Compositions and methods for treating spinal muscular atrophy

Abstract

Disclosed herein is a method for treating spinal muscular atrophy (SMA) involving 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 SMA. Also disclosed are pharmaceutical compositions and kits of parts containing (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

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 spinal muscular atrophy (SMA), pharmaceutical compositions thereof for use in the treatment of SMA, and methods of treatment thereof. [Background technology]

[0002] Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and, if left untreated, is the most common genetic cause of infant death. It can also present later in life, with a milder disease course. A common feature is progressive weakness of voluntary muscles, with the arms, legs, and respiratory muscles affected first. Associated problems can include poor head control, difficulty swallowing, scoliosis, and joint contractures.

[0003] Spinal muscular atrophy is caused by mutations in the SMN1 gene, which encodes SMN, a protein necessary for motor neuron survival. Loss of motor neurons results in impaired transmission of electrical signals that must travel from the brain to skeletal muscle fibers to activate their contraction. SMN2 is a separate gene that evolved in humans. It is a duplicate gene but is not identical to SMN1. The SMN2 gene has a single nucleotide difference in exon 7, meaning that its protein product differs from SMN1 and SMN2. Therefore, approximately 90% of the SMN protein product from SMN2 is truncated and nonfunctional, while the remaining SMN protein product from SMN2 is intact and fully functional. Given that different people have different gene copy numbers for SMN2, it is considered a disease-modifying gene in SMA. Individuals with more SMN2 copies have more intact SMN protein from SMN2. The more SMN2 gene copies an SMA patient has, the better the patient is protected from SMN1 loss of function and the milder the disease is expected to be.

[0004] There are five types of SMA: type 0, type 1 (also known as Wernig-Hoffmann disease), type 2 (also known as Dubowitz disease), type 3 (also known as Kugelberg-Welander disease), and type 4. SMA type 0 is usually present before birth, and if untreated, children typically only survive a few weeks, even with 24 / 7 respiratory support. SMA type 1 is diagnosed in approximately 50% of patients, with onset typically occurring between 0 and 6 months. Untreated infants diagnosed with SMA type 1 typically do not survive beyond the age of 2 years. SMA type 2 is diagnosed in approximately 20% of patients, with onset typically occurring between 6 and 18 months. Patients are typically able to maintain a sitting position but do not learn to walk unassisted. Disease progression in patients with SMA type 2 varies, but typically patients survive well into adulthood, although their physical muscles weaken. Respiratory system involvement is a major concern, as are muscle contractures and curvature of the spine. SMA type 3 is diagnosed in approximately 30% of patients, with the age of onset usually >12 months. The disease progresses gradually, and most people with SMA type 3 lose the ability to walk and require mobility assistance at some point in their lives. SMA type 4 is diagnosed in approximately 5% of patients, usually with onset in the 30s or 40s. Symptoms consist of gradual weakening of the leg muscles, which frequently requires patients to use walking aids.

[0005] Recently approved therapies include 1) an antisense oligonucleotide (ASO) (nusinersen) to improve accurate splicing of SMN2, 2) gene therapy (onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene to generate intact SMN protein for use in patients up to 2 years of age, and 3) a small molecule (risdiplam) to improve SMN2 splicing.

[0006] Patients with SMA exhibit fatigue when tested in continuous, repetitive tasks (Stam et al., 2018a), a symptom associated with decreased neuromuscular junction (NMJ) function (Bartels et al., 2019). While the current standard of care targeting SMN upregulation has shown promise (Maggi et al., 2020), recent neurophysiological data suggest that many adult SMA patients continue to show evidence of NMJ defects despite up to 14 months of ASO therapy (Arnold et al., 2021). Furthermore, patients receiving ASO therapy demonstrated persistent deficits in clinical outcome measures, including a 6-minute walk test, which correlated with indices of NMJ function, such as compound muscle action potential (CMAP) reduction (Arnold et al., 2021). The presence and persistence of such neuromuscular junction defects in SMA patients even after receiving SMN upregulation therapy suggests the potential benefit of administering therapies targeting NMJ activity both as monotherapy and as add-on therapy to SMN upregulation therapy.

[0007] Skeletal muscle-specific ClC-1 chloride ion channels conduct inhibitory currents that oppose neuromuscular transmission at the NMJ. Inhibition of ClC-1 reduces the inhibitory current, thereby increasing muscle membrane excitability and improving neuromuscular transmission. This has been shown to result in recovery of muscle function under conditions that mimic neuromuscular disorders (Pedersen et al., 2021).

[0008] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid (hereafter NMD670) is an inhibitor of the skeletal muscle-specific ClC-1 channel. The chemical structure of NMD670 is provided below.

[0009] [ka]

[0010] NMD670 modifies the voltage sensitivity of ClC-1 channels, resulting in increased Cl in muscle fibers. -Inhibition of ClC-1 with NMD670 restores muscle activation under conditions of impaired neuromuscular transmission or impaired muscle fiber excitability, and under these conditions, NMD670 can restore force generation in skeletal muscle.

[0011] Therefore, ClC-1 channel has emerged as a target for potential drugs, but its potential has not been realized to a large extent.US Patent No. 10,385,028 discloses the synthesis of compounds designed to inhibit the action of ClC-1 channel to treat neuromuscular disorders.One of the compounds discussed in US Patent No. 10,385,028 is NMD670.

[0012] U.S. Patent No. 10,385,028 discloses a series of compounds that can inhibit ClC-1 channels to treat neuromuscular disorders, but does not discuss how these compounds can be used to design treatments that can effectively alleviate the wide range of symptoms associated with SMA. WO2020 / 254554 (incorporated herein by reference) discloses methods for producing NMD670.

[0013] Thus, there is a need for safe and effective therapies to improve muscle function in patients with all forms of SMA, including those patients receiving SMN1 gene therapy and / or treated with SMN2 upregulation therapy. 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 spinal muscular atrophy 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; The present disclosure further 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 a compound that increases the amount of functional SMN protein produced by SMN2. [Brief explanation of the drawings]

[0015] [Figure 1] Compound muscle action potential (CMAP) recordings are shown from 67-day-old SMA (Delta-7) animals. Mice were treated with a morpholino ASO directed against ISS-N1 to increase full-length SMN protein production from SMN2 at postnatal day 2 to ensure survival to approximately 90 days. CMAP recordings were obtained from the triceps surae muscle and evoked by electrical stimulation of the sciatic nerve at 50 Hz for 10 stimuli. Evidence of pre-treatment NMJ defects (left (gray) trace, pre-treatment) can be seen from the progressive decrease in CMAP amplitude with repeated stimulation of the innervating nerve (see Methods). After treatment with a ClC-1 inhibitor, amplitude was similar for all 10 stimuli with only a slight decrease (right (black) trace), indicating improved neuromuscular transmission. [Figure 2] The mean level of CMAP amplitude reduction from the first to tenth nerve stimulations when evoked at frequencies ranging from 10 to 50 Hz (as in Figure 1) is shown. Pretreatment (gray squares) and posttreatment with ClC-1 inhibitors (black triangles) are shown. The relative amplitude from the tenth stimulation to the first stimulation is shown as a reduction, with more negative values ​​indicating a greater deficit / reduction, indicating a greater neuromuscular transmission disorder from the nerve to the muscle. The reduction was not significant at all frequencies in all animals, but was statistically significantly different between pretreatment and treated animals only from 20 to 50 Hz, but not at 10 Hz. [Figure 3]Figure 1 shows the latency to fall (seconds) in 9-week-old SMA (Delta-7 mice) animals treated with a morpholino ASO directed against ISS-N1 to increase full-length SMN protein production from SMN2 on postnatal day 2, before (gray bars) and after (black bars) treatment with a ClC-1 inhibitor. All animals were able to stay on the rotorod longer after treatment. [Figure 4] Figure 1 shows the study design for a double-blind, placebo-controlled, two-arm crossover study of ambulatory male and female participants diagnosed with SMA type 3 with neuromuscular junction (NMJ) defects. Abbreviations: BL = baseline; EOS = end of study; EOT = end of treatment; R = randomization; V = visit. [Figure 5A] Figure 1 shows the schedule of activities during the clinical trial. Abbreviations: 6MWT = 6-minute walk test; AE = adverse event; bid = twice-daily dosing; CMAP = compound muscle action potential; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ESNHPT = endurance shuttle 9-hole peg test; FSS = Fatigue Severity Scale; HIV = human immunodeficiency virus; INQoL = individualized neuromuscular quality of life; MFM-32 = motor function index 32; PK = pharmacokinetics; qd = once-daily dosing; RNS = repetitive nerve stimulation; SAE = serious adverse event; sfEMG = single-fiber electromyography; SMA = spinal muscular atrophy; V = visit; WOCBP = women of childbearing potential. [Figure 5B] Figure 1 shows the schedule of activities during the clinical trial. Abbreviations: 6MWT = 6-minute walk test; AE = adverse event; bid = twice-daily dosing; CMAP = compound muscle action potential; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ESNHPT = endurance shuttle 9-hole peg test; FSS = Fatigue Severity Scale; HIV = human immunodeficiency virus; INQoL = individualized neuromuscular quality of life; MFM-32 = motor function index 32; PK = pharmacokinetics; qd = once-daily dosing; RNS = repetitive nerve stimulation; SAE = serious adverse event; sfEMG = single-fiber electromyography; SMA = spinal muscular atrophy; V = visit; WOCBP = women of childbearing potential. DETAILED DESCRIPTION OF THE INVENTION

[0016] Note When possible, assessments will be performed in the order shown in the table unless otherwise specified. When possible, the 6MWT will be performed 2 hours after the afternoon dose. Visit 6, the day before the start of Treatment Period 2, occurs after a 6 (±1) day washout period after Visit 5, so the intertreatment period between the last day of Treatment Period 1 and the first day of Treatment Period 2 is 7 (±1) days. During each treatment period, participants will be contacted by telephone on days 7 and 14 of treatment. When possible, RNS assessment will be performed after ensuring other eligibility criteria are met to avoid unnecessary testing.

[0017] definition All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0018] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0019] The term "patient" or "subject" refers to a human (e.g., male or female human) who has been diagnosed with spinal muscular atrophy (SMA). A consensus statement on the diagnosis of children with SMA was first developed (Wang et al., 2007) and later updated (Mercuri et al., 2018). Confirmation of the diagnosis can be performed by genetic testing (i.e., homozygous deletion of the survival of motor neurons 1 gene [SMN1]).

[0020] The term "improvement" refers to a reduction in the symptoms of spinal muscular atrophy (SMA) symptoms in a patient when the patient is administered a composition described herein. The improvement can be a reduction in the patient's SMA symptoms after the patient is administered a composition described herein compared to before administration of the composition. The term "improvement" can also refer to a reduction in the SMA symptoms in a group of patients after the group of patients is administered a composition described herein, as assessed, for example, based on comparative test scores between a group of patients administered a composition described herein and a control group receiving, for example, a placebo. Improvement in SMA symptoms may be determined, for example, as an increase in total distance walked during a 6-minute walk test; an increase in muscle strength as determined by measuring grip strength, elbow flexor / extensor strength, knee flexor strength, and / or shoulder abduction strength using a handheld dynamometer; an increase in the Revised Hammersmith Scale score; improved endurance in the Endurance Shuttle 9-Hole Peg Test; a reduction in dropout rates in the Endurance Shuttle 9-Hole Peg Test; a reduction in fatigue as determined using a fatigue index calculated from the 6-minute walk test; an increase in the Motor Function Index 32-item score; a decrease in the Fatigue Severity Scale score; a decrease in the Individualized Neuromuscular Quality of Life score; a reduction in jitter; a reduction in blocking; an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Examination score; an increase in the Hammersmith Functional Motor Scale score; an increase in the Extended Hammersmith Functional Motor Scale score; an increase in the Hammersmith Infant Neurological Examination score; an increase in the PedsQL Neuromuscular Model score; an increase in the Patient-Reported Outcomes Measurement Information System score; an increase in the Revised Upper Limb Module score; and / or an increase in the WHO Multicenter Growth Reference Study score. In an exemplary embodiment, improvement in SMA symptoms includes an increase in total distance walked during a 6-minute walk test.

[0021] The term "jitter" refers to the variability in arrival times of muscle fiber action potentials at the recording electrode between successive discharges when single fiber electromyography (sfEMG) is used to measure neuromuscular function.

[0022] The term "blocking" refers to the complete failure of NMJ transmission of muscle fiber action potentials to the recording electrode between successive discharges when sfEMG is used to measure neuromuscular function.

[0023] The term "placebo" refers to a dosage form that possesses no therapeutic activity.

[0024] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0025] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" are used interchangeably and may refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used in formulating a pharmaceutical product.

[0026] The term "pharmaceutical composition" refers to a preparation in which 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 will be administered.

[0027] The term "pharmaceutically acceptable" refers to the attributes of a substance that is generally safe, non-toxic, not biologically or otherwise undesirable, and useful in preparing pharmaceutical compositions that are acceptable for veterinary and human pharmaceutical use.

[0028] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffering or acidifying agents, excipients, stabilizers, or preservatives.

[0029] The term "solid dosage form release" refers to the amount of compound released or dissolved into solution after a specified period of time when using 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.

[0030] The term “C max (expressed in units of ng / mL) refers to the maximum observed plasma concentration of NMD670. max " is an individual C max means the arithmetic mean of the values.

[0031] "T max ” (time unit or T in the study population) max (expressed as the median number of hours after drug administration) max If it occurs at multiple time points, T max is defined as the first time point with this value.

[0032] The term "dose" refers to the dose of NMD670 as the free acid given to a subject. The term "dose" can also include NMD670 in combination with a pharmaceutically acceptable salt.

[0033] The term "therapeutically effective dose," as used herein, refers to the amount of NMD670 required to elicit a therapeutic response in a subject. The terms "therapeutically effective dose" and "therapeutic dose" are used interchangeably herein.

[0034] A composition comprising a (therapeutic) dose can be administered in one or more unit dosage forms. As used herein, "unit dosage form" refers to a physically separate unit suitable for human and animal subjects. Each unit dosage contains a predetermined amount of a therapeutically active compound, optionally associated 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, for example, in blister packs, as is known in the art. Unit dosage forms can be administered in fractions or multiples thereof.

