a decrease in block as determined using single fiber electromyography.

[0162] In an exemplary embodiment, the subject experiences a decrease in their individual neuromuscular quality of life score after treatment with NMD670 (Vincent et al, Neurology, 2007, 68(13):1051-7). In an exemplary embodiment, the decrease in their individual neuromuscular quality of life score can be determined by comparing the change from baseline in their individual neuromuscular quality of life score after a defined period of NMD670 treatment (e.g., 21 days) with the change from baseline in their individual neuromuscular quality of life score after a defined period of placebo treatment (e.g., 21 days). In an exemplary embodiment, the subject experiences a decrease in their individual neuromuscular quality of life score after treatment with NMD670, the score decreasing by 0.5 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, for example at least 5 points, such as 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.

[0163] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing a decrease in an individual neuromuscular quality of life score.

[0164] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being taken orally, and the subject experiencing a decrease in an individual neuromuscular quality of life score.

[0165] 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 from baseline in Fatigue Severity Scale score after a specified period (e.g., 21 days) of NMD670 treatment with the change from baseline in Fatigue Severity Scale score after a specified period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, the subject or group of subjects experiences a reduction in Fatigue Severity Scale score following treatment with NMD670, the score being reduced by 0.5 points, such as at least 0.75 points, for example at least 1 point, such as at least 1.5 points, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points, such as between 0.5 and 30 points, for example between 1 and 20 points, such as between 0.5 and 10 points.

[0166] In an exemplary embodiment, the 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, the composition being 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, wherein the composition is administered twice daily, the composition being in a solid dosage form and being administered orally, and wherein the subject experiences a decrease in Fatigue Severity Scale score.

[0167] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being administered orally, and wherein the subject experiences a decrease in Fatigue Severity Scale score.

[0168] In exemplary embodiments, a subject or group of subjects experiences improved pulmonary function following 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 exemplary embodiments, the improvement in pulmonary function can be determined by comparing the change from baseline in pulmonary function after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in pulmonary function after a defined period (e.g., 21 days) of placebo treatment. In exemplary embodiments, a subject or group of subjects experiences improved lung function following treatment with NMD670 as determined by measuring forced vital capacity (FVC), wherein the FVC is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%. In an exemplary embodiment, a 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%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, for example between 5% and 80%, such as between 10% and 50%.In exemplary embodiments, a subject or group of subjects experiences an improvement in lung function following treatment with NMD670 as determined by measuring maximum inspiratory pressure (MIP), wherein MIP is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%. In exemplary embodiments, a subject or group of subjects experiences 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%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%.

[0169] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being administered orally, and the subject experiencing improved pulmonary function.

[0170] In an exemplary embodiment, the 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, the composition being 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 being administered twice daily, the composition being in a solid dosage form and being administered orally, and the subject experiencing improved pulmonary function.

[0171] 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 for 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 used 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.

[0172] In an exemplary embodiment, the compositions used are for administration at therapeutic doses as defined herein.

[0173] In one aspect, the invention relates to 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.

[0174] Pharmaceutical Composition Another aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 for use in treating or ameliorating the symptoms of myasthenia gravis in a patient suffering from myasthenia gravis. A further aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 in treating or ameliorating the symptoms of myasthenia gravis in a patient suffering from myasthenia gravis. All of the following exemplary embodiments of the composition can be used in the methods of treatment described herein.

[0175] In one aspect, the present invention 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. In one embodiment, the composition comprises 50 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 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, comprising 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid. In an exemplary embodiment, the composition further comprises at least one pharmaceutically acceptable adjuvant and / or excipient. In an exemplary embodiment, the composition is for oral administration. In an exemplary embodiment, the composition further comprises a pharmaceutically acceptable adjuvant and / or excipient 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 adjuvant and / or excipient selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate, and croscarmellose sodium.

[0176] In an exemplary embodiment, the composition contains 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 contains 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 contains 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 contains 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 contains 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 contains 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 contains 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 contains 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.

[0177] In an exemplary embodiment, the composition comprises 10% to 80% by weight, such as 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the composition comprises 10% to 80% by weight, such as 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0178] In an exemplary embodiment, the composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; and e. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of a disintegrant, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0179] In an exemplary embodiment, the composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; e. 0.25 to 5% by weight, for example, 0.3 to 2.5% by weight of a disintegrant; and f. 1-10% by weight of film coating, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0180] In an exemplary embodiment, the composition comprises: a. 10 to 80% by weight, such as 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, such as about 53% by weight, for example about 56% by weight, 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% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. f. 0.25-3% by weight, for example 0.4-2.0% by weight, of magnesium stearate; and f. 0.25-5% by weight, for example 0.3-2.5% by weight, of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0181] In an exemplary embodiment, the composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, for example, 20 to 40% by weight, for example, 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example, 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example, 1.5 to 7% by weight, for example, 1.8 to 6.0% by weight of maltodextrin; e. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of magnesium stearate; and f. It comprises or consists of 0.25-5 wt. % of croscarmellose sodium, e.g., 0.3-2.5 wt. % of croscarmellose sodium, and 1-10 wt. % of a film coating composition such as g. Opadry White, with the proviso that the sum of the wt. % of the ingredients does not exceed 100 wt. %.

[0182] In an exemplary embodiment, the present disclosure relates 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.

[0183] In an exemplary embodiment, the disclosure relates 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.

[0184] In an exemplary embodiment, the disclosure relates to a composition formulated as a solid dosage form, the composition 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.

[0185] 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 (such as sprinkle capsules and gelatin capsules), tablets (such as plain tablets, coated tablets, and sustained-release tablets), and sprinkles. In an exemplary embodiment, the composition is in the form of a liquid, liquid suspension, oil, emulsion, or syrup. In an exemplary embodiment, the solid dosage form releases 80% or more of the compound after 30 minutes as measured in a United States Pharmacopoeia (USP) Type 2 dissolution apparatus in 900 mL of pH 6.8 phosphate / citrate buffer at a temperature of 37°C ± 0.5°C and a paddle speed of 75 rpm.

[0186] method In exemplary embodiments, a method of treating a patient suffering from symptoms of myasthenia gravis may result in an improvement in the patient's quantitative Myasthenia Gravis Total Score, hand grip strength, compound muscle action potential, and / or muscle wasting. In exemplary embodiments, a method of treating a patient suffering from symptoms of myasthenia gravis may result in a decrease in the quantitative Myasthenia Gravis Total Score, 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 (MG-QOL15) score, improved health status as determined using the EQ-5D scale, a decrease in jitter, a decrease in blockages, a decrease in individual Neuromuscular Quality of Life scores, a decrease in Fatigue Severity Scale scores, and / or improved pulmonary function.

[0187] Accordingly, one aspect of the present disclosure relates to methods of treating myasthenia gravis that result in an improvement in a patient's quantitative total myasthenia gravis 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.

[0188] In one aspect, the 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]propanoic 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]propanoic acid.

[0189] In one aspect, the present disclosure relates to a method for improving the quantitative myasthenia gravis total score in a subject suffering from myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate. In an exemplary embodiment, 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. In an exemplary embodiment, 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, compared with placebo at the same time point. In exemplary embodiments, the decrease in QMG total score after treatment is between 2 and 5 hours, 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.

[0190] Another aspect of the present disclosure relates to methods for treating myasthenia gravis that result in an improvement in a 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 exemplary embodiments, the patient's hand grip strength improves 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. Measurement of hand grip strength is part of the QMG test (see Example 13, as well as 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 NY Acad Sci 1998, 841:769-72).

[0191] In one aspect, the present disclosure relates to a method for improving the grip strength of the right hand of a subject suffering from myasthenia gravis, comprising administering to the subject a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.In exemplary embodiments, the improvement of the grip strength of the right hand after treatment is at least 2.0 kg, for example, at least 2.5 kg.In exemplary embodiments, the improvement of the grip strength of the right hand is at least 2.0 kg, for example, at least 2.5 kg, compared with placebo at the same time point.

[0192] Another aspect of the present disclosure relates to methods for treating myasthenia gravis, resulting in an improvement in compound muscle action potential in a patient, 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 compound muscle action potential improves 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 repeated nerve simulation (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).

[0193] Another aspect of the present disclosure relates to methods of treating myasthenia gravis that result in reversal of muscle wasting in a patient, 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 wasting improves by at least 10%, at least 20%, at least 30%, or at least 40% compared to the patient's muscle wasting before administering the therapeutically effective dose of NMD670.

[0194] In one aspect, the present disclosure relates to a method for reducing EMG decline with repetitive nerve stimulation in a subject suffering from myasthenia gravis, the method comprising administering to the subject 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. Reversal of muscle decline 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).

[0195] In one aspect, the present disclosure relates to a method for improving symptoms of diplopia in a subject suffering from myasthenia gravis, comprising administering to the subject 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. Measurement of diplopia is part of the QMG test (see Example 13, as well as 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 NY Acad Sci 1998,841:769-72).

[0196] In one aspect, the present disclosure relates to a method for improving symptoms of ptosis in a subject suffering from myasthenia gravis, comprising administering to the subject 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. Measurement of ptosis is part of the QMG test (see Example 13, as well as 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 NY Acad Sci 1998,841:769-72).

[0197] In one aspect, the present disclosure relates to a method for improving symptoms of dysarthria in a subject suffering from myasthenia gravis, comprising administering to the subject 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. Measurement of dysarthria is part of the QMG test (see Example 13, as well as 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 NY Acad Sci 1998, 841:769-72).

[0198] One aspect of the present disclosure relates to methods of treating myasthenia gravis, resulting in a reduction in the MG Activities of Daily Living Profile (MG-ADL) 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. The improvement in the MG Activities of Daily Living Profile (MG-ADL) score is a reduction in the score (Wolfe et al., Neurology 1999, 52(7):1487-9; Muppidi et al., Muscle Nerve, 2022, 65(6):630-639).

[0199] One aspect of the present disclosure relates to methods for treating myasthenia gravis, resulting in increased muscle strength, 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. Improved muscle strength can be determined by measuring grip strength using a handheld dynamometer (see Example 13, as well as 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 NY Acad Sci 1998, 841:769-72).

[0200] One aspect of the present disclosure relates to methods of treating myasthenia gravis, resulting in a reduction in the Myasthenia Gravis Composite Scale (MGC), 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 Scale (MGC) is a reduction in the score (Burns et al., Neurology 2010, 74(18):1434-40).

[0201] One aspect of the present disclosure relates to methods of treating myasthenia gravis that result in a decrease in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score, 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. An improvement in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score is 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).

[0202] One embodiment of the present disclosure relates to methods for treating myasthenia gravis that result in an improvement in health status as measured using the EQ-5D scale, 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 health status can be measured using the EQ-5D scale, where the score is an increase (Rabin and Charro, Ann Med. 2001, 33(5):337-43).

[0203] One aspect of the present disclosure relates to methods for treating myasthenia gravis, resulting in a reduction in jitter, 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 jitter can be determined using single-fiber electromyography (Sanders et al., Clin Neurophysiol. 2019, 130(8):1417-1439).

[0204] One aspect of the present disclosure relates to methods for treating myasthenia gravis, resulting in a reduction in block, 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 block can be determined using single-fiber electromyography (Sanders et al., Clin Neurophysiol. 2019, 130(8):1417-1439).

