A chloride ion channel 1 inhibitor for use in disease modifying effects in the treatment of a neuromuscular disease

Abstract

The present disclosure relates to methods for providing disease modifying effects in a subject in need thereof that modify the course and / or severity of a neuromuscular disease. These methods include administering a therapeutically effective amount of a CIC-1 inhibitor (chloride ion channel 1 inhibitor), and optionally an immunomodulating or immunosuppressive agent, to a subject suffering from a neuromuscular disease.

Description

[0001] P7593PC00

[0002] 1

[0003] Method of Providing Disease Modifying Effects Using a CIC-1 Inhibitor

[0004] Technical field

[0005] The present disclosure relates to methods for providing disease modifying effects in a subject in need thereof. In particular, the present disclosure is directed towards providing methods of modifying the course and severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease.

[0006] Background

[0007] Walking, breathing, and eye movement are examples of essential everyday physiological activities that are powered by the contractile activity of skeletal muscle. Skeletal muscles are inherently under a resting state, and contractile activity occurs exclusively in response to commands from the central nervous system (CNS). Such neuronal commands take the form of action potentials that travel from the brain to the muscle fibers in several steps, and it is at the neuromuscular junction (NMJ) where neuronal action potentials are transmitted to muscular action potentials in a one-to-one fashion via synaptic transmission.

[0008] NMJs are a highly specialized membrane area on muscle fibers where motor neurons come into close contact with the muscle fibers. NMJs play an essential role in voluntary muscle contraction, including without limitation the contraction of skeletal muscles. In NMJs, a neuromuscular transmission from a motor neuron is transmitted to a corresponding muscle fiber to promote muscle contraction. For the motor neuron to release the neuromuscular transmission, its action potential threshold must be met ( / .e., its membrane potential must reach around -50 to -55 mV). When a neuron’s action potential threshold is met, an influx of Ca2+through voltage-gated P / Q-type Ca2+channels occurs in the neuron’s terminal membrane. This influx causes a rise in cytosolic Ca2+in the neuron terminal that triggers exocytosis of acetylcholine (ACh). Released ACh subsequently diffuses across the synaptic cleft to activate nicotinic acetylcholine receptors (AChRs) in the post-synaptic, muscle fiber membrane. Upon activation, AChRs convey an excitatory current flow of Na+into the muscle fiber, whichP7593PC00

[0009] 2

[0010] results in a local depolarization of the muscle fiber at the NMJ (the endplate potential, EPP). If the EPP is sufficiently high, voltage-gated Na+channels in the muscle fiber will activate, and an action potential in the muscle fiber will ensue. This action potential then propagates from the NMJ throughout the muscle fiber and triggers a release of Ca2+from the sarcoplasmic reticulum. The released Ca2+activates the contractile proteins within the muscle fibers, thus resulting in a contraction of the fiber.

[0011] Damages to NMJs, such as from autoimmune attack on AChRs, can contribute to various neuromuscular conditions, such as myasthenia gravis, and lead to denervation of neurons involved in NMJs. Other disease states that can negatively affect the efficiency of the NMJ include, but are not limited to, Lambert Eaton syndrome, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, and spinal muscular atrophy.

[0012] Failure to excite and / or propagate action potentials in muscle can also arise from reduced muscle excitability such as the case in critical illness myopathy (CIM).

[0013] While autoimmune attack on AChR can cause denervation at the NMJ, there are other mechanisms that can negatively impact the efficiency of an NMJ. For example, muscle fibers at the NMJ possess the muscle-specific CIC-1 chloride channel which plays a crucial role in contraction of muscle fibers by stabilizing the resting membrane potential and thereby preventing abnormal muscle contractions by regulating the flow of chloride ions into the muscle cell. Though these chloride channels help prevent excessive muscle contraction, in disease states where denervation and / or damage has occurred at NMJs, the inhibition of these chloride channels could help restore the function and efficiency of NMJs.

[0014] Drug regimens that have the ability to re-innervate damaged NMJs and help stimulate muscle fibers at NMJs can provide novel treatment methods for many neuromuscular diseases. Unfortunately, currently there are no approved drug regimens for treatment of such conditions. Surprising, the methods and compositions disclosed herein provide a novel approach to both re-innervation of damaged NMJs and stimulation of muscle fibers.

[0015] To date the published data on CIC-1 inhibitors has shown that the effect of CIC-1 inhibition is exposure dependent, i.e. as exposure to a CIC-1 inhibitor reduces theP7593PC00

[0016] 3

[0017] beneficial effect on muscle function reduces. Having an effect on muscle function after discontinuing treatment with an a CIC-1 inhibitor could be beneficial.

[0018] Summary of the Disclosure

[0019] An objective of the present disclosure is to provide methods of modifying the course and severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease. A further objective of the present disclosure is to provide methods of providing re-innervation in a subject in need thereof. In some embodiments, the method includes administering to the subject a composition comprising a therapeutically effective amount of a CIC-1 inhibitor. In some embodiments, the method includes administering to the subject a composition including a first therapeutically effective amount of a CIC-1 inhibitor and a second therapeutically effective amount of an immunomodulating or immunosuppressive agent. In some embodiments, the method includes assessing a state of innervation of the subject as a function of one or more predetermined criteria and administering to the subject a composition including a therapeutically effective amount of a CIC-1 inhibitor as a function of the assessment.

[0020] Another objective of the present disclosure is to provide methods for promoting disease-modifying effects of CIC-1 inhibitors in treating a neuromuscular condition. The method includes administering to a subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent alongside a composition including a CIC-1 inhibitor.

[0021] Another objective of the present disclosure is to provide methods of inducing, promoting, and / or enhancing re-innervation of one or more skeletal muscle fibers. These methods include administering to a subject in need thereof a therapeutically effective amount of a CIC-1 inhibitor and, optionally, an immunomodulating or immunosuppressive agent.

[0022] Another objective of the present disclosure is to provide methods of improving nerve health and / or nerve performance. These methods include administering to a subject in need thereof a therapeutically effective amount of a CIC-1 inhibitor and, optionally, an immunomodulating or immunosuppressive agent.P7593PC00

[0023] 4

[0024] Another objective of the present disclosure is to provide methods for improving skeletal muscle fiber health and / or skeletal muscle performance. These methods include administering to a subject in need thereof a therapeutically effective amount of a CIC-1 inhibitor and, optionally, an immunomodulating or immunosuppressive agent.

[0025] Another aspect of the present disclosure is to provide methods of modulating an immune system. These methods include administering to a subject in need thereof a therapeutically effective amount of a CIC-1 inhibitor and at least one immunomodulating or immunosuppressive agent.

[0026] In some embodiments, the subject in need thereof is administered a therapeutically effective amount of a CIC-1 inhibitor for period of at least 21 days; the improvement in course and severity of a neuromuscular disease is determined by improvements in muscle function, such as muscle strength, motor function and patient reported disease burden; and said improvements are maintained at least 7 days after discontinuation of treatment of a CIC-1 inhibitor.

[0027] These and other aspects and features of nonlimiting embodiments of the present disclosure will become apparent to those skilled in the art upon review of the following description of specific nonlimiting embodiments of the disclosure in conjunction with the accompanying drawings.

[0028] Brief Description of Drawings

[0029] For the purpose of illustrating aspects of the present disclosure, the drawings show one or more exemplary embodiments of the disclosure. It should be understood that the present disclosure is not limited to the precise arrangements and instrumentalities shown in the drawings.

[0030] FIG. 1 depicts a schematic illustration of a nerve crush rat model for evaluation of the disease-modifying effect of CIC-1 inhibition in a re-innervation process; specifically, the effect of CIC-1 inhibition on re-innervation was monitored using such a generic model after inducing a nerve injury by sciatic nerve crush.P7593PC00

[0031] 5

[0032] FIG. 2 depicts accelerated re-innervation data collected from three groups of rat in a nerve crush rat model, i.e., rats without injury or treatment (sham), nerve crush rat models treated with NMD712 (a CIC-1 inhibitor), and nerve crush rat models treated with vehicles only, respectively. NMD712 or vehicle was administered once daily at a dosage of 50 mg / kg per os (p.o.); the data are recorded based on the Sciatic Functional Index; treatment using NMD712 result in a faster and more complete (approximately 60%) recovery in neuromuscular function compared to treatment using vehicle only. Statistics were determined using a 2-way ANOVA with uncorrected Fisher's LSD, and * signifies p<0.05.

[0033] FIG. 3 depicts information pertaining to the Sciatic Functional Index and CatWalkXT 10.6, a gait analysis tool for measuring general muscle function.

[0034] FIG. 4 depicts a schematic illustration of a re-innervation process upon treatment using a CIC-1 inhibitor, showing denervated, partially innervated, and (fully) innervated states on a continuous scale.

[0035] FIG. 5 depicts immunohistochemistry data taken during CIC-1 inhibition treatment of rats in a nerve crush rat model. Arrow ‘A represents acetylcholine receptors (AChRs) in muscle fibres on post-synaptic side. Arrow ‘B’ represents motoneurons supposed to overlap with AChRs in muscle fibers.

[0036] FIG. 6 depicts an exemplary experimental workflow for scoring NMJ innervation status; the gastrocnemius muscle of rats from a nerve crush rat model was harvested 20 days after injury, with 18 days of dosing starting day 3 post injury; the muscle samples were analyzed by scoring of NMJ innervation status.

[0037] FIG. 7A depicts data showing the effects that NMD712 has on promoting innervation in nerve crush rat model. (A) depicts the percentages of NMJ innervation, under denervated, partially innervated, and fully innervated states, for nerve crush rat models treated with vehicle and NMD712, respectively for 18 days (starting day 3 post injury) and harvested 20 days post injury (DPI). The innervation status of data points represents n = 2 animals from each dosing group, with 37-59 NMJs analyzed per animal.P7593PC00

[0038] 6

[0039] FIG. 7B depicts the percentages of analyzed NMJs that are denervated, partially innervated, and fully innervated for nerve crush rat model where rats are treated with vehicle or NMD712. Innervation status 20 days post injury (DPI) from 5 animals in both vehicle and NMD712 groups, with 37-81 NMJs analyzed per animal.

[0040] FIG. 8 depicts immunohistochemical data of denervated, partially innervated, and fully innervated states for rats from nerve crush model treated with vehicle (upper row) and NMD712 (lower row).

[0041] FIG. 9 depicts a schematic illustration of a genetic axonal neuropathic model of Charcot-Marie-Tooth disease (CMT) type 2D mouse for evaluation of the diseasemodifying effect of CIC-1 inhibition.

[0042] FIG. 10 depicts data showing percentages of denervated, partially innervated, and fully innervated states of NMJs for wild-type (WT) mouse, CMT type 2D mouse treated with vehicle, and CMT type 2D mouse treated with NMD712, respectively; data points represent n = 4 animal from each dosing group. Treatment using NMD712 resulted in a higher percentage of fully innervated NMJs.

[0043] FIG. 11 depicts immunohistochemical data recorded for AChRs, nerves, and composites thereof for WT mouse, CMT type 2D mouse treated with vehicle, and CMT type 2D mouse treated with NMD712, respectively. NMJ morphology of innervation was assessed using immunohistochemistry (IHC) and confocal microscopy on the plantaris muscle from the mice.

[0044] FIG. 12 depicts a schematic illustration of a muscle-specific kinase myasthenia gravis (MuSK-MG) rat model for evaluation of the disease-modifying effect of CIC-1 inhibition in a post- synaptic autoimmune disease.

[0045] FIG. 13 depicts an exemplary experimental workflow for analyzing NMJ changes in the plantaris muscles of MuSK-MG rat administered compositions disclosed herein.

[0046] FIG. 14 depicts data showing percentages of denervated, partially innervated, and fully innervated states of NMJs from the plantaris muscle for MuSK-MG animals (rats) treated with vehicle (n=5) and NMD712 (n=6), respectively. Grey data points highlightP7593PC00

[0047] 7

[0048] rats exhibiting disease remission (i.e., moving from disease score 2 back to 0), a phenomenon only occurring in the NMD712-dosed group. Bars are means ± SD. The P-values above bars are results from statistical testing by Student’s t-test in vehicle vs. NMD712 groups. P <0.05 was considered significant.

[0049] FIG. 15 depicts immunohistochemical data of neuromuscular junctions in the plantaris muscle of a vehicle-treated MuSK-MG rat (upper row), and an NMD712-treated MuSK-MG rat (lower row).

[0050] FIG. 16 depicts the average number of fragments (AChR fragments >1 pm2) per NMJ and the average area of the analyzed fragments in the plantaris muscle of vehicle-treated MuSK-MG rats and NMD712-treated MuSK-MG rats. Grey data points highlight rats exhibiting disease remission (i.e., moving from disease score 2 back to 0), a phenomenon only occurring in the NMD712-dosed group.

[0051] FIG. 17A depicts the mean fiber area of Type I, Type Ila, Type llb / xand all fibers in vehicle-dosed (n=5, white bars) and NMD712-dosed (n=6, grey bars) MuSK-MG rats. Patterned data points highlight rats exhibiting disease remission (i.e., moving from disease score 2 back to 0), a phenomenon only occurring in the NMD712-dosed group. Bars are means ± SD. The P-values above bars are results from statistical testing by post-hoc pairwise comparisons in vehicle vs. NMD712 groups. P <0.05 was considered significant.

[0052] FIG. 17B depicts the mean fiber area of Type I, Type Ila, Type llb / x and all fibers in vehicle-dosed MuSK-MG rats (n=5, white bars), NMD712-dosed (n=6, grey bars) MuSK-MG rats, and sham-immunized rats (n=3, no active antigen received). Grey data points highlight rats exhibiting disease remission (i.e., moving from disease score 2 back to 0), a phenomenon only occurring in the NMD712-dosed group. Bars are means ± SD. P-values are derived from unpaired post-hoc Fisher’s LSD test.

[0053] FIG. 18 depicts representative visualizations by fluorescence microscopy of plantaris muscle fiber cross-sectional area and fiber types in a vehicle- (left panel) and NMD712-dosed (right panel) MuSK-MG rat. Muscle fiber borders were labeled by green laminin staining. Type I slow- oxidative fibers were labeled by additional green staining of the myosin heavy chain isoform 7. Type Ila fast-oxidative fibers were labeled by redP7593PC00

[0054] 8

[0055] staining of the myosin heavy chain isoform 2. Non- positive (dark) fibers were categorized as type llb / x.