[0035] The term “T 1 / 2" (expressed in units of hours) refers to the terminal elimination half-life of NMD670 in plasma.

[0036] The term “AUC 0-無限大 ” (expressed in units of h ng / mL) means 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. The term “mean AUC 0-無限大 ” is the individual AUC 0-無限大 means the arithmetic mean of the values.

[0037] The term “AUC 0-24時間 ” (expressed in units of h ng / mL) means 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. The term “mean AUC 0-24時間 ” is the individual AUC 0~24時間 means the arithmetic mean of the values.

[0038] As used within the disclosure that follows, the term "NMD670" refers to (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, in addition to any pharmaceutically acceptable salts, hydrates, polymorphs, tautomers, or solvates thereof.

[0039] (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):

[0040] [ka]

[0041] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0042] Detailed Description Previous preclinical and clinical studies have shown that NMJ transmission defects are evident in animal models of SMA (Kong et al., 2009; Foust et al., 2010) and in patients with SMA (Wadman et al., 2012; Pera et al., 2017; Arnold et al., 2021). In particular, the 6-minute walk test (6MWT) can identify fatigue in ambulatory type 3 patients with concurrent neuromuscular junction dysfunction (Pera et al., 2017), and this dysfunction remains evident even after patients are treated with the SMN-upregulating therapy nusinersen (Arnold et al., 2021).

[0043] Herein, we demonstrate that after administration of a ClC-1 inhibitor in a mouse model of SMA (Foust et al, 2010), the decline was surprisingly improved (75% improvement at 50 Hz), and that this improvement in decline was associated with improved running distance.

[0044] The inventors have been able to develop compositions for use in, and methods for treating, SMA as described herein. Illustrative embodiments of these compositions and methods are provided below. The compositions and methods described herein are not intended to be limited to the following illustrative embodiments.

[0045] Compositions for use One embodiment of the present disclosure relates to a composition for use in a method for treating spinal muscular atrophy in a subject, the method 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 therapeutically effective dose for treating spinal muscular atrophy is in the range of 100 mg to 1500 mg.

[0046] 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 for treating spinal muscular atrophy 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.

[0047] 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.

[0048] In exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, at least 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, or at least 1450 mg.

[0049] In 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, e.g., about 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, e.g., about 1200 mg. In exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is about 100 mg. In exemplary embodiments, the therapeutically effective dose of NMD670 administered to a patient is about 150 mg. In exemplary embodiments, 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.

[0050] 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.

[0051] In an exemplary embodiment, the therapeutic dose is administered once daily, i.e., 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 about 100 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 150 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 200 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 250 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 300 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 350 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 400 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 500 mg and is administered once daily. In an exemplary embodiment, the therapeutic dose is about 600 mg and is administered once daily.

[0052] In an exemplary embodiment, the therapeutic dose is administered twice daily, i.e., 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 about 100 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 150 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 200 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 250 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 300 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 350 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 400 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 500 mg and is administered twice daily. In an exemplary embodiment, the therapeutic dose is about 600 mg and is administered twice daily.

[0053] In an exemplary embodiment, the therapeutic dose is administered three times daily, i.e., 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 about 100 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 150 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 200 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 250 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 300 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 350 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 400 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 500 mg and is administered three times daily. In an exemplary embodiment, the therapeutic dose is about 600 mg and is administered three times daily.

[0054] The composition containing the therapeutic dose can be administered in one or more unit dosage forms. For example, a 400 mg therapeutic dose can 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.

[0055] In an exemplary embodiment, the therapeutic dose is a total daily dosage.

[0056] In an exemplary embodiment, the composition for use is administered orally. In an exemplary embodiment, the composition for use is a solid dosage form. In an exemplary embodiment, the solid dosage form is administered orally. In an exemplary embodiment, the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, slow-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 with paddles at 75 rpm.

[0057] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, with a mean C max is 12,760 to 27,440 ng / mL, such as 15,000 to 25,000 ng / mL, for example, 16,000 to 24,000 ng / mL, for example, 16,080 to 25,125 ng / mL, such as 17,000 to 23,000 ng / mL, for example, 18,000 to 22,000 ng / mL, for example, 19,000 to 21,000 ng / mL, for example, about 20,100 ng / mL, 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. In an exemplary embodiment, the mean C max is 20,100 ng / mL, and the standard deviation is 7,340 ng / mL.

[0058] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, with a mean C max is about 80% to about 125%, e.g., 80.00% to 125.00%, of 20,100 ng / mL 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.

[0059] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, comprising a mean AUC 0-無限大 is 66,300 to 109,100 h·ng / mL, for example, 70,000 to 105,000 h·ng / mL, for example, 70,160 to 109,625 h·ng / mL, for example, 75,000 to 100,000 h·ng / mL, for example, 80,000 to 95,000 h·ng / mL, for example, 85,000 to 90,000 h·ng / mL, for example, about 87,700 h·ng / mL, 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. In an exemplary embodiment, the mean AUC 0-無限大 is 87,700 ng / mL, with a standard deviation of 21,400 ng / mL.

[0060] In an exemplary embodiment, the composition for use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, comprising a mean AUC 0-無限大 is about 80% to about 125%, e.g., 80.00% to 125.00%, of 87,700 h 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.

[0061] In an exemplary embodiment, the composition or use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, that achieves a Tmax of 1000 or more within 1 to 6 hours after administration, for example, about 2 hours after administration. max to reach.

[0062] In an exemplary embodiment, the composition or use is administered orally using a solid dosage form and provides a plasma concentration-time profile of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, that achieves a Tmax of 1.0 within 3 to 7 hours after administration. max to reach.

[0063] In an exemplary embodiment, the AUC 0-24 , AUC 0-無限大 , C max or T max is measured after administration of a single dose to a human subject suffering from spinal muscular atrophy.

[0064] Compositions for use as described herein may be formulated for administration either orally, parenterally, intravenously, via inhalation, topically, enterally, rectally, buccally or as an aerosol.

[0065] In an exemplary embodiment, the composition for use further comprises at least one pharmaceutically acceptable adjuvant and / or excipient. In an exemplary embodiment, the composition for use further 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 for use 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.

[0066] In an exemplary embodiment, the composition for use comprises 10-80 wt %, e.g., 40-65 wt %, e.g., 50-55 wt %, e.g., about 53 wt % (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0067] In an exemplary embodiment, the composition for use comprises 10-80 wt%, for example, 40-65 wt%, for example, 50-60 wt%, for example, 50-55 wt%, for example, 55-60 wt%, for example, about 53 wt%, for example, about 56 wt%, of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0068] In an exemplary embodiment, the composition for use comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; and e. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of a disintegrant in the form of one or more solid dosage forms, wherein the sum of the wt% of the ingredients does not exceed 100 wt%.

[0069] In an exemplary embodiment, the composition for use comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; e. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt %, of a disintegrant; and f. 1 to 10 wt% film coating in the form of one or more solid dosage forms, wherein the sum of the wt% of the ingredients does not exceed 100 wt%.

[0070] In an exemplary embodiment, the composition for use comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25 to 3 wt %, for example, 0.4 to 2.0 wt % magnesium stearate; and f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt% croscarmellose sodium in the form of one or more solid dosage forms, wherein the sum of the wt% of the ingredients does not exceed 100 wt%.

[0071] In an exemplary embodiment, the composition for use is in the form of a solid dosage form, a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25 to 3 wt %, for example, 0.4 to 2.0 wt % magnesium stearate; and f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt% croscarmellose sodium in the form of one or more solid dosage forms, wherein the sum of the wt% of the ingredients does not exceed 100 wt%.

[0072] In an exemplary embodiment, the composition for use comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-55 wt %, for example, about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25 to 3 wt %, for example, 0.4 to 2.0 wt % magnesium stearate; and f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt% croscarmellose sodium g. 1 to 10 wt. % of a film coating composition, such as Opadry White in the form of one or more solid dosage forms comprising or consisting of, provided that the sum of the wt% of the ingredients does not exceed 100 wt%.

[0073] In an exemplary embodiment, the composition for use is in the form of a solid dosage form, a. 10-80 wt %, for example, 40-65 wt %, for example, 50-55 wt %, for example, about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25-3 wt %, e.g., 0.4-2.0 wt % magnesium stearate; f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of croscarmellose sodium; and g. 1 to 10 wt. % of a film coating composition, such as Opadry White in the form of one or more solid dosage forms comprising or consisting of, provided that the sum of the wt% of the ingredients does not exceed 100 wt%.

[0074] In an exemplary embodiment, the subject has a serum uric acid level of less than 6.5 mg / dL.

[0075] In an exemplary embodiment, the subject has been diagnosed with SMA. In an exemplary embodiment, the subject has a deletion or mutation in each survival motor neuron 1 (SMN1) allele. In an exemplary embodiment, the subject is homozygous for the SMN1 gene mutation.

[0076] In an exemplary embodiment, the subject has been diagnosed with SMA type 0. In an exemplary embodiment, the subject has been diagnosed with SMA type 0 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production. In an exemplary embodiment, the subject has been diagnosed with SMA type 0 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production, and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2. In an exemplary embodiment, the subject has been diagnosed with SMA type 0 and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2.

[0077] In an exemplary embodiment, the subject has been diagnosed with SMA type 1. In an exemplary embodiment, the subject has been diagnosed with SMA type 1 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene that results in increased SMN protein. In an exemplary embodiment, the subject has been diagnosed with SMA type 1 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene that results in increased SMN protein production, and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2. In an exemplary embodiment, the subject has been diagnosed with SMA type 1 and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2.

[0078] In an exemplary embodiment, the subject has been diagnosed with SMA type 2. In an exemplary embodiment, the subject has been diagnosed with SMA type 2 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production. In an exemplary embodiment, the subject has been diagnosed with SMA type 2 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production, and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2. In an exemplary embodiment, the subject has been diagnosed with SMA type 2 and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2.

[0079] In an exemplary embodiment, the subject has been diagnosed with SMA type 3. In an exemplary embodiment, the subject has been diagnosed with SMA type 3 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production. In an exemplary embodiment, the subject has been diagnosed with SMA type 3 and is receiving gene therapy (e.g., onasemnogene abeparvovec-xioi) to provide an alternative source of the SMN1 gene, resulting in increased SMN protein production, and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2. In an exemplary embodiment, the subject has been diagnosed with SMA type 3 and is treated with a therapy (e.g., nusinersen and / or risdiplam) that increases the amount of functional SMN protein produced by SMN2.

[0080] In an exemplary embodiment, the subject has been diagnosed with SMA type 4. In an exemplary embodiment, the subject has been diagnosed with SMA type 4 and is treated with a therapy that increases the amount of functional SMN protein produced by SMN2 (e.g., nusinersen and / or risdiplam).

[0081] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 once daily. It relates to a composition.

[0082] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 once daily. It relates to a composition.

[0083] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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. It relates to a composition.

[0084] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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. It relates to a composition.

[0085] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 three times daily. It relates to a composition.

[0086] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 three times daily. It relates to a composition.

[0087] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 four times daily. It relates to a composition.

[0088] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 four times daily. It relates to a composition.

[0089] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 once daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0090] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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. It relates to a composition.

[0091] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 three times daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0092] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 four times daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0093] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 once daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0094] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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. It relates to a composition.

[0095] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 three times daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0096] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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 four times daily; The composition is in the form of a solid dosage form and is administered orally. It relates to a composition.

[0097] In an exemplary embodiment, the subject experiences a reduction in the symptoms of spinal muscular atrophy.

[0098] In an exemplary embodiment, a subject or group of subjects experiences an increase in total distance walked after treatment with NMD670. The increase in total distance walked can be determined using a 6-minute walk test (ATS, 2002). In an exemplary embodiment, the increase in total distance walked can be determined by comparing the change from baseline in total distance walked after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in total distance walked after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in total distance walked as determined using a 6-minute walk test after treatment with NMD670. In an exemplary embodiment, a subject or group of subjects experiences an increase in total distance walked as determined using a 6 minute walk test after treatment with NMD670, wherein the total distance walked 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 5% and 400%, for example, between 5% and 200%, for example, between 10% and 200%. In an exemplary embodiment, a subject or group of subjects experiences an increase in total distance walked as determined using a 6 minute walk test after treatment with NMD670, wherein the total distance walked is increased by at least 20 meters, such as at least 30 meters, for example, at least 40 meters, for example, at least 50 meters, for example, at least 60 meters, for example, at least 80 meters, for example, at least 100 meters, for example, at least 150 meters, for example, at least 200 meters, for example, at least 250 meters, for example, at least 300 meters, for example, 20 to 400 meters, for example, 30 to 300 meters, for example, 40 to 200 meters.

[0099] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in total distance walked as determined using the 6-minute walk test, It relates to a composition.

[0100] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in total distance walked as determined using the 6-minute walk test, It relates to a composition.

[0101] In exemplary embodiments, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670. Grip strength is one indicator of muscle strength and can be used to determine the maximum force / tension generated by forearm muscles. Grip strength can be used as a screening tool for measuring upper body strength and whole body strength. In exemplary embodiments, an increase in muscle strength can also be determined by measuring the strength of the thigh (knee flexors), upper arm (elbow flexors and elbow extensors), and / or shoulder (shoulder abductors). In exemplary embodiments, 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 (Febrer et al., 2010; Merlini et al., 2002). In exemplary embodiments, an 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 of 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 10% and 400%, for example, between 15% and 200%, for example, between 20% and 100%. In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, as determined by measuring muscle strength using a handheld dynamometer, wherein 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 10% and 400%, for example, between 15% and 200%, for example, between 20% and 100%.

[0102] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in muscle strength, It relates to a composition.

[0103] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in muscle strength, It relates to a composition.

[0104] 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, wherein 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 0.25-5.0 kg, for example, 0.25-4.0 kg, for example, 0.5-4.0 kg.

[0105] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670 as determined by measuring knee flexor strength using a handheld dynamometer, and 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, for example, at least 5.0 kg, for example, at least 7.5 kg, such as, for example, 0.25 to 15.0 kg, for example, 0.25 to 10.0 kg, for example, 0.5 to 5.0 kg.