[0205] One aspect of the present disclosure relates to methods of treating myasthenia gravis, resulting in a reduction in an individual neuromuscular quality of life score, 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 the individual neuromuscular quality of life score is a reduction in the score (Vincent et al., Neurology, 2007, 68(13):1051-7).

[0206] One aspect of the present disclosure relates to methods of treating myasthenia gravis, resulting in a reduction in Fatigue Severity Scale score, 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 Fatigue Severity Scale score is a reduction in the score (Werlauff et al., Qual Life Res., 2014, 23:1479-1488).

[0207] One aspect of the present disclosure relates to methods for treating myasthenia gravis, resulting in improved pulmonary function, 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. Improved pulmonary 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).

[0208] 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0209] 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.

[0210] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0211] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0212] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0213] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0214] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0215] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0216] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0217] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200-600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0218] 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 twice daily.

[0219] 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 three times daily.

[0220] 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 daily.

[0221] 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]propanoic acid, and the composition is administered twice daily.

[0222] 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]propanoic acid, and the composition is administered three times daily.

[0223] 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]propanoic acid, and the composition is administered four times daily.

[0224] 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 once daily.

[0225] 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 twice daily.

[0226] 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 three times daily.

[0227] 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 daily.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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 daily.

[0232] 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.

[0233] 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 twice daily.

[0234] 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 three times daily.

[0235] 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 four times daily.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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 daily.

[0240] 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.

[0241] 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 twice daily.

[0242] 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 three times daily.

[0243] 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 daily.

[0244] 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]propanoic acid, and the composition is administered once daily.

[0245] 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]propanoic acid, and the composition is administered twice daily.

[0246] 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]propanoic acid, and the composition is administered three times daily.

[0247] 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 once daily.

[0248] 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.

[0249] 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 three times daily.

[0250] Restoring muscle wasting in a patient can include, but is not limited to, strengthening neuromuscular transmission in a patient and / or restoring skeletal muscle function in a patient.

[0251] The methods of treatment disclosed herein may further include the administration of other active agents known to treat, prevent, and / or ameliorate neuromuscular disorders, including acetylcholinesterase inhibitors such as neostigmine or pyridostigmine, immunosuppressants, compounds used in antimyotonic treatments, Ca inhibitors of muscle contractile filaments, and the like. 2+ Compounds that enhance sensitivity and / or voltage-dependent K + The compound may enhance Ach release by blocking the channel.

[0252] In one aspect, the present disclosure relates to a method of treating myasthenia gravis, comprising administering (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 to a subject in need thereof.

[0253] In some exemplary embodiments, the method of treatment comprises administering a therapeutically effective dose of NMD670 in combination with one or more of the following compounds: amifapridine, prednisolone, prednisone, azathioprine, soliris, rituximab, efgartigimod alfa, zilcoplan, rozanolixizumab, cholecalciferol, and immune globulin.

[0254] In exemplary embodiments, the method of treatment comprises administering therapeutically effective doses of an active agent and NMD670 to a patient simultaneously. In other exemplary embodiments, the active agent and therapeutically effective doses of NMD670 are administered to a patient at different times. In some embodiments, the active agent and therapeutically effective doses of NMD670 are administered sequentially.

[0255] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in an improvement in quantitative myasthenia gravis total score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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 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 experiences a reduction of at least 0.9 points in the patient's quantitative myasthenia gravis score compared to placebo at the same time point.

[0256] In an exemplary embodiment, the therapeutically effective dose of the compound has an AUC in the range of 15,000 ng / mL to 500,000 ng / mL in a patient. inf In an exemplary embodiment, the therapeutically effective dose of the compound provides a T in the range of 1 to 5 hours in a patient. max In an exemplary embodiment, the therapeutically effective dose of the compound has a half-life in the patient ranging from 3 hours to 7 hours. In an exemplary embodiment, the therapeutically effective dose of the compound is orally administered to the patient. In an exemplary embodiment, the patient experiences at least a 1.0 point reduction, e.g., at least a 1.5 point reduction, e.g., at least a 2.0 point reduction, in the patient's quantitative myasthenia gravis score. In an exemplary embodiment, the patient's Myasthenia Gravis Foundation of America (MGFA) clinical classification prior to treatment is class I, IIa, IIb, IIIa, IIIb, IVa, IVb, or V.

[0257] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in improved right hand grip strength in a patient in need thereof, 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, and wherein the C in the range of 5,000 ng / mL to 14,000 ng / mL is achieved in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences an improvement in the patient's hand grip strength of at least 1 kg compared to the patient's hand grip strength before administration.

[0258] In an exemplary embodiment, an improvement of at least 1 kg in the patient's hand grip strength occurs at least 3 hours after administration of a therapeutically effective dose of the compound. In an exemplary embodiment, the therapeutically effective dose of the compound provides an AUC in the range of 15,000 h·ng / mL to 500,000 h·ng / mL in the patient. inf In an exemplary embodiment, the therapeutically effective dose of the compound provides a T in the range of 1 to 5 hours in a patient. maxIn an exemplary embodiment, a therapeutically effective dose of the compound has a half-life in a patient ranging from 3 hours to 7 hours.

[0259] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a reduction in a quantitative myasthenia gravis (QMG) total score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C in the range of 2,790 ng / mL to 76,700 ng / mL is achieved in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in Quantitative Myasthenia Gravis (QMG) total score.

[0260] In an exemplary embodiment, a subject or group of subjects experiences a reduction in Quantitative Myasthenia Gravis (QMG) total score following treatment with NMD670, the score being reduced by at least 0.9 points, such as at least 1.0 point, for example at least 1.5 points, such as at least 2.0 points, for example at least 3.0 points.

[0261] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a decrease in MG Activities of Daily Living Profile (MG-ADL) score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C value ranges from 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in MG Activities of Daily Living Profile (MG-ADL) score.

[0262] In an exemplary embodiment, the subject experiences a decrease in MG-ADL score following treatment with NMD670, wherein the score is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0263] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in increased muscle strength in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C ranges from 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength.

[0264] In exemplary embodiments, a 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 the muscle strength is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 10% and 400%, such as between 15% and 200%, for example between 20% and 100%.

[0265] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength following treatment with NMD670 as determined by measuring hand grip strength using a handheld dynamometer, wherein the hand grip strength increases by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, such as at least 3.0 kg, for example between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, for example between 0.5 and 4.0 kg.

[0266] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a reduction in Myasthenia Gravis Composite Scale (MGC) in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the therapeutically effective dose results in a C of 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in Myasthenia Gravis Composite Scale (MGC).

[0267] In an exemplary embodiment, the subject experiences a reduction in the MGC scale following treatment with NMD670, wherein the score is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0268] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a decrease in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C is in the range of 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score.

[0269] In an exemplary embodiment, the subject experiences a decrease in MG-QOL15 score following treatment with NMD670, the score being reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0270] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in improved health status as measured using the EQ-5D scale in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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 and results in a C of 2,790 ng / mL to 76,700 ng / mL in the patient. maxand after administration of a therapeutically effective dose of the compound, the patient experiences an improvement in health status as determined using the EQ-5D scale.

[0271] In an exemplary embodiment, the subject experiences an improvement on the EQ-5D scale following treatment with NMD670, the score increasing by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0272] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a reduction in jitter in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C in the range of 2,790 ng / mL to 76,700 ng / mL is achieved in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in jitters.

[0273] In exemplary embodiments, the subject experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein the jitter is reduced by at least 10%, such as at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%. In an exemplary embodiment, the subject experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein the jitter is reduced by at least 5 μs, such as at least 10 μs, for example at least 15 μs, such as at least 20 μs, for example at least 25 μs, such as at least 30 μs, for example at least 40 μs, such as at least 50 μs, for example at least 75 μs, such as at least 100 μs, for example between 5 μs and 200 μs, for example between 5 μs and 100 μs, such as between 10 μs and 50 μs.

[0274] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a reduction of block in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C ranges from 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in block.

[0275] In exemplary embodiments, the subject experiences a reduction in block following treatment with NMD670 as determined using single fiber electromyography, wherein the block is reduced by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%, such as between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0276] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a decrease in an individual neuromuscular quality of life score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C in the range of 2,790 ng / mL to 76,700 ng / mL is achieved in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in their individual neuromuscular quality of life score.

[0277] In an exemplary embodiment, the subject experiences a decrease in their individual neuromuscular quality of life score following treatment with NMD670, the score being reduced by 0.5 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points, such as between 0.5 and 30 points, for example between 1 and 20 points, for example between 0.5 and 10 points.

[0278] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in a decrease in Fatigue Severity Scale score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C in the range of 2,790 ng / mL to 76,700 ng / mL is achieved in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in Fatigue Severity Scale score.

[0279] In an exemplary embodiment, the subject or group of subjects experiences a reduction in Fatigue Severity Scale score following treatment with NMD670, the score being reduced by 0.5 points, such as at least 0.75 points, for example at least 1 point, such as at least 1.5 points, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points, such as between 0.5 and 30 points, for example between 1 and 20 points, such as between 0.5 and 10 points.

[0280] In one aspect, the disclosure relates to a method of treating myasthenia gravis resulting in improved pulmonary function in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C ranges from 2,790 ng / mL to 76,700 ng / mL in the patient. max and after administration of a therapeutically effective dose of the compound, the patient experiences improved lung function.

[0281] In exemplary embodiments, a subject or group of subjects experiences improved lung function following treatment with NMD670 as determined by measuring forced vital capacity (FVC), wherein the FVC is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%.

[0282] In an exemplary embodiment, a 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%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, for example between 5% and 80%, such as between 10% and 50%.

[0283] In exemplary embodiments, a subject or group of subjects experiences an improvement in lung function following treatment with NMD670 as determined by measuring maximum inspiratory pressure (MIP), wherein MIP is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%.

[0284] In exemplary embodiments, a subject or group of subjects experiences 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%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, such as between 5% and 80%, for example between 10% and 50%.

[0285] In an exemplary embodiment, a therapeutically effective dose of the compound is orally administered 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.

[0286] In one aspect, the disclosure relates to a method of treating a patient 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.

[0287] In one aspect, the disclosure relates to 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.

[0288] The disclosed methods may further include administering a second therapeutically effective dose of NMD670 to the patient either 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or at least 7 days after the first therapeutically effective dose is administered. 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 dosage 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.

[0289] In other exemplary embodiments, the methods of the present disclosure further include administering a third therapeutically effective dose of NMD670 to the patient one day, two days, three days, four days, five days, six days, or at least seven days after the second therapeutically effective dose is administered. 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 dosage 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.

[0290] In some exemplary embodiments, administration of a therapeutically effective dose of NMD670 is repeated at least 1, 2, 3, 4, 5, or 6 times weekly, hi other exemplary embodiments, administration is repeated at least 1-3 times weekly, 2-5 times weekly, or 3-6 times weekly.

[0291] In some exemplary embodiments, administration of a therapeutically effective dose of NMD670 is repeated daily. Administration of a therapeutically effective dose of NMD670 may be repeated, for example, 1, 2, 3, 4, 5, 6, 7, or 8 times daily. In other embodiments, administration is repeated 1-8 times daily, or 2-5 times daily.

[0292] In some embodiments, the therapeutically effective dose of NMD670 is administered at least once daily. In an exemplary embodiment, the therapeutically effective dose of NMD670 is administered once daily.