[0056] FIG. 19 depicts the mean data of compound muscle action potential (CMAP) decrement at 50 Hz for five dosing groups (i.e., treatment with vehicles only, treatment with Dexamethasone, treatment with NMD712 only, treatment with both NMD712 and FcRn blocker (1G3), and treatment with FcRn blocker (1G3) only). CMAP decrement was recorded using a myasthenia gravis with anti-acetylcholine receptor antibody positive (AChR AB+ MG) rat model. The data has been normalized relative to study entry (study day 0) (absolute difference in %). CMAP amplitude decrement was measured at 50 Hz and to allow statistical analysis, last observation carried forward (LOCR) values were inserted when data points were missing due to premature termination. Differences between groups were assessed using a two-way repeated measures ANOVA, followed by Tukey's multiple comparison test. Error bars showing the standard error of the mean (SEM) has been omitted from the figure to improve visual representation of the data. One asterisk (*) indicates a significance of P<0.05 and two asterisks (**) indicate a significance of P<0.01 between two treatment groups. Group n=15-16.

[0057] FIG. 20 depicts the area under the curve (AUC) data of mean CMAP amplitude decrement (50Hz) recorded across five dosing groups of AChR AB+ MG rat models ( / .e., treatment with vehicles only, treatment with Dexamethasone, treatment with NMD712 only, treatment with both NMD712 and FcRn blocker (1G3), and treatment with FcRn blocker (1G3) only) that has been normalized relative to study entry (study day 0). To allow statistical analysis, LOCF values were inserted when data points were missing due to premature termination. Differences between groups were assessed using a one-way ANOVA, followed by Tukey's multiple comparison test. Error bars indicate the standard error of the mean (SEM). One asterisk (*) indicates a significance of P<0.05 and two or more asterisks indicate a significance of P<0.01.

[0058] FIG. 21 depicts an illustrative representation of a method for measuring the grip strength of AChR AB+ MG rat models.

[0059] FIG. 22 depicts the mean grip strength-to-body weight ratio GS:BW (force (g) / BW(g)) across five dosing groups ( / .e., treatment with vehicles only, treatment withP7593PC00

[0060] 9

[0061] Dexamethasone, treatment with NMD712 only, treatment with both NMD712 and FcRn blocker (1G3), and treatment with FcRn blocker (1G3) only) over a course of 14 days of treatment that has been normalized relative to the GS:BW at baseline (study day 0), which was given the index value 100, for the mean values. To allow statistical analysis, LOCF values were inserted when data points were missing due to premature termination. Differences between groups were assessed using a two-way repeated measures ANOVA, followed by Tukey's multiple comparison test. Error bars showing the standard error of the mean (SEM) has been omitted from the figure to improve visual representation of the data. One asterisk (*) indicates a significance of P<0.05 and two asterisks (**) indicate a significance of P<0.01 between two treatment groups. Group n=15-16.

[0062] FIG. 23 depicts the area under the curve (AUG) of mean GS:BW (force (g) / BW(g)) across five dosing groups ( / .e., treatment with vehicles only, treatment with Dexamethasone, treatment with NMD712 only, treatment with both NMD712 and FcRn blocker (1G3), and treatment with FcRn blocker (1G3) only) over a course of 14 days of treatment that has been normalized relative to the GS:BW at baseline (study day 0). LOCF was applied to the dataset to fill-in values at places with missing values due to premature termination. Differences between groups were assessed using a one-way ANOVA, followed by Tukey's multiple comparison test. Error bars indicate the standard error of the mean (SEM). One asterisk (*) indicates a significance of P<0.05 and two or more asterisks indicate a significance of P<0.01.

[0063] FIG. 24 depicts data of total immunoglobin G (IgG) concentrations (mg / mL) measured across five dosing groups of AChR AB+ MG rat models ( / .e., treatment with vehicles only, treatment with Dexamethasone, treatment with NMD712 only, treatment with both NMD712 and FcRn blocker (1G3), and treatment with FcRn blocker (1G3) only); data are presented and displayed as group averages accompanied by SEMs and analyzed by 2-way ANOVA, Tukeys post hoc test comparing all group means; significant differences between groups are indicated (*p < 0.05; ***, p<0.001; ****, p<0.0001).

[0064] FIG. 25 depicts the progress of normalized grip strength (GS) after treatment with vehicle or NMD712 after seven days (mean GS ± SEM). Healthy WT mice had stable GS, and the vehicle group showed some increase to 111.5 % on study day 7. However, the group treated with NMD712 increased GS to 128.9 % on day 7.P7593PC00

[0065] 10

[0066] FIG. 26A depicts the mean data of compound muscle action potential (CMAP) decrement difference at 50 Hz for three dosing groups (i.e., healthy wild-type mouse, vehicle-treated CMT type 2D mouse and NMD712-treated CMT type 2D mouse).

[0067] FIG. 26B depicts the mean data of compound muscle action potential (CMAP) decrement difference at 3 Hz, 10 Hz, 20 Hz, 30 Hz, 40 Hz and 50 Hz for three dosing groups ( / .e., healthy wild-type mouse, vehicle-treated CMT type 2D mouse and NMD712-treated CMT type 2D mouse).

[0068] FIG. 27 depicts the mean data of compound muscle action potential (CMAP) decrement difference at baseline (i.e. , before treatment), 3-days post treatment and 7-days post treatment for vehicle-treated CMT type 2D mouse and NMD712-treated CMT type 2D mouse. Statistical significance was determined with a one-way ANOVA with uncorrected Fisher’s LSD post-hoc test. Mean ± SEM, n=7. *p=0.0213 between baseline and study day 7 for NMD712 treated group. No significant difference in vehicle group.

[0069] FIG. 28 depicts sciatic nerve function data collected over 56 days of treatment from three groups of rats in a nerve crush rat model, i.e., rats without injury or treatment (sham, n=5), nerve crush rat models treated with NMD712 (a CIC-1 inhibitor, n=8), and nerve crush rat models treated with vehicles only (n=8), respectively. Treatment period is coloured light grey and runs from days 3 to day 58. Statistics were determined using a 2-way ANOVA with uncorrected Fisher's LSD, and * signifies p<0.05.

[0070] FIG. 29 depicts peroneal nerve function data collected after 56 days of treatment from three groups of rats in a nerve crush rat model, i.e., rats without injury or treatment (sham, n=5), nerve crush rat models treated with NMD712 (a CIC-1 inhibitor, n=8), and nerve crush rat models treated with vehicles only (n=8), respectively. Treatment period is coloured light grey and runs from days 3 to day 58. Statistics were determined using a 2-way ANOVA with uncorrected Fisher's LSD, and * signifies p<0.05.

[0071] FIG. 30 depicts the measured muscle mass of the tibialis anterior (TA), extensor digitorum longus (EDL) and soleus (SOL) of NMD712-dosed or vehicle-dosed animals at either day 20 (Figure 30A) or 63 (Figure 30B) post-injury. Muscle mass wasP7593PC00

[0072] 11

[0073] measured as wet tissue weight in connection to animal termination at either day 20 or 63 post-injury. In general, the muscles harvested in the control leg of the NMD712-dosed animals showed an overall trend of greater muscle mass when compared to the vehicle-dosed control legs. Thus, the treatment introduces a bias in the NMD712 dosing group when seeking to normalize the muscle mass of the crushed leg to the control leg. To circumvent this, the muscle mass of sham-crushed legs in sham animals was averaged for each muscle type and used as a factor for the normalization of the muscle mass from the crushed legs of the two dosing groups. These results are displayed in this figure. At 20 days post-injury, no effect of dosing was observed. At 63 days post injury, a main effect of dosing was observed, favouring an overall higher muscle mass in the crushed legs of NMD712-dosed animals closer to that of the sham animals, when compared to vehicles (p<0.01).

[0074] FIG. 31 depicts the fraction of polyinnervated endplates per field view of lumbrical muscles 9 weeks after nerve crush in a nerve crush rat model as analysed by immunohistochemistry, n values: vehicle group: 5 muscles / animals, 301 NMJs;

[0075] NMD712 group: 5 muscles / animals, 314 NMJs. Data is Mean ± SEM.

[0076] FIG. 32 depicts Neurotrophin-4 (NT-4) protein expression in gastrocnemius muscle 9 weeks after nerve crush in a nerve crush rat model as analysed by Western Blot. Protein expression was normalised to total loaded protein for each sample and presented in arbitrary units. There was a statistically significant increase in NT-4 expression in the NMD712 treated group compared to sham treated animals and a 43% greater mean NT-4 expression compared to vehicle (p = 0.085).

[0077] FIG. 33 depicts the percentage of failure of quantal release at the neuromuscular synapse at an excitation frequency of 120 Hz for two dosing groups ( / .e., vehicle-treated CMT type 2D mouse and NMD712-treated CMT type 2D mouse). Release failure was statistically more frequent in the vehicle dosed grouped than in the NMD712 dosed (ordinarily two-way ANOVA with Sidak’s multiple comparisons test between NMD712 and vehicle group, p < 0.05). 2 mice per group and 21 (vehicle) or 33 (NMD712 treated) synapse per group. Mean ± SEM.

[0078] FIG. 34 depicts the study design of a Phase 2a Charcot-Tooth Marie (CMT) clinical trial. Following screening, participants were dosed either NMD670 (400mg) or placeboP7593PC00

[0079] 12

[0080] twice daily for 21 days. Measurements were taken at baseline (prior to first dose), on days 7 and 21 of treatment and on day 28, which is 7 days after discontinuing treatment. N is the number of participants in each group.

[0081] FIG. 35 depicts the change from baseline in the CMT functional outcome measure (CMT-FOM) total score from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the CMT-FOM total score on day 21 compared to day 7, and improved further on day 28, 7 days after discontinuing treatment. On day 28, there was a statistically significant (** p = 0.06) improvement for the NMD670 group over the placebo group. Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0082] FIG. 36 depicts the change from baseline in hand grip force (measured in newtons) from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in muscle strength on day 21 compared to day 7, and the improvement in muscle strength was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28 there were statistically significant (*** p < 0.05; **** p < 0.01) improvements for the NMD670 group over the placebo group. Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0083] FIG. 37 depicts the change from baseline in the time to complete a 9-hole peg test (9HPT) from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the time to complete the test on day 21 compared to day 7, and the improvement in time was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28 there were statistically significant (* p < 0.2; ** p < 0.1) improvements for the NMD670 group over the placebo group. Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0084] FIG. 38 depicts the change from baseline in the patient reported outcome of the CMT health index (CMT-HI) total score from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the CMT-HI total score on day 21 compared toP7593PC00

[0085] 13

[0086] day 7, and the improvement in CMT-HI total score was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28, the improvement was larger than -3.2 points for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein etal, 2024). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0087] FIG. 39 depicts the change from baseline in the patient reported outcome of the CMT health index (CMT-HI) short form from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the CMT-HI short form score on day 21 compared to day 7, and the improvement in CMT-HI short form score was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -2.8 points for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein etal, 2024). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0088] FIG. 40 depicts the change from baseline in the patient reported outcome of the CMT-HI hand / finger subscale from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the CMT-HI hand / finger subscale on day 21 compared to day 7, and the improvement in CMT-HI hand / finger subscale was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -1.8 points for NMD670, which is considered to be a clinically meaningful change (Rehbein etal, 2024). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0089] FIG. 41 depicts the change from baseline in the time to cover 10 metres in the timed 10 metres walk / run test from the Phase 2a CMT clinical trial after 7 and 21 days of treatment and on day 28, which is 7 days after discontinuing treatment. The NMD670 group improved numerically in the time to cover 10 metres on day 21 compared to day 7, and the reduction in time to cover 10 metres was maintained on day 28, 7 days after discontinuing treatment. On day 28, there was a statistically significant (p < 0.2) improvement for the NMD670 group over the placebo group. Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).P7593PC00

[0090] 14

[0091] FIG. 42 depicts the change from baseline in hand grip force (measured in newtons) from the Phase 2a CMT clinical trial for CMT Type 1 patients. The NMD670 group (n=28) improved numerically in muscle strength on day 21 compared to day 7, and the improvement in muscle strength was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28 there were statistically significant (** p < 0.1) improvements for the NMD670 group over the placebo group (n=25). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0092] FIG. 43 depicts the change from baseline in hand grip force (measured in newtons) from the Phase 2a CMT clinical trial for CMT Type 2 patients. The NMD670 group (n=13) improved numerically in muscle strength on day 21 compared to day 7, and the improvement in muscle strength was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28 there were statistically significant (** p < 0.1; *** p < 0.05) improvements for the NMD670 group over the placebo group (n=13). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0093] FIG. 44 depicts the change from baseline in the time to complete a 9-hole peg test (9HPT) from the Phase 2a CMT clinical trial for CMT Type 1 patients. The NMD670 group (n=28) improved numerically in the time to complete the test on day 21 compared to day 7, and the improvement in force was maintained on day 28, 7 days after discontinuing treatment. On day 7 there was a statistically significant (* p < 0.2) improvement for the NMD670 group over the placebo group (n=25). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0094] FIG. 45 depicts the change from baseline in the time to complete a 9-hole peg test (9HPT) from the Phase 2a CMT clinical trial for CMT Type 2 patients. The NMD670 group (n=13) improved numerically in the time to complete the test on day 21 compared to day 7, and the improvement in force was maintained on day 28, 7 days after discontinuing treatment. On day 21 there was a statistically significant (** p < 0.1) improvement for the NMD670 group over the placebo group (n=13). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0095] FIG. 46 depicts the change from baseline in the patient reported outcome of the CMT health index (CMT-HI) short form from the Phase 2a CMT clinical trial for CMT Type 1 patients. The NMD670 group (n=28) improved numerically in the CMT-HI short formP7593PC00

[0096] 15

[0097] score on day 21 compared to day 7, and the improvement in CMT-HI short form score was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -2.8 points (dotted horizontal line) for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein et al, 2024). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0098] FIG. 47 depicts the change from baseline in the patient reported outcome of the CMT health index (CMT-HI) short form from the Phase 2a CMT clinical trial for CMT Type 2 patients. The improvement in CMT-HI short form score was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -2.8 points (dotted horizontal line) for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein etal, 2024). On days 7, 21 and 28 there was a statistically significant (** p < 0.1; *** p < 0.05) improvement for the NMD670 group over the placebo group (n=13). Data is presented as least squares mean (LSM) change from baseline ± standard error (SE).

[0099] The drawings are not necessarily to scale and can be illustrated by phantom lines, diagrammatic representations and fragmentary views. In certain instances, details that are not necessary for an understanding of the embodiments or that render other details difficult to perceive may have been omitted.

[0100] Definitions

[0101] All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0102] The nomenclature used in the present application is based on IIIPAC systematic nomenclature, unless indicated otherwise.

[0103] The term "jitter" refers to the variability in the arrival time of muscle fibre action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using single fiber electromyography (sfEMG).P7593PC00

[0104] 16

[0105] The term "blocking" refers to complete NMJ transmission failure of muscle fibre action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using sfEMG.

[0106] The term “placebo” refers to a dosage form possessing no therapeutic activity.

[0107] The term "active pharmaceutical ingredient" (or "API") denotes the compound or molecule in a pharmaceutical composition that has a particular biological activity.