[0106] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670 as determined by measuring elbow flexor strength using a handheld dynamometer, and 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.

[0107] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in muscle strength as determined by measuring muscle strength using a handheld dynamometer, It relates to a composition.

[0108] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in muscle strength as determined by measuring muscle strength using a handheld dynamometer, It relates to a composition.

[0109] In exemplary embodiments, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670. In exemplary embodiments, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, as determined by measuring muscle strength using a stationary dynamometer (e.g., an isokinetic dynamometer) (Anders et al., 2012; Harbo et al., 2012). In exemplary embodiments, 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 an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, as determined by measuring muscle strength using a stationary dynamometer, wherein 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 10% and 400%, for example, between 15% and 200%, for example, between 20% and 100%.

[0110] In an exemplary embodiment, a subject or group of subjects experiences an increase in muscle strength after treatment with NMD670, as determined by measuring ankle dorsiflexion muscle strength using a stationary dynamometer, wherein ankle dorsiflexion 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, for example, 0.25-5.0 kg, for example, 0.25-4.0 kg, for example, 0.5-4.0 kg.

[0111] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in isometric muscle strength as determined by measuring muscle strength using a stationary dynamometer, It relates to a composition.

[0112] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in isometric muscle strength as determined by measuring muscle strength using a stationary dynamometer, It relates to a composition.

[0113] In an exemplary embodiment, a subject or group of subjects experiences an increase in modified Hammersmith Scale score after treatment with NMD670 (Ramsey et al., 2017). In an exemplary embodiment, the increase in modified Hammersmith Scale score can be determined by comparing the change from baseline in modified Hammersmith Scale score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in modified Hammersmith Scale score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, the subject or group of subjects experiences an increase in their Modified Hammersmith Scale score after treatment with NMD670, wherein the score increases 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 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0114] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in their Revised Hammersmith Scale score, It relates to a composition.

[0115] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in their Revised Hammersmith Scale score, It relates to a composition.

[0116] In an exemplary embodiment, a subject or group of subjects experiences improved endurance after treatment with NMD670. In an exemplary embodiment, a subject experiences improved endurance after treatment with NMD670, as determined using the Endurance Shuttle 9-Hole Peg Test (Bartels et al., 2019; Bartels et al., 2020). In an exemplary embodiment, improved endurance can be determined by comparing the change from baseline in the Endurance Shuttle 9-Hole Peg Test after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in the Endurance Shuttle 9-Hole Peg Test after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences improved endurance following treatment with NMD670 as determined using an endurance shuttle 9-hole peg test, wherein endurance 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 5% and 400%, for example, between 10% and 300%, for example, between 10% and 200%.

[0117] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an improvement in endurance as determined using the endurance shuttle 9-hole peg test, It relates to a composition.

[0118] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an improvement in endurance as determined using the endurance shuttle 9-hole peg test, It relates to a composition.

[0119] In an exemplary embodiment, a subject or group of subjects experiences a reduction in dropout rate in the Endurance Shuttle 9-Hole Peg Test after treatment with NMD670 (Bartels et al., 2020). In an exemplary embodiment, the reduction in dropout rate can be determined by comparing the change from baseline in dropout rate in the Endurance Shuttle 9-Hole Peg Test after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in dropout rate in the Endurance Shuttle 9-Hole Peg Test after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences a reduction in dropout rate in the endurance shuttle 9-hole peg test after treatment with NMD670, wherein the dropout rate 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, such as between 5% and 100%, for example, between 10% and 80%, for example, between 5% and 60%.

[0120] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a reduced dropout rate in the endurance shuttle 9-hole peg test. It relates to a composition.

[0121] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a reduced dropout rate in the endurance shuttle 9-hole peg test. It relates to a composition.

[0122] In an exemplary embodiment, a subject or group of subjects experiences a reduction in fatigue after treatment with NMD670, as determined using a fatigue index. The fatigue index is calculated from the distance walked at the first minute to the distance walked at the sixth minute of a six-minute walk test. In an exemplary embodiment, the reduction in fatigue can be determined by comparing the change from baseline in the fatigue index after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in the fatigue index after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences a reduction in fatigue after treatment with NMD670 as determined using a fatigue index, wherein fatigue 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, between 5% and 95%, for example, between 5% and 80%, for example, between 10% and 50%.

[0123] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a reduction in fatigue as determined using a fatigue index. It relates to a composition.

[0124] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a reduction in fatigue as determined using a fatigue index. It relates to a composition.

[0125] In an exemplary embodiment, a subject or group of subjects experiences an increase in the 32-item Motor Function Index score after treatment with NMD670 (Vuillerot et al. 2013). In an exemplary embodiment, the increase in the 32-item Motor Function Index score can be determined by comparing the change from baseline in the 32-item Motor Function Index score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in the 32-item Motor Function Index score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in the 32-item motor function index score after treatment with NMD670, wherein the score increases 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, between 5% and 95%, for example, between 5% and 80%, for example, between 10% and 50%.

[0126] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; Subjects will experience an increase in scores on 32 motor function indexes. It relates to a composition.

[0127] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; Subjects will experience an increase in scores on 32 motor function indexes. It relates to a composition.

[0128] In an exemplary embodiment, a subject or group of subjects experiences a decrease in fatigue severity scale score after treatment with NMD670 (Kizina et al., 2020). 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 defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in fatigue severity scale score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences a reduction in Fatigue Severity Scale score after treatment with NMD670, wherein the score is reduced by 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0129] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a decrease in fatigue severity scale score. It relates to a composition.

[0130] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a decrease in fatigue severity scale score. It relates to a composition.

[0131] In an exemplary embodiment, a subject or group of subjects experiences a decrease in personalized neuromuscular quality of life score after treatment with NMD670 (Vincent et al. 2007). In an exemplary embodiment, the decrease in personalized neuromuscular quality of life score can be determined by comparing the change from baseline in personalized neuromuscular quality of life score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in personalized neuromuscular quality of life score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences a decrease in their individualized neuromuscular quality of life score after treatment with NMD670, wherein the score is reduced by 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0132] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a decrease in an individualized neuromuscular quality of life score. It relates to a composition.

[0133] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences a decrease in an individualized neuromuscular quality of life score. It relates to a composition.

[0134] In an exemplary embodiment, a subject or group of subjects experiences a reduction in jitter after treatment with NMD670. In an exemplary embodiment, a subject or group of subjects experiences a reduction in jitter after treatment with NMD670, as determined using single-fiber electromyography (Sanders et al., 2019). 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 an exemplary embodiment, a subject or group of subjects experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein jitter is reduced by at least 10%, such as at least 15%, 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%. In an exemplary embodiment, a subject or group of subjects experiences a reduction in jitter after treatment with NMD670 as determined using single fiber electromyography, wherein jitter is reduced by at least 5 μs, such as at least 10 μs, for example, at least 15 μs, for example, at least 20 μs, such as at least 25 μs, for example, 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, such as between 5 μs and 200 μs, for example, between 5 μs and 100 μs, for example, between 10 μs and 50 μs.

[0135] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences a reduction in jitter as determined using single fiber electromyography; It relates to a composition.

[0136] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences a reduction in jitter as determined using single fiber electromyography; It relates to a composition.

[0137] In an exemplary embodiment, a subject or group of subjects experiences a reduction in blocking after treatment with NMD670. In an exemplary embodiment, a subject or group of subjects experiences a reduction in blocking after treatment with NMD670, as determined using single-fiber electromyography (Sanders et al., 2019). In an exemplary embodiment, the reduction in blocking can be determined by comparing the change from baseline in blocking after a defined time (e.g., 21 days) of NMD670 treatment with the change from baseline in blocking after the same defined time (e.g., 21 days) of placebo treatment. In exemplary embodiments, a subject or group of subjects experiences a reduction in blocking after treatment with NMD670 as determined using single fiber electromyography, wherein the blocking 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%.

[0138] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences a reduction in blocking as determined using single fiber electromyography; It relates to a composition.

[0139] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences a reduction in blocking as determined using single fiber electromyography; It relates to a composition.

[0140] In an exemplary embodiment, a subject or group of subjects experiences an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Trial (CHOP INTEND) score after treatment with NMD670 (Glanzman et al., 2010). In an exemplary embodiment, the increase in CHOP INTEND score can be determined by comparing the change from baseline in CHOP INTEND score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in CHOP INTEND score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in CHOP INTEND score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0141] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Examination score, It relates to a composition.

[0142] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Examination score, It relates to a composition.

[0143] In an exemplary embodiment, a subject or group of subjects experiences an increase in Hammersmith Functional Motor Scale (HFMS) score after treatment with NMD670 (Main et al., 2003). In an exemplary embodiment, the increase in HFMS score can be determined by comparing the change from baseline in HFMS score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in HFMS score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in HFMS score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0144] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in Hammersmith Functional Motor Scale score. It relates to a composition.

[0145] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in Hammersmith Functional Motor Scale score. It relates to a composition.

[0146] In an exemplary embodiment, a subject or group of subjects experiences an increase in Hammersmith Functional Motor Scale-Extended (HFMSE) score after treatment with NMD670 (O'Hagen et al., 2007). In an exemplary embodiment, the increase in HFMSE score can be determined by comparing the change from baseline in HFMSE score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in HFMSE score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in HFMSE score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0147] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in the Extended Hammersmith Functional Motor Scale score. It relates to a composition.

[0148] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in the Extended Hammersmith Functional Motor Scale score. It relates to a composition.

[0149] In an exemplary embodiment, a subject or group of subjects experiences an increase in Hammersmith Infant Neurological Examination (HINE) score after treatment with NMD670 (De Sanctis et al., 2016). In an exemplary embodiment, the increase in HINE score can be determined by comparing the change from baseline in HINE score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in HINE score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in HINE score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0150] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in Hammersmith Infant Neurological Examination score, It relates to a composition.

[0151] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; the subject experiences an increase in Hammersmith Infant Neurological Examination score, It relates to a composition.

[0152] In an exemplary embodiment, a subject or group of subjects experiences an increase in PedsQL neuromuscular model score after treatment with NMD670 (Mapi Research Trust, Lyon, France). In an exemplary embodiment, the increase in PedsQL neuromuscular model score can be determined by comparing the change from baseline in PedsQL neuromuscular model score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in PedsQL neuromuscular model score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in PedsQL neuromuscular model score after treatment with NMD670, wherein the score increases 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 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0153] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in PedsQL neuromuscular model score. It relates to a composition.

[0154] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in PedsQL neuromuscular model score. It relates to a composition.

[0155] In an exemplary embodiment, a subject or group of subjects experiences an increase in Patient-Reported Outcomes Measurement Information System (PROMIS) score after treatment with NMD670 (Rodday et al., 2017). In an exemplary embodiment, the increase in PROMIS score can be determined by comparing the change from baseline in PROMIS score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in PROMIS score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in PROMIS score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0156] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; Subjects experience an increase in Patient-Reported Outcomes Measurement Information System scores, It relates to a composition.

[0157] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; Subjects experience an increase in Patient-Reported Outcomes Measurement Information System scores, It relates to a composition.

[0158] In an exemplary embodiment, a subject or group of subjects experiences an increase in the Revised Upper Limb Module (RULM) score after treatment with NMD670 (Mazzone et al., 2016). In an exemplary embodiment, the increase in RULM score can be determined by comparing the change from baseline in RULM score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in RULM score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in RULM score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0159] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in the revised upper extremity module score, It relates to a composition.

[0160] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in the revised upper extremity module score, It relates to a composition.

[0161] In an exemplary embodiment, a subject or group of subjects experiences an increase in WHO Multicenter Growth Reference Study (MGRS) score after treatment with NMD670 (WHO, 2006). In an exemplary embodiment, the increase in MGRS score can be determined by comparing the change from baseline in MGRS score after a defined period (e.g., 21 days) of NMD670 treatment with the change from baseline in MGRS score after a defined period (e.g., 21 days) of placebo treatment. In an exemplary embodiment, a subject or group of subjects experiences an increase in MGRS score after treatment with NMD670, wherein the score increases by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points, such as 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0162] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in WHO Multicenter Growth Reference Study score, It relates to a composition.

[0163] In an exemplary embodiment, the disclosure provides 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 spinal muscular atrophy in a subject, the method comprising: 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; The subject experiences an increase in WHO Multicenter Growth Reference Study score, It relates to a composition.

[0164] 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 spinal muscular atrophy in a subject, wherein the subject has a serum uric acid level of less than 6.5 mg / dL. In an exemplary embodiment, the composition for use is for administration at a therapeutic dose as defined herein. In an exemplary embodiment, the composition for use is for administration at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0165] In one aspect, the disclosure relates to the use of a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, in the manufacture of a medicament for the treatment of spinal muscular atrophy 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.

[0166] In one aspect, the disclosure 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, for use in a method of treating spinal muscular atrophy in a subject, wherein the (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid is for administration at a therapeutic dose of 100 to 1500 mg.

[0167] Pharmaceutical Compositions Another aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 for use in treating or ameliorating symptoms of spinal muscular atrophy in patients suffering from spinal muscular atrophy. A further aspect of the present disclosure relates to a composition comprising a therapeutically effective dose of NMD670 in treating or ameliorating symptoms of spinal muscular atrophy in patients suffering from spinal muscular atrophy. All of the following exemplary embodiments of the composition may be used in the methods of treatment described herein.

[0168] In one aspect, 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. 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 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, formulated as a solid dosage form, wherein the composition comprises 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. In one embodiment, (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 the only active pharmaceutical ingredient of the composition.

[0169] 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.

[0170] In an exemplary embodiment, the composition comprises 10-80 wt %, e.g., 40-65 wt %, e.g., 50-55 wt %, e.g., about 53 wt % (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 10-80 wt%, e.g., 40-65 wt%, e.g., 50-60 wt%, e.g., 50-55 wt%, e.g., 55-60 wt%, e.g., about 53 wt%, e.g., about 56 wt%, of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0171] In an exemplary embodiment, the composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; and e. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of a disintegrant However, the total wt% of the components does not exceed 100 wt%.

[0172] In an exemplary embodiment, the composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; e. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt %, of a disintegrant; and f. 1 to 10 wt% film coating However, the total wt% of the components does not exceed 100 wt%.