[0293] In other embodiments, the therapeutically effective dose of NMD670 is administered either twice daily, three times daily, or four times daily.

[0294] In exemplary embodiments, the therapeutically effective dose of NMD670 is 100-600 mg, 300-500 mg, or about 400 mg, administered once daily. In exemplary embodiments, the therapeutically effective dose of NMD670 is 200-600 mg, 300-500 mg, or about 400 mg, administered once daily.

[0295] In other exemplary embodiments, the therapeutically effective dose of NMD670 is 100-600 mg, 300-500 mg, or about 400 mg administered twice daily. In other exemplary embodiments, the therapeutically effective dose of NMD670 is 200-600 mg, 300-500 mg, or about 400 mg administered twice daily.

[0296] In some exemplary embodiments, the therapeutically effective dose of NMD670 is a daily dosage of NMD670. In these embodiments, the daily dosage of NMD670 can be administered as a single dosage or in smaller dosages throughout each day. That is, in some embodiments, the daily dosage of NMD670 is administered once a day, or at least once daily, twice a day, or at least at two different times throughout the day, or three times a day, or at least at three different times throughout the day.

[0297] In other exemplary embodiments, the patient receiving 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).

[0298] In some exemplary embodiments, the patient receiving 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.

[0299] In other exemplary embodiments, the patient receiving a therapeutically effective dose of NMD670 does not have hyperuricemia. For example, the patient receiving a therapeutically effective dose of NMD670 has a serum uric acid level less than 6.5 mg / dL. Patients with serum uric acid levels greater than 6.5 mg / dL may not be suitable for receiving a therapeutically effective dose. In exemplary embodiments in which the patient has a serum uric acid level greater 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 between 20 mg and 150 mg, e.g., between 25 mg and 100 mg, e.g., between 25 mg and 50 mg. Once the patient's serum uric acid level drops to less than 6.5 mg / dL, the patient can begin receiving a therapeutically effective dose of NMD670.

[0300] Parts kit In one aspect, the present invention relates to a kit-of-parts 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.

[0301] In an exemplary embodiment, the kit-of-parts contains 100 to 1500 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 one embodiment, the acetylcholinesterase inhibitor is pyridostigmine.

[0302] In one aspect, the present invention relates to (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 acetylcholinesterase for use in the treatment of myasthenia gravis.

[0303] In one aspect, the present invention relates to a method of treating myasthenia gravis, comprising administering (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 to a subject in need thereof.

[0304] In one aspect, the kit of parts is used in a method for treating myasthenia gravis in a subject.

[0305] In one aspect, the invention relates to the use of a kit-of-parts 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 the manufacture of a medicament for the treatment of myasthenia gravis.

[0306] In exemplary embodiments, the active agent is an acetylcholinesterase inhibitor, which may be, for example, delta-9-tetrahydrocannabinol, a carbamate, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, a phenanthrene derivative, galantamine, caffeine (non-competitive), piperidine, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine, lactucopicrin, or any combination thereof.

[0307] In another exemplary embodiment, the active agent may be an immunosuppressant. Immunosuppressants are drugs that suppress or reduce the strength of the body's immune system. They are also known as anti-rejection drugs. Immunosuppressants that may be administered to a patient include, but are not limited to, glucocorticoids, corticosteroids, cytostatics, antibodies, drugs that act on immunophilins, or any combination thereof. In an exemplary embodiment, the active agent is prednisone.

[0308] In some exemplary embodiments, the active agent is an agent used in anti-myotonic treatment. Such an agent may be, for example, a voltage-gated Na + channel blockers, and aminoglycosides.

[0309] In some exemplary embodiments, the active agent induces Ca release from contractile filaments in muscle. 2+ Such an agent can be, for example, a tirasemative.

[0310] In another exemplary embodiment, the active agent is a voltage-dependent K + An agent that blocks the channel increases ACh release. Such an agent can be, for example, 3,4-aminopyridine.

[0311] In some exemplary embodiments, a patient can be administered a therapeutically effective dose of NMD670 to treat or alleviate the symptoms of myasthenia gravis: diplopia, ptosis, dysarthria, or any combination thereof.

[0312] Terms 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 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.

[0313] 2. The composition for use according to clause 1, wherein said therapeutic dose is less than 1500 mg, such as less than 1450 mg, for example less than 1300 mg, for example less than 1250 mg, such as less than 1200 mg, for example less than 1150 mg, for example less than 1100 mg, such as less than 1050 mg, for example less than 1000 mg, such as less than 950 mg, for example less than 900 mg, for example less than 850 mg, such as less than 800 mg, for example less than 750 mg, such as less than 700 mg, for example less than 650 mg, such as less than 600 mg, for example less than 550 mg, for example less than 500 mg, such as less than 450 mg, for example less than 400 mg, for example less than 350 mg, such as less than 300 mg, for example less than 250 mg.

[0314] 3. A composition for use according to any one of the preceding clauses, wherein said therapeutic dose is at least 100 mg, such as at least 150 mg, for example at least 200 mg, such as at least 250 mg, for example at least 300 mg, such as at least 350 mg, for example at least 400 mg, such as at least 450 mg, for example at least 500 mg, such as at least 550 mg, for example at least 600 mg, such as at least 650 mg, for example at least 700 mg, such as at least 750 mg, for example at least 800 mg, such as at least 850 mg, for example at least 900 mg, such as at least 950 mg, for example at least 1000 mg, such as at least 1050 mg, for example at least 1100 mg, such as at least 1150 mg, for example at least 1200 mg, such as at least 1250 mg, for example at least 1300 mg, such as at least 1350 mg, for example at least 1400 mg, such as at least 1450 mg.

[0315] 4. The composition for use according to clause 1, wherein said therapeutic dose is 200-600 mg, such as 250-550 mg, for example 300-500 mg, for example 350-450 mg, for example 375-425 mg, for example 400 mg.

[0316] 5. The composition for use according to clause 1, wherein said therapeutic dose is 700 to 1400 mg, such as 800 to 1350 mg, for example 900 to 1300 mg, for example 1000 to 1250 mg, for example 1100 to 1250 mg, for example about 1200 mg.

[0317] 6. The composition for use according to clause 1, wherein the therapeutic dose is about 100 mg.

[0318] 7. The composition for use according to clause 1, wherein the therapeutic dose is about 150 mg.

[0319] 8. The composition for use according to clause 1, wherein the therapeutic dose is about 200 mg.

[0320] 9. The composition for use according to clause 1, wherein the therapeutic dose is about 250 mg.

[0321] 10. The composition for use according to clause 1, wherein the therapeutic dose is about 300 mg.

[0322] 11. The composition for use according to clause 1, wherein the therapeutic dose is about 350 mg.

[0323] 12. The composition for use according to clause 1, wherein the therapeutic dose is about 400 mg.

[0324] 13. The composition for use according to clause 1, wherein the therapeutic dose is about 500 mg.

[0325] 14. The composition for use according to clause 1, wherein the therapeutic dose is about 600 mg.

[0326] 15. A composition for use according to any one of the preceding clauses, wherein the therapeutic dose is administered at least once daily.

[0327] 16. A composition for use according to any one of the preceding clauses, wherein the therapeutic dose is administered once daily.

[0328] 17. A composition for use according to any one of clauses 1 to 14, wherein the therapeutic dose is administered twice daily.

[0329] 18. A composition for use according to any one of clauses 1 to 14, wherein the therapeutic dose is administered three times daily.

[0330] 19. The composition for use according to any one of clauses 1 to 14, wherein the therapeutic dose is administered four times daily.

[0331] 20. The composition for use according to clause 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered once daily.

[0332] 21. The composition for use according to clause 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered once daily.

[0333] 22. The composition for use according to clause 1, wherein the therapeutic dose is 300-500 mg and the composition is administered once daily.

[0334] 23. The composition for use according to clause 1, wherein the therapeutic dose is about 100 mg and the composition is administered once daily.

[0335] 24. The composition for use according to clause 1, wherein the therapeutic dose is about 150 mg and the composition is administered once daily.

[0336] 25. The composition for use according to clause 1, wherein the therapeutic dose is about 200 mg and the composition is administered once daily.

[0337] 26. The composition for use according to clause 1, wherein the therapeutic dose is about 250 mg and the composition is administered once daily.

[0338] 27. The composition for use according to clause 1, wherein the therapeutic dose is about 300 mg and the composition is administered once daily.

[0339] 28. The composition for use according to clause 1, wherein the therapeutic dose is about 350 mg and the composition is administered once daily.

[0340] 29. The composition for use according to clause 1, wherein the therapeutic dose is about 400 mg and the composition is administered once daily.

[0341] 30. The composition for use according to clause 1, wherein the therapeutic dose is about 500 mg and the composition is administered once daily.

[0342] 31. The composition for use according to clause 1, wherein the therapeutic dose is about 600 mg and the composition is administered once daily.

[0343] 32. The composition for use according to clause 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered twice daily.

[0344] 33. The composition for use according to clause 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered twice daily.

[0345] 34. A composition for use according to any one of the preceding clauses, wherein the therapeutic dose is 300 to 500 mg and the composition is administered twice daily.

[0346] 35. The composition for use according to clause 1, wherein the therapeutic dose is about 100 mg and the composition is administered twice daily.

[0347] 36. The composition for use according to clause 1, wherein the therapeutic dose is about 150 mg and the composition is administered twice daily.

[0348] 37. The composition for use according to clause 1, wherein the therapeutic dose is about 200 mg and the composition is administered twice daily.

[0349] 38. The composition for use according to clause 1, wherein the therapeutic dose is about 250 mg and the composition is administered twice daily.

[0350] 39. The composition for use according to clause 1, wherein the therapeutic dose is about 300 mg and the composition is administered twice daily.

[0351] 40. The composition for use according to clause 1, wherein the therapeutic dose is about 350 mg and the composition is administered twice daily.

[0352] 41. The composition for use according to clause 1, wherein the therapeutic dose is about 400 mg and the composition is administered twice daily.

[0353] 42. The composition for use according to clause 1, wherein the therapeutic dose is about 500 mg and the composition is administered twice daily.

[0354] 43. The composition for use according to clause 1, wherein the therapeutic dose is about 600 mg and the composition is administered twice daily.

[0355] 44. The composition for use according to clause 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered three times daily.

[0356] 45. The composition for use according to clause 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered three times daily.

[0357] 46. ​​The composition for use according to clause 1, wherein the therapeutic dose is 300 to 500 mg and the composition is administered three times daily.

[0358] 47. The composition for use according to clause 1, wherein the therapeutic dose is about 100 mg and the composition is administered three times daily.

[0359] 48. The composition for use according to clause 1, wherein the therapeutic dose is about 150 mg and the composition is administered three times daily.

[0360] 49. The composition for use described in clause 1, wherein the therapeutic dose is about 200 mg and the composition is administered three times daily.

[0361] 50. The composition for use described in clause 1, wherein the therapeutic dose is about 250 mg and the composition is administered three times daily.

[0362] 51. The composition for use according to clause 1, wherein the therapeutic dose is about 300 mg and the composition is administered three times daily.

[0363] 52. The composition for use according to clause 1, wherein the therapeutic dose is about 350 mg and the composition is administered three times daily.

[0364] 53. The composition for use according to clause 1, wherein the therapeutic dose is about 400 mg and the composition is administered three times daily.