[0108] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0109] The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered.

[0110] The term "pharmaceutically acceptable" denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

[0111] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer or acidifier, excipient, stabilizer, or preservative.

[0112] To facilitate the understanding of this disclosure, a number of terms are defined below and throughout the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one ofP7593PC00

[0113] 17

[0114] ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification, including definitions, will control. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not limit the disclosure, except as outlined in the claims. All publications, patent disclosures, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0115] It is to be understood that any aspect and / or element of any embodiment of the method(s) described herein or otherwise can be combined in any way to form additional embodiments of the method(s) all of which are within the scope of the method(s).

[0116] Where a process is described herein, those of ordinary skill in the art will appreciate that the process can operate without any user intervention. In other embodiments, the process includes some human intervention (e.g., a step is performed by or with the assistance of a human).

[0117] As used herein, including the claims, the phrase “at least some” means “one or more” and includes the case of only one.

[0118] As used herein, including the claims, the term “at least one” should be understood as meaning “one or more” and therefore includes both embodiments that include one or multiple components. Furthermore, dependent claims that referto independent claims that describe features with “at least one” have the same meaning, both when the feature is referred to as “the” and “the at least one”.

[0119] For regulatory purposes, a disease modifying effect will be considered when a pharmacologic treatment delays the underlying pathological or pathophysiological disease processes and when this is accompanied by improvement in clinical signs and symptoms of the dementing condition.” (EMA guideline on medicinal products for the treatment of Alzheimer’s disease and other dementias)P7593PC00

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[0121] Detailed Description

[0122] An objective of the present disclosure is to provide methods of modifying the course and severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease.

[0123] One aspect of the present disclosure is directed towards methods for disease modification and / or promoting a disease-modifying effect in a subject in need thereof. These methods include administering to a subject in need thereof a therapeutically effective amount of a CIC-1 inhibitor.

[0124] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a diseasemodifying treatment of a neuromuscular disease. In some embodiments, the CIC-1 inhibitor is for use as a disease-modifying agent. In one aspect, the present invention relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease. In one aspect, the present invention relates to a CIC-1 inhibitor for use as a disease-modifying agent in the method of a diseasemodifying treatment of a neuromuscular disease. In one aspect, the present invention relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein the disease modifying effect is determined by at least one of re-innervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and improved immune system modulation.

[0125] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of modifying or improving the course and / or severity of a neuromuscular disease, said method comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease.

[0126] “Disease modification” can include changes in the disease state and / or progression that are influenced by the treatments and / or compositions disclosed herein. Disease modification can also include changes brought on by the treatments and / or compositions disclosed herein that affect the underlying pathophysiology of the disease and have beneficial outcomes on the clinical course of the disease. For example, aP7593PC00

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[0128] disease-modifying effect remains after the treatment has ended. Disease modification can also include therapeutic interventions that alter the underlying pathological processes in addition to the direct mode of action of a drug and / or pharmaceutical formulation rather than merely addressing symptoms.

[0129] A “disease-modifying” treatment, for example, can include any treatment and / or administration of a composition disclosed herein that favourably alters the course of a disease by remediating its pathogenetic mechanism. A disease-modifying treatment results in one or more disease-modifying effects, which the disease-modifying treatment can be measured by. A disease-modifying treatment can be curative. For example, a disease-modifying treatment can be contrastingly different from a symptomatic treatment that involves only alleviating the symptoms of the disease and does not target and / or correct the underlying molecular cause of the disease.

[0130] According to exemplary aspects, methods described herein can constitute a “diseasemodifying” treatment. According to another exemplary aspect, methods described herein can provide a “disease-modifying” potential, for example, the methods can have the potential to favourably alter the course of a disease by remediating its pathogenetic mechanism. A primary goal of disease-modifying therapies is to slow progress of, halt, or reverse disease progression, thereby possibly improving long-term clinical outcomes and quality of life for patients.

[0131] In exemplary embodiments, a disease modifying effect is determined by measuring one or more skeletal muscle parameters before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration of the CIC-1 inhibitor, measuring the same skeletal muscle parameters that were measured before administration of the CIC-1 inhibitor, and comparing the one or more skeletal muscle parameters before administration of the CIC-1 inhibitor to the one or more skeletal muscle parameters after administration of the CIC-1 inhibitor. If an at least partial improvement in the skeletal muscle parameter has occurred after comparing the skeletal muscle parameter before administration of the CIC-1 inhibitor to the skeletal muscle parameter after administration of the CIC-1 inhibitor, then a disease modifying effect has occurred. In exemplary embodiments, a disease modifying effect is determined by measuring one or more immune system parameters before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration ofP7593PC00

[0132] 20

[0133] the CIC-1 inhibitor, measuring the same immune system parameters that were measured before administration of the CIC-1 inhibitor, and comparing the one or more immune system parameters before administration of the CIC-1 inhibitor to the one or more immune system parameters after administration of the CIC-1 inhibitor.

[0134] In exemplary embodiments, a disease modifying effect is determined by measuring one or more skeletal muscle parameters and / or immune system parameters in a CIC-1 inhibitor treatment group and a placebo group, administering the CIC-1 inhibitor to the treatment group for a period of time, administering a placebo to the placebo group for a period of time that is identical to the period of time the treatment group receives the CIC-1 inhibitor, waiting for a period of time after stopping administration of the CIC-1 inhibitor and the placebo, measuring the same skeletal muscle parameters and / or immune system parameters that were measured before administration of the CIC-1 inhibitor and placebo in the treatment groups, and comparing the one or more skeletal muscle parameters and / or immune system parameters measured before administration of the CIC-1 inhibitor and placebo to the one or more skeletal muscle parameters and / or immune system parameters measured after administration of the CIC-1 inhibitor and placebo. In exemplary embodiments, a disease modifying effect has occurred if the comparing shows that an improvement in at least one skeletal muscle parameter and / or immune system parameter has occurred in the CIC-1 inhibitor treatment group and not in the placebo group.

[0135] In exemplary embodiments, a disease modifying effect is determined by measuring one or more biomarkers indicative of disease progression before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration of the CIC-1 inhibitor, measuring the same biomarkers indicative of disease progression that were measured before administration of the CIC-1 inhibitor, and comparing the one or more biomarkers indicative of disease progression before administration of the CIC-1 inhibitor to the one or more biomarkers indicative of disease progression after administration of the CIC-1 inhibitor. In exemplary embodiments, a disease modifying effect has occurred if the comparing shows that at least one biomarker for disease progression has decreased and / or at least one biomarker for disease recovery or alleviation has increased.P7593PC00

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[0137] In exemplary embodiments, the disease modifying effect is re-innervation and / or innervation and the re-innervation and / or innervation is determined by measuring one or more biomarkers of nerve repair and / or nerve growth. These biomarkers can include, but are not limited to, increased expression of growth-associated genes in axotomized motor neurons (e.g., increased expression of c-Jun, p75 neurotrophic factor receptor (p75NTR), cell cycle division 2 (Cdc2), GAP-43, tubulin, actin, GDNF, adhesion molecules, mitogens, receptors, and cytokines).

[0138] In exemplary embodiments, a disease modifying effect is determined by measuring one or more biomarkers indicative of disease progression in a CIC-1 inhibitor treatment group and a placebo group, administering the CIC-1 inhibitor to the treatment group for a period of time, administering the placebo to a placebo group for a period of time that is identical to the period of time the treatment group receives the CIC-1 inhibitor, waiting for a period of time after stopping administration of the CIC-1 inhibitor and the placebo, measuring the same biomarkers indicative of disease progression that were measured before administration of the CIC-1 inhibitor and placebo in the treatment groups, and comparing the one or more biomarkers indicative of disease progression measured before administration of the CIC-1 inhibitor and placebo to the one or more biomarkers indicative of disease progression measured after administration of the CIC-1 inhibitor and placebo. In exemplary embodiments, a disease modifying effect has occurred if the comparing shows that at least one biomarker for disease progression has decreased and / or at least one biomarker for disease recovery or alleviation has increased in the CIC-1 treatment group and not in the placebo group.

[0139] In some embodiments, the disease modifying effect is measured as a neuromuscular transmission of the subject by at least 10%, such as by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, etc.

[0140] In some embodiments, the disease modifying effect is an improvement in compound muscle action potential (CMAP) decrement measured at a frequency of at least 5 Hz and no greater than 100 Hz. As nonlimiting examples, the CMAP decrement can be measured at frequencies such as, without limitation, about 2 Hz, about 5 Hz, about 10 Hz, about 20 Hz, about 30, Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 70 Hz,P7593PC00

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[0142] about 80 Hz, about 90 Hz, or about 100 Hz. In some embodiments, the CMAP decrement is measured at a frequency of 50 Hz.

[0143] In some embodiments, the disease modifying effect is an improvement in the grip strength of the subject by at least 5%, such as by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or by 100%, etc.

[0144] In some embodiments, the disease modifying effect is a restoration of at least 5% of the grip strength of the subject, such as at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% of the grip strength of the subject.

[0145] In exemplary embodiments, the disease modifying effect is an effect caused by any one of the treatments and / or compositions disclosed herein that alleviates and / or slows the progression of a disease. In exemplary embodiments, the disease modifying effect is an effect caused by any one of the treatments and / or compositions disclosed herein that targets at least one molecular mechanism of the disease that contributes to the underlying pathophysiology of the disease. In exemplary embodiments, the diseasemodifying effect is an effect that persists for a specific time period after treatment with the CIC-1 inhibitor and optionally the immunomodulating or immunosuppressive agent has been terminated (i.e., after the last administration of the CIC-1 inhibitor and optionally the immunomodulating or immunosuppressive agent). In exemplary embodiments, the disease-modifying effect is an effect provided by the treatment with the CIC-1 inhibitor and optionally the immunomodulating or immunosuppressive agent that persists at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year or more than one year after treatment with the CIC-1 inhibitor and optionally the immunomodulating or immunosuppressive agent has been terminated. In exemplary embodiments, the disease-modifying effect is reinnervation or innervation of a NMJ. The compositions disclosed herein can perform a therapeutic function or functions by increasing the degree of innervation or promoting / enhancing re-innervation in the subject by, without limitation, restoring aP7593PC00

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[0147] body part of the subject from an at least a partially denervated state to an at least partially innervated state.

[0148] In exemplary embodiments, the disease modifying effect is not an acute effect. An “acute effect” can include any effect (positive or negative) that produces a maximum biological, chemical or electrical response in an organism either immediately after or within the time when the maximum concentration of the drug, compound or pharmaceutical composition is present in blood or plasma following the administration of a drug, compound or pharmaceutical composition and declines in correlation with the concentration of the drug, compound or pharmaceutical composition in the organism (i.e., declines with decreasing concentrations of the drug, compound or pharmaceutical composition). In exemplary embodiments, an acute effect does not include effects that inversely correlate with the concentration of the drug, compound or pharmaceutical composition in the organism and / or effects that persist in the organism after a portion and / or all of the drug, compound or pharmaceutical composition has been eliminated from the organism.

[0149] In some embodiments, the disease modifying effect is a change in muscle architecture selected from: increased number of neuron connections with a muscle tissue, increased muscle volume, increased muscle fiber length, increased muscle pennation angle, increased physiological cross-sectional area (PCSA), and longer axons in motor neurons.

[0150] In some embodiments, the disease modifying treatment is determined by at least one disease modifying effect, and said disease modifying effect is determined by reinnervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and / or improved immune system modulation. In some embodiments, the disease modifying effect is determined by at least one of re-innervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and improved immune system modulation.P7593PC00

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[0152] In one aspect, the present invention relates to a CIC-1 inhibitor for use as diseasemodifying agent in a disease-modifying treatment of a neuromuscular disease, wherein said use is in:

[0153] a. promoting re-innervation of muscle fibres in the subject suffering from the neuromuscular disorder,

[0154] b. improving nerve health in the subject suffering from the neuromuscular disorder,

[0155] c. improving nerve performance in the subject suffering from the neuromuscular disorder,

[0156] d. improving muscle fiber health in the subject suffering from the neuromuscular disorder,

[0157] e. improving muscle fiber performance in the subject suffering from the neuromuscular disorder, and / or

[0158] f. modulating the immune system in the subject suffering from the neuromuscular disorder.

[0159] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of disease-modifying treatment of a neuromuscular disorder in a subject in need thereof, the method comprising administering a CIC-1 inhibitor,

[0160] wherein said method is for use in promoting re-innervation of muscle fibres in the subject suffering from the neuromuscular disorder, wherein said method is for use in improving nerve health in the subject suffering from the neuromuscular disorder,

[0161] wherein said method is for use in improving nerve performance in the subject suffering from the neuromuscular disorder,

[0162] wherein said method is for use in improving skeletal muscle fiber health in the subject suffering from the neuromuscular disorder, wherein said method is for use in improving muscle fiber performance in the subject suffering from the neuromuscular disorder, and / or wherein said method is for use in modulating the immune system the subject suffering from the neuromuscular disorder.

[0163] Another aspect of the present disclosure is the use of a composition comprising a CIC-1 inhibitor and optionally an immunomodulating or immunosuppressive agent to ameliorate symptoms of neuromuscular conditions, prevent the progression ofP7593PC00

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[0165] neuromuscular conditions, and / or restore neuromuscular functions in a subject in need thereof including, without limitation, reversing the detrimental effects of a drug-induced neuromuscular blockade.

[0166] Re-innervation

[0167] In exemplary embodiments, the disease modifying effect is re-innervation and / or innervation. One aspect of the present disclosure is directed towards methods for providing re-innervation and / or innervation to a subject in need thereof. The terms “providing re-innervation and / or innervation” and “promoting re-innervation and / or innervation” are used interchangeably herein. The terms “re-innervation of muscle fibers” and “re-innervation of skeletal muscle fibers” are used interchangeably herein. In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of promoting re-innervation of muscle fibers, preferably in a subject suffering from a neuromuscular disorder.

[0168] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by re-innervation of muscle fibres.

[0169] In exemplary embodiments, “innervation” includes supplying one or more motor nerve pathways and / or branches to one or more muscle fibers and / or muscle fascicles in a motor unit. Innervation can aid in the formation of new NMJs and can aid in the regulation and / or activation of skeletal muscles. Innervation can also include forming one or more new endoneurial tubes in the axon of a motor neuron or nerve cell.

[0170] Innervation can also include forming one or more new Schwann cell connections in the axon of a motor neuron. Innervation can form new NMJs to allow improved control, regulation and / or activation of skeletal muscles. Innervation can also include any of the hallmarks for innervation discussed in Gordon, 2020 and Kostrominova, 2022, the entire content of which is incorporated by reference herein.