[0173] In an exemplary embodiment, the composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25 to 3 wt %, for example, 0.4 to 2.0 wt % magnesium stearate; and f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt% croscarmellose sodium However, the total wt% of the components does not exceed 100 wt%.

[0174] In an exemplary embodiment, the composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-55 wt %, for example, about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1 to 15 wt %, for example, 1.5 to 7 wt %, for example, 1.8 to 6.0 wt % maltodextrin; and e. 0.25-3 wt %, e.g., 0.4-2.0 wt % magnesium stearate; f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of croscarmellose sodium; and g. 1 to 10 wt. % of a film coating composition, such as Opadry White comprising or consisting of, provided that the sum of the wt% of the components does not exceed 100 wt%.

[0175] In an exemplary embodiment, the 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.

[0176] In an exemplary embodiment, the disclosure provides 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. The present invention relates to a composition. 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 given once per given day. In an exemplary embodiment, the therapeutically effective dose is given twice per given day. In an exemplary embodiment, the therapeutically effective dose is given three times per given day. In an exemplary embodiment, the therapeutically effective dose is given four times per given day.

[0177] In an exemplary embodiment, the present disclosure relates to a composition formulated as a solid dosage form comprising 50 mg to 400 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an exemplary embodiment, the solid dosage form comprises 100 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 150 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 200 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 250 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 300 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 350 mg of NMD670. In an exemplary embodiment, the solid dosage form comprises 400 mg of NMD670.

[0178] In an exemplary embodiment, the composition is a solid dosage form. In an exemplary embodiment, the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, slow-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 with paddles at 75 rpm.

[0179] method In one aspect, the disclosure relates to a method of treating spinal muscular atrophy in a subject, the method 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.

[0180] In an exemplary embodiment, a method for treating a patient suffering from symptoms of spinal muscular atrophy includes improving muscle strength (increase may be determined by measuring grip strength, elbow flexor / extensor strength, knee flexor strength, and / or shoulder abduction strength using a handheld dynamometer), improving endurance (improvement is determined as an increase in the time before failure in the Endurance Shuttle 9-Hole Peg Test or a decrease in failure rate in the Endurance Shuttle 9-Hole Peg Test), reducing fatigue (reduction is a decrease in fatigue index), improving neuromuscular junction transmission (improvement is determined as an increase in the time before failure in the Endurance Shuttle 9-Hole Peg Test ... may result in a reduction in jitter and / or blocking as measured using fEMG), an increase in the Motor Function Index 32-item score, a decrease in the Fatigue Severity Scale score, a decrease in the Individualized Neuromuscular Quality of Life score, an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Examination score, an increase in the Hammersmith Functional Motor Scale score, an increase in the Extended Hammersmith Functional Motor Scale score, an increase in the Hammersmith Infant Neurological Examination score, an increase in the PedsQL Neuromuscular Model score, an increase in the Patient-Reported Outcomes Measurement Information System score, an increase in the Revised Upper Extremity Module score, and / or an increase in the WHO Multicenter Growth Reference Study score.

[0181] Accordingly, one embodiment of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in total distance walked 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. The increase in total distance walked can be determined using the 6-minute walk test (ATS, 2002).

[0182] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in increased muscle strength, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. Increased muscle strength can be determined by measuring the strength of the thigh (knee flexors), upper arm (elbow flexors and elbow extensors), and / or shoulder (shoulder abduction) or by measuring muscle strength using a handheld dynamometer (Febrer et al., 2010; Merlini et al., 2002).

[0183] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in the modified Hammersmith 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 modified Hammersmith Scale score improvement is an increase in the score (Ramsey et al., 2017).

[0184] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in improved endurance, 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 improved endurance can be determined using the endurance shuttle 9-hole peg test (Bartels et al., 2019; Bartels et al., 2020).

[0185] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in a reduction in dropout rate in an endurance shuttle 9-hole peg test, the methods comprising administering to a patient a therapeutically effective dose of NMD670, wherein the therapeutic dose is in the range of 100 mg to 1500 mg. The reduction in dropout rate can be determined using the endurance shuttle 9-hole peg test (Bartels et al., 2020).

[0186] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in reduced fatigue, 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. Reduction in fatigue can be calculated from the distance walked at the first minute to the distance walked at the sixth minute of the 6-minute walk test (ATS, 2002).

[0187] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in the 32-item motor function index 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 32-item motor function index score is an increase in the score (Vuillerot et al., 2013).

[0188] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result 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 (Kizina et al., 2020).

[0189] One embodiment of the present disclosure relates to methods for treating spinal muscular atrophy that result in a reduction in a personalized 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 personalized neuromuscular quality of life score is a reduction in the score (Vincent et al. 2007).

[0190] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in improved neuromuscular junction transmission, 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 improved neuromuscular junction transmission can be a reduction in jitter and / or blocking, and can be determined using single-fiber electromyography (Sanders et al., 2019).

[0191] One embodiment of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in the Children's Hospital of Philadelphia Infant Neuromuscular Disorders Test 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 Children's Hospital of Philadelphia Infant Neuromuscular Disorders Test score is an increase in the score (Glanzman et al., 2010).

[0192] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in an increase in Hammersmith Functional Motor 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 Hammersmith Functional Motor Scale score is an increase in score (Main et al., 2003).

[0193] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in the Extended Hammersmith Functional Motor 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 the Extended Hammersmith Functional Motor Scale score is an increase in the score (O'Hagen et al., 2007).

[0194] One aspect of the present disclosure relates to methods for treating spinal muscular atrophy that result in an increase in Hammersmith Infant Neurological Examination 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 Hammersmith Infant Neurological Examination score is an increase in score (De Sanctis et al., 2016).

[0195] One embodiment of the present disclosure relates to methods for spinal muscular atrophy that result in an increase in PedsQL neuromuscular model 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 PedsQL neuromuscular model score is an increase in the score (Mapi Research Trust, Lyon, France).

[0196] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in an increase in Patient-Reported Outcome Measure Information System 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 Patient-Reported Outcome Measure Information System score is an increase in the score (Rodday et al., 2017).

[0197] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in an increase in the revised Upper Extremity Module 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 revised Upper Extremity Module score is an increase in the score (Mazzone et al., 2016).

[0198] One aspect of the present disclosure relates to methods for spinal muscular atrophy that result in an increase in WHO Multicenter Growth Reference Study 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 WHO Multicenter Growth Reference Study score is an increase in score (WHO, 2006).

[0199] In one aspect, the disclosure relates to a method for treating spinal muscular atrophy 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.

[0200] In one aspect, the disclosure relates to a method for improving recovery of neuromuscular transmission and / or 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, at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0201] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0202] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once daily.

[0203] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0204] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice daily.

[0205] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0206] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered three times daily.

[0207] In an exemplary embodiment, the composition is administered at a therapeutic dose of 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0208] In an exemplary embodiment, the composition is administered at a therapeutic dose of 200 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered four times daily.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] The methods of treatment disclosed herein may further include the administration of additional active agents known to treat, prevent, and / or ameliorate neuromuscular disorders. These additional active agents may be agents for enhancing accurate splicing of SMN2 and / or for enhancing SMN2 splicing.

[0242] Recently approved therapies include antisense oligonucleotides (ASOs) to improve accurate splicing of SMN2 (e.g., nusinersen), gene therapy to provide an alternative source of the SMN1 gene (e.g., onasemnogene abeparvovec-xioi), which typically results in increased SMN protein production in patients by 2 years of age, and small molecules to improve SMN2 splicing (e.g., risdiplam).

[0243] In one aspect, the disclosure relates to a method for treating spinal muscular atrophy, comprising administering to a subject in need thereof (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 antisense oligonucleotide (ASO) for enhancing accurate splicing of SMN2. In one exemplary embodiment, the antisense oligonucleotide (ASO) for enhancing accurate splicing of SMN2 is nusinersen or BIIB115.

[0244] In one aspect, the disclosure relates to a method for treating spinal muscular atrophy, comprising administering to a subject in need thereof (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 a compound for enhancing SMN2 splicing. In one exemplary embodiment, the compound for enhancing SMN2 splicing is risdiplam.

[0245] In one aspect, the present disclosure relates to a method for treating spinal muscular atrophy, 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 a myostatin inhibitor. In one exemplary embodiment, the myostatin inhibitor is apiteglomab. In one exemplary embodiment, the myostatin inhibitor is GYM329. In one exemplary embodiment, the myostatin inhibitor is taldefglobep.

[0246] In some exemplary embodiments, the treatment method comprises administering a therapeutically effective dose of NMD670 with one or more of the following compounds: risdiplam, nusinersen, BIIB115, salbutamol, GYM329, SRK-015, branapram, tirasemtib, reldesemtib, talditercept alfa, taldefglobep alfa, pyridostigmine, RG-6237, apitegromab, amifampridine, nipocalimab, EXG-001307, and / or ACTX-401.

[0247] In exemplary embodiments, the method of treatment comprises administering a therapeutically effective dose of NMD670 and an additional active agent to a patient simultaneously. In other exemplary embodiments, the therapeutically effective dose of NMD670 and the additional active agent are administered to a patient at different times. In some embodiments, the therapeutically effective dose of NMD670 and the additional active agent are administered sequentially.

[0248] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in total distance walked in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein, after administration of a therapeutically effective dose of the compound, the patient experiences an increase in total distance walked as determined using a 6-minute walk test.

[0249] In exemplary embodiments, the patient experiences an increase in total distance walked of 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 5% and 400%, for example, between 5% and 200%, for example, between 10% and 200%. In an exemplary embodiment, the patient experiences an increase in total distance walked of at least 20 meters, such as at least 30 meters, for example, at least 40 meters, for example, at least 50 meters, for example, at least 60 meters, for example, at least 80 meters, for example, at least 100 meters, for example, at least 150 meters, such as at least 200 meters, for example, at least 250 meters, for example, at least 300 meters, for example, from 20 to 400 meters, for example, from 30 to 300 meters, for example, from 40 to 200 meters.

[0250] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in increased muscle strength in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein, after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength as determined using a handheld dynamometer.

[0251] In exemplary embodiments, the patient experiences an increase in muscle strength of 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, from 10% to 400%, for example, from 15% to 200%, for example, from 20% to 100%.

[0252] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in increased muscle strength in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength as determined by measuring grip strength using a handheld dynamometer, and 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.

[0253] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in increased muscle strength in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength as determined by measuring knee flexor strength using a handheld dynamometer, and the knee flexor 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, such as at least 1.75 kg, for example, at least 2.0 kg, such as at least 2.5 kg, for example, at least 3.0 kg, for example, at least 5.0 kg, for example, at least 7.5 kg, such as, for example, 0.25 to 15.0 kg, for example, 0.25 to 10.0 kg, for example, 0.5 to 5.0 kg.

[0254] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in increased muscle strength in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. maxwherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in muscle strength as determined by measuring elbow flexor strength using a handheld dynamometer, and the elbow flexor 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.

[0255] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in the modified Hammersmith Scale score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in the Revised Hammersmith Scale score.

[0256] In an exemplary embodiment, the patient experiences an increase in the Modified Hammersmith Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0257] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in improved endurance in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences improved endurance as determined using the endurance shuttle 9-hole peg test.

[0258] In exemplary embodiments, the patient experiences an improvement in endurance of 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%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, between 5% and 400%, for example, between 10% and 300%, for example, between 10% and 200%.

[0259] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in a reduced dropout rate in an endurance shuttle 9-hole peg test in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences a reduced dropout rate in an endurance shuttle 9-hole peg test.

[0260] In exemplary embodiments, the patient experiences a reduction in dropout rate of 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, between 5% and 100%, for example, between 10% and 80%, for example, between 5% and 60%.

[0261] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in reduced fatigue in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in fatigue as determined using a fatigue index.

[0262] In exemplary embodiments, the patient experiences a reduction in fatigue of 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, between 5% and 95%, for example, between 5% and 80%, for example, between 10% and 50%.

[0263] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in a 32-item motor function index score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in the 32-item motor function index score.

[0264] In an exemplary embodiment, the patient experiences an increase in the 32-item motor function index score of at least 5%, e.g., at least 10%, e.g., at least 15%, e.g., at least 20%, e.g., at least 25%, e.g., at least 30%, e.g., at least 40%, e.g., at least 50%, e.g., at least 60%, e.g., at least 70%, e.g., at least 80%, e.g., 5% to 95%, e.g., 5% to 80%, e.g., 10% to 50%.

[0265] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in a decrease in Fatigue Severity Scale score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in fatigue severity scale score.

[0266] In an exemplary embodiment, the patient experiences a reduction in Fatigue Severity Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0267] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in a reduction in an individualized neuromuscular quality of life score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences a decrease in a personalized neuromuscular quality of life score.

[0268] In an exemplary embodiment, the patient experiences a decrease in their personalized neuromuscular quality of life score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0269] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in a reduction of jitter in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences a reduction in jitter as determined using single fiber electromyography.

[0270] In exemplary embodiments, the patient experiences a reduction in jitter of at least 15%, such as at least 10%, for example, at least 20%, for example, at least 25%, for example, at least 30%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, 5% to 95%, for example, 5% to 80%, for example, 10% to 50%.

[0271] In an exemplary embodiment, the patient experiences a reduction in jitter of at least 5 μs, such as at least 10 μs, for example, at least 15 μs, for example, at least 20 μs, for example, at least 25 μs, for example, at least 30 μs, for example, at least 40 μs, for example, at least 50 μs, for example, at least 75 μs, for example, at least 100 μs, for example, from 5 μs to 200 μs, for example, from 5 μs to 100 μs, for example, from 10 μs to 50 μs.

[0272] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in reduced blocking in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences reduced blocking as determined using single fiber electromyography.

[0273] In exemplary embodiments, the patient experiences a reduction in blocking of at least 10%, such as at least 15%, for example, at least 20%, for example, at least 25%, for example, at least 30%, for example, at least 50%, for example, at least 75%, for example, at least 100%, for example, at least 150%, for example, at least 200%, for example, 5% to 95%, for example, 5% to 80%, for example, 10% to 50%.