[0365] 54. The composition for use according to clause 1, wherein the therapeutic dose is about 500 mg and the composition is administered three times daily.

[0366] 55. The composition for use described in clause 1, wherein the therapeutic dose is about 600 mg and the composition is administered three times daily.

[0367] 56. The composition for use described in clause 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered four times daily.

[0368] 57. The composition for use described in clause 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered four times daily.

[0369] 58. A composition for use according to any one of the preceding clauses, wherein the therapeutic dose is a total daily dosage.

[0370] 59. A composition for use according to any one of the preceding clauses, wherein the composition is administered orally, parenterally, intravenously, by inhalation, topically, enterally, rectally, buccally or as an aerosol.

[0371] 60. A composition for use according to any one of clauses 1 to 59, wherein the composition is in the form of a liquid, liquid suspension, oil, emulsion or syrup.

[0372] 61. A composition for use according to any one of clauses 1 to 59, wherein the composition is in solid dosage form.

[0373] 62. The composition of claim 61, wherein the solid dosage form is administered orally.

[0374] 63. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 100 to 600 mg, and the composition is administered once daily.

[0375] 64. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 200 to 600 mg, and the composition is administered once daily.

[0376] 65. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 100 to 600 mg, and the composition is administered twice daily.

[0377] 66. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 200 to 600 mg, and the composition is administered twice daily.

[0378] 67. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 100 to 600 mg, and the composition is administered three times daily.

[0379] 68. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 200 to 600 mg, and the composition is administered three times daily.

[0380] 69. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 100 to 600 mg, and the composition is administered four times daily.

[0381] 70. A composition for use according to any one of clauses 1 to 62, wherein the composition is in the form of a solid dosage form and is taken orally, the therapeutic dose is 200 to 600 mg, and the composition is administered four times daily.

[0382] 71. The composition for use according to any one of clauses 61 to 70, wherein the solid dosage form is selected from the group consisting of capsules (such as sprinkle capsules and gelatin capsules), tablets (such as plain tablets, coated tablets, and sustained-release tablets) and sprinkles.

[0383] 72. The composition for use according to any one of clauses 61 to 71, wherein the solid dosage form releases 80% or more of the compound after 30 minutes when measured in a United States Pharmacopoeia (USP) Type 2 dissolution apparatus in 900 mL of pH 6.8 phosphate / citrate buffer at a temperature of 37°C ± 0.5°C and a paddle speed of 75 rpm.

[0384] 73. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, that achieves a T 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 2. A composition for use according to any one of the preceding clauses, wherein

[0385] 74. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a T 1 -T 2 -T 3 -T 4 -T 5 -T 6 -H 2 O 3 -T 1 -T 2 ... max The composition for use according to any one of clauses 1 to 72,

[0386] 75. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a T value within 3 to 7 hours after administration. max The composition for use according to any one of clauses 1 to 72,

[0387] 76. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C of 400 mg after administration of a single 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. max is 13,000 to 32,000 ng / mL, such as 15,000 to 30,000 ng / mL, for example 15,730 to 27,670 ng / mL, for example 16,000 to 27,000 ng / mL, such as 17,360 to 27,125 ng / mL, for example 18,000 to 25,000 ng / mL, such as 20,000 to 23,000 ng / mL, for example about 21,700 ng / mL.

[0388] 77. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C of 400 mg after administration of a single 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. max is about 80% to about 125%, for example 80.00% to 125.00%, of 21,700 ng / mL.

[0389] 78. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C of 1200 mg after administration of a single 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. max is 40,000 to 110,000 ng / mL, such as 46,300 to 107,100 ng / mL, for example 50,000 to 100,000 ng / mL, for example 60,000 to 90,000 ng / mL, such as 61,360 to 95,875 ng / mL, for example 70,000 to 80,000 ng / mL, such as about 76,700 ng / mL.

[0390] 79. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C of 1200 mg after administration of a single 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. max is about 80% to about 125%, for example 80.00% to 125.00%, of 76,700 ng / mL.

[0391] 80. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and the mean AUC after administration of a single dose of 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. 0-infinity 5. A composition for use according to any one of the preceding clauses, wherein the IL-10 concentration is 60,000 to 130,000 h·ng / mL, such as 64,100 to 123,300 h·ng / mL, for example 70,000 to 120,000 h·ng / mL, such as 74,960 to 117,125 h·ng / mL, for example 80,000 to 110,000 h·ng / mL, such as 90,000 to 100,000 h·ng / mL, for example about 93,700 h·ng / mL.

[0392] 81. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and the mean AUC after administration of a single dose of 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. 0-infinity is about 80% to about 125%, for example 80.00% to 125.00%, of 93,700 h·ng / mL.

[0393] 82. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and the mean AUC after administration of a single dose of 1200 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. 0-infinity 2. A composition for use according to any one of the preceding clauses, wherein the IL-10 concentration is 250,000 to 500,000 h·ng / mL, such as 265,000 to 491,000 h·ng / mL, for example 280,000 to 480,000 h·ng / mL, such as 302,400 to 472,500 h·ng / mL, for example 320,000 to 450,000 h·ng / mL, such as 340,000 to 425,000 h·ng / mL, for example 360,000 to 400,000 h·ng / mL, such as about 378,300 h·ng / mL.

[0394] 83. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and the mean AUC after administration of a single dose of 1200 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. 0-infinity is about 80% to about 125%, for example 80.00% to 125.00%, of 378,300 h·ng / mL.

[0395] 84. AUC 0-24 infinity , C max or T max 10. The composition for use according to any one of the preceding clauses, wherein the IL-10 level is measured after administration of a single dose to a human subject suffering from myasthenia gravis.

[0396] 85. A composition for use according to any one of the preceding clauses, wherein the composition further comprises at least one pharmaceutically acceptable adjuvant and / or excipient.

[0397] 86. The composition for use according to clause 85, wherein the pharmaceutically acceptable adjuvants and / or excipients are selected from the group consisting of fillers, binders, lubricants and disintegrants.

[0398] 87. The composition for use according to clause 85, wherein the pharmaceutically acceptable adjuvant and / or excipient is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate and croscarmellose sodium.

[0399] 88. A composition for use according to any one of clauses 61 to 87, wherein the composition comprises 10 to 80% by weight, such as 40 to 65% by weight, such as 50 to 55% by weight, for example about 53% by weight, 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.

[0400] 89. A composition for use according to any one of clauses 61 to 87, wherein the composition comprises 10 to 80% by weight, such as 40 to 65% by weight, for example 50 to 60% by weight, such as 50 to 55% by weight, for example 55 to 60% by weight, such as about 53% by weight, for example 56% by weight, 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.

[0401] 90. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; and e. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of a disintegrant, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0402] 91. The composition comprises: a. 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, such as about 53% by weight, for example about 56% by weight, 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% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. 88. A composition for use according to any one of clauses 61 to 87, comprising: f. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight, of magnesium stearate; and f. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0403] 92. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; e. 0.25 to 5% by weight, for example, 0.3 to 2.5% by weight of a disintegrant; and f. 1-10% by weight of a film coating, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0404] 93. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; e. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight of magnesium stearate; and f. 88. A composition for use according to any one of clauses 61 to 87, comprising or consisting of 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of croscarmellose sodium and g. 1 to 10% by weight of a film coating composition such as Opadry White, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0405] 94. A composition for use according to any one of the preceding clauses, wherein the composition is administered in one or more unit dosage forms.

[0406] 95. A composition for use according to any one of the preceding clauses, wherein the subject's serum uric acid level is less than 6.5 mg / dL.

[0407] 96. A composition for use according to any one of the preceding clauses, wherein the subject's Myasthenia Gravis Foundation of America (MGFA) clinical classification before treatment is class I, IIa, IIb, IIIa, IIIb, IVa, IVb or V.

[0408] 97. The composition for use according to clause 96, wherein the pre-treatment MGFA clinical classification is I, IIa, IIb, or IIIb.

[0409] 98. A composition for use according to any one of the preceding clauses, wherein the subject experiences a reduction in Quantitative Myasthenia Gravis (QMG) total score following treatment.

[0410] 99. The composition for use according to clause 98, wherein the reduction in QMG total score after said treatment is at least 0.9 points between 2 and 5 hours, such as at 2 hours after treatment, such as at 3 hours after treatment, such as at 4 hours after treatment, or such as at 5 hours after treatment.

[0411] 100. A composition for use according to any one of the preceding clauses, wherein the Quantitative Myasthenia Gravis (QMG) total score is reduced compared to placebo at the same time point after treatment.

[0412] 101. The composition for use according to clause 100, wherein the reduction in the QMG total score compared to placebo at the same time point after treatment is at least 0.9 points between 2 and 5 hours, 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.

[0413] 102. The composition for use according to clause 98, wherein the QMG total score is determined by comparing the change from baseline in the decrease in the QMG total score after a specified period of treatment with the 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, to the change from baseline in the decrease in the QMG total score after a specified period of placebo treatment.

[0414] 103. The composition for use according to clause 102, wherein said period is 21 days.

[0415] 104. A composition for use according to any one of clauses 98 to 103, wherein the reduction in the QMG total score is at least 1.0 point, such as at least 1.5 points, such as at least 2.0 points, for example at least 3.0 points.

[0416] 105. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a decrease in MG Activities of Daily Living Profile (MG-ADL) score after treatment with the composition.

[0417] 106. The composition for use according to clause 105, wherein the MG-ADL score is determined by comparing the change from baseline in the MG-ADL score after a specified period of treatment with the 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, to the change from baseline in the MG-ADL score after a specified period of placebo treatment.

[0418] 107. The composition for use according to clause 106, wherein said period is 21 days.

[0419] 108. A composition for use according to any one of the preceding clauses, wherein the MG-ADL score is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points.

[0420] 109. A composition for use according to any one of the preceding clauses, wherein the MG-ADL score is reduced by 0.3 to 10 points, such as 0.5 to 6 points, for example 0.3 to 5 points.

[0421] 110. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in the MG Activities of Daily Living Profile score.

[0422] 111. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in the MG Activities of Daily Living Profile score.

[0423] 112. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences an increase in muscle strength after treatment with the composition.

[0424] 113. The composition for use according to clause 112, wherein said muscle strength is measured using a handheld dynamometer.

[0425] 114. A composition for use according to any one of clauses 112 or 113, wherein said muscle strength is measured as grip strength.

[0426] 115. A composition for use according to any one of clauses 112 or 113, wherein the muscle strength is measured as muscle strength of the thigh (knee flexors), upper arm (elbow flexors and extensors) and / or shoulder (shoulder abductors).

[0427] 116. The composition for use according to any one of clauses 112 to 115, wherein the increase in muscle strength is determined by comparing the change from baseline in muscle strength after a specified period of treatment with the 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, to the change from baseline in muscle strength after a specified period of placebo treatment.

[0428] 117. The composition for use according to clause 116, wherein said period is 21 days.

[0429] 118. A composition for use according to any one of clauses 112 to 117, wherein the muscle strength is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%.

[0430] 119. A composition for use according to any one of clauses 112 to 118, wherein the muscle strength is increased by 10% to 400%, for example by 15% to 200%, for example by 20% to 100%.

[0431] 120. A composition for use according to any one of clauses 112 to 119, wherein the muscle strength, as determined by measuring grip strength using a handheld dynamometer, is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%.