[0171] In exemplary embodiments, “denervation” includes losing one or more motor nerve pathways and / or branches to one or more muscle fibers and / or muscle fascicles in a motor unit. Denervation can also include losing one or more endoneurial tubes in the axon of a motor neuron or nerve cell. Denervation can also include losing one or more Schwann cell connections in the axon of a motor neuron. Denervation can cause existing NMJs to lose their ability to regulate and / or activate skeletal muscles. NMJsP7593PC00

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[0173] are essential for maintaining normal muscle structure and function, and loss of motor innervation (i.e., denervation) disrupts these junctions, leading to muscle degeneration. Denervation can also decrease the number of active NMJs in a subject and cause muscle atrophy in the subject. Denervation can include the loss of nerve signal transmission to a body part, or the progression to a state under which a motor unit or muscle fiber is no longer structurally and / or functionally connected to one or more motor nerves. Denervation can be caused by various factors including, but not limited to, nerve injury, aging-related loss of motor neurons, diseases, chemical exposure, surgical intervention, certain disorders (e.g., autoimmune disorders), and other abnormalities. Denervation can also include any of the hallmarks for denervation discussed in Gordon, 2020 and Kostrominova, 2022, the entire content of which is incorporated by reference herein.

[0174] In exemplary embodiments, “re-innervation” includes a process of restoring one or more damaged and / or destroyed motor nerve pathways and / or branches to one or more muscle fibers and / or muscle fascicles in a motor unit. Re-innervation can also include recovering one or more damaged and / or destroyed endoneurial tubes in the axon of a motor neuron or nerve cell. Re-innervation can also include restoring one or more Schwann cell connections in the axon of a motor neuron. Re-innervation can allow damaged and / or destroyed NMJs in a subject to regain their ability to regulate and / or activate skeletal muscles. Re-innervation can also restore and / or increase the number of active NMJs in a subject. Re-innervation can also restore nerve signal transmission to a body part that is losing or has lost at least part of its nerve signal transmission pathway. In exemplary embodiments, re-innervation can restore a body part and / or skeletal muscle from a denervated state to at least a partially innervated state. In exemplary embodiments, re-innervation can restore a body part and / or skeletal muscle from a denervated state to a fully innervated state. In exemplary embodiments, re-innervation can restore a body part and / or skeletal muscle from a partially denervated state or a partially innervated state to a fully innervated state. Additional details will be provided below in this disclosure. Re-innervation can also include any of the hallmarks for re-innervation discussed Gordon, 2020 and Kostrominova, 2022, the entire content of which is incorporated by reference herein.

[0175] In some embodiments, the method for providing re-innervation comprises improving neuromuscular junction (NMJ) function in the subject.P7593PC00

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[0177] In some embodiments, the method for providing re-innervation includes improving or restoring a NMJ function in a damaged and / or denervated NMJ in the subject. In some embodiments, the method restores at least 60% of a neuromuscular function in a damaged and / or denervated NMJ in the subject. As nonlimiting examples, the method can restore at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or by 100%, etc., of a neuromuscular function in a damaged and / or denervated NMJ in the subject. A neuromuscular function can be an ability of one or more muscles to contract via a coordination between the nervous system (e.g., a motor neuron) and one or more muscles (e.g., muscle fibers). In these embodiments, the method can improve or restore a damaged or denervated NMJ’s ability to induce muscle contraction by at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or by 100%.

[0178] In some embodiments, improvement in NMJ function is evaluated from decrements on repetitive nerve stimulation (RNS). As used herein, a “decrement on repetitive nerve stimulation” or a “decrement on RNS” is a decrease in the magnitude of the compound muscle action potential (CMAP) in response to repeated nerve stimulation. It’s an indication of NMJ dysfunction and is often used to diagnose myasthenia gravis and other neuromuscular disorders, consistent with details described elsewhere in this disclosure.

[0179] In some embodiments, providing the re-innervation includes increasing an average percentage of partially innervated NMJs to at least 60%. As nonlimiting examples, providing the re-innervation can include increasing an average percentage of partially innervated NMJs to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%, etc.

[0180] In some embodiments, providing the re-innervation includes increasing an average percentage of fully innervated NMJs to at least 35%. As nonlimiting examples, providing the re-innervation can include increasing an average percentage of fully innervated NMJs to at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%, etc.P7593PC00

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[0182] In some embodiments, providing the re-innervation includes increasing an average percentage of partially innervated fibers in the subject to at least 60%. As nonlimiting examples, providing the re-innervation can include increasing an average percentage of partially innervated fibers to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%, etc.

[0183] In some embodiments, providing the re-innervation includes increasing an average percentage of fully innervated fibers in the subject to at least 35%. As nonlimiting examples, providing the re-innervation can include increasing an average percentage of fully innervated fibers to at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, 100%, etc.

[0184] In some embodiments, re-innervation comprises restoring at least 60% of a neuromuscular function. In some embodiments, re-innervation comprises increasing an average percentage of fully innervated NMJs to at least 35%. In some embodiments, re-innervation comprises increasing an average percentage of fully innervated NMJs to at least 60%. In some embodiments, re-innervation comprises increasing an average percentage of partially innervated fibers to at least 35%. In some embodiments, reinnervation comprises increasing an average percentage of partially innervated fibers to at least 60%.

[0185] In some embodiments, the proportion of polyinnervated NMJs during reinnervation is lower after administration of the CIC-1 inhibitor compared to vehicle treatment. In some embodiments, the prevalence of polyinnervated neuromuscular junctions is reduced by at least 30% relative to a vehicle-treated control.

[0186] In some embodiments, providing the re-innervation includes reducing endplate fragmentation in the subject. As used herein, an “endplate” or “motor endplate” is a part of a muscle fiber where a motor neuron's axon terminal meets the muscle fiber.

[0187] In some embodiments, providing the re-innervation includes reducing an average NMJ fragmentation in the subject to no greater than 10 fragments per NMJ that are above 1 pm2. As nonlimiting examples, providing the re-innervation can include reducing an average NMJ fragmentation in the subject to no greater than 5 fragments, no greaterP7593PC00

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[0189] than 6 fragments, no greater than 7 fragments, no greater than 8 fragments, no greater than 9 fragments, etc., that are above 1 pm2per NMJ.

[0190] In some embodiments, providing the re-innervation includes increasing an average fragment size of AChR in the subject to at least 15 pm2of AChR per fragment. As nonlimiting examples, providing the re-innervation can include increasing an average fragment size of AChR in the subject to at least 16 pm2, at least 17 pm2, at least 18 pm2, at least 19 pm2, at least 20 pm2, etc., of AChR per fragment.

[0191] In some embodiments, providing the re-innervation can include increasing a colocalization between a nerve and an AChR in the subject.

[0192] In some embodiments, providing the re-innervation includes increasing a cross-sectional area of a muscle fiber in the subject by at least 15%. As nonlimiting examples, providing the re-innervation can include increasing a cross-sectional area of a muscle fiber in the subject by at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, etc. In some embodiments, the muscle fiber can include a type Ila fiber, a type lib fiber, a type x fiber, and / or the like.

[0193] In some embodiments, the method of providing re-innervation includes administering to the subject a composition including a therapeutically effective amount of a CIC-1 inhibitor. In some embodiments, the method includes assessing a state of innervation of the subject as a function of one or more predetermined criteria and administering to the subject a composition including a therapeutically effective amount of a CIC-1 inhibitor as a function of the assessment.

[0194] In some embodiments, providing re-innervation includes improving a neuromuscular transmission of the subject by at least 10%. As nonlimiting examples, providing the reinnervation includes improving a neuromuscular transmission of the subject by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, etc.

[0195] In some embodiments, providing re-innervation includes improving a compound muscle action potential (CMAP) decrement measured at a frequency of at least 5 Hz and noP7593PC00

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[0197] greater than 100 Hz. As nonlimiting examples, the CMAP decrement can be measured at frequencies such as, without limitation, about 2 Hz, about 5 Hz, about 10 Hz, about 20 Hz, about 30, Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 70 Hz, about 80 Hz, about 90 Hz, or about 100 Hz. In some embodiments, the CMAP decrement is measured at a frequency of 50 Hz.

[0198] In some embodiments, providing re-innervation includes improving the grip strength of the subject by at least 5%. As nonlimiting examples, providing re-innervation includes improving the grip strength of the subject by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or by 100%, etc.

[0199] In some embodiments, providing re-innervation includes restoring at least 5% of the grip strength of the subject. As nonlimiting examples, providing re-innervation includes restoring at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% of the grip strength of the subject.

[0200] In some embodiments, the method for providing re-innervation includes suppressing a reduction in Immunoglobulin G (IgG) level of the subject.

[0201] The method of providing re-innervation and / or innervation includes administering a composition to a subject in need thereof. The composition includes a therapeutically effective amount of a chloride ion channel 1 (CIC-1) inhibitor. As used herein, a “chloride ion channel 1 inhibitor” or “CIC-1 inhibitor” is a drug that blocks the chloride ion channel (CIC-1) in skeletal muscles. Optionally, the composition further includes a therapeutically effective amount of an immunomodulating or immunosuppressive agent, as described in further detail below.

[0202] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method for providing reinnervation in a subject in need thereof, wherein the method comprises administering a) a CIC-1 inhibitor; and b) an immunomodulating or immunosuppressive agent.P7593PC00

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[0204] Another aspect of the present disclosure is a method for providing re-innervation and / or innervation to a subject in need thereof comprising: providing an at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or an at least 35% improvement in the subject’s average percentage of fully innervated NMJs by (i) administering a composition containing a therapeutically effective amount of a CIC-1 inhibitor; and obtaining an improvement in the subject’s neuromuscular function, architecture and / or performance. The improvement can include any one or more of the disease-modifying effects discussed herein that are related to improvements in the subject’s NMJ performance (e.g., jitter, blocking, RNS, an average percentage of partially innervated NMJs, average percentage of fully innervated NMJs, average percentage of partially innervated fibers, average percentage of fully innervated fibers, proportion of polyinnervated NMJs, endplate fragmentation, average NMJ fragmentation, average fragment size of AChR, co-localization between a nerve and an AChR, cross-sectional area of a muscle fiber, neuromuscular transmission, compound muscle action potential (CMAP) decrement, grip strength, muscle strength, and muscle force). For example, the improvement could include an at least 65% improvement in the subject’s NMJ’s ability to induce muscle contraction after the administering of the CIC-1 inhibitor when compared to the subject’s NMJ’s ability to induce muscle contraction before the administering of the CIC-1 inhibitor. This improvement can be determined by monitoring the subject’s NMJ’s ability to induce muscle contraction during the administering of the CIC-1 inhibitor and optionally can be obtained by increasing or decreasing the therapeutically effective amount of the CIC-1 inhibitor in the composition.

[0205] In one aspect, the present invention relates to a method for providing re-innervation and / or innervation to a subject in need thereof comprising:

[0206] • providing an at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or an at least 35% improvement in the subject’s average percentage of fully innervated NMJs by:

[0207] • administering a composition containing a therapeutically effective amount of a CIC-1 inhibitor; and

[0208] • obtaining an at least 65% improvement in the NMJ’s ability to induce muscle contraction after the administering when compared to the NMJ’s ability to induce muscle contraction before the administering by monitoring the NMJ’s ability to induce muscle contraction during the administering and optionallyP7593PC00

[0209] 32

[0210] increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0211] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an at least 60% improvement in the NMJ’s average percentage of partially innervated fibers after the administering when compared to the NMJ’s average percentage of partially innervated fibers before the administering by monitoring the NMJ’s average percentage of partially innervated fibers during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0212] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an at least 35% improvement in the NMJ’s average percentage of fully innervated fibers after the administering when compared to the NMJ’s average percentage of fully innervated fibers before the administering by monitoring the NMJ’s average percentage of fully innervated fibers during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0213] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining a reduction in the subject’s average NMJ fragmentation of no more than 10 fragments per NMJ that are above 1 pm2after the administering by monitoring the average NMJ fragmentation during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition. In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an increase in the subject’s average fragment size of AChR of at least 15 pm2of AChR per fragment after the administering by monitoring the average fragment size of AChR during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.P7593PC00

[0214] 33

[0215] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an increase in the subject’s cross-sectional area of a muscle fiber of at least 15% after the administering when compared to the cross-sectional area of the muscle fiber before the administering by monitoring the cross-sectional area of the muscle fiber during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0216] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an increase in neuromuscular transmission in the subject of at least 10% after the administering when compared to the neuromuscular transmission in the subject before the administering by monitoring neuromuscular transmission in the subject during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0217] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an at least 5% improvement in the subject’s grip strength after the administering when compared to the subject’s grip strength before the administering by monitoring the subject’s grip strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0218] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises restoring at least 5% of the subject’s grip strength after the administering by monitoring the subject’s grip strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition. In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an increase in the subject’s muscle strength by at least 0.10 kg after the administering when compared to the subject’s muscle strength before the administeringP7593PC00

[0219] 34

[0220] by monitoring the subject’s muscle strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0221] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an increase in the subject’s muscle force by at least 3.0 newtons after the administering when compared to the subject’s muscle force before the administering by monitoring the subject’s muscle force during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0222] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an at least 5% increase in the subject’s muscle strength after the administering when compared to the subject’s muscle strength before the administering by monitoring the subject’s muscle strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0223] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an improvement in the subject’s forced vital capacity (FVC) of at least 5% after the administering when compared to the subject’s FVC before the administering by monitoring the subject’s FVC during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition. In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an improvement in the subject’s forced expiratory volume in 1 second (FEV1) of at least 5% after the administering when compared to the subject’s FEV1 before the administering by monitoring the subject’s FEV1 during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.P7593PC00

[0224] 35

[0225] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an improvement in the subject’s maximal inspiratory pressure (MIP) of at least 5% after the administering when compared to the subject’s MIP before the administering by monitoring the subject’s MIP during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0226] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining an improvement in the subject’s maximal expiratory pressure (MEP) of at least 5% after the administering when compared to the subject’s MEP before the administering by monitoring the subject’s MEP during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0227] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining a reduction in blocking in the NMJs of at least 5% after the administering when compared to a degree of blocking in the NMJs before the administering by monitoring blocking in the NMJs during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition. In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises obtaining a reduction in jitter of at least 5% after the administering when compared to a degree of jitter presented by the subject before the administering by monitoring jitter during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0228] In some embodiments, providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises reducing jitter in the subject to no more than 30 ps, no more than 25 ps, no more than 20 ps, no more than 15 ps or no more than 10 ps after the administering.P7593PC00

[0229] 36

[0230] In some embodiments, providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[0231] • obtaining a reduction in blocking in the NMJs of at least 5% after the administering when compared to a degree of blocking in the NMJs before the administering by measuring blocking in the NMJs during the administering with single fibre electromyography (sfEMG) and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition; and • obtaining a reduction in jitter of at least 5% after the administering when compared to a degree of jitter presented by the subject before the administering by measuring jitter during the administering with sfEMG and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[0232] In some embodiments, the providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises reducing jitter in the subject to no more than 30 ps, no more than 25 ps, no more than 20 ps, no more than 15 ps or no more than 10 ps after the administering by measuring jitter during the administering with sfEMG.