[0274] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in the Children's Hospital of Philadelphia Infant Neuromuscular Disorders Examination score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in the Children's Hospital of Philadelphia Infant Neuromuscular Disorders Examination score.

[0275] In an exemplary embodiment, the patient experiences an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Test score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0276] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in Hammersmith Functional Motor Scale score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in Hammersmith Functional Motor Scale score.

[0277] In an exemplary embodiment, the patient experiences an increase in Hammersmith Functional Motor Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0278] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in an Extended Hammersmith Functional Motor Scale score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in Extended Hammersmith Functional Motor Scale score.

[0279] In an exemplary embodiment, the patient experiences an increase in Extended Hammersmith Functional Motor Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0280] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in Hammersmith Infant Neurological Examination score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. maxwherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in Hammersmith Infant Neurological Examination score.

[0281] In an exemplary embodiment, the patient experiences an increase in Hammersmith Infant Neurological Examination score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0282] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in PedsQL neuromuscular model score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in PedsQL neuromuscular model score.

[0283] In an exemplary embodiment, the patient experiences an increase in PedsQL neuromuscular model score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0284] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in Patient-Reported Outcomes Measurement Information System score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in Patient Reported Outcome Measurement Information System score.

[0285] In an exemplary embodiment, the patient experiences an increase in Patient Reported Outcomes Measurement Information System score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0286] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in modified upper extremity module score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. max wherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in revised upper extremity module score.

[0287] In an exemplary embodiment, the patient experiences an increase in the Revised Upper Extremity Module score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0288] In one aspect, the disclosure provides a method of treating spinal muscular atrophy, resulting in an increase in WHO Multicenter Growth Reference Study score in a patient in need thereof, the method comprising administering a therapeutically effective dose of the compound (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]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. maxwherein after administration of a therapeutically effective dose of the compound, the patient experiences an increase in WHO Multicenter Growth Reference Study score.

[0289] In an exemplary embodiment, the patient experiences an increase in WHO Multicenter Growth Reference Study score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0290] In an exemplary embodiment, the therapeutically effective dose of the compound is a dose that produces an AUC in the range of 16,700 ng / mL to 534,000 ng / mL in a patient. inf In an exemplary embodiment, the therapeutically effective dose of the compound is in the range of 1 to 6 hours after administration of the compound. max In an exemplary embodiment, the therapeutically effective dose of the compound has a half-life in a patient ranging from 3 hours to 7 hours. In an exemplary embodiment, the therapeutically effective dose of the compound is administered orally to a patient.

[0291] In an exemplary embodiment, the subject is diagnosed with SMA type 0. In an exemplary embodiment, the subject is diagnosed with SMA type 1. In an exemplary embodiment, the subject is diagnosed with SMA type 2. In an exemplary embodiment, the subject is diagnosed with SMA type 3. In an exemplary embodiment, the subject is diagnosed with SMA type 4.

[0292] 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.

[0293] In one aspect, the disclosure relates to a method for treating a patient suffering from symptoms of spinal muscular atrophy, 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.

[0294] In one aspect, the disclosure relates to the use of a composition comprising (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, in the manufacture of a medicament for the treatment of spinal muscular atrophy 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.

[0295] 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.

[0296] In other exemplary embodiments, the methods of the present disclosure further comprise administering to the patient a third therapeutically effective dose of NMD670 either 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or at least 7 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.

[0297] 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. In other exemplary embodiments, administration is repeated at least 1-3 times weekly, 2-5 times weekly, or 3-6 times weekly.

[0298] In some exemplary embodiments, administration of a therapeutically effective dose of NMD670 is repeated daily. Administration of a therapeutically effective dose of NMD670 can be repeated, for example, 1, 2, 3, 4, 5, 6, 7, or 8 times daily. In other embodiments, administration is repeated 1 to 8 times daily or 2 to 5 times daily.

[0299] 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.

[0300] In other embodiments, a therapeutically effective dose of NMD670 is administered either twice daily, three times daily, or four times daily.

[0301] 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.

[0302] 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.

[0303] In other exemplary embodiments, the therapeutically effective dose of NMD670 is 100-600 mg, 300-500 mg, or about 400 mg administered three times per day. In other exemplary embodiments, the therapeutically effective dose of NMD670 is 200-600 mg, 300-500 mg, or about 400 mg administered three times per day.

[0304] In other exemplary embodiments, the therapeutically effective dose of NMD670 is 100-600 mg, 300-500 mg, or about 400 mg administered four times per day. In other exemplary embodiments, the therapeutically effective dose of NMD670 is 200-600 mg, 300-500 mg, or about 400 mg administered four times per day.

[0305] 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 the day. That is, in some embodiments, the daily dosage of NMD670 is administered either once a day or at least once a day, twice a day or at least two different times throughout the day, or three times a day or at least three different times throughout the day.

[0306] 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 of 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, they may begin receiving a therapeutically effective dose of NMD670.

[0307] Kit of Parts In one aspect, the present disclosure provides a method for producing a medicament for a medicament 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 Compounds that increase the amount of functional SMN protein produced by SMN2 Kit of parts including:

[0308] In an exemplary embodiment, the kit of parts includes 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 compound that increases the amount of functional SMN protein produced by SMN2 is risdiplam. In one embodiment, the compound that increases the amount of functional SMN protein produced by SMN2 is nusinersen. In one embodiment, the compound that increases the amount of functional SMN protein produced by SMN2 is branapram. In one embodiment, the compound that increases the amount of functional SMN protein produced by SMN2 is BIIB115.

[0309] In an exemplary embodiment, the kit-of-parts includes: 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, and 0.2 to 5 mg of risdiplam, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof Includes.

[0310] In an exemplary embodiment, the kit-of-parts includes: 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, and 12 to 60 mg of nusinersen, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof Includes.

[0311] In one embodiment, the kit-of-parts is for use in a method of treating spinal muscular atrophy in a subject.

[0312] In one aspect, the disclosure 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, for use in the treatment of spinal muscular atrophy, and compounds that increase the amount of functional SMN protein produced by SMN2.

[0313] In one aspect, the kit of parts is for use in a method of treating spinal muscular atrophy in a subject. In an exemplary embodiment, the kit of parts is for use in a method of treating spinal muscular atrophy in a subject, wherein the composition is for administration of a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid. In one aspect, the kit of parts is for use in treating spinal muscular atrophy in a subject.

[0314] In one aspect, the disclosure relates to a method for the treatment of spinal muscular atrophy, comprising administering to a subject in need thereof (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 a compound that increases the amount of functional SMN protein produced by SMN2.

[0315] In one aspect, the disclosure 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 a compound that increases the amount of functional SMN protein produced by SMN2, for the manufacture of a medicament for the treatment of spinal muscular atrophy.

[0316] In one aspect, the present disclosure provides a method for producing a medicament for a medicament 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 myostatin inhibitors Kit of parts including:

[0317] In one exemplary embodiment, the myostatin inhibitor is apiteglomab. In one exemplary embodiment, the myostatin inhibitor is GYM329. In one exemplary embodiment, the myostatin inhibitor is taldef globep.

[0318] In another exemplary embodiment, the kit-of-parts comprises a Ca signaling molecule that encodes the Ca signaling molecule of contractile filaments in muscle. 2+ Further included are agents for increasing sensitivity, such as tirasemtib or lerdesemtib.

[0319] In other exemplary embodiments, the kit-of-parts further comprises one or more additional compounds, such as salbutamol, GYM329, SRK-015, talditercept alfa, taldefglobep alfa, pyridostigmine, RG-6237, apitegromab, amifampridine, nipocalimab, EXG-001307, and / or ACTX-401.

[0320] item 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 spinal muscular atrophy 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.

[0321] 2. The composition for use according to item 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, for example less than 1200 mg, such as less than 1150 mg, for example less than 1100 mg, for example less than 1050 mg, such as less than 1000 mg, for example less than 950 mg, such as less than 900 mg, for example less than 850 mg, for example less than 800 mg, such as less than 750 mg, for example less than 700 mg, such as less than 650 mg, for example less than 600 mg, such as 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, for example less than 300 mg, such as less than 250 mg.

[0322] 3. The therapeutic dose may be at least 100 mg, such as at least 150 mg, for example, at least 200 mg, for example, at least 250 mg, for example, at least 300 mg, such as at least 350 mg, for example, at least 400 mg, for example, at least 450 mg, such as at least 500 mg, for example, at least 550 mg, for example, at least 600 mg, for example, at least 650 mg, for example, at least 700 mg, for example, at least 750 mg, for example, at least 800 mg, e.g. The composition for use according to any one of the preceding items, for example, at least 850 mg, such as at least 900 mg, for example, at least 950 mg, for example, at least 1000 mg, such as at least 1050 mg, for example, at least 1100 mg, for example, at least 1150 mg, such as at least 1200 mg, for example, at least 1250 mg, such as at least 1300 mg, for example, at least 1350 mg, such as at least 1400 mg, for example, at least 1450 mg.

[0323] 4. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg, for example, 250 to 550 mg, for example, 300 to 500 mg, for example, 350 to 450 mg, for example, 375 to 425 mg, for example, 400 mg.

[0324] 5. The composition for use according to item 1, wherein the therapeutic dose is 700 to 1400 mg, for example, 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.

[0325] 6. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg.

[0326] 7. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg.

[0327] 8. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg.

[0328] 9. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg.

[0329] 10. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg.

[0330] 11. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg.

[0331] 12. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg.

[0332] 13. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg.

[0333] 14. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg.

[0334] 15. The composition for use according to any one of the preceding items, wherein the therapeutic dose is administered at least once daily.

[0335] 16. The composition for use according to any one of the preceding items, wherein the therapeutic dose is administered once daily.

[0336] 17. The composition for use according to any one of items 1 to 15, wherein the therapeutic dose is administered twice a day.

[0337] 18. The composition for use according to any one of items 1 to 15, wherein the therapeutic dose is administered three times a day.

[0338] 19. The composition for use according to any one of items 1 to 15, wherein the therapeutic dose is administered four times a day.

[0339] 20. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered once a day.

[0340] 21. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered once a day.

[0341] 22. The composition for use according to item 1, wherein the therapeutic dose is 300 to 500 mg and the composition is administered once a day.

[0342] 23. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is administered once a day.

[0343] 24. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is administered once a day.

[0344] 25. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is administered once a day.

[0345] 26. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg and the composition is administered once a day.

[0346] 27. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is administered once a day.

[0347] 28. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is administered once a day.

[0348] 29. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is administered once a day.

[0349] 30. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is administered once a day.

[0350] 31. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg and the composition is administered once a day.

[0351] 32. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered twice a day.

[0352] 33. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered twice a day.

[0353] 34. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 300-500 mg and the composition is administered twice daily.

[0354] 35. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is administered twice a day.

[0355] 36. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is administered twice a day.

[0356] 37. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is administered twice a day.

[0357] 38. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg and the composition is administered twice a day.

[0358] 39. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is administered twice a day.

[0359] 40. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is administered twice a day.

[0360] 41. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is administered twice a day.

[0361] 42. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is administered twice a day.

[0362] 43. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg and the composition is administered twice a day.

[0363] 44. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered three times a day.

[0364] 45. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered three times a day.

[0365] 46. ​​The composition for use according to item 1, wherein the therapeutic dose is 300 to 500 mg and the composition is administered three times a day.

[0366] 47. The composition for use according to item 1, wherein the therapeutic dose is about 100 mg and the composition is administered three times a day.

[0367] 48. The composition for use according to item 1, wherein the therapeutic dose is about 150 mg and the composition is administered three times a day.

[0368] 49. The composition for use according to item 1, wherein the therapeutic dose is about 200 mg and the composition is administered three times a day.

[0369] 50. The composition for use according to item 1, wherein the therapeutic dose is about 250 mg and the composition is administered three times a day.

[0370] 51. The composition for use according to item 1, wherein the therapeutic dose is about 300 mg and the composition is administered three times a day.

[0371] 52. The composition for use according to item 1, wherein the therapeutic dose is about 350 mg and the composition is administered three times a day.

[0372] 53. The composition for use according to item 1, wherein the therapeutic dose is about 400 mg and the composition is administered three times a day.

[0373] 54. The composition for use according to item 1, wherein the therapeutic dose is about 500 mg and the composition is administered three times a day.

[0374] 55. The composition for use according to item 1, wherein the therapeutic dose is about 600 mg and the composition is administered three times a day.

[0375] 56. The composition for use according to item 1, wherein the therapeutic dose is 100 to 600 mg and the composition is administered four times a day.

[0376] 57. The composition for use according to item 1, wherein the therapeutic dose is 200 to 600 mg and the composition is administered four times a day.

[0377] 58. A composition for use according to any one of items 1 to 6, wherein the therapeutic dose is a total daily dosage.

[0378] 59. A composition for use according to any one of the preceding items, wherein the composition is administered orally, parenterally, intravenously, by inhalation, topically, enterally, rectally, buccally or as an aerosol.

[0379] 60. The composition for use according to any one of items 1 to 59, wherein the composition is in the form of a liquid, a liquid suspension, an oil, an emulsion, or a syrup.

[0380] 61. A composition for use according to any one of items 1 to 59, wherein the composition is in solid dosage form.

[0381] 62. The composition for use according to item 61, wherein the solid dosage form is administered orally.

[0382] 63. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 100 to 600 mg, and the composition is administered once a day.

[0383] 64. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 200 to 600 mg, and the composition is administered once a day.

[0384] 65. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 100 to 600 mg, and the composition is administered twice a day.

[0385] 66. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 200 to 600 mg, and the composition is administered twice a day.

[0386] 67. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 100 to 600 mg, and the composition is administered three times a day.

[0387] 68. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 200 to 600 mg, and the composition is administered three times a day.

[0388] 69. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 100 to 600 mg, and the composition is administered four times a day.

[0389] 70. A composition for use according to any one of items 1 to 62, wherein the composition is in the form of a solid dosage form and is administered orally, the therapeutic dose is 200 to 600 mg, and the composition is administered four times a day.

[0390] 71. The composition for use according to any of items 61 to 70, wherein the solid dosage form is selected from the group consisting of capsules (e.g., sprinkle capsules and gelatin capsules), tablets (e.g., uncoated tablets, coated tablets, slow-release tablets) and sprinkles.