[0432] 121. A composition for use according to any one of clauses 112 to 120, wherein the muscle strength, as determined by measuring grip strength using a handheld dynamometer, is increased by 10% to 400%, for example 15% to 200%, for example 20% to 100%.

[0433] 122. A composition for use according to any one of clauses 112 to 121, wherein the 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, for example at least 0.75 kg, for example at least 1.0 kg, such as at least 1.25 kg, for example at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg.

[0434] 123. A composition for use according to any one of clauses 112 to 122, wherein the muscle strength, as determined by measuring grip strength using a handheld dynamometer, is increased by 0.25 to 5.0 kg, for example 0.25 to 4.0 kg, for example 0.5 to 4.0 kg.

[0435] 124. A composition for use according to any one of clauses 112 to 123, wherein the muscle strength, as determined by measuring knee flexion muscle strength using a handheld dynamometer, is increased by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg.

[0436] 125. A composition for use according to any one of clauses 112 to 124, wherein the muscle strength, as determined by measuring knee flexion muscle strength using a handheld dynamometer, is increased by 0.25 to 5.0 kg, for example 0.25 to 4.0 kg, for example 0.5 to 4.0 kg.

[0437] 126. A composition for use according to any one of clauses 112 to 125, wherein the muscle strength, as determined by measuring elbow flexion muscle strength using a handheld dynamometer, is increased by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, such as at least 1.0 kg, for example at least 1.25 kg, such as at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg.

[0438] 127. A composition for use according to any one of clauses 112 to 126, wherein the muscle strength, as determined by measuring elbow flexion muscle strength using a handheld dynamometer, is increased by 0.25 to 5.0 kg, for example 0.25 to 4.0 kg, for example 0.5 to 4.0 kg.

[0439] 128. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences an increase in muscle strength.

[0440] 129. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences an increase in muscle strength.

[0441] 130. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a reduction in the Myasthenia Gravis Composite (MGC) scale after treatment with the composition.

[0442] 131. The composition for use according to clause 130, wherein the reduction in the MGC scale is determined by comparing the change from baseline in the MGC scale after a specified period of treatment with the 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, to the change from baseline in the MGC scale after a specified period of placebo treatment.

[0443] 132. The composition for use according to clause 131, wherein said period is 21 days.

[0444] 133. A composition for use according to any one of clauses 130 to 132, wherein the MGC scale is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points.

[0445] 134. A composition for use according to any one of clauses 130 to 133, wherein the MGC scale is reduced by 0.3 to 10 points, such as 0.5 to 6 points, such as 0.3 to 5 points.

[0446] 135. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a reduction in Myasthenia Gravis Composite Scale.

[0447] 136. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a reduction in Myasthenia Gravis Composite Scale.

[0448] 137. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a decrease in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score after treatment with the composition.

[0449] 138. The composition for use according to clause 137, wherein the reduction in the MG-QCL15 score is determined by comparing the change from baseline in the reduction in the MG-QCL15 score after a specified period of treatment with the 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, to the change from baseline in the reduction in the MG-QCL15 score after a specified period of placebo treatment.

[0450] 139. The composition for use according to clause 138, wherein said period is 21 days.

[0451] 140. A composition for use according to any one of clauses 137 to 139, wherein the MG-QCL15 score is reduced by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points.

[0452] 141. A composition for use according to any one of clauses 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.

[0453] 142. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in Myasthenia Gravis Quality of Life 15 score.

[0454] 143. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in Myasthenia Gravis Quality of Life 15 score.

[0455] 144. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects, after treatment with the composition, experiences an improvement in their health status as determined using the EQ-5D scale.

[0456] 145. The composition for use according to clause 144, wherein said improvement in said EQ-5D scale is determined by comparing the change from baseline in said EQ-5D scale after a specified period of treatment with said 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, to the change from baseline in said EQ-5D scale after a specified period of placebo treatment.

[0457] 146. The composition for use according to clause 145, wherein said period is 21 days.

[0458] 147. A composition for use according to any one of clauses 144 to 146, wherein the EQ-5D scale is increased by at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points.

[0459] 148. A composition for use according to any one of clauses 144 to 147, wherein the EQ-5D scale increases by 0.3 to 10 points, such as by 0.5 to 6 points, such as by 0.3 to 5 points.

[0460] 149. A composition for use according to any one of the preceding clauses, 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 being administered twice daily, the composition being in a solid dosage form and being administered orally, and the subject experiencing an improvement in health status as determined using the EQ-5D scale.

[0461] 150. The composition for use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences an improvement in health status as determined using the EQ-5D scale.

[0462] 151. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a reduction in jitter after treatment with the composition.

[0463] 152. A composition for use according to clause 151, wherein said jitter is determined using single fibre electromyography.

[0464] 153. The composition for use according to any one of clauses 151 or 152, wherein said reduction in jitter is determined by comparing the change from baseline in jitter after a specified period of treatment with said 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, to the change from baseline in jitter after a specified period of placebo treatment.

[0465] 154. A composition for use according to clause 153, wherein said period is 21 days.

[0466] 155. A composition for use according to any one of clauses 151 to 154, wherein the jitter is reduced by at least 10%, such as at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%.

[0467] 156. A composition for use according to any one of clauses 151 to 154, wherein the jitter is reduced by 5% to 95%, such as by 5% to 80%, such as by 10% to 50%.

[0468] 157. A composition for use according to any one of clauses 151 to 154, wherein the jitter determined using single fibre electromyography is reduced by at least 5 μs, such as at least 10 μs, for example at least 15 μs, such as at least 20 μs, for example at least 25 μs, such as at least 30 μs, for example at least 40 μs, such as at least 50 μs, for example at least 75 μs, for example at least 100 μs.

[0469] 158. A composition for use according to any one of clauses 151 to 154, wherein the jitter determined using single fibre electromyography is reduced by 5 μs to 200 μs, such as 5 μs to 100 μs, for example 10 μs to 50 μs.

[0470] 159. The composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in jitter as determined using single fiber electromyography.

[0471] 160. The composition for use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in jitter as determined using single fiber electromyography.

[0472] 161. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a reduction in blockage after treatment with the composition.

[0473] 162. The composition for use according to clause 161, wherein the block is determined using single-fiber electromyography.

[0474] 163. The composition for use according to any one of clauses 161 or 162, wherein the reduction in block is determined by comparing the change from baseline in block after a specified period of treatment with the 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, to the change from baseline in block after a specified period of placebo treatment.

[0475] 164. The composition for use according to clause 163, wherein said period is 21 days.

[0476] 165. The composition for use according to any one of clauses 161 to 164, wherein the blockage is reduced by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%.

[0477] 166. A composition for use according to any one of clauses 161 to 165, wherein the block is reduced by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0478] 167. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in block as determined using single fiber electromyography.

[0479] 168. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a reduction in block as determined using single fiber electromyography.

[0480] 169. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a decrease in their individual neuromuscular quality of life score after treatment with the composition.

[0481] 170. The composition for use according to clause 169, wherein the decrease in the individual neuromuscular quality of life score is determined by comparing the change from baseline in the individual neuromuscular quality of life score after a specified period of treatment with the 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, to the change from baseline in the individual neuromuscular quality of life score after a specified period of placebo treatment.

[0482] 171. The composition for use according to clause 170, wherein said period is 21 days.

[0483] 172. A composition for use according to any one of clauses 169 to 171, wherein the individual neuromuscular quality of life score is reduced by 0.5 points, such as at least 0.75 points, for example at least 1 point, such as at least 1.5 points, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points.

[0484] 173. A composition for use according to any one of the preceding clauses, wherein the individual neuromuscular quality of life score is reduced by 0.5 to 30 points, such as 1 to 20 points, for example 0.5 to 10 points.

[0485] 174. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in the form of a solid dosage form and is administered orally, and the subject experiences a decrease in an individual neuromuscular quality of life score.

[0486] 175. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in the form of a solid dosage form and is administered orally, and the subject experiences a decrease in an individual neuromuscular quality of life score.

[0487] 176. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences a decrease in Fatigue Severity Scale score after treatment with the composition.

[0488] 177. The composition for use according to clause 176, wherein said reduction in said Fatigue Severity Scale score is determined by comparing the change from baseline in said Fatigue Severity Scale score after a specified period of treatment with said 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, to the change from baseline in said Fatigue Severity Scale score after a specified period of placebo treatment.

[0489] 178. The composition for use according to Clause 177, wherein said period is 21 days.

[0490] 179. A composition for use according to any one of clauses 176 to 178, wherein the Fatigue Severity Scale score is reduced by 0.5 points, such as at least 0.75 points, for example at least 1 point, such as at least 1.5 points, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points.

[0491] 180. A composition for use according to any one of clauses 176 to 179, wherein the Fatigue Severity Scale score is reduced by 1 to 20 points, for example 0.5 to 10 points.

[0492] 181. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in Fatigue Severity Scale score.

[0493] 182. The use of any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences a decrease in Fatigue Severity Scale score.

[0494] 183. A composition for use according to any one of the preceding clauses, wherein the subject or group of subjects experiences improved lung function after treatment with the composition.

[0495] 184. The composition for use according to clause 183, wherein the improvement in pulmonary function is determined by comparing the change from baseline in pulmonary function after a specified period of treatment with the 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, to the change from baseline in pulmonary function after a specified period of placebo treatment.

[0496] 185. The composition for use according to Clause 184, wherein said period is 21 days.

[0497] 186. A composition for use according to any one of clauses 183 to 185, wherein the lung function is determined by measuring forced vital capacity (FVC).

[0498] 187. The composition for use according to clause 186, wherein said FVC is increased by at least 5%, such as at least 10%, for example at least 15%, such as at least 20%, for example at least 25%, such as at least 30%, for example at least 50%, such as at least 75%, for example at least 100%, such as at least 150%, for example at least 200%.

[0499] 188. The composition for use according to clause 186, wherein the FVC is increased by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0500] 189. A composition for use according to any one of clauses 183 to 185, wherein the pulmonary function is determined by measuring the forced expiratory volume in one second (FEV1).

[0501] 190. The composition for use according to clause 189, wherein said FEV1 is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%.

[0502] 191. The composition for use according to clause 189, wherein the FEV1 is increased by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0503] 192. A composition for use according to any one of clauses 183 to 185, wherein the pulmonary function is determined by measuring maximum inspiratory pressure (MIP).

[0504] 193. The composition for use according to clause 192, wherein said MIP is increased by at least 5%, such as at least 10%, for example at least 15%, such as at least 20%, for example at least 25%, such as at least 30%, for example at least 50%, such as at least 75%, for example at least 100%, such as at least 150%, for example at least 200%.

[0505] 194. The composition for use according to clause 192, wherein the MIP is increased by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0506] 195. A composition for use according to any one of clauses 183 to 185, wherein the pulmonary function is determined by measuring maximum expiratory pressure (MEP).

[0507] 196. The composition for use according to clause 195, wherein the MEP is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%.

[0508] 197. The composition for use according to clause 195, wherein the MEP is increased by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0509] 198. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences improved pulmonary function.

[0510] 199. A composition for use according to any one of the preceding clauses, 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 administered twice daily, the composition is in a solid dosage form and is administered orally, and the subject experiences improved pulmonary function.

[0511] 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 for treating myasthenia gravis in a subject with a serum uric acid level of less than 6.5 mg / dL.