[0233] In some embodiments, providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises detecting a disease modifying effect in the subject during the administering by subjecting the subject to one or more MRI techniques.

[0234] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method for providing re-innervation and / or innervation in a subject in need thereof, wherein the method comprises:

[0235] • administering to the subject a composition comprising a first therapeutically effective amount of a CIC-1 inhibitor and, optionally, a second therapeutically effective amount of an immunomodulating or immunosuppressive agent for a period of time;

[0236] • terminating administration of the composition for a period of time,P7593PC00

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[0238] • measuring one or more re-innervation parameters in the subject after the period of time following termination; and

[0239] • beginning administration of the composition again when the one or more reinnervation parameters fall below a threshold, wherein the threshold is a set value of a re-innervation parameter.

[0240] Muscle architecture

[0241] In exemplary embodiments, a disease modifying effect is a change in muscle architecture. Muscle architecture can include muscle volume, muscle fiber length, muscle pennation angle, and / or physiological cross-sectional area (PCSA). PCSA equals the sum of the cross-sectional areas (CSAs) of all fibers in a muscle and can be directly proportional to the muscle’s maximum force-generating capacity. A change in muscle architecture can be determined from anatomical MR images, where muscle volumes can be obtained accurately and reliably. Other analytical techniques that can be used to determine if a change in muscle architecture and / or an improvement in skeletal muscle fiber health has occurred are those disclosed in Hooijmans etal., 2024, the entire content of which is incorporated by reference herein. For example, Quantitative Magnetic Resonance Imaging (qMRI), a technique that involves acquiring multiple MRI images with specific parameter manipulations and then fitting the resulting data to computational models to generate maps of tissue properties, can be used to determine if muscle atrophy or hypertrophy is present or has changed in a subject / patient / human after administration of any one of the compositions and / or after treatment of any one of the methods disclosed herein through characterization of muscle deformation during the passive lengthening / shortening and / or active contractions of muscle fibers. Multi-Echo Spin Echo,1H MRS,31P MRS, CEST, and / or I VIM can also be used to determine if a change in muscle architecture has occurred. The examination of fat infiltration into contractile muscle tissue can also determine if a change in muscle architecture has occurred.

[0242] In many neuromuscular disorders, as well as in aging, a reduction in the quality of the remaining muscle tissue has been shown through correlating contractile CSA with strength measures Hooijmans etal., 2024, the entire content of which is incorporated by reference herein.P7593PC00

[0243] 38

[0244] Skeletal muscle fiber health and performance

[0245] In exemplary embodiments, the methods and / or compositions disclosed herein can improve skeletal muscle fiber health (e.g., improve the function, structure, longevity and resilience of a skeletal muscle fiber) and / or skeletal muscle performance (e.g., improve the ability of a skeletal muscle to communicate with motor neurons at a NMJ, and improve the ability of a skeletal muscle to contract and relax in response to stimuli).

[0246] In some embodiments, the disease modifying effect is an improvement in skeletal muscle fiber health. In some embodiments, the compositions and / or methods disclosed herein provide improved skeletal muscle fiber health. In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of improving skeletal muscle fiber health, preferably in a subject suffering from a neuromuscular disorder. Examples of improved skeletal muscle fiber health can include, but are not limited to, reduced fat content / fat fraction percent in muscle fibers when compared to the fat content of the muscle fibers before administration of the compositions / compounds / methods disclosed herein, reduced water T2 relaxation times in muscle fibers when compared to the water T2 relaxation times of the muscle fibers before administration of the compositions / compounds / methods disclosed herein, reduced water T1 relaxation times in muscle fibers when compared to the water T1 relaxation times of the muscle fibers before administration of the compositions / compounds / methods disclosed herein, increased fractional anisotropy values in muscle fibers when compared to the fractional anisotropy values before administration of the compositions / compounds / methods disclosed herein, reduced mean diffusivity values in muscle fibers when compared to the mean diffusivity values of the muscle fibers before administration of the compositions / compounds / methods disclosed herein, and a reduction in 2D / 3D muscle strain measurements (e.g., principal strain, shear strain) in muscle fibers when compared to the 2D / 3D muscle strain measurements of the muscle fibers before administration of the compositions / compounds / methods disclosed herein.

[0247] In some embodiments, the disease modifying effect is determined by an improvement in skeletal muscle performance. In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by an improvement in skeletal muscle performance. In some embodiments, the compositions and / or methods disclosed herein provide improved skeletal muscle fiber performance. In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of improvingP7593PC00

[0248] 39

[0249] skeletal muscle fiber performance, preferably in a subject suffering from a neuromuscular disorder.

[0250] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein the disease modifying effect is determined by skeletal muscle performance and skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction).

[0251] In some embodiments, skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

[0252] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein the disease modifying effect is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

[0253] In some embodiments, the strength has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, the muscle strength has increased by between 10% and 400%, such as between 15% and 200%, such as between 20% and 100%.

[0254] In some embodiments, the disease modifying effect is an improvement in skeletal muscle performance determined by measuring grip strength.

[0255] In some embodiments, grip strength of the subject is increased by at least 5%, such as by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or by 100%, etc.P7593PC00

[0256] 40

[0257] In some embodiments, at least 5% of the grip strength of the subject is restored, such as at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% of the grip strength of the subject.

[0258] In some embodiments, grip strength is measured using a handheld dynamometer and the methods and / or administration of the compositions disclosed herein increase grip strength of a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, or at least 200%.

[0259] In some embodiments, the methods and / or administration of the compositions disclosed herein improve grip strength by about 10% to 400%, about 15% to 200%, or about 20% to 100%.

[0260] In some embodiments, the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force. In some embodiments, the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip strength.

[0261] In some embodiments, the methods and / or administration of the compositions disclosed herein increase muscle strength, as determined by measuring grip strength using a handheld dynamometer, by at least 0.10 kg, at least 0.15 kg, at least 0.20 kg, at least 0.25 kg, at least 0.50 kg, at least 0.75 kg, at least 1.0 kg, at least 1.25 kg, at least 1.5 kg, at least 1.75 kg, at least 2.0 kg, at least 2.5 kg, or at least 3.0 kg.

[0262] In some embodiments, the methods and / or administration of the compositions disclosed herein improve muscle strength, as determined by measuring grip strength using a handheld dynamometer, by 0.25 to 5.0 kg, by 0.25 to 4.0 kg, or by 0.5 to 4.0 kg.

[0263] In some embodiments, the methods and / or administration of the compositions disclosed herein increase muscle strength, as determined by measuring grip strengthP7593PC00

[0264] 41

[0265] using a handheld dynamometer, by at least 0.05 newtons, at least 0.10 newtons, at least 0.15 newtons, or at least 0.20 newtons.

[0266] In some embodiments, the methods and / or administration of the compositions disclosed herein increase muscle force, as determined by measuring hand grip strength using a handheld dynamometer, by at least 3.0 newtons, at least 4.0 newtons, at least 5.0 newtons, at least 7.5 newtons, at least 10.0 newtons, at least 12.5 newtons, or at least 15.0 newtons.

[0267] In some embodiments, the methods and / or administration of the compositions disclosed herein increase muscle force, as determined by measuring hand grip strength using a handheld dynamometer, by 3.0 to 50 newtons, by 4.0 to 40 newtons, by 5.0 to 30 newtons, or by 7.5 to 25 newtons.

[0268] In some embodiments, muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg. In some embodiments, muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0269] In some embodiments, muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg. In some embodiments, muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0270] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by improved skeletal muscle fiber health. In some embodiments, skeletal muscle fiber health is determined by measuring one or more parametersP7593PC00

[0271] 42

[0272] selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

[0273] In some embodiments, pulmonary function is determined by measuring forced vital capacity (FVC).ln some embodiments, the FVC has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, the FVC has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%. In some embodiments, the pulmonary function is determined by measuring forced expiratory volume in 1 second (FEV1).ln Some embodiments, FEV1 has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, FEV1 has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%. In some embodiments, the pulmonary function is determined by measuring maximal inspiratory pressure (MIP). In some embodiments, MIP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, the MIP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%. In some embodiments, the pulmonary function is determined by measuring maximal expiratory pressure (MEP).ln some embodiments, the MEP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, the MEP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0274] In some embodiments, blocking is determined using single fibre electromyography. In some embodiments, blocking has been reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, blocking has been reducedP7593PC00

[0275] 43

[0276] by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0277] In some embodiments, jitter is determined using single fibre electromyography. In some embodiments, jitter has been reduced by at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%. In some embodiments, jitter has been reduced by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%. In some embodiments, jitter determined using single fibre electromyography has been reduced by at least 5 ps, such as at least 10 ps, such as at least 15 ps, such as at least 20 ps, such as at least 25 ps, such as at least 30 ps, such as at least 40 ps, such as at least 50 ps, such as at least 75 ps, such as at least 100 ps. In some embodiments, jitter determined using single fibre electromyography has been reduced by between 5 ps and 200 ps, such as between 5 ps and 100 ps, such as between 10 ps and 50 ps.

[0278] Nerve health and performance

[0279] In some embodiments, the compositions and / or methods disclosed herein provide improved nerve health. In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of improving nerve health, preferably in a subject suffering from a neuromuscular disorder. Improved nerve health can include, but is not limited to, increased nerve conduction velocity in nerve cells when compared to the nerve conduction velocity of nerve cells before administration of the compositions / compounds / methods disclosed herein. Other indications of improved nerve health, and methods for determining if improved nerve health has occurred, can be found in Manganelli et al. (see for example Manganelli, etal, 2016), the entire content of which is incorporated by reference herein.

[0280] In some embodiments, the compositions and / or methods disclosed herein provide improved nerve performance. In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of improving nerve performance, preferably in a subject suffering from a neuromuscular disorder.

[0281] In exemplary embodiments, the methods and / or compositions disclosed herein can improve nerve health (e.g., improve the function, structure (for example motor neuronP7593PC00

[0282] 44

[0283] size), longevity and resilience of a nerve cell or system) and / or nerve performance (e.g., improve the ability of a nerve to transmit electrical and / or chemical signals to other parts of a body or to other nerve cells).

[0284] In addition to CIC-1 inhibitor(s), the composition(s) described herein can also include one or more active ingredients, agents, and / or or other components to increase the efficiency of treatment of the composition. Therefore, in some embodiments, the composition(s) described herein, and the method(s) associated thereto, can include at least one active agent in addition to CIC-1 inhibitor(s). In other words, the composition(s) described herein can include or otherwise implement the strategy of a combination therapy. It is appreciated that the active agent is suitable for treating, preventing, and / or ameliorating said neuromuscular condition. Nonlimiting examples of such embodiments are provided below in this disclosure.

[0285] In exemplary embodiments, the methods and / or compositions disclosed herein can improve immune system function or modulate the immune system (e.g., decrease the occurrence of autoimmune attack on cell receptors and NMJ). In one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of modulating the immune system, preferably in a subject suffering from a neuromuscular disorder.

[0286] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by immune system modulation. In some embodiments, immune system modulation is determined by a reduction in total IgG levels.

[0287] In some embodiments, the method includes protecting the subject against a loss of body weight. In some embodiments, the method includes increasing a survival rate of the subject. In some embodiments, the method provides an improved pulmonary function to the subject. In some embodiments, in the method provides an improved gait to the subject.

[0288] Neuromuscular disorders

[0289] The terms “neuromuscular disorder", “neuromuscular disease”, and “neuromuscular condition” are used interchangeably herein.P7593PC00

[0290] 45

[0291] In some embodiments, the method described herein can be used to treat, ameliorate, and / or prevent a neuromuscular condition. In some embodiments, the method can be used to provide re-innervation in one or more neuromuscular conditions such as, without limitation, myasthenia gravis (MG) (including autoimmune myasthenia gravis), congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and / or multiple sclerosis.

[0292] In some embodiments, the disclosure relates to a CIC-1 inhibitor for use as diseasemodifying agent in a disease-modifying treatment of a neuromuscular disease, wherein the neuromuscular disease is selected form the list consisting of myasthenia gravis (MG) (including autoimmune myasthenia gravis), congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and / or multiple sclerosis.

[0293] In exemplary embodiments, the neuromuscular disease is selected form the list consisting of myasthenia gravis (MG) (including autoimmune myasthenia gravis), congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptorP7593PC00

[0294] 46

[0295] antibodies (AChRAB+ MG); spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D.

[0296] In exemplary embodiments, a “neuromuscular condition” includes a disease that affects the nerves and muscles that control movement. A neuromuscular condition can cause muscles to weaken, waste away, or stop working. Neuromuscular conditions can include, for example, disorders with symptoms of muscle weakness and fatigue. Such disorders can include conditions with a reduced neuromuscular transmission safety factor (i.e. , with a reduced ability of neuromuscular transmission to remain effective under various physiological conditions and stresses).

[0297] In some embodiments, the neuromuscular condition includes a motor neuron disorder. In exemplary embodiments, a “motor neuron disorder” includes a disorder with reduced safety in neuromuscular transmission. Motor neuron disorders can include, but are not limited to, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), X-linked spinal and bulbar muscular atrophy, Kennedy’s disorder, multifocal motor neuropathy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, sarcopenia, and / or the like. In some embodiments, the neuromuscular condition includes one or more neuromuscular dysfunctions.

[0298] In some embodiments, the neuromuscular condition includes ALS. In some embodiments, the neuromuscular condition includes SMA. In some embodiments, the neuromuscular condition includes CMT. As used herein, “Charcot-Marie-Tooth disease” or “CMT” is a group of genetic conditions that affect the nerves connecting the brain and spinal cord to the rest of the body. CMT is a commonly inherited neuropathy. In some embodiments, the neuromuscular condition includes sarcopenia. In some embodiments, the neuromuscular condition includes critical illness myopathy (CIM).

[0299] In some embodiments, the neuromuscular condition includes, for example and without limitation, one or more disorders with symptoms of muscle weakness and fatigue. Such disorder(s) include, for example and without limitation, diabetes.

[0300] In some embodiments, the method(s) described herein are used to prevent a neuromuscular condition. The composition can, for example and without limitation, beP7593PC00

[0301] 47

[0302] used prophylactically against nerve gas that is known to cause symptoms of muscle weakness and fatigue.

[0303] In some embodiments, the neuromuscular condition includes chronic fatigue syndrome. As used herein, “chronic fatigue syndrome” or “CFS” is the common name for a medical condition characterized by debilitating symptoms, including fatigue that lasts for a minimum of six months in adults. CFS can also be referred to as systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), and / or by several other terms. Symptoms of CFS can include, without limitation, malaise after exertion, unrefreshing sleep, widespread muscle and joint pain, physical exhaustion, and / or muscle weakness, among others.