[0391] 72. The composition for use according to any of items 61 to 71, wherein 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 with paddles at 75 rpm.

[0392] 73. The composition 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, and provides a T 1 -T 2 -T 3 -T 4 -T 5 -T 6 -H 2 O 3 -T 1 -T 2 ... max 2. A composition for use according to any one of the preceding items, wherein the composition reaches

[0393] 74. The composition 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, and provides a T 1 concentration-time profile within 3 to 7 hours after administration. max 2. A composition for use according to any one of the preceding items, wherein the composition reaches

[0394] 75. The composition 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, and provides a mean C max is 12,760 to 27,440 ng / mL, such as 15,000 to 25,000 ng / mL, for example, 16,000 to 24,000 ng / mL, such as 16,080 to 25,125 ng / mL, for example, 17,000 to 23,000 ng / mL, such as 18,000 to 22,000 ng / mL, for example, 19,000 to 21,000 ng / mL, such as about 20,100 ng / mL 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.

[0395] 76. The composition 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, wherein the mean C max 76. The composition for use according to item 75, wherein the mean serum concentration is 20,100 ng / mL and the standard deviation is 7,340 ng / mL.

[0396] 77. The composition 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, and provides a mean C max is about 80% to about 125%, e.g., 80.00% to 125.00%, of 20,100 ng / mL 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.

[0397] 78. The composition 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, and provides a mean AUC 0-無限大is 66,300 to 109,100 h ng / mL, such as 70,000 to 105,000 h ng / mL, for example 70,160 to 109,625 h ng / mL, such as 75,000 to 100,000 h ng / mL, for example 80,000 to 95,000 h ng / mL, such as 85,000 to 90,000 h ng / mL, for example about 87,700 h ng / mL, 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.

[0398] 79. The composition 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, and provides a mean AUC 0-無限大 Item 10. The composition for use according to any one of the preceding items, wherein the saturation level is 87,700 ng / mL and the standard deviation is 21,400 ng / mL.

[0399] 80. The composition 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, and provides a mean AUC 0-無限大 is about 80% to about 125%, e.g., 80.00% to 125.00%, of 87,700 h ng / mL 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.

[0400] 81. AUC 0-24 , AUC 無限大 , Cmax or T max is measured after administration of a single dose to a human subject suffering from spinal muscular atrophy.

[0401] 82. A composition for use according to any one of the preceding items, wherein the composition further comprises at least one pharmaceutically acceptable adjuvant and / or excipient.

[0402] 83. The composition for use according to item 82, wherein the pharmaceutically acceptable adjuvants and / or excipients are selected from the group consisting of fillers, binders, lubricants and disintegrants.

[0403] 84. The composition for use according to item 82, 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.

[0404] 85. A composition for use according to any of items 61 to 84, wherein the composition comprises 10 to 80 wt%, for example 40 to 65 wt%, for example 50 to 55 wt%, for example about 53 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0405] 86. The composition comprises: 85. A composition for use according to any of items 61 to 84, comprising 10 to 80 wt%, such as 40 to 65 wt%, for example, 50 to 60 wt%, for example, 50 to 55 wt%, for example, 55 to 60 wt%, such as about 53 wt%, for example, 56 wt% of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0406] 87. The composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; and e. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of a disintegrant 85. The composition for use according to any of items 61 to 84, comprising:

[0407] 88. The composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25 to 3 wt %, for example, 0.4 to 2.0 wt % magnesium stearate; and f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt% croscarmellose sodium 85. The composition for use according to any of items 61 to 84, comprising:

[0408] 89. The composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-60 wt %, for example, 50-55 wt %, for example, 55-60 wt %, for example, about 53 wt %, for example, about 56 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 20-80 wt%, e.g., 25-50 wt%, of filler; c. 2-20 wt%, e.g., 3-16 wt%, of binder; d. 0.25 to 3 wt %, e.g., 0.4 to 2.0 wt %, of a lubricant; e. 0.25 to 5 wt %, e.g., 0.3 to 2.5 wt %, of a disintegrant; and f. 1 to 10 wt% film coating 85. The composition for use according to any one of items 61 to 84, comprising:

[0409] 90. The composition comprises: a. 10-80 wt %, for example, 40-65 wt %, for example, 50-55 wt %, for example, about 53 wt % of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof; b. 5-60 wt%, e.g., 20-40 wt%, e.g., 21-37 wt% silicified microcrystalline cellulose; c. 2-60 wt%, e.g., 5-16 wt%, microcrystalline cellulose; d. 1-15 wt% maltodextrin, for example, 1.5-7 wt%, for example, 1.8-6.0 wt%; e. 0.25-3 wt %, e.g., 0.4-2.0 wt % magnesium stearate; f. 0.25 to 5 wt%, for example, 0.3 to 2.5 wt%, of croscarmellose sodium; and g. 1 to 10 wt. % of a film coating composition, such as Opadry White 85. A composition for use according to any of items 61 to 84, comprising or consisting of, with the proviso that the sum of said wt% of components does not exceed 100 wt%.

[0410] 91. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 100 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally once daily.

[0411] 92. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 200 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally once daily.

[0412] 93. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 100 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally twice daily.

[0413] 94. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 200 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally twice daily.

[0414] 95. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 100 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally three times a day.

[0415] 96. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 200 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally three times a day.

[0416] 97. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 100 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally four times a day.

[0417] 98. A composition for use according to any one of the preceding items, wherein the therapeutic dose is 200 to 600 mg, and the composition is in the form of a solid dosage form and is administered orally four times a day.

[0418] 99. A composition for use according to any one of the preceding items, wherein the composition is administered as one or more unit dosage forms.

[0419] 100. The composition for use according to any one of the preceding items, wherein the subject has a serum uric acid level of less than 6.5 mg / dL.

[0420] 101. The composition for use according to any one of the preceding items, wherein the subject experiences a reduction in symptoms of spinal muscular atrophy.

[0421] 102. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in total distance walked as determined using a 6-minute walk test after treatment with the composition.

[0422] 103. The composition for use according to item 102, wherein the increase in total distance walked is determined by comparing the change from baseline in the total distance walked after a defined 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 total distance walked after a defined period of placebo treatment.

[0423] 104. The composition for use according to item 103, wherein the period is 21 days.

[0424] 105. A composition for use according to any one of the preceding items, wherein the total distance walked 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%, for example, at least 200%.

[0425] 106. A composition for use according to any one of the preceding items, wherein the total distance walked is increased by 5% to 400%, for example, by 5% to 200%, for example, by 10% to 200%.

[0426] 107. The composition for use according to any one of the preceding items, wherein the total distance walked is increased by at least 20 meters, such as at least 30 meters, for example, at least 40 meters, for example, at least 50 meters, for example, at least 60 meters, for example, at least 80 meters, for example, at least 100 meters, for example, at least 150 meters, such as at least 200 meters, for example, at least 250 meters, for example, at least 300 meters.

[0427] 108. A composition for use according to any one of the preceding items, wherein the total distance walked is increased by 20 to 400 meters, for example, 30 to 300 meters, for example, 40 to 200 meters.

[0428] 109. The composition for use of any one of the preceding items, 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 an increase in total distance walked as determined using a 6-minute walk test.

[0429] 110. The composition for use of any one of the preceding items, 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 an increase in total distance walked as determined using a 6-minute walk test.

[0430] 111. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in muscle strength after treatment with the composition.

[0431] 112. The composition for use according to item 111, wherein the muscle strength is measured as grip strength.

[0432] 113. The composition for use according to item 112, wherein the grip strength is measured using a handheld dynamometer.

[0433] 114. The composition for use according to item 111, wherein the muscle strength is measured as strength of the thigh (knee flexors), upper arm (elbow flexors and elbow extensors) and / or shoulder (shoulder abduction).

[0434] 115. The composition for use according to any one of items 111 to 114, wherein the increase in muscle strength is determined by comparing the change from baseline in muscle strength after a defined 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 defined period of placebo treatment.

[0435] 116. The composition for use according to item 115, wherein the period is 21 days.

[0436] 117. A composition for use according to any one of the preceding items, 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%, for example at least 200%.

[0437] 118. A composition for use according to any one of the preceding items, wherein the muscle strength is increased by 10% to 400%, for example, 15% to 200%, for example, 20% to 100%.

[0438] 119. A composition for use according to any one of the preceding items, 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%.

[0439] 120. A composition for use according to any one of the preceding items, 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%.

[0440] 121. A composition for use according to any one of the preceding items, 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, for example, at least 1.25 kg, for example, at least 1.5 kg, for example, at least 1.75 kg, for example, at least 2.0 kg, for example, at least 2.5 kg, for example, at least 3.0 kg.

[0441] 122. A composition for use according to any one of the preceding items, 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.

[0442] 123. A composition for use according to any one of the preceding items, wherein the muscle strength, as determined by measuring knee flexor 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, for example, at least 5.0 kg, for example, at least 7.5 kg.

[0443] 124. A composition for use according to any one of the preceding items, wherein the muscle strength, as determined by measuring knee flexor strength using a handheld dynamometer, is increased by 0.25 to 15.0 kg, for example, 0.25 to 10.0 kg, for example, 0.5 to 5.0 kg.

[0444] 125. A composition for use according to any one of the preceding items, wherein the muscle strength, as determined by measuring elbow flexor 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, for example, at least 1.25 kg, such as at least 1.5 kg, for example, at least 1.75 kg, for example, at least 2.0 kg, for example, at least 2.5 kg, for example, at least 3.0 kg.

[0445] 126. A composition for use according to any one of the preceding items, wherein the muscle strength, as determined by measuring elbow flexor 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.

[0446] 127. The composition for use of any one of the preceding items, 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 an increase in muscle strength as determined by measuring grip strength using a handheld dynamometer.

[0447] 128. The composition for use of any one of the preceding items, 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 an increase in muscle strength as determined by measuring grip strength using a handheld dynamometer.

[0448] 129. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in the Revised Hammersmith Scale score after treatment with the composition.

[0449] 130. The composition for use according to item 129, wherein the increase in the modified Hammersmith Scale score is determined by comparing the change from baseline in the modified Hammersmith Scale score after a defined 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 modified Hammersmith Scale score after a defined period of placebo treatment.

[0450] 131. The composition for use according to item 130, wherein the period is 21 days.

[0451] 132. The composition for use according to any one of the preceding items, wherein the Revised Hammersmith Scale score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0452] 133. A composition for use according to any one of the preceding items, wherein the Revised Hammersmith Scale score is increased by 0.5 to 30 points, for example, by 1 to 20 points, for example, by 0.5 to 10 points.

[0453] 134. The composition for use of any one of the preceding items, 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 an increase in the Revised Hammersmith Scale score.

[0454] 135. The composition for use of any one of the preceding items, 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 an increase in the Revised Hammersmith Scale score.

[0455] 136. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences a durable improvement after treatment with the composition.

[0456] 137. The composition for use according to item 136, wherein the improvement in endurance is determined using an endurance shuttle 9-hole peg test.

[0457] 138. The composition for use according to item 137, wherein the improvement in endurance is determined by comparing the change from baseline in the endurance shuttle 9-hole peg test after a defined 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 endurance shuttle 9-hole peg test after a defined period of placebo treatment.

[0458] 139. The composition for use according to item 138, wherein the period is 21 days.

[0459] 140. A composition for use according to any one of the preceding items, wherein the endurance determined using an endurance shuttle 9-hole peg test 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%.

[0460] 141. A composition for use according to any one of the preceding items, wherein the endurance, as determined using an endurance shuttle 9-hole peg test, is increased by 5% to 400%, for example, by 10% to 300%, for example, by 10% to 200%.

[0461] 142. The composition for use of any one of the preceding items, 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 improved manual dexterity as determined using an endurance shuttle 9-hole peg test.

[0462] 143. The composition for use of any one of the preceding items, 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 improved manual dexterity as determined using an endurance shuttle 9-hole peg test.

[0463] 144. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences a reduced dropout rate in an endurance shuttle 9-hole peg test after treatment with the composition.

[0464] 145. The composition for use according to item 137, wherein the reduction in dropout rate in the endurance shuttle 9-hole peg test is determined by comparing the change from baseline in dropout rate in the endurance shuttle 9-hole peg test after a defined 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 dropout rate in the endurance shuttle 9-hole peg test after a defined period of placebo treatment.

[0465] 146. The composition for use according to item 145, wherein the period is 21 days.

[0466] 147. A composition for use according to any one of the preceding items, wherein the reduction in the dropout rate in the endurance shuttle 9-hole peg test is 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%, for example at least 40%, for example at least 50%, for example at least 60%, for example at least 70%, for example at least 80%.

[0467] 148. A composition for use according to any one of the preceding items, wherein the reduction in dropout rate in the endurance shuttle 9-hole peg test is reduced by 5% to 100%, for example, by 10% to 80%, for example, by 5% to 60%.

[0468] 149. A composition for use according to any one of the preceding items, 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 reduced dropout rate in the endurance shuttle 9-hole peg test.

[0469] 150. A composition for use according to any one of the preceding items, 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 reduced dropout rate in the endurance shuttle 9-hole peg test.

[0470] 151. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences reduced fatigue after treatment with the composition.

[0471] 152. The composition for use according to item 151, wherein the reduction in fatigue is determined using a fatigue index calculated from the distance walked in the first minute to the distance walked in the sixth minute of a 6-minute walking test.

[0472] 153. The composition for use according to item 151, wherein the reduction in fatigue is determined by comparing the change from baseline in the fatigue index after a defined 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 dropout rate in the fatigue index after a defined period of placebo treatment.

[0473] 154. The composition for use according to item 153, wherein the period is 21 days.

[0474] 155. A composition for use according to any one of the preceding items, wherein the reduction in fatigue, as determined using a fatigue index, is 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%, for example at least 40%, for example at least 50%, for example at least 60%, for example at least 70%, for example at least 80%.

[0475] 156. A composition for use according to any one of the preceding items, wherein the reduction in fatigue, as determined using a fatigue index, is reduced by 5% to 95%, for example, by 5% to 80%, for example, by 10% to 50%.