[0512] 201. A composition for use according to clause 200, for administration in a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0513] 202. A composition for use according to any one of clauses 200-201, wherein said therapeutic dose is as defined in any one of clauses 2-57.

[0514] 203. 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 contains 50 to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0515] 204. The composition of clause 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.

[0516] 205. The composition of clause 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.

[0517] 206. The composition of clause 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.

[0518] 207. The composition of clause 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.

[0519] 208. The composition of clause 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.

[0520] 209. The composition of clause 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.

[0521] 210. The composition described in clause 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.

[0522] 211. The composition of any one of clauses 203 to 209, further comprising at least one pharmaceutically acceptable adjuvant and / or excipient.

[0523] 212. A composition according to any one of clauses 203 to 211, which is administered orally.

[0524] 213. The composition of any one of clauses 203 to 212, wherein the solid dosage form is selected from the group consisting of capsules (such as sprinkle capsules and gelatin capsules), tablets (such as plain tablets, coated tablets, and sustained-release tablets), and sprinkles.

[0525] 214. The composition of any one of clauses 211 to 213, wherein the pharmaceutically acceptable adjuvants and / or excipients are selected from the group consisting of fillers, binders, lubricants and disintegrants.

[0526] 215. The composition of any one of clauses 211 to 213, wherein the pharmaceutically acceptable adjuvant and / or excipient is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, maltodextrin, magnesium stearate, and croscarmellose sodium.

[0527] 216. The composition according to any one of clauses 203 to 215, wherein the composition comprises 10 to 80% by weight, such as 40 to 65% by weight, such as 50 to 55% by weight, for example about 53% by weight, 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.

[0528] 217. The composition according to any one of clauses 203 to 215, wherein the composition comprises 10 to 80% by weight, such as 40 to 65% by weight, for example 50 to 60% by weight, such as 50 to 55% by weight, for example 55 to 60% by weight, such as about 53% by weight, for example about 56% by weight 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.

[0529] 218. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; and e. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of a disintegrant, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0530] 219. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. 0.25-3% by weight, for example 0.4-2.0% by weight, of magnesium stearate; and f. 0.25-5% by weight, for example 0.3-2.5% by weight, of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0531] 220. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20 to 80% by weight, for example, 25 to 50% by weight of a filler; c. 2 to 20% by weight, for example, 3 to 16% by weight of a binder; d. 0.25 to 3% by weight, for example, 0.4 to 2.0% by weight of a lubricant; e. 0.25 to 5% by weight, for example, 0.3 to 2.5% by weight of a disintegrant; and f. 1-10% by weight of a film coating, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0532] 221. The composition comprises: a. 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5 to 60% by weight, for example 20 to 40% by weight, for example 21 to 37% by weight of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight of microcrystalline cellulose; d. 1 to 15% by weight, for example 1.5 to 7% by weight, for example 1.8 to 6.0% by weight of maltodextrin; and e. 1. A composition according to any one of clauses 203 to 215, comprising or consisting of: f. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight, of magnesium stearate; f. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight, of croscarmellose sodium; and g. 1 to 10% by weight of a film coating composition such as Opadry White, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

[0533] 222. 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.

[0534] 223. The composition described in clause 222, wherein the therapeutically effective dose is 400 mg.

[0535] 224. The composition described in clause 222, wherein the therapeutically effective dose is 350 mg.

[0536] 225. The composition described in clause 222, wherein the therapeutically effective dose is 300 mg.

[0537] 226. The composition described in clause 222, wherein the therapeutically effective dose is 250 mg.

[0538] 227. The composition described in clause 222, wherein the therapeutically effective dose is 200 mg.

[0539] 228. The composition described in clause 222, wherein the therapeutically effective dose is 150 mg.

[0540] 229. The composition described in clause 222, wherein the therapeutically effective dose is 100 mg.

[0541] 230. The composition described in clause 222, wherein the therapeutically effective dose is administered once daily.

[0542] 231. The composition described in clause 222, wherein the therapeutically effective dose is administered twice daily.

[0543] 232. The composition described in clause 222, wherein the therapeutically effective dose is administered three times daily.

[0544] 233. A composition according to any one of clauses 203 to 232, for oral administration.

[0545] 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]propanoic 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]propanoic acid.

[0546] 235. The method includes the following: a. a decrease in the Quantitative Myasthenia Gravis Total Score; b. a decrease in the MG Activities of Daily Living Profile (MG-ADL) score; c. an increase in muscle strength; d. a decrease in the Myasthenia Gravis Composite (MGC) scale; e. a decrease in the Myasthenia Gravis Quality of Life 15 (MG-QOL15) score; f. an improvement in health status as measured using the EQ-5D scale; g. a decrease in jitter; h. a decrease in blocks; i. a decrease in individual neuromuscular quality of life scores; j. a decrease in the Fatigue Severity Scale score; and / or k. improved lung function.

[0547] 236. A method of treating myasthenia gravis in a subject, the method resulting in a decrease in MG Activities of Daily Living Profile (MG-ADL) score, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0548] 237. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 236, providing

[0549] 238. The method of any one of clauses 236 or 237, wherein the subject experiences a decrease in MG-ADL score of at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0550] 239. A method for treating myasthenia gravis in a subject, the method resulting in an increase in muscle strength, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0551] 240. The method of clause 239, wherein the improvement in muscle strength is determined by measuring grip strength using a handheld dynamometer.

[0552] 241. The therapeutically effective dose is a dose that produces a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max 240. The method of claim 239, wherein the method provides:

[0553] 242. A method according to any one of clauses 239 to 241, wherein the muscle strength is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, such as at least 200%, for example between 10% and 400%, for example between 15% and 200%, such as between 20% and 100%.

[0554] 243. A method according to any one of clauses 239 to 241, wherein the grip strength is increased by at least 0.25 kg, such as at least 0.50 kg, for example at least 0.75 kg, for example at least 1.0 kg, such as at least 1.25 kg, for example at least 1.5 kg, for example at least 1.75 kg, such as at least 2.0 kg, for example at least 2.5 kg, for example at least 3.0 kg, such as 0.25 to 5.0 kg, for example 0.25 to 4.0 kg, for example 0.5 to 4.0 kg.

[0555] 244. A method of treating myasthenia gravis in a subject, the method resulting in a reduction 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]propanoic 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.

[0556] 245. The therapeutically effective dose is a dose that produces a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 244 provides:

[0557] 246. The method of any one of clauses 244 or 245, wherein the subject experiences a decrease in the MGC scale of at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0558] 247. A method of treating myasthenia gravis in a subject, the method resulting in a decrease in Myasthenia Gravis Quality of Life 15 (MG-QOL15) score, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0559] 248. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 247 provides:

[0560] 249. The method of any one of clauses 247 or 248, wherein the subject experiences a decrease in MG-QOL15 score of at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0561] 250. A method of treating myasthenia gravis in a subject, the method resulting in an improvement in health status as measured 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]propanoic 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.

[0562] 251. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 250, providing

[0563] 252. The method of any one of clauses 250 or 251, wherein said subject experiences an improvement on the EQ-5D scale of at least 0.3 points, such as at least 0.5 points, for example at least 0.75 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as between 0.3 and 10 points, for example between 0.5 and 6 points, such as between 0.3 and 5 points.

[0564] 253. A method of treating myasthenia gravis in a subject, the method resulting in a reduction in jitter, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0565] 254. The method of clause 253, wherein the reduction in jitter is determined using single-fiber electromyography.

[0566] 255. The therapeutically effective dose is a dose that produces a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max 254. The method of claim 253, wherein the method provides:

[0567] 256. A method according to any one of clauses 253 to 255, wherein said jitter is reduced by at least 10%, such as at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example by 5% to 95%, for example by 5% to 80%, such as by 10% to 50%.

[0568] 257. A method according to any one of clauses 253 to 256, wherein said jitter is reduced by at least 5 μs, such as by at least 10 μs, for example by at least 15 μs, such as by at least 20 μs, for example by at least 25 μs, such as by at least 30 μs, for example by at least 40 μs, such as by at least 50 μs, for example by at least 75 μs, such as by at least 100 μs, for example between 5 μs and 200 μs, such as between 5 μs and 100 μs, for example between 10 μs and 50 μs.

[0569] 258. A method of treating myasthenia gravis in a subject, the method resulting in a reduction in blockage, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0570] 259. The method of clause 258, wherein the reduction in block is determined using single-fiber electromyography.

[0571] 260. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max 259. The method of claim 258 or 259,

[0572] 261. The method of any one of clauses 258 to 260, wherein the block is reduced by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%, such as between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0573] 262. A method of treating myasthenia gravis in a subject, the method resulting in a decrease in an individual's 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]propanoic 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.

[0574] 263. The therapeutically effective dose is a dose that produces a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 262 provides:

[0575] 264. A method according to any one of clauses 262 or 263, wherein the individual neuromuscular quality of life score is reduced by at least 0.5 points, such as at least 1 point, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points, such as between 0.5 and 30 points, for example between 1 and 20 points, such as between 0.5 and 10 points.

[0576] 265. A method of treating myasthenia gravis in a subject, the method resulting in a reduction 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]propanoic 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.

[0577] 266. The therapeutically effective dose is a dose that produces a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 265 provides:

[0578] 267. The method of any one of clauses 265 or 266, wherein the fatigue severity scale score is reduced by at least 0.5 points, such as at least 0.75 points, for example at least 1 point, such as at least 1.5 points, for example at least 2 points, such as at least 3 points, for example at least 4 points, such as at least 5 points, for example at least 6 points, such as at least 8 points, for example at least 10 points, such as at least 15 points, for example at least 20 points, such as between 0.5 and 30 points, for example between 1 and 20 points, such as between 0.5 and 10 points.

[0579] 268. A method for treating myasthenia gravis in a subject, the method resulting in improved pulmonary function, comprising administering to the subject 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 therapeutic dose is in the range of 100 mg to 1500 mg.

[0580] 269. The method of clause 268, wherein the improvement in lung function is determined by measuring forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum inspiratory pressure (MIP), and / or maximum expiratory pressure (MEP).

[0581] 270. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max 269. The method of claim 268 or 269,

[0582] 271. The method of any one of clauses 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring forced vital capacity (FVC), and the FVC is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0583] 272. The method of any one of clauses 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring forced expiratory volume in 1 second (FEV1), and FEV1 is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%, such as between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0584] 273. The method of any one of clauses 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring maximum inspiratory pressure (MIP), and MIP is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, such as at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, for example between 5% and 80%, such as between 10% and 50%.

[0585] 274. The method of any one of clauses 268 to 270, wherein the subject experiences an improvement in lung function as determined by measuring maximum expiratory pressure (MEP), and MEP is increased by at least 5%, such as at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, such as at least 50%, for example at least 75%, such as at least 100%, for example at least 150%, such as at least 200%, for example between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0586] 275. A method of treating myasthenia gravis in a subject, the method resulting in a reduction in 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]propanoic 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.

[0587] 276. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max The method of clause 275 provides:

[0588] 277. The method of any one of clauses 275-276, wherein the subject experiences a decrease in the QMG total score of at least 0.9 points, such as at least 1.0 point, for example at least 1.5 points, for example at least 2.0 points, for example at least 3.0 points.