[0304] In some embodiments, the neuromuscular condition includes myotubular myopathy. In some embodiments, the neuromuscular condition includes Duchenne muscular dystrophy.

[0305] In some embodiments, the neuromuscular condition includes a critical illness polyneuropathy or CIM. Critical illness polyneuropathy and CIM are overlapping syndromes of widespread muscle weakness and neurological dysfunction developing in critically ill patients.

[0306] In some embodiments, the neuromuscular condition includes metabolic myopathy and / or mitochondrial myopathy. Metabolic myopathies result from defects in biochemical metabolism that primarily affects muscle and can include, without limitation, glycogen storage disorders, lipid storage disorder, 3-phosphocreatine storage disorder, and / or the like. As used herein, “mitochondrial myopathy” is a type of myopathy associated with mitochondrial disorder. Symptoms of mitochondrial myopathies can include muscular and neurological problems such as muscle weakness, exercise intolerance, hearing loss, and / or trouble with balance and coordination, among others.

[0307] In some embodiments, the neuromuscular condition includes periodic paralysis, in particular hypokalemic periodic paralysis, and / or hyperkalemic periodic paralysis. As used herein, “hypokalemic periodic paralysis” is a disorder of skeletal muscleP7593PC00

[0308] 48

[0309] excitability that presents with recurrent episodes of weakness, often triggered by exercise, stress, or carbohydrate-rich meals. As used herein, “hyperkalemic periodic paralysis” is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood.

[0310] In some embodiments, the neuromuscular condition includes a myasthenic condition. As used herein, a “myasthenic condition” is a condition characterized by muscle weakness and neuromuscular transmission failure. In exemplary embodiments, myasthenic conditions include congenital myasthenia gravis. As used herein, “congenital myasthenia gravis” is an inherited neuromuscular condition caused by defects of several types at the neuromuscular junction.

[0311] Myasthenia gravis and Lambert-Eaton syndrome are additional examples of myasthenic conditions. Accordingly, in some embodiments, the neuromuscular condition pertaining to the disclosure described herein includes myasthenia gravis. As used herein, “myasthenia gravis” is either an autoimmune or congenital neuromuscular condition that leads to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block AChRs at the postsynaptic NMJs, inhibiting the excitatory effects of the neurotransmitter ACh on nicotinic AChRs at the NMJs.

[0312] As used herein, “muscle-specific kinase myasthenia gravis” or “MuSK-MG” is a specific subtype of myasthenia gravis where the body produces antibodies against the MuSK protein, leading to muscle weakness, particularly affecting the facial and bulbar muscles including swallowing and speaking due to impaired neuromuscular transmission at the nerve-muscle junction. MuSK-MG is considered a more severe form of myasthenia gravis compared to a more typical acetylcholine receptor antibodypositive myasthenia gravis, which will be described in further detail below. As used herein, a “muscle-specific kinase” or “MuSK” is a protein that plays a crucial role in the formation and maintenance of neuromuscular junctions, essentially acting as a key signalling molecule for muscle cells to develop proper connections with motor neurons. MuSK is a receptor tyrosine kinase activated by a protein called agrin, which is released by the nerve terminal, and is for clustering AchRs at the postsynaptic membrane.P7593PC00

[0313] 49

[0314] As used herein, “myasthenia gravis with anti-AChR antibodies”, “AChR antibodypositive myasthenia gravis”, or “AChR AB+ MG” is a condition where a subject with myasthenia gravis has developed antibodies that specifically target AChRs, a protein crucial for muscle contraction, causing muscle weakness as the body’s immune system attacks these receptors at the NMJ, hindering nerve signals to muscles. AChR AB+ MG is one of the commons forms of myasthenia gravis.

[0315] In some embodiments, the neuromuscular condition includes Lambert-Eaton myasthenic syndrome. As used herein, “Lambert-Eaton myasthenic syndrome”, also known as LEMS, Lambert-Eaton syndrome, or Eaton-Lambert syndrome, is a rare autoimmune disorder that is characterized by muscle weakness of the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated Ca2+channels, and likely other nerve terminal proteins, in the neuromuscular junction.

[0316] In some embodiments, the subject is a human. In some embodiments, the subject is suffering from a neuromuscular disorder.

[0317] CIC-1 inhibitor

[0318] The CIC-1 inhibitor can be any type of CIC-1 inhibitor deemed suitable or relevant by a person of ordinary skill in the art upon reviewing the entirety of this disclosure. In some embodiments, the CIC-1 inhibitor includes any chemical composition, compound, species, agent, and / or the like (for example, a singular compound or a combination of compounds). The CIC-1 inhibitor can be prepared using any process, method, or technique disclosed herein or known by those of ordinary skill in the art. The CIC-1 inhibitor can be used, applied, or administered via any suitable means in accordance with details disclosed in any one or more of the following patent disclosures, and publications, the entirety of each of which is incorporated herein by reference in the entireties: international patent disclosure publication serial No. WO2019 / 115781, U.S. patent disclosure serial No. 15 / 842,823, U.S. patent disclosure serial No. 16 / 221,006, international patent disclosure publication serial No. WO2020 / 254554, U.S. patent disclosure serial No. 17 / 619,312, international patent disclosure publication serial No. WO2024 / 068862, U.S. patent disclosure serial No. 63 / 488,055, U.S. patent disclosure serial No. 63 / 488,058, international patent disclosure publication serial No.

[0319] WO2024 / 180201, international patent disclosure publication serial No.P7593PC00

[0320] 50

[0321] WO2024 / 180199, international patent disclosure publication serial No.

[0322] WO2020 / 254559, U.S. patent disclosure serial No. 17 / 620,294, international patent disclosure publication serial No. WO2024 / 056865, international patent disclosure publication serial No. WO2016 / 202341, U.S. patent disclosure serial No. 15 / 736,756, international patent disclosure publication serial No. WO 2019 / 115777, U.S. patent disclosure serial No. 15 / 842,807, U.S. patent disclosure serial No. 16 / 220,640, international patent disclosure publication serial No. WO2019 / 115780, U.S. patent disclosure serial No. 15 / 842,814, U.S. patent disclosure serial No. 16 / 221,069, international patent disclosure publication serial No. WO2017 / 097311, U.S. patent disclosure serial No. 16 / 061,293, U.S. patent disclosure serial No. 18 / 671,217, international patent disclosure publication serial No. WO2020 / 254553, U.S. patent disclosure serial No. 17 / 619,329, international patent disclosure publication serial No. WO2020 / 254558, and U.S. patent disclosure serial No. 17 / 620,316.

[0323] In some embodiments, the CIC-1 inhibitor is a compound of Formula (I):

[0324]

[0325] Formula (I)

[0326] wherein:

[0327] - R1is selected from the group consisting of Cl and Br;

[0328] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0329] - R3is selected from the group consisting of deuterium, Cl and F;P7593PC00

[0330] 51

[0331] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0332] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0333] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0334] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0335] - n is an integer 0, 1, 2, or 3,

[0336] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0337] In some embodiments of the compound of Formula I, R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5-yl and 1,2-oxazol-3-yl.

[0338] In some embodiments of the compound of Formula I, R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0339] In some embodiments of the compound of Formula I, n is 0 or 1.

[0340] In some embodiments, the compound is of Formula I, wherein

[0341] R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, - CF2-Me, -CF2-CH2Me, 1 ,2-oxazol-5-yl and 1,2-oxazol-3-yl; and R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0342] In some embodiments, the compound is of Formula I, whereinP7593PC00

[0343] 52

[0344] R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, - CF2-Me, -CF2-CH2Me, 1 ,2-oxazol-5-yl and 1,2-oxazol-3-yl;

[0345] R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl; and

[0346] n is 0 or 1.

[0347] In exemplary embodiments, the CIC-1 inhibitor is a compound of Formula (I) and has a EC50 at the CIC-1 channel of less than 20 pM, less than 15 pM, less than 10 pM, less than 8 pM, less than 6 pM, less than 4 pM, or less than 2 pM.

[0348] In exemplary embodiments, the CIC-1 inhibitor has a half-life in rats of about 2 hours to about 20 hours, about 3 hours to about 15 hours, about 4 hours to about 10 hours, about 7 hours, or any half-life or range of half-lives that fall withing the range of about 2 hours to about 20 hours.

[0349] In exemplary embodiments, the CIC-1 inhibitor has a half-life in humans of about 3 hours to about 7 hours, of about 4 hours to about 6 hours, or any half-life or range of half-lives that fall withing the range of about 3 hours to about 7 hours.

[0350] In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid or (S)-2-(p-bromophenoxy)butyric acid. In some embodiments, the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)-3-methylbutyric acid. In some embodiments, the CIC-1 inhibitor is (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid. In some embodiments, the CIC-1 inhibitor is (R)-2-(p-bromophenoxy)-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid (NMD670). In some embodiments, the CIC-1 inhibitor is (S)-2-(4-bromo-2-fluorophenoxy)butyric acid. In some embodiments, the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid (NMD712). In some embodiments, the CIC-1 inhibitor is (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-P7593PC00

[0351] 53

[0352] (4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid. In some embodiments, the CIC-1 inhibitor is (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid. In some embodiments, the CIC-1 inhibitor is (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid. In some embodiments, the CIC-1 inhibitor is (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid.

[0353] Administration

[0354] In some embodiments, CIC-1 inhibitor is administered daily. In some embodiments, the CIC-1 inhibitor is administered for at least seven days. In some embodiments, the CIC-1 inhibitor is administered orally. In some embodiments, the composition used for providing a disease modifying effect is administered daily. In some embodiments, the composition used for providing a disease modifying effect is administered for at least seven days. In some embodiments, the composition used for providing a disease modifying effect is administered orally. In some embodiments, the composition used for providing re-innervation is administered daily. In some embodiments, the composition used for providing re-innervation is administered for at least seven days. In some embodiments, the composition used for providing re-innervation is administered orally.

[0355] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by: measuring one or more parameters before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration of the CIC-1 inhibitor, measuring the parameters that were measured before administration of the CIC-1 inhibitor, and comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor.P7593PC00

[0356] 54

[0357] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by:

[0358] • identifying a subject in need thereof that suffers from one or more of: a neuromuscular disability, a neuromuscular disorder, or denervation, • measuring one or more parameters before administration of the CIC-1 inhibitor,

[0359] • administering the CIC-1 inhibitor for a period of time, and

[0360] • measuring the one or more parameters after a washout period. In some embodiments, the washout period is any time or time range falling within a range of about 3 days to about six months.

[0361] In some embodiments, the improvement in course and severity of a neuromuscular disease is determined by:

[0362] • identifying a subject in need thereof that suffers from one or more of: a neuromuscular disability, a neuromuscular disorder, or denervation,

[0363] • measuring one or more parameters before administration of the CIC-1 inhibitor, • administering the CIC-1 inhibitor for a period of time, and

[0364] • measuring the one or more parameters after stopping administration of the CIC- 1 inhibitor for a period of time.

[0365] in one aspect, the present invention relates to a CIC-1 inhibitor for use in a method of treating a neuromuscular disorder, wherein said method comprises administration of said CIC-1 inhibitor to a subject in need thereof 1 to 4 times daily for in the range of 10 to 60 days followed by a break, where said CIC-1 inhibitor is not administered to said subject for at least 5 days. In some embodiments, the present invention relates to a composition comprising a CIC-1 inhibitor in a therapeutically effective amount for use in a method of treating a neuromuscular disorder, wherein said method comprises administration of said CIC-1 inhibitor to a subject in need thereof 1 to 4 times daily for in the range of 10 to 60 days followed by a break, where said CIC-1 inhibitor is not administered to said subject for at least 5 days. In some embodiments, said method comprises administration of said CIC-1 inhibitor to a subject in need thereof 1 to 4 times daily for at least 21 days followed by a break, where said CIC-1 inhibitor is notP7593PC00

[0366] 55

[0367] administered to said subject for at least 7 days. In some embodiments, said method comprises administration of said CIC-1 inhibitor to a subject in need thereof 1 or 2 times daily for 21 days followed by a break, where said CIC-1 inhibitor is not administered to said subject for 7 days.

[0368] In some embodiments, the CIC-1 inhibitor is administered for a period of at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, or at least 24 months.

[0369] In some embodiments, the period of time after stopping administration of the CIC-1 inhibitor is at least 6 half-lives (ti / 2S) of the CIC-1 inhibitor, at least 9 half-lives, or at least 12 half-lives.

[0370] In some embodiments, the period of time after stopping administration of the CIC-1 inhibitor is at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, or at least 28 days. In some embodiments, the period of time after stopping administration of the CIC-1 inhibitor is at least one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year or more than one year.

[0371] In some embodiments, the CIC-1 inhibitor is administered as a pharmaceutical composition. In some embodiments, the (pharmaceutical) composition is a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule.

[0372] In exemplary embodiments, the compositions disclosed herein contain a CIC-1 inhibitor in a therapeutically effective amount, wherein the therapeutically effective amount 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.P7593PC00

[0373] 56

[0374] In exemplary embodiments, the compositions disclosed herein contain a CIC-1 inhibitor in a therapeutically effective amount, wherein the therapeutically effective amount 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.

[0375] In exemplary embodiments, the methods disclosed herein include administering a composition containing a CIC-1 inhibitor and optionally an immunomodulating or immunosuppressive agent to a patient at a therapeutically effective dose, wherein the therapeutically effective dose is from 100 to 600 mg, from 200 to 600 mg, from 250 to 550 mg, from 300 to 500 mg, from 350 to 450 mg, from 375 to 425 mg, or 400 mg. In other exemplary embodiments, the therapeutically effective dose is from 700 to 1400 mg, from 800 to 1350 mg, from 900 to 1300 mg, from 1000 to 1250 mg, from 1100 to 1250 mg, or about 1200 mg. In exemplary embodiments, the therapeutically effective dose is about 100 mg. In exemplary embodiments, the therapeutically effective dose is about 150 mg. In exemplary embodiments, the therapeutically effective dose is about 200 mg. In exemplary embodiments, the therapeutically effective dose is about 250 mg. In exemplary embodiments, the therapeutically is about 300 mg. In exemplary embodiments, the therapeutically effective dose is about 350 mg. In exemplary embodiments, the therapeutically effective dose is about 400 mg. In exemplary embodiments, the therapeutically effective dose is about 500 mg. In exemplary embodiments, the therapeutically effective dose is about 600 mg.

[0376] In some embodiments, the therapeutically effective amount of a CIC-1 inhibitor is between 100 mgs and 1500 mgs.

[0377] In exemplary embodiments, the therapeutic dose is administered one time daily, i.e. the therapeutic dose is the total daily dosage. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 200 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 300 to 500 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 100 mg and isP7593PC00

[0378] 57

[0379] administered one time daily. In exemplary embodiments, the therapeutic dose is about 150 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 200 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 250 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 300 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 350 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 400 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 500 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is about 600 mg and is administered one time daily.