[0476] 157. A composition for use according to any one of the preceding items, 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 reduction in fatigue as determined using a fatigue index.

[0477] 158. A composition for use according to any one of the preceding items, 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 reduction in fatigue as determined using a fatigue index.

[0478] 159. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in a 32-item motor function index score after treatment with the composition.

[0479] 160. The composition for use according to item 159, wherein the increase in the 32-item motor function index score is determined by comparing the change from baseline in the 32-item motor function index score after a defined 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 32-item motor function index score after a defined period of placebo treatment.

[0480] 161. The composition for use according to item 160, wherein the period is 21 days.

[0481] 162. A composition for use according to any one of the preceding items, wherein the 32-item motor function index score 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%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%.

[0482] 163. A composition for use according to any one of the preceding items, wherein the 32-item motor function index score is increased by 5% to 95%, for example, by 5% to 80%, for example, by 10% to 50%.

[0483] 164. The composition for use of any one of the preceding items, 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 an increase in a 32-item motor function index score.

[0484] 165. The composition for use of any one of the preceding items, 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 an increase in a 32-item motor function index score.

[0485] 166. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences a decrease in Fatigue Severity Scale score after treatment with the composition.

[0486] 167. The composition for use according to item 166, wherein the reduction in the fatigue severity scale score is determined by comparing the change from baseline in the fatigue severity scale score after a defined 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 fatigue severity scale score after a defined period of placebo treatment.

[0487] 168. The composition for use according to item 167, wherein the period is 21 days.

[0488] 169. The composition for use according to any one of items 166 to 168, 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, for example at least 1.5 points, such as at least 2 points, for example at least 3 points, such as at least 4 points, for example at least 5 points, such as at least 6 points, for example at least 8 points, such as at least 10 points, for example at least 15 points, for example at least 20 points.

[0489] 170. A composition for use according to any one of items 166 to 169, wherein the fatigue severity scale score is reduced by 1 to 20 points, for example, by 0.5 to 10 points.

[0490] 171. The composition for use of any one of the preceding items, 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 fatigue severity scale score.

[0491] 172. The composition for use of any one of the preceding items, 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 fatigue severity scale score.

[0492] 173. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences a decrease in an individualized neuromuscular quality of life score after treatment with the composition.

[0493] 174. The composition for use according to item 173, wherein the reduction in the personalized neuromuscular quality of life score is determined by comparing the change from baseline in the personalized neuromuscular quality of life score after a defined 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 personalized neuromuscular quality of life score after a defined period of placebo treatment.

[0494] 175. The composition for use according to item 174, wherein the period is 21 days.

[0495] 176. The composition for use according to any one of the preceding items, wherein the individualised neuromuscular quality of life score is reduced by 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0496] 177. A composition for use according to any one of the preceding items, wherein the individualised neuromuscular quality of life score is reduced by 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0497] 178. The composition for use of any one of the preceding items, 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 individualized neuromuscular quality of life score.

[0498] 179. The composition for use of any one of the preceding items, 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 individualized neuromuscular quality of life score.

[0499] 180. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences a reduction in jitter after treatment with the composition.

[0500] 181. The composition for use according to item 180, wherein the jitter is determined using single fiber electromyography.

[0501] 182. The composition for use according to any one of items 180 or 181, wherein the reduction in jitter is determined by comparing the change from baseline in the jitter after a defined 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 jitter after a defined period of placebo treatment.

[0502] 183. The composition for use according to item 182, wherein the period is 21 days.

[0503] 184. The composition for use according to any one of items 180 to 183, wherein the jitter is reduced by at least 10%, such as 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%.

[0504] 185. A composition for use according to any one of items 180 to 183, wherein the jitter is reduced by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0505] 186. A composition for use according to any one of items 180 to 183, wherein the jitter determined using single fiber 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.

[0506] 187. A composition for use according to any one of items 180 to 183, wherein the jitter determined using single fiber electromyography is reduced by 5 μs to 200 μs, for example by 5 μs to 100 μs, for example by 10 μs to 50 μs.

[0507] 188. A composition for use according to any one of the preceding items, 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 reduction in jitter as determined using single fiber electromyography.

[0508] 189. A composition for use according to any one of the preceding items, 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 reduction in jitter as determined using single fiber electromyography.

[0509] 190. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences reduced blocking after treatment with the composition.

[0510] 191. The composition for use according to item 190, wherein the blocking is determined using single fiber electromyography.

[0511] 192. The composition for use according to any one of items 190 or 191, wherein the reduction in blocking is determined by comparing the change from baseline in blocking after a defined 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 blocking after a defined period of placebo treatment.

[0512] 193. The composition for use according to item 192, wherein the period is 21 days.

[0513] 194. The composition for use according to any one of items 190 to 193, wherein the blocking 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%.

[0514] 195. A composition for use according to any one of items 190 to 194, wherein the blocking is reduced by 5% to 95%, for example by 5% to 80%, for example by 10% to 50%.

[0515] 196. The composition for use of any one of the preceding items, 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 reduced blocking as determined using single fiber electromyography.

[0516] 197. The composition for use of any one of the preceding items, 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 reduced blocking as determined using single fiber electromyography.

[0517] 198. The composition for use of any one of the preceding items, wherein the subject or group of subjects experiences an increase in Children's Hospital of Philadelphia Infant Trial of Neuromuscular Disorders (CHOP INTEND) score after treatment with the composition.

[0518] 199. The composition for use according to item 198, wherein the increase in the CHOP INTEND score is determined by comparing the change from baseline in the CHOP INTEND score after a defined 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 CHOP INTEND score after a defined period of placebo treatment.

[0519] 200. The composition for use according to item 199, wherein the period is 21 days.

[0520] 201. The composition for use according to any one of items 199 to 200, wherein the CHOP INTEND score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0521] 202. The composition for use according to any one of items 199 to 201, wherein the CHOP INTEND score is increased by 0.5 to 30 points, for example, 1 to 20 points, for example, 0.5 to 10 points.

[0522] 203. The composition for use of any one of the preceding items, 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 an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Test score.

[0523] 204. The composition for use of any one of the preceding items, 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 an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Test score.

[0524] 205. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in Hammersmith Functional Motor Scale (HFMS) score after treatment with the composition.

[0525] 206. The composition for use according to item 205, wherein the increase in the HFMS score is determined by comparing the change from baseline in the HFMS score after a defined 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 HFMS score after a defined period of placebo treatment.

[0526] 207. The composition for use according to item 206, wherein the period is 21 days.

[0527] 208. The composition for use according to any one of items 205 to 207, wherein the HFMS score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0528] 209. The composition for use according to any one of items 205 to 207, wherein the HFMS score is increased by 0.5 to 30 points, for example, by 1 to 20 points, for example, by 0.5 to 10 points.

[0529] 210. The composition for use of any one of the preceding items, 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 an increase in Hammersmith Functional Motor Scale score.

[0530] 211. The composition for use of any one of the preceding items, 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 an increase in Hammersmith Functional Motor Scale score.

[0531] 212. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in Hammersmith Functional Motor Scale-Extended (HFMSE) score after treatment with the composition.

[0532] 213. The composition for use according to item 212, wherein the increase in the HFMSE score is determined by comparing the change from baseline in the HFMSE score after a defined 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 HFMSE score after a defined period of placebo treatment.

[0533] 214. The composition for use according to item 213, wherein the period is 21 days.

[0534] 215. The composition for use according to any one of items 213 or 214, wherein the HFMSE score is increased 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.

[0535] 216. The composition for use according to any one of items 213 or 214, wherein the HFMSE score is increased by 0.5 to 30 points, for example, by 1 to 20 points, for example, by 0.5 to 10 points.

[0536] 217. A composition for use according to any one of the preceding items, 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 an increase in the Extended Hammersmith Functional Motor Scale score.

[0537] 218. A composition for use according to any one of the preceding items, 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 an increase in the Extended Hammersmith Functional Motor Scale score.

[0538] 219. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in Hammersmith Infant Neurological Examination (HINE) score after treatment with the composition.

[0539] 220. The composition for use according to item 219, wherein the increase in the HINE score is determined by comparing the change from baseline in the HINE score after a defined 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 HINE score after a defined period of placebo treatment.

[0540] 221. The composition for use according to item 220, wherein the period is 21 days.

[0541] 222. A composition for use according to any one of items 219 to 221, wherein the HINE score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0542] 223. The composition for use according to any one of items 219 to 221, wherein the HINE score is increased by 0.5 to 30 points, for example, by 1 to 20 points, for example, by 0.5 to 10 points.

[0543] 224. A composition for use according to any one of the preceding items, 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 an increase in infant neurological examination score.

[0544] 225. The composition for use of any one of the preceding items, 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 an increase in infant neurological examination score.

[0545] 226. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in PedsQL neuromuscular model score after treatment with the composition.

[0546] 227. The composition for use according to item 226, wherein the increase in the PedsQL neuromuscular model score is determined by comparing the change from baseline in the PedsQL neuromuscular model score after a defined 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 PedsQL neuromuscular model score after a defined period of placebo treatment.

[0547] 228. The composition for use according to item 227, wherein the period is 21 days.

[0548] 229. The composition for use according to any one of items 226 to 228, wherein the PedsQL neuromuscular model score is increased 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.

[0549] 230. The composition for use according to any one of items 226 to 228, wherein the PedsQL neuromuscular model score is increased by 0.5 to 30 points, for example by 1 to 20 points, for example by 0.5 to 10 points.

[0550] 231. The composition for use of any one of the preceding items, 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 an increase in PedsQL neuromuscular model score.

[0551] 232. The composition for use of any one of the preceding items, 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 an increase in PedsQL neuromuscular model score.

[0552] 233. The composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in Patient-Reported Outcomes Measurement Information System (PROMIS) score after treatment with the composition.

[0553] 234. The composition for use according to item 233, wherein the increase in the PROMIS score is determined by comparing the change from baseline in the PROMIS score after a defined 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 PROMIS score after a defined period of placebo treatment.

[0554] 235. The composition for use according to item 234, wherein the period is 21 days.

[0555] 236. A composition for use according to any one of items 233 to 235, wherein the PROMIS score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0556] 237. A composition for use according to any one of items 233 to 235, wherein the PROMIS score is increased by 0.5 to 30 points, for example by 1 to 20 points, for example by 0.5 to 10 points.

[0557] 238. The composition for use of any one of the preceding items, 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 an increase in Patient-Reported Outcomes Measurement Information System score.

[0558] 239. The composition for use of any one of the preceding items, 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 an increase in Patient-Reported Outcomes Measurement Information System score.

[0559] 240. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in the Revised Upper Limb Module (RULM) score after treatment with the composition.

[0560] 241. The composition for use according to item 240, wherein the increase in the RULM score is determined by comparing the change from baseline in the RULM score after a defined 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 RULM score after a defined period of placebo treatment.

[0561] 242. The composition for use according to item 241, wherein the period is 21 days.

[0562] 243. A composition for use according to any one of items 240 to 242, wherein the RULM score is increased by at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as 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, such as at least 15 points, for example, at least 20 points.

[0563] 244. A composition for use according to any one of items 240 to 242, wherein the RULM score is increased by 0.5 to 30 points, for example, by 1 to 20 points, for example, by 0.5 to 10 points.

[0564] 245. The composition for use of any one of the preceding items, 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 an increase in the revised Upper Extremity Module score.

[0565] 246. The composition for use of any one of the preceding items, 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 an increase in the revised Upper Extremity Module score.

[0566] 247. A composition for use according to any one of the preceding items, wherein the subject or group of subjects experiences an increase in WHO Multicenter Growth Reference Study (MGRS) score after treatment with the composition.

[0567] 248. The composition for use according to item 247, wherein the increase in the MGRS score is determined by comparing the change from baseline in the MGRS score after a defined 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 MGRS score after a defined period of placebo treatment.

[0568] 249. The composition for use according to item 248, wherein the period is 21 days.

[0569] 250. The composition for use according to any one of items 247 to 249, wherein the MGRS score is increased 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.

[0570] 251. A composition for use according to any one of items 247 to 249, wherein the MGRS score is increased by 0.5 to 30 points, for example by 1 to 20 points, for example by 0.5 to 10 points.

[0571] 252. The composition for use of any one of the preceding items, 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 an increase in WHO Multicenter Growth Reference Study score.

[0572] 253. The composition for use of any one of the preceding items, 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 an increase in WHO Multicenter Growth Reference Study score.

[0573] 254. 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 spinal muscular atrophy in a subject, wherein the subject has a serum uric acid level of less than 6.5 mg / dL.

[0574] 255. The composition for use according to item 254, wherein the composition 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.

[0575] 256. A method for treating spinal muscular atrophy in a subject, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0576] 257. The method comprises: a) Increase in total distance walked in the 6-minute walk test; b) increases in muscle strength as determined, for example, by measuring grip strength, elbow flexor / extensor strength, knee flexor strength, and / or shoulder abduction strength using a handheld dynamometer; c) an increase in the Revised Hammersmith Scale score; d) improved endurance, as determined, for example, as an increase in the time before failure in the endurance shuttle 9-hole peg test or a decrease in the failure rate in the endurance shuttle 9-hole peg test; e) reduction in fatigue (e.g., reduction is a decrease in fatigue index); f) improved neuromuscular junction transmission, e.g., reduced jitter and / or blocking when measured using sfEMG; g) Increase in the 32-item motor function index score; h) reduction in fatigue severity scale scores; i) a decrease in the individualized neuromuscular quality of life score; j) Increased Children's Hospital of Philadelphia Neuromuscular Disorders Infant Test scores; k) increased Hammersmith Functional Motor Scale score; l) increased Extended Hammersmith Functional Motor Scale score; m) increased Hammersmith Infant Neurological Examination scores; n) Increased PedsQL neuromuscular model score; o) Increased Patient-Reported Outcomes Measurement Information System scores; p) an increase in the revised upper extremity module score; and / or q) Increase in WHO Multicenter Growth Reference Study score Item 256. The method of claim 256,

[0577] 258. A method for treating spinal muscular atrophy in a subject, resulting in an increase in total distance walked, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0578] 259. The method of item 258, wherein the increase in total distance walked is determined using a 6-minute walk test.