[0589] 278. A method for improving the quantitative myasthenia gravis total score in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0590] 279. The method of clause 278, wherein the reduction in the QMG total score after treatment is at least 0.9 points, such as at least 1.0 point, such as at least 1.5 points, such as at least 2.0 points, for example at least 3.0 points.

[0591] 280. The method according to clause 278, wherein the reduction in the QMG total score after treatment is at least 0.9 points, such as at least 1.0 point, such as at least 1.5 points, such as at least 2.0 points, for example at least 3.0 points, compared to placebo at the same time point.

[0592] 281. The method described in clause 278, wherein the decrease in the QMG total score after treatment is between 2 and 5 hours, 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.

[0593] 282. A method for improving right hand grip strength in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0594] 283. The method of clause 282, wherein the improvement in grip strength in the right hand is at least 2.0 kg, for example at least 2.5 kg.

[0595] 284. The method of clause 282, wherein the improvement in grip strength in the right hand is at least 2.0 kg, such as at least 2.5 kg, compared to placebo at the same time point.

[0596] 285. A method for reducing EMG decline with repetitive nerve stimulation in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0597] 286. A method for ameliorating the symptoms of diplopia in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0598] 287. A method for improving the symptoms of ptosis in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0599] 288. A method for improving symptoms of dysarthria in a subject suffering from myasthenia gravis, comprising administering to the subject 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.

[0600] 289. A method for enhancing neuromuscular transmission and / or restoring skeletal muscle function, comprising administering to the subject 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.

[0601] 290. A method of treating myasthenia gravis, comprising administering (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 to a subject in need thereof.

[0602] 291. A method of treating myasthenia gravis resulting in an improvement in quantitative myasthenia gravis total score in a patient in need thereof, the method comprising administering a therapeutically effective dose of a compound 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, and wherein the C in the range of 5,000 ng / mL to 14,000 ng / mL is achieved in the patient. max wherein, after administration of the therapeutically effective dose of the compound, the patient experiences a reduction of at least 0.9 points in the patient's quantitative myasthenia gravis score compared to placebo at the same time point.

[0603] 292. The therapeutically effective dose of the compound is a dose that produces an AUC in the range of 15,000 ng / mL to 500,000 ng / mL in a patient. inf The method of clause 291 further provides:

[0604] 293. The therapeutically effective dose of the compound has a T in the range of 1 to 5 hours in a patient. max 292. The method of claim 291, comprising:

[0605] 294. The method of clause 291, wherein the therapeutically effective dose of the compound has a half-life in the patient ranging from 3 hours to 7 hours.

[0606] 295. The method of clause 291, wherein the therapeutically effective dose of the compound is administered orally to the patient.

[0607] 296. The method of clause 291, wherein the patient experiences at least a 1.0 point decrease, such as at least a 1.5 point decrease, such as at least a 2.0 point decrease, in the patient's quantitative myasthenia gravis score.

[0608] 297. The method of clause 291, wherein the patient's Myasthenia Gravis Foundation of America (MGFA) clinical classification before treatment is class I, IIa, IIb, IIIa, IIIb, IVa, IVb, or V.

[0609] 298. A method for treating myasthenia gravis in a patient in need thereof, resulting in an improvement in right hand grip strength, said 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 said therapeutically effective dose is in the range of 100 mg to 1500 mg, and wherein said method results in an improvement in right hand grip strength in the patient, said C in the range of 5,000 ng / mL to 14,000 ng / mL. max wherein after administering the therapeutically effective dose of the compound, the patient experiences an improvement in the patient's hand grip strength of at least 1 kg compared to the patient's hand grip strength prior to administration.

[0610] 299. The method of clause 298, wherein the at least 1 kg improvement in the patient's hand grip strength occurs at least 3 hours after administration of the therapeutically effective dose of the compound.

[0611] 300. The therapeutically effective dose of the compound has an AUC in the range of 15,000 h·ng / mL to 500,000 h·ng / mL in a patient. inf The method of clause 298 further provides:

[0612] 301. The therapeutically effective dose of the compound has a T in the range of 1 to 5 hours in a patient. max 299. The method of claim 298, comprising:

[0613] 302. The method of clause 298, wherein the therapeutically effective dose of the compound has a half-life in the patient ranging from 3 hours to 7 hours.

[0614] 303. The method of clause 298, wherein the therapeutically effective dose of the compound is administered orally to the patient.

[0615] 304. The method of clause 298, wherein the therapeutically effective dose is in the range of 100 mg to 600 mg.

[0616] 305. The method of clause 298, wherein the therapeutically effective dose is in the range of 200 mg to 600 mg.

[0617] 306. The method of clause 298, wherein the therapeutically effective dose is 400 mg.

[0618] 307. The method of clause 298, wherein the therapeutically effective dose is 350 mg.

[0619] 308. The method of clause 298, wherein the therapeutically effective dose is 300 mg.

[0620] 309. The method of clause 298, wherein the therapeutically effective dose is 250 mg.

[0621] 310. The method of clause 298, wherein the therapeutically effective dose is 200 mg.

[0622] 311. The method of clause 298, wherein the therapeutically effective dose is 150 mg.

[0623] 312. The method of clause 298, wherein the therapeutically effective dose is 100 mg.

[0624] 313. The method of clause 298, wherein the therapeutically effective dose is administered once, twice, or three times daily.

[0625] 314. A method of treating a patient suffering from symptoms of myasthenia gravis, said 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 said therapeutically effective dose is in the range of 100 mg to 1500 mg.

[0626] 315. The method of clause 314, wherein the therapeutically effective dose is in the range of 100 mg to 600 mg.

[0627] 316. The method of clause 314, wherein the therapeutically effective dose is in the range of 200 mg to 600 mg.

[0628] 317. The method of clause 314, wherein the therapeutically effective dose is 100 mg.

[0629] 318. The method of clause 314, wherein the therapeutically effective dose is 150 mg.

[0630] 319. The method of clause 314, wherein the therapeutically effective dose is 200 mg.

[0631] 320. The method of clause 314, wherein the therapeutically effective dose is 250 mg.

[0632] 321. The method of clause 314, wherein the therapeutically effective dose is 300 mg.

[0633] 322. The method of clause 314, wherein the therapeutically effective dose is 350 mg.

[0634] 323. The method of clause 314, wherein the therapeutically effective dose is 400 mg.

[0635] 324. The method of clause 314, wherein the therapeutically effective dose is 500 mg.

[0636] 325. The method of clause 314, wherein the therapeutically effective dose is 600 mg.

[0637] 326. The method of clause 314, wherein the therapeutically effective dose is administered once, twice, three times, or four times daily.

[0638] 327. The method of any one of clauses 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.

[0639] 328. The method of any one of clauses 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.

[0640] 329. The method of any one of clauses 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.

[0641] 330. The method of any one of clauses 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.

[0642] 331. The method of any one of clauses 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.

[0643] 332. The method of any one of clauses 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.

[0644] 333. The method of any one of clauses 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.

[0645] 334. The method of any one of clauses 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.

[0646] 335. The method of any one of clauses 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.

[0647] 336. The method of any one of clauses 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 once daily.

[0648] 337. The method of any one of clauses 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 twice daily.

[0649] 338. The method of any one of clauses 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.

[0650] 339. The method of any one of clauses 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.

[0651] 340. The method of any one of clauses 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 administered once daily.

[0652] 341. The method of any one of clauses 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 administered twice daily.

[0653] 342. The method of any one of clauses 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 administered three times daily.

[0654] 343. The method of any one of clauses 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 administered four times daily.

[0655] 344. The method of any one of clauses 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 once daily.

[0656] 345. The method of any one of clauses 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 twice daily.

[0657] 346. The method of any one of clauses 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 three times daily.

[0658] 347. The method of any one of clauses 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.

[0659] 348. The method of any one of clauses 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 once daily.

[0660] 349. The method of any one of clauses 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 twice daily.

[0661] 350. The method of any one of clauses 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 three times daily.

[0662] 351. The method of any one of clauses 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.

[0663] 352. The method of any one of clauses 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.

[0664] 353. The method of any one of clauses 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.

[0665] 354. The method of any one of clauses 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.

[0666] 355. The method of any one of clauses 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.

[0667] 356. The method of any one of clauses 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 once daily.

[0668] 357. The method of any one of clauses 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 twice daily.

[0669] 358. The method of any one of clauses 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.

[0670] 359. The method of any one of clauses 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.

[0671] 360. The method of any one of clauses 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 administered once daily.

[0672] 361. The method of any one of clauses 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.

[0673] 362. The method of any one of clauses 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.

[0674] 363. The method of any one of clauses 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.

[0675] 364. The method of any one of clauses 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.

[0676] 365. The method of any one of clauses 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.

[0677] 366. The method of any one of clauses 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.

[0678] 367. The method of any one of clauses 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.

[0679] 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 manufacture of a medicament for the treatment of 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.

[0680] 369. A kit of parts 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.

[0681] 370. A kit of parts or composition for use according to clause 369, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, is for administration in a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0682] 371. A kit of parts or composition for use according to any one of clauses 369-370, wherein said therapeutic dose is as defined in any one of clauses 2-57.

[0683] 372. The kit of parts or composition according to any one of items 369 to 371, wherein the (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 the acetylcholinesterase inhibitor are administered simultaneously.

[0684] 373. The kit of parts or composition according to any one of items 369 to 371, wherein the (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 the acetylcholinesterase inhibitor are administered sequentially.

[0685] 374. A kit of parts or composition for use according to any one of clauses 369 to 373, wherein the acetylcholinesterase inhibitor is pyridostigmine.

[0686] 375. Use of a kit of parts 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 the manufacture of a medicament for the treatment of myasthenia gravis.

[0687] 376. A composition, method, or combination for use according to any one of the preceding clauses, wherein the subject is a human.

[0688] 377. A composition, method, or combination used according to any one of the preceding clauses, wherein the subject is suffering from myasthenia gravis.

[0689] 378. The composition, method, or combination used of any one of the preceding clauses, wherein the subject 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).

[0690] 379. The composition, method, or combination of use of any one of the preceding clauses, wherein the subject is also administered one or more compounds selected from the list consisting of amifapridine, eculizumab, prednisolone, prednisone, azathioprine, soliris, rituximab, efgartigimod alfa, zilucoplan, rozanolixizumab, cholecalciferol, and immune globulin. [Example]

[0691] Example 1: EAMG model All animal handling, use, and care, including euthanasia, complied with European and Danish animal welfare regulations. To test the efficacy of ClC-1 inhibition in conditions of impaired neuromuscular transmission, experimental autoimmune MG (EAMG) in rats was selected as a model of impaired neuromuscular transmission, a commonly accepted model for determining the efficacy of medical treatments for MG (Losen, et al., Exp. Neurol. 2015, 270:18-28). All activities related to the handling, disease induction, and testing of novel compounds were covered by license numbers 2018-15-0201-01408 and 2018-15-0201-01420.

[0692] To induce EAMG, 250 μL of an emulsion of complete Freund's adjuvant (composed of heat-inactivated Mycobacterium tuberculosis H37Ra in non-metabolizable oil) was injected subcutaneously into anesthetized 7-week-old Lewis rats along with phosphate-buffered saline (PBS) and 80 μg of the extracellular α-domain peptide fragment of the human nicotinic acetylcholine receptor (antigen). The disease-inducing antigen was provided by the Pasteur Institute, Greece. The emulsion was deposited at the base of the tail, left hind leg, and right foreleg. After injection, the animals recovered and were returned to their home cages, maintained in ventilated racks under controlled temperature (20–22°C) and humidity (approximately 55%), with food and water available ad libitum under a 12-hour light / 12-hour dark cycle. The animals were kept pathogen-free, and the housing and replacement systems were designed to ensure that pathogen-free conditions were maintained throughout the study period. EAMG rats were observed, weighed, and scored for MG symptoms weekly until they developed symptoms of MG, after which the animals were observed daily.