[0380] In exemplary embodiments, the therapeutic dose is administered two times daily, i.e. the total daily dosage is twice the therapeutic dose. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is 200 to 600 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is 300 to 500 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 100 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 150 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 200 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 250 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 300 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 350 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 400 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 500 mg and is administered two times daily. In exemplary embodiments, the therapeutic dose is about 600 mg and is administered two times daily.

[0381] In exemplary embodiments, the therapeutic dose is administered three times daily, i.e. the total daily dosage is three times the therapeutic dose. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is 200 to 600 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is 300 to 500 mg and is administered three times daily. In exemplary embodiments, the therapeutic doseP7593PC00

[0382] 58

[0383] is about 100 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 150 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 200 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 250 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 300 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 350 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 400 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 500 mg and is administered three times daily. In exemplary embodiments, the therapeutic dose is about 600 mg and is administered three times daily.

[0384] The composition comprising the therapeutic dose may be administered in one or more unit dosage forms. A therapeutic dose of 400 mg may for example be administered as one unit dosage form comprising 400 mg, or two unit dosage forms comprising 200 mg, or four unit dosage forms comprising 100 mg.

[0385] Combination with immunomodulating or immunosuppressive agent

[0386] In some embodiments, the methods provided herein includes administering to the subject a composition including a first therapeutically effective amount of a CIC-1 inhibitor and a second therapeutically effective amount of an immunomodulating or immunosuppressive agent. In some embodiments, the method comprises administering to a subject in need thereof an immunomodulating or immunosuppressive agent and a composition comprising a CIC-1 inhibitor. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent and a composition comprising a CIC-1 inhibitor.

[0387] In some embodiments, the method of providing re-innervation includes administering to the subject a composition including a first therapeutically effective amount of a CIC-1 inhibitor and a second therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[0388] In one aspect, the present invention relates to a CIC-1 inhibitor for use in a disease modifying treatment of a neuromuscular disease, wherein the method comprises administering a) a CIC-1 inhibitor; and b) an immunomodulating or immunosuppressiveP7593PC00

[0389] 59

[0390] agent. In one aspect, the present invention relates to a combination of a CIC-1 inhibitor and an immunomodulating or immunosuppressive agent for use in a disease modifying treatment of a neuromuscular disease. In one aspect, the present invention relates to a combination of a CIC-1 inhibitor and an immunomodulating or immunosuppressive agent for use in a method of promoting re-innervation of muscle fibres, preferably in a subject suffering from a neuromuscular disorder.

[0391] In one aspect, the present invention relates to a CIC-1 inhibitor for use as diseasemodifying agent in a disease-modifying treatment of a neuromuscular disease, wherein the CIC-1 inhibitor is co-administered with an immunomodulating or immunosuppressive agent.

[0392] In some embodiments, wherein the method comprises administering to the subject a therapeutically effective amount of an immunomodulating or immunosuppressive agent, the neuromuscular disease is selected from the group consisting of autoimmune myasthenia gravis, AChR antibody-positive myasthenia gravis, Lambert-Eaton syndrome, multifocal motor neuropathy, Guillain-Barre syndrome and multiple sclerosis.

[0393] In one aspect, the present invention relates to a combination of a CIC-1 inhibitor and an immunomodulating or immunosuppressive agent for use in the disease modifying treatment of a neuromuscular disease selected from the group consisting of autoimmune myasthenia gravis, AChR antibody-positive myasthenia gravis, Lambert-Eaton syndrome, multifocal motor neuropathy, Guillain-Barre syndrome and multiple sclerosis.

[0394] In some embodiments, the immunomodulating or immunosuppressive agent is a neonatal Fc receptor (FcRn) blocker. As used herein, an “Fc receptor blocker”, “FcRn blocker”, or “FcRn antagonist” is a chemical species that targets and inactivates FcRns. As used herein, a “neonatal Fc receptor” or “FcRn” is a non-classical Fc gamma (y) receptor (FcyR) with near-ubiquitous expression. FcRns can be detected on multiple cell types (e.g., epithelial cells), in secondary lymphoid organs (e.g., spleen), and in the placenta. FcRn’s role in disease pathogenesis results from its affinity for Immunoglobulin G (IgG). Since FcRns allow for recycling IgG from lysosomal degradation, an FcRn blocker accelerates the removal of autoantibodies and shortensP7593PC00

[0395] 60

[0396] their half-life. Additionally, an FcRn blocker can induce macrophage phagocytosis of IgG-opsonized antigens and initiate adaptive immune responses by retrieving and presenting immune complexes in lymphoid structures. Although FcRn does not bind other immunoglobulin isotypes, it does bind albumin, thereby protecting albumin from lysosomal catabolism and prolonging its circulatory half-life. Nonlimiting examples of FcRn blockers include, but are not limited to, Efgartigimod such as Efgartigimod alfa (Vyvgart), Rozanolixizumab (Rystiggo), Nipocalimab (Imaavy), Batoclimab (HBM9161 1 RVT-1401), IMVT-1402, ALXN 1830, M281, Orilanolimab (SYNT001), and / or the like.

[0397] It is worth noting the agent(s) for combination therapy with CIC-1 inhibitor(s) are not limited to FcRn blockers only. The composition described herein can also include any immunomodulating and / or immunosuppressive compound, composition, species, agent, and / or the like that is deemed relevant or appropriate by a person of ordinary skill in the art, upon reviewing the entirety of this disclosure.

[0398] Specific Embodiments

[0399] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0400] • the disease-modifying agent results in a disease modifying effect;

[0401] • the disease modifying effect is an improvement in skeletal muscle performance;

[0402] • skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction);

[0403] • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;

[0404] Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis andP7593PC00

[0405] 61

[0406] hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis; and

[0407] • the CIC-1 inhibitor is a compound of Formula (I):

[0408]

[0409] Formula (I)

[0410] wherein:

[0411] - R1is selected from the group consisting of Cl and Br;

[0412] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0413] - R3is selected from the group consisting of deuterium, Cl and F;

[0414] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0415] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;P7593PC00

[0416] 62

[0417] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0418] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0419] - n is an integer 0, 1, 2, or 3,

[0420] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0421] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0422] • the disease-modifying agent results in a disease modifying effect;

[0423] • the disease modifying effect is an improvement in skeletal muscle performance;

[0424] • skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction);

[0425] • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and

[0426] • the CIC-1 inhibitor is selected from the list consisting of:

[0427] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0428] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0429] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0430] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0431] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0432] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0433] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0434] (S)-2-(p-bromophenoxy)butyric acid;

[0435] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0436] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0437] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0438] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;P7593PC00

[0439] 63

[0440] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0441] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0442] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0443] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0444] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0445] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0446] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0447] and

[0448] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0449] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0450] In exemplary embodiments, the present disclosure relates to a CIC-1 inhibitor for use in as a disease-modifying agent in disease-modifying treatment of a neuromuscular disease, wherein:

[0451] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid or (S)-2-(p-bromophenoxy)butyric acid; and

[0452] • the neuromuscular disease is myasthenia gravis, Charcot-Marie-Tooth disease, or spinal muscular atrophy.

[0453] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0454] • the disease-modifying agent results in a disease modifying effect;

[0455] • the disease modifying effect is an improvement in skeletal muscle fiber health;

[0456] • skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait; • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;P7593PC00

[0457] 64

[0458] Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis; and

[0459] • the CIC-1 inhibitor is a compound of Formula (I):

[0460]

[0461] Formula (I)

[0462] wherein:

[0463] - R1is selected from the group consisting of Cl and Br;

[0464] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0465] - R3is selected from the group consisting of deuterium, Cl and F;

[0466] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different,P7593PC00

[0467] 65

[0468] substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0469] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0470] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0471] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0472] - n is an integer 0, 1, 2, or 3,

[0473] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0474] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0475] • the disease-modifying agent results in a disease modifying effect;

[0476] • the disease modifying effect is an improvement in skeletal muscle fiber health;

[0477] • skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait; • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and

[0478] • the CIC-1 inhibitor is selected from the list consisting of:

[0479] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0480] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0481] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0482] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0483] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0484] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;P7593PC00

[0485] 66

[0486] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0487] (S)-2-(p-bromophenoxy)butyric acid;

[0488] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0489] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0490] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0491] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[0492] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0493] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0494] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0495] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0496] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0497] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0498] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0499] and

[0500] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0501] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0502] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0503] • the disease-modifying agent results in a disease modifying effect;

[0504] • the disease modifying effect is the re-innervation of skeletal muscle fibres;

[0505] • the re-innervation of skeletal muscle fibres is determined by an improvement in neuromuscular junction (NMJ) function;

[0506] • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;

[0507] Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-P7593PC00

[0508] polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis; and

[0509] • the CIC-1 inhibitor is a compound of Formula (I):

[0510]

[0511] Formula (I)

[0512] wherein:

[0513] - R1is selected from the group consisting of Cl and Br;

[0514] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0515] - R3is selected from the group consisting of deuterium, Cl and F;

[0516] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;P7593PC00

[0517] 68

[0518] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0519] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0520] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0521] - n is an integer 0, 1, 2, or 3,

[0522] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0523] In exemplary embodiments, the disclosure relates to a CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease, wherein:

[0524] • the disease-modifying agent results in a disease modifying effect;

[0525] • the disease modifying effect is the re-innervation of skeletal muscle fibres; • the re-innervation of skeletal muscle fibres is determined by an improvement in neuromuscular junction (NMJ) function;

[0526] • the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and

[0527] • the CIC-1 inhibitor is selected from the list consisting of:

[0528] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0529] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0530] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0531] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0532] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0533] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0534] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0535] (S)-2-(p-bromophenoxy)butyric acid;

[0536] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0537] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;P7593PC00

[0538] 69

[0539] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0540] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[0541] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0542] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0543] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0544] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0545] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0546] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0547] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0548] and

[0549] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0550] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0551] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0552] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is Charcot-Marie-Tooth disease;

[0553] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0554] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0555] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0556] 70

[0557] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0558] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is Charcot-Marie-Tooth disease;

[0559] • the CIC-1 inhibitor is administered for at least 21 days;

[0560] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0561] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0562] • hand grip force is improved by at least 3.0 newtons.

[0563] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0564] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0565] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is myasthenia gravis;

[0566] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0567] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0568] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0569] 71

[0570] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0571] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is myasthenia gravis;

[0572] • the CIC-1 inhibitor is administered for at least 21 days;

[0573] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0574] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0575] • hand grip force is improved by at least 3.0 newtons.

[0576] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0577] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0578] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is spinal muscular atrophy;

[0579] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0580] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0581] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0582] 72

[0583] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0584] • the CIC-1 inhibitor is (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; • the neuromuscular disease is spinal muscular atrophy;

[0585] • the CIC-1 inhibitor is administered for at least 21 days;

[0586] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0587] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0588] • hand grip force is improved by at least 3.0 newtons.

[0589] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0590] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0591] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0592] • the neuromuscular disease is Charcot-Marie-Tooth disease;

[0593] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0594] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0595] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0596] 73

[0597] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0598] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0599] • the neuromuscular disease is Charcot-Marie-Tooth disease;

[0600] • the CIC-1 inhibitor is administered for at least 21 days;

[0601] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0602] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0603] • hand grip force is improved by at least 3.0 newtons.

[0604] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0605] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0606] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0607] • the neuromuscular disease is myasthenia gravis;

[0608] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0609] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0610] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0611] 74

[0612] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0613] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0614] • the neuromuscular disease is myasthenia gravis;

[0615] • the CIC-1 inhibitor is administered for at least 21 days;

[0616] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0617] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0618] • hand grip force is improved by at least 3.0 newtons.

[0619] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0620] In some embodiments, the present disclosure is directed towards a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease for a period of at least 21 days, wherein the administration of the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease wherein:

[0621] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0622] • the neuromuscular disease is spinal muscular atrophy;

[0623] • the disease modifying effect is an improvement in skeletal muscle performance determined by measuring hand grip force; and

[0624] • wherein the improvement is measured after a period of time after stopping administration of the CIC-1 inhibitor is at least at least 6 days.

[0625] In some embodiments, the present disclosure is directed to a method of improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the improvement in course and severity of a neuromuscular disease is determined by: I. measuring one or more parameters before administration of the CIC-1 inhibitor, II. measuring said parameters after a period of time after stopping administration of the CIC-1 inhibitor, andP7593PC00

[0626] 75

[0627] III. comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor, wherein:

[0628] • the CIC-1 inhibitor is (S)-2-(p-bromophenoxy)butyric acid;

[0629] • the neuromuscular disease is spinal muscular atrophy;

[0630] • the CIC-1 inhibitor is administered for at least 21 days;

[0631] • the period of time after stopping administration of the CIC-1 inhibitor is at least 6 days;

[0632] • the one or more parameters is skeletal muscle performance as determined by measuring hand grip force; and

[0633] • hand grip force is improved by at least 3.0 newtons.

[0634] In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered one time daily. In exemplary embodiments, the therapeutic dose is 100 to 600 mg and is administered two times daily.

[0635] Items

[0636] 1. A method of modifying or improving the course and / or severity of a neuromuscular disease, comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease.

[0637] 2. The method of item 1, wherein the disease modifying effect is determined by at least one of re-innervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and improved immune system modulation.

[0638] 3. The method of item 1 or item 2, wherein the CIC-1 inhibitor is of Formula (I):P7593PC00

[0639] 76

[0640]

[0641] Formula (I)

[0642] wherein:

[0643] - R1is selected from the group consisting of Cl and Br;

[0644] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0645] - R3is selected from the group consisting of deuterium, Cl and F;

[0646] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0647] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0648] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0649] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;

[0650] - n is an integer 0, 1, 2, or 3; andP7593PC00

[0651] 77

[0652] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0653] 4. The method according to item 3, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5- yl and 1,2-oxazol-3-yl.

[0654] 5. The method according to any one of items 3 to 4, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0655] 6. The method according to any one of items 3 to 5, wherein n is 0 or 1.

[0656] 7. The method according to any one of items 1 to 3, wherein the CIC-1 inhibitor is selected from the group consisting of:

[0657] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0658] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0659] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0660] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0661] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0662] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0663] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0664] (S)-2-(p-bromophenoxy)butyric acid;

[0665] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0666] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0667] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0668] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[0669] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0670] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0671] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0672] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0673] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0674] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0675] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0676] andP7593PC00

[0677] 78

[0678] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0679] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0680] 8. The method according to any one of items 1 to 7, wherein the method comprises further administering to the subject a therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[0681] 9. The method of item 8, wherein the immunomodulating or immunosuppressive agent is selected form the group consisting of Efgartigimod such as Efgartigimod alfa (Vyvgart), Rozanolixizumab (Rystiggo), Nipocalimab (Imaavy), Batoclimab (HBM9161 I RVT-1401), IMVT-1402, ALXN1830, M281, and Orilanolimab (SYNT001).

[0682] 10. The method according to any one of items 1 to 9, wherein the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy;

[0683] Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;

[0684] Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis.

[0685] 11. The method according to any one of items 1 to 10, wherein the improvement in course and severity of a neuromuscular disease is determined by measuring one or more parameters before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration of the CIC-1 inhibitor, measuring the parameters that were measured before administration of the CIC-1 inhibitor, and comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor.P7593PC00

[0686] 79

[0687] 12. The method according to any one of items 1 to 10, wherein the improvement in course and severity of a neuromuscular disease is determined by:

[0688] identifying a subject in need thereof that suffers from one or more of: a neuromuscular disability, a neuromuscular disorder, or denervation, measuring one or more parameters before administration of the CIC-1 inhibitor,

[0689] administering the CIC-1 inhibitor for a period of time, and measuring the one or more parameters after stopping administration of the CIC-1 inhibitor for a period of time.

[0690] 13. The method of item 12, wherein the period of time after stopping administration of the CIC-1 inhibitor is any time or time range falling within a range of about 3 days to about six months.

[0691] 14. The method according to any one of items 11 to 13, wherein the CIC-1 inhibitor is administered for a period of at least 21 days, such as at least 1 month, such as at least 2 months, such as at least 3 months, such as at least 6 months, such as at least 12 months, such as at least 24 months.

[0692] 15. The method according to any one of items 11 to 14, wherein the period of time after stopping administration of the CIC-1 inhibitor is at least 6 half-lives of the compound, such as at least 9 half-lives, at least 12 half-lives.

[0693] 16. The method according to any one of items 11 to 14, wherein the period of time after stopping administration of the CIC-1 inhibitor is at least 3 days, such as at least 4 days, such as at least 5 days, such as at least 6 days, such as at least 7 days, such as at least 10 days, such as at least 14 days, such as at least 21 days, such as at least 28 days.

[0694] 17. The method according to any one of items 1 to 16, wherein the improvement in course and severity of a neuromuscular disease is determined by an improvement in skeletal muscle performance.

[0695] 18. The method of item 17, wherein skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction).P7593PC00

[0696] 80

[0697] 19. The method of item 18, wherein muscle strength has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0698] 20. The method of item 18, wherein muscle strength has increased by between 10% and 400%, such as between 15% and 200%, such as between 20% and 100%.

[0699] 21. The method of item 18, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0700] 22. The method of item 18, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by between 10% and 400%, such as between 15% and 200%, such as between 20% and 100%.

[0701] 23. The method of item 18, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0702] 24. The method of item 18, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0703] 25. The method of item 18, wherein muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0704] 26. The method of item 18, wherein muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.P7593PC00

[0705] 81

[0706] 27. The method of item 18, wherein muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0707] 28. The method of item 18, wherein muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0708] 29. The method according to any one of items 1 to 10, wherein the improvement in course and severity of a neuromuscular disease is determined by skeletal muscle fiber health.

[0709] 30. The method of item 29, wherein skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

[0710] 31. The method of item 30, wherein pulmonary function is determined by measuring forced vital capacity (FVC).

[0711] 32. The method of item 31 , wherein the FVC has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0712] 33. The method of item 31 , wherein the FVC has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0713] 34. The method of item 30, wherein the pulmonary function is determined by measuring forced expiratory volume in 1 second (FEV1).

[0714] 35. The method of item 34, wherein FEV1 has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.P7593PC00

[0715] 82

[0716] 36. The method of item 34, wherein FEV1 has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0717] 37. The method of item 30, wherein the pulmonary function is determined by measuring maximal inspiratory pressure (MIP).

[0718] 38. The method of item 37, wherein the MIP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0719] 39. The method of item 37, wherein the MIP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0720] 40. The method of item 30, wherein the pulmonary function is determined by measuring maximal expiratory pressure (MEP).

[0721] 41. The method of item 40, wherein the MEP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0722] 42. The method of item 40, wherein the MEP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0723] 43. The method of item 30, wherein blocking is determined using single fibre electromyography.

[0724] 44. The method of item 43, wherein blocking has been reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0725] 45. The method of item 43, wherein blocking has been reduced by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0726] 46. The method of item 30, wherein jitter is determined using single fibre

[0727] electromyography.P7593PC00

[0728] 83

[0729] 47. The method of item 46, wherein jitter has been reduced by at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0730] 48. The method of item 46, wherein jitter has been reduced by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0731] 49. The method of item 46, wherein jitter determined using single fibre electromyography has been reduced by at least 5 ps, such as at least 10 ps, such as at least 15 ps, such as at least 20 ps, such as at least 25 ps, such as at least 30 ps, such as at least 40 ps, such as at least 50 ps, such as at least 75 ps, such as at least 100 ps.

[0732] 50. The method of item 46, wherein jitter determined using single fibre electromyography has been reduced by between 5 ps and 200 ps, such as between 5 ps and 100 ps, such as between 10 ps and 50 ps.

[0733] 51. The method according to any one of items 1 to 10, wherein the improvement in course and severity of a neuromuscular disease is determined by re-innervation of muscle fibres.

[0734] 52. The method of item 51, wherein re-innervation comprises restoring at least 60% of a neuromuscular function.

[0735] 53. The method of item 51, wherein re-innervation comprises increasing an average percentage of fully innervated NMJs to at least 35%.

[0736] 54. The method of item 51, wherein re-innervation comprises increasing an average percentage of partially innervated fibers to at least 60%.

[0737] 55. The method according to any one of items 1 to 10, wherein the improvement in course and severity of a neuromuscular disease is determined by immune system modulation.

[0738] 56. The method of item 55, wherein immune system modulation is determined by a reduction in total IgG levels.P7593PC00

[0739] 84

[0740] 57. A method for promoting a disease-modifying effect of CIC-1 inhibitors, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent and a composition comprising a CIC-1 inhibitor.

[0741] 58. A method for providing re-innervation and / or innervation to a subject in need thereof, wherein the method comprises administering to the subject a composition comprising a therapeutically effective amount of a CIC-1 inhibitor.

[0742] 59. The method according to item 57 or 58, wherein the CIC-1 inhibitor is of Formula (I):

[0743]

[0744] Formula (I)

[0745] wherein:

[0746] - R1is selected from the group consisting of Cl and Br;

[0747] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0748] - R3is selected from the group consisting of deuterium, Cl and F;

[0749] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different,P7593PC00

[0750] 85

[0751] substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0752] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0753] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0754] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;

[0755] - n is an integer 0, 1, 2, or 3; and

[0756] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0757] 60. The method of item 59, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5-yl and 1,2-oxazol- 3-yl.

[0758] 61. The method according to item 59 or item 60, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0759] 62. The method according to any one of items 59 to 61 , wherein n is 0 or 1.

[0760] 63. The method of item 57 or 58, wherein the CIC-1 inhibitor is selected from the group consisting of:

[0761] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0762] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0763] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0764] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0765] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0766] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0767] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0768] (S)-2-(p-bromophenoxy)butyric acid;

[0769] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0770] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0771] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0772] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;P7593PC00

[0773] 86

[0774] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0775] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0776] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0777] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0778] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0779] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0780] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0781] and

[0782] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0783] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0784] 64. The method according to item 58, wherein providing the re-innervation comprises improving a neuromuscular junction (NMJ) function in the subject.

[0785] 65. The method according to any one of items 58 to 64, wherein providing the reinnervation comprises restoring at least 60% of a neuromuscular function in the subject.

[0786] 66. The method according to any one of items 58 to 65, wherein providing the reinnervation comprises increasing an average percentage of partially innervated NMJs to at least 60%.

[0787] 67. The method according to any one of items 58 to 65, wherein providing the reinnervation comprises increasing an average percentage of fully innervated NMJs to at least 35%.

[0788] 68. The method according to any one of items 58 to 67, wherein providing the reinnervation comprises increasing an average percentage of partially innervated fibers to at least 60%.

[0789] 69. The method according to any one of items 58 to 68, wherein providing the reinnervation comprises increasing an average percentage of fully innervated fibers in the subject to at least 35%.P7593PC00

[0790] 87

[0791] 70. The method according to any one of items 58 to 69, wherein providing the reinnervation comprises reducing endplate fragmentation in the subject.

[0792] 71. The method according to any one of items 58 to 70, wherein providing the reinnervation comprises reducing an average NMJ fragmentation in the subject to no greater than 10 fragments per NMJ that are above 1 pm2.

[0793] 72. The method according to any one of items 58 to 71 , wherein providing the reinnervation comprises increasing an average fragment size of acetylcholine receptor (AChR) in the subject to at least 15 pm2of AChR per fragment.

[0794] 73. The method according to any one of items 58 to 72, wherein providing the reinnervation comprises increasing a co-localization between a nerve and an AChR in the subject.

[0795] 74. The method according to any one of items 58 to 73, wherein providing the reinnervation comprises increasing a cross-sectional area of a muscle fiber in the subject by at least 15%.

[0796] 75. The method according to item 74, wherein the muscle fiber includes one or more members selected from a group consisting of a type Ila fiber, a type lib fiber, and a type x fiber.

[0797] 76. The method according to any one of items 58 to 75, wherein the method is used to provide re-innervation in one or more neuromuscular conditions selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy;

[0798] Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-ToothP7593PC00

[0799] 88

[0800] disease (CMT) including CMT type 1, CMT type 2 and CMT type 2D and multiple sclerosis.

[0801] 77. The method according to any one of items 58 to 76, wherein the method is used to prevent a neuromuscular condition in the subject.

[0802] 78. The method according to any one of items 58 to 77, wherein the method further comprises protecting the subject against a loss of body weight.

[0803] 79. The method according to any one of items 58 to 78, wherein the method further comprises increasing a survival rate of the subject.

[0804] 80. The method according to any one of items 58 to 79, wherein providing the reinnervation results in an improved pulmonary function in the subject.

[0805] 81. The method according to any one of items 58 to 80, wherein providing the reinnervation results in an improved gait of the subject.

[0806] 82. The method according to any one of items 58 to 81, wherein the composition is administered daily to the subject.

[0807] 83. The method according to any one of items 58 to 82, wherein the composition is administered to the subject for at least seven days.

[0808] 84. A method for providing reinnervation in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising:

[0809] a first therapeutically effective amount of a CIC-1 inhibitor; and a second therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[0810] 85. The method of item 84, wherein the immunomodulating or immunosuppressive agent comprises a neonatal Fc receptor (FcRn) blocker, such as selected from Efgartigimod alfa (Vyvgart), Rozanolixizumab (Rystiggo), Nipocalimab (Imaavy), Batoclimab (HBM9161 I RVT-1401), IMVT-1402, ALXN1830, M281, and Orilanolimab (SYNT001).

[0811] 86. The method according to item 84 or item 85, wherein providing the reinnervation comprises improving a neuromuscular transmission of the subject by at least 10%.P7593PC00

[0812] 89

[0813] 87. The method according to any one of items 84 to 86, wherein providing the reinnervation comprises improving a compound muscle action potential (CMAP) decrement measured at a frequency of about 50 Hz.

[0814] 88. The method according to any one of items 84 to 87, wherein providing the reinnervation comprises improving a grip strength of the subject by at least 5%.

[0815] 89. The method according to any one of items 84 to 88, wherein providing the reinnervation comprises restoring at least 5% of a grip strength of the subject.

[0816] 90. The method according to any one of items 84 to 89, wherein providing the reinnervation comprises reducing the level of Immunoglobulin G (IgG) of the subject.

[0817] 91. The method according to any one of items 84 to 90, wherein the method is used to provide re-innervation in one or more neuromuscular conditions selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy;

[0818] Lambert Eaton syndrome; critical illness myopathy; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis.

[0819] 92. A method for providing re-innervation and / or innervation in a subject in need thereof, wherein the method comprises:

[0820] administering to the subject a composition comprising a first therapeutically effective amount of a CIC-1 inhibitor and, optionally, a second therapeutically effective amount of an immunomodulating or immunosuppressive agent for a period of time;

[0821] terminating administration of the composition for a period of time,P7593PC00

[0822] 90

[0823] measuring one or more re-innervation parameters in the subject after the period of time following termination; and

[0824] beginning administration of the composition again when the one or more re-innervation parameters fall below a threshold, wherein the threshold is a set value of a re-innervation parameter; and wherein the CIC-1 inhibitor has a half-life in humans of about 3 hours to about 7 hours

[0825] 93. A CIC-1 inhibitor for use in a method of modifying or improving the course and / or severity of a neuromuscular disease, said method comprising administering a CIC-1 inhibitor to a subject suffering from the neuromuscular disease, wherein the CIC-1 inhibitor results in a disease modifying effect of said neuromuscular disease.

[0826] 94. A CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease.

[0827] 95. A CIC-1 inhibitor for use in a method of disease-modifying treatment of a neuromuscular disorder in a subject in need thereof, the method comprising administering a CIC-1 inhibitor,

[0828] wherein said method is for use in promoting re-innervation of muscle fibres in the subject suffering from the neuromuscular disorder, wherein said method is for use in improving nerve health in the subject suffering from the neuromuscular disorder,

[0829] wherein said method is for use in improving nerve performance in the subject suffering from the neuromuscular disorder,

[0830] wherein said method is for use in improving skeletal muscle fiber health in the subject suffering from the neuromuscular disorder, wherein said method is for use in improving muscle fiber performance in the subject suffering from the neuromuscular disorder, and / or wherein said method is for use in modulating the immune system the subject suffering from the neuromuscular disorder.

[0831] 96. The CIC-1 inhibitor for use of any of items 93 to 95, wherein the disease modifying effect is determined by at least one of re-innervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and improved immune system modulation.P7593PC00

[0832] 91

[0833] 97. A CIC-1 inhibitor for use in a method for promoting a disease-modifying effect, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent and a composition comprising a CIC-1 inhibitor.

[0834] 98. The CIC-1 inhibitor for use of any of items 93 to 97, wherein the CIC-1 inhibitor is of Formula (I):

[0835]

[0836] Formula (I)

[0837] wherein:

[0838] - R1is selected from the group consisting of Cl and Br;

[0839] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0840] - R3is selected from the group consisting of deuterium, Cl and F;

[0841] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0842] - R6is independently selected from the group consisting of deuterium and F;P7593PC00

[0843] 92

[0844] - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0845] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0846] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0847] - n is an integer 0, 1, 2, or 3;

[0848] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0849] 99. The CIC-1 inhibitor for use of item 98, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5- yl and 1,2-oxazol-3-yl.

[0850] 100. The CIC-1 inhibitor for use of any of items 98 and 99, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0851] 101. The CIC-1 inhibitor