[0579] 260. The method of item 258, wherein the subject experiences an increase in total distance walked of 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%, for example at least 50%, for example at least 75%, for example at least 100%, for example at least 150%, for example at least 200%.

[0580] 261. The method according to any one of items 259 or 260, wherein the subject experiences an increase in total distance walked of between 5% and 400%, such as between 5% and 200%, such as between 10% and 200%.

[0581] 262. The method of any one of items 259 or 260, wherein the subject experiences an increase in total distance walked of at least 20 meters, such as at least 30 meters, for example at least 40 meters, for example at least 50 meters, such as at least 60 meters, for example at least 80 meters, for example at least 100 meters, for example at least 150 meters, such as at least 200 meters, for example at least 250 meters, for example at least 300 meters.

[0582] 263. The method of any one of items 259 or 260, wherein the subject experiences an increase in total distance walked of 20 to 400 meters, such as 30 to 300 meters, such as 40 to 200 meters.

[0583] 264. A method for treating spinal muscular atrophy in a subject, resulting in increased muscle strength, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0584] 265. The method described in item 264, wherein the increase in muscle strength is determined by measuring the strength of the thigh (knee flexors), upper arm (elbow flexors and elbow extensors) and / or shoulder (shoulder abductors) or by measuring grip strength using a handheld dynamometer.

[0585] 266. The method of any one of items 264 or 265, wherein the subject experiences an increase in muscle strength of 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%.

[0586] 267. The method according to one of items 264 to 266, wherein the subject experiences an increase in muscle strength of 10% to 400%, for example 15% to 200%, for example 20% to 100%.

[0587] 268. The method of item 264, wherein the subject experiences an increase in muscle strength as determined by measuring grip strength using a handheld dynamometer, and the grip strength has increased by at least 0.25 kg, for example, at least 0.50 kg, for example, at least 0.75 kg, for example, at least 1.0 kg, for example, at least 1.25 kg, for example, at least 1.5 kg, for example, at least 1.75 kg, for example, at least 2.0 kg, for example, at least 2.5 kg, for example, at least 3.0 kg, for example, 0.25 to 5.0 kg, for example, 0.25 to 4.0 kg, for example, 0.5 to 4.0 kg.

[0588] 269. The method of item 264, wherein the subject experiences an increase in muscle strength as determined by measuring elbow flexor strength using a handheld dynamometer, and the elbow flexor strength is increased by at least 0.25 kg, for example, at least 0.50 kg, for example, at least 0.75 kg, for example, at least 1.0 kg, for example, at least 1.25 kg, for example, at least 1.5 kg, for example, at least 1.75 kg, for example, at least 2.0 kg, for example, at least 2.5 kg, for example, at least 3.0 kg, for example, 0.25 to 5.0 kg, for example, 0.25 to 4.0 kg, for example, 0.5 to 4.0 kg.

[0589] 270. The method of item 264, wherein the subject experiences an increase in muscle strength as determined by measuring knee flexor strength using a handheld dynamometer, and the knee flexor 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, for example, at least 1.25 kg, for example, at least 1.5 kg, for example, at least 1.75 kg, for example, at least 2.0 kg, for example, at least 2.5 kg, for example, at least 3.0 kg, for example, at least 5.0 kg, for example, at least 7.5 kg, for example, 0.25 to 15.0 kg, for example, 0.25 to 10.0 kg, for example, 0.5 to 5.0 kg.

[0590] 271. A method for treating spinal muscular atrophy in a subject, resulting in an increase in the Revised Hammersmith Scale score, the method 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.

[0591] 272. 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 Item 271, the method of claim 271,

[0592] 273. The method of one of items 271 or 272, wherein the subject experiences an increase in the Modified Hammersmith Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0593] 274. A method for treating spinal muscular atrophy in a subject resulting in improved endurance, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0594] 275. The method according to item 274, wherein the improvement in endurance is determined using an endurance shuttle 9-hole peg test.

[0595] 276. 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 Item 275, the method of claim 275,

[0596] 277. The method according to one of items 274 to 276, wherein the subject experiences an improvement in endurance of 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 400%, for example between 10% and 300%, for example between 10% and 200%.

[0597] 278. A method for treating spinal muscular atrophy in a subject, resulting in a reduced dropout rate in an endurance shuttle 9-hole peg test, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0598] 279. The therapeutically effective dose is a C in the range of 2,790 ng / mL to 76,700 ng / mL in the subject. max Item 279. The method of Item 278, wherein

[0599] 280. The method according to any one of items 278 to 279, wherein the subject experiences a reduction in dropout rate of 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 40%, for example at least 50%, such as at least 60%, for example at least 70%, for example at least 80%, such as between 5% and 100%, for example between 10% and 80%, for example between 5% and 60%.

[0600] 281. A method for treating spinal muscular atrophy in a subject, resulting in reduced fatigue, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0601] 282. The method according to item 281, wherein the reduction in fatigue is calculated from the distance walked in the first minute to the distance walked in the sixth minute of a 6-minute walk test.

[0602] 283. The method of any one of items 281 or 282, wherein the subject experiences a reduction in fatigue of 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 40%, for example at least 50%, for example at least 60%, such as at least 70%, for example at least 80%, such as between 5% and 95%, for example between 5% and 80%, for example between 10% and 50%.

[0603] 284. A method for treating spinal muscular atrophy in a subject, resulting in an increase in a 32-item motor function index score, the method 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.

[0604] 285. The method of item 284, wherein the subject experiences an increase in the motor function index 32-item score of at least 5%, for example, at least 10%, for example, at least 15%, for example, at least 20%, for example, at least 25%, for example, at least 30%, for example, at least 40%, for example, at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, 5% to 95%, for example, 5% to 80%, for example, 10% to 50%.

[0605] 286. A method for treating spinal muscular atrophy in a subject, resulting in a decrease in fatigue severity scale score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0606] 287. The method of item 286, wherein the subject experiences a reduction in the fatigue severity scale score of 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0607] 288. A method for treating spinal muscular atrophy in a subject, resulting in a decrease in an individualized neuromuscular quality of life score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0608] 289. The method of item 288, wherein the subject experiences a decrease in the individualized neuromuscular quality of life score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as at least 4 points, for example, at least 5 points, such as at least 6 points, for example, at least 8 points, such as at least 10 points, for example, at least 15 points, such as at least 20 points, for example, from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0609] 290. A method for treating spinal muscular atrophy in a subject, resulting in improved neuromuscular junction transmission, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0610] 291. The method according to item 290, wherein the improvement in the neuromuscular junction is a reduction in jitter and / or blocking, as determined using single fiber electromyography.

[0611] 292. The method of any one of items 290 or 291, wherein the subject experiences a reduction in jitter of at least 15%, such as at least 10%, 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%.

[0612] 293. The method of any one of items 290 or 291, wherein the subject experiences a reduction in jitter of at least 5 μs, such as at least 10 μs, for example at least 15 μs, for example at least 20 μs, such as at least 25 μs, for example 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 from 5 μs to 200 μs, for example from 5 μs to 100 μs, for example from 10 μs to 50 μs.

[0613] 294. The method of any one of items 290 or 291, wherein the subject experiences a reduction in blocking of at least 10%, such as 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 5% to 95%, for example, 5% to 80%, for example, 10% to 50%.

[0614] 295. A method for treating spinal muscular atrophy in a subject, resulting in an increase in the Children's Hospital of Philadelphia Neuromuscular Disorders Infant Examination score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0615] 296. The method of item 295, wherein the subject experiences an increase in the Children's Hospital of Philadelphia Infant Neuromuscular Disorders Test score of 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 from 0.5 to 30 points, for example, from 1 to 20 points, such as from 0.5 to 10 points.

[0616] 297. A method for treating spinal muscular atrophy in a subject, resulting in an increase in Hammersmith Functional Motor Scale score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0617] 298. The method of item 297, wherein the subject experiences an increase in the Hammersmith Functional Motor Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as at least 4 points, for example, at least 5 points, such as at least 6 points, for example, at least 8 points, such as at least 10 points, for example, at least 15 points, such as at least 20 points, for example, from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0618] 299. A method for treating spinal muscular atrophy in a subject, resulting in an increase in the Extended Hammersmith Functional Motor Scale score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0619] 300. The method of item 299, wherein the subject experiences an increase in the Extended Hammersmith Functional Motor Scale score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, such as at least 8 points, for example, at least 10 points, for example, at least 15 points, such as at least 20 points, for example, from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0620] 301. A method for treating spinal muscular atrophy in a subject, resulting in an increase in Hammersmith Infant Neurological Examination score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0621] 302. The method of item 301, wherein the subject experiences an increase in the Hammersmith Infant Neurological Examination score of 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0622] 303. A method for treating spinal muscular atrophy in a subject, resulting in an increase in PedsQL neuromuscular model score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0623] 304. The method of item 303, wherein the subject experiences an increase in the PedsQL neuromuscular model score of 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0624] 305. A method for treating spinal muscular atrophy in a subject, resulting in an increase in a Patient-Reported Outcomes Measurement Information System score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0625] 306. The method of item 305, wherein the subject experiences an increase in the Patient-Reported Outcomes Measurement Information System score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, 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, 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0626] 307. A method for treating spinal muscular atrophy in a subject, resulting in an increase in a revised upper extremity module score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0627] 308. The method of item 307, wherein the subject experiences an increase in the revised Upper Extremity Module score of at least 0.5 points, such as at least 0.75 points, for example, at least 1 point, for example, at least 1.5 points, such as at least 2 points, for example, at least 3 points, such as at least 4 points, for example, at least 5 points, such as at least 6 points, for example, at least 8 points, such as at least 10 points, for example, at least 15 points, such as at least 20 points, for example, from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0628] 309. A method for treating spinal muscular atrophy in a subject, resulting in an increase in WHO Multicenter Growth Reference Study score, said method comprising administering to said 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 said therapeutic dose is in the range of 100 mg to 1500 mg.

[0629] 310. The method of item 309, wherein the subject experiences an increase in the WHO Multicenter Growth Reference Study score of 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 from 0.5 to 30 points, for example, from 1 to 20 points, for example, from 0.5 to 10 points.

[0630] 311. A method for treating a subject suffering from symptoms of spinal muscular atrophy, 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.

[0631] 312. A method for the treatment of spinal muscular atrophy in a subject having a serum uric acid level greater than 6.5 mg / dL, said method comprising administering to said subject a low 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, until the patient's serum uric acid level is reduced to less than 6.5 mg / dL; and then administering to the subject a therapeutic 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 low dose is in the range of 20 mg to 150 mg, e.g., 25 mg to 100 mg, e.g., 25 mg to 50 mg, and the therapeutic dose is in the range of 200 mg to 1500 mg.

[0632] 313. A method for improving recovery of neuromuscular transmission and / or 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, at a therapeutic dose of 100 to 1500 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0633] 314. 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 according to one of items 256 to 313,

[0634] 315. The therapeutically effective dose is a dose that produces an AUC in the range of 16,700 ng / mL to 534,000 ng / mL in the subject. inf The method according to one of items 256 to 314,

[0635] 316. The therapeutically effective dose of the compound is a T in the subject in the range of 1 to 6 hours. max The method according to one of items 256 to 315, comprising:

[0636] 317. The therapeutically effective dose of the compound is a dose that induces a T in the subject in the range of 3 hours to 7 hours. max The method according to one of items 256 to 315, comprising:

[0637] 318. The method according to one of items 256 to 317, wherein the therapeutically effective dose is in the range of 100 mg to 600 mg.

[0638] 319. The method according to one of items 256 to 317, wherein the therapeutically effective dose is in the range of 200 mg to 600 mg.

[0639] 320. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 100 mg.

[0640] 321. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 150 mg.

[0641] 322. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 200 mg.

[0642] 323. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 250 mg.

[0643] 324. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 300 mg.

[0644] 325. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 350 mg.

[0645] 326. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 400 mg.

[0646] 327. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 500 mg.

[0647] 328. The method according to one of items 256 to 317, wherein the therapeutically effective dose is 600 mg.

[0648] 329. The method according to one of items 256 to 328, wherein the therapeutically effective dose is administered once, twice, three or four times daily.

[0649] 330. The method according to one of items 256 to 313, wherein the therapeutically effective dose is 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered once a day.

[0650] 331. The method according to one of items 256 to 313, wherein the therapeutically effective dose is 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and the composition is administered twice a day.

[0651] 332. The method according to one of items 256 to 313, wherein the therapeutically effective dose is 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 a day.

[0652] 333. The method according to one of items 256 to 313, wherein the therapeutically effective dose is 100 to 600 mg of (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and...

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 for treating spinal muscular atrophy 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 for use according to claim 1, wherein the therapeutic dose is 200 to 600 mg.

3. 10. A composition for use according to any one of the preceding claims, wherein the therapeutic dose is administered once, twice or three times daily.

4. 10. A composition for use according to any one of the preceding claims, wherein the therapeutic dose is 400 mg and the therapeutic dose is administered twice daily.

5. 10. A composition for use according to any one of the preceding claims, wherein the composition is for oral administration.

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

7. 7. The composition for use according to claim 6, wherein the composition comprises silicified microcrystalline cellulose.

8. 10. The composition for use according to any one of the preceding claims, wherein the subject has a deletion or mutation in each survival motor neuron 1 (SMN1) allele.

9. 10. The composition for use according to any one of the preceding claims, wherein the subject is affected with SMA type 0, SMA type 1, SMA type 2, SMA type 3 or SMA type 4.

10. The composition 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, having a mean C ｍａｘ 12,760 to 27,440 ng / mL 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.

11. 10. The composition for use according to any one of the preceding claims, wherein the subject experiences an increase in total distance walked as determined using a 6-minute walk test after treatment with (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. 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 Compounds that increase the amount of functional SMN protein produced by SMN2 The kit of parts includes:

13. 13. The kit of parts of claim 12, wherein the kit of parts comprises 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.

14. The kit of parts according to any one of claims 12 to 13, wherein the SMN2 alternative splicing compound is selected from the group consisting of risdiplam, nusinersen, branapram and BIIB115.

15. 15. The kit-of-parts according to any one of items 12 to 14, for use in a method for treating spinal muscular atrophy in a subject, wherein the composition is for administration of 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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