[0693] Scoring of MG symptoms consisted of visual inspection of the animals as described elsewhere (Losen et al., Exp. Neurol. 2015, 270:18-28). If obvious signs of fatigue were observed, the animal was not tested further. However, if no obvious signs of fatigue were observed, the animal underwent forced exercise, in which the animal pulled on the device grid to measure grip strength, for at least 10 30-second sessions. This was done to reveal any muscle fatigue. After the exercise, the animal was observed again, and if clinical signs of fatigue appeared, the animal was given a score of 1 according to the following scoring system: 0: No clinical signs were observed. 1: No clinical signs are observed before fatiguing exercise, but symptoms of fatigue / weakness appear after exercise. 2: Clinical symptoms observed before fatiguing exercise. Symptoms may include hunching, head rest, fatigue, and / or trembling. 3; Paralysis of hind legs, difficulty breathing, impaired movement, lack of ability to grasp, and / or obvious fatigue (humane endpoint). 4; moribund (humane endpoint).

[0694] The onset of illness was expected 5–7 weeks after immunization. If an animal showed symptoms equivalent to an EAMG score of 1, the frequency of weighing and disease scoring was increased to three times per week, and the standard diet was supplemented with softened feed chow and / or diet gel to mitigate the possibility of rapid weight loss. If an animal showed symptoms equivalent to an EAMG score of 2, the animal was weighed and scored once per day and examined at least daily in the morning and afternoon. Animals with small wounds at the site of immunization emulsion injection were treated with antibacterial ointment until the wounds healed. Animals showing clinical signs of moderate pain, moderate distress, or any degree of suffering were treated appropriately, including discontinuing treatment or euthanizing the animal.

[0695] No animals required discontinuation of treatment with either ClC-1 inhibitor. The disease severity limit requiring humane euthanasia of animals complied with European and Danish legislation on laboratory animals. Specifically, this included animals showing disease progression to an EAMG score of 3 or animals with a weight loss of more than 20% compared to their individual maximum weight before disease induction. Animals were handled by trained personnel under veterinary supervision. Health monitoring of the animal facility was performed according to standard operating procedures. Daily records and decisions regarding animal welfare were kept.

[0696] Experiments with isolated nerve-muscle preparations from healthy and EAMG rats To enable measurements of electrophysiological properties and force at the cellular level, it was necessary to isolate a neuromuscular preparation from rats. For this purpose, animals were sacrificed, and muscles were excised along with 1–3 cm of intact nerve. The neuromuscular preparation was then transferred to an organ bath used for the specific experiment (see below) and perfused with standard Krebs-Ringer (NKR) solution. This solution consisted of 122 mM NaCl, 25 mM NaHCO3, 2.8 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 1.27 mM CaCl2, and 5 mM D-glucose. This NKR solution was continuously supplied with a mixture of 95% oxygen and 5% CO2 to maintain a pH of approximately 7.4. In some experiments, methyl sulfate was used to remove Cl from the solution. - All chemicals used were of analytical grade.

[0697] Example 2: Membrane conductance and basal current in muscle fibers of isolated nerve-muscle preparations The ability of compounds to inhibit ClC-1 in native tissue was assessed by measuring the resting membrane conductance (G) in single myofibers of freshly excised intact muscle from adult rats. m The effect of the steroids on the immune system was evaluated by measuring the effect on the immune system. m 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 a G mIt is known to be involved in approximately 80% of the surface membrane Cl - ion channels (Pedersen et al., J. Gen. Physiol. 2016, 147:291-308). m Any changes in ClC-1 activity can be considered to primarily reflect changes in ClC-1 function. - Between experiments, both with and without G m By comparing the recordings, it is possible to isolate the effect of the compound on ClC-1.

[0698] For the experiments, we used soleus or diaphragm muscles from healthy rats and EAMG rats with scores of 0, 1, or 2. After resection, the muscles were placed in an organ bath chamber perfused with NKR solution at a temperature of 30–31°C and a pH of 7.4–7.5. To allow for the selection of fibers to measure, the chamber was placed on the XY table of a Nikon upright microscope (Eclipse FN1, DFA, Glostrup, Denmark), allowing for movement of the chamber and visual inspection of the fibers and electrodes. Before starting the experiment, the muscles were allowed to rest in the solution for 30 min.

[0699] Resting G mwas measured using an electrophysiological technique involving the insertion of three intracellular microelectrodes into individual muscle fibers, as described in detail elsewhere (Riisager, A., Aarhus University, 2015). Briefly, three electrodes (E1–E3) were placed on the same muscle fiber, allowing three different interelectrode distances to be distinguished: E1 → E2 = X1; E2 → E3 = X2; E1 → E3 = X3, where X2 is approximately twice the distance of X1. All electrodes recorded membrane potential, and two electrodes were used to inject current protocols. First, a 50-ms steady-state current (I) of -30 to 50 nA was injected by E1, and the steady-state membrane potential response (ΔV) was measured by E2 and E3, obtaining recordings at X1 and X3, respectively. Subsequently, a current of the same duration and magnitude was injected by E3, measuring ΔV at E1 and E2, obtaining another recording at X3, and another recording at X2. Overall, this resulted in measurements of ΔV at three different distances along the fiber (X1, X2, X3), with X3 being recorded twice at both E1 and E3. From these recordings, the resistance to movement (ΔV / I) at the three distances was calculated and the G m was able to determine.

[0700] Once inside the fiber, G m Once this was determined, a series of 25-ms positive currents of increasing amplitude from 5 nA to 70 nA in 5 nA increments were injected through E1. This was done to determine the current required to elicit AP in the impaled fiber. This current, known as the rheobase, is a measure of the fiber's excitability. This was included to explore the hypothesis that ClC-1 inhibition increases muscle fiber excitability, which would be reflected in a decrease in the rheobase following the addition of a ClC-1 inhibitor compound.

[0701] Compound G mTo examine the effects on ClC-1 and rheobase, recordings were first obtained from a set of muscle fibers before compound addition, and then compounds were added at various concentrations. Muscle preparations were incubated with each compound concentration for 20–30 min before measurements began, and recordings were obtained from approximately 10 fibers per concentration per muscle. The affinity of NMD670 for ClC-1 inhibition was measured by measuring the G before compound addition and at different compound concentrations. m The apparent affinities were determined from plots of the α- and β-actin concentrations, where a four-parameter Hill function with variable slope was fitted to these compound concentrations to extract the apparent affinities.

[0702] To demonstrate the effect of NMD670 on ClC-1 inhibition and excitability in muscle fibers from EAMG animals, we measured G activity in intact EAMG soleus muscle fibers before and after adding 20 μM NMD670 to the experimental solution. m The membrane conductance (G) in the rat soleus muscle of healthy (n = 20) and EAMG animals (n = 12) was determined (Fig. 1). m The effect of NMD670 on muscle contractility was measured using mean G values ​​measured in muscle before (closed circles or open squares, respectively) and after (closed triangles or inverted open triangles, respectively) the addition of 20 μM NMD670. m The addition of NMD670 increased G in both healthy and EAMG animals. m There was a statistically significant decrease.

[0703] The effect of NMD670 on skeletal muscle fiber excitability, assessed by rheobase in rat soleus muscles from healthy (n = 20) and EAMG (n = 12) animals, before (closed circles or open squares, respectively) and after (closed triangles or inverted open triangles, respectively) the addition of 20 μM NMD670, is shown in Figure 2. Addition of NMD670 significantly reduced rheobase in muscle fibers from both groups of rats.

[0704] NMD670 inhibits ClC-1 channels, resulting in G m To confirm that Cl -Experiments were performed with increasing concentrations of NMD670 in a bath solution free of G m did not reduce the

[0705] Example 3: Endplate potential The effects of ClC-1 inhibition on neuromuscular transmission were investigated at the cellular level by recording endplate potentials (EPPs) with intracellular electrodes in isolated nerve muscle preparations from healthy and EAMG rats (scores 0-2). The muscle preparations used in the experiments were the diaphragm or levator auricle longus (LAL), which offered the advantage of allowing the excision of 1-3 cm of intact motor nerve. After excision, the preparations were immediately placed in a chamber perfused with NKR at a temperature of 30-31°C and a pH of 7.4-7.5. The preparations were left in the solution for 30 min before starting the experiment.

[0706] To establish stable and reliable stimulation of motor nerves, a field stimulation electrode was developed to selectively stimulate motor nerves. The electrode consisted of two silver wires insulated except for the tips. The electrode was positioned so that the nerve was between the two uninsulated ends of the wires. A micromanipulator placed on the microscope's XY table positioned the pipette holder, and the wires were attached to a g...

Claims

1. 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 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.

2. The composition of claim 1, wherein the therapeutic dose is 200 to 600 mg.

3. 10. The use of a composition according to any one of the preceding claims, wherein the therapeutic dose is administered twice daily.

4. 10. The use of any one of the preceding claims, wherein the composition is administered orally.

5. 10. A composition for use according to any one of the preceding claims, wherein the composition is in solid dosage form.

6. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a T ｍａｘ 10. The composition for use according to any one of the preceding claims, wherein the

7. The composition is taken 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]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, and provides a mean C of 400 mg after administration of a single 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. ｍａｘ 4. The composition for use according to any one of the preceding claims, wherein the IL-10 is between 13,000 and 32,000 ng / mL.

8. 10. A composition for use according to any one of the preceding claims, wherein the quantitative myasthenia gravis (QMG) total score is reduced compared to placebo at the same time point after treatment, and wherein the reduction in the QMG total score after treatment is at least 0.9 points.

9. 10. The composition for use according to any one of the preceding claims, wherein the subject is suffering 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. 1. 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. 11. The composition of claim 10, comprising 10 to 80% by weight 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, further comprising at least one pharmaceutically acceptable adjuvant and / or excipient selected from the group consisting of fillers, binders, lubricants and disintegrants.

13. The composition comprises: a. 10-80% by weight, such as 40-65% by weight, for example 50-60% by weight, such as 50-55% by weight, for example 55-60% by weight, such as about 53% by weight, for example about 56% by weight 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. 5-60% by weight, such as 20-40% by weight, such as 21-37% by weight, of silicified microcrystalline cellulose; c. 2 to 60% by weight, for example 5 to 16% by weight, of microcrystalline cellulose; d. 1 to 15 wt. % of maltodextrin, for example, 1.5 to 7 wt. %, for example, 1.8 to 6.0 wt. %; 13. The composition of any one of claims 10 to 12, comprising: e. 0.25 to 3% by weight, for example 0.4 to 2.0% by weight, of magnesium stearate; and f. 0.25 to 5% by weight, for example 0.3 to 2.5% by weight of croscarmellose sodium, with the proviso that the sum of the weight percentages of the ingredients does not exceed 100% by weight.

14. 1. A kit of parts 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. 15. The kit of parts for use according to claim 14, wherein (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, 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.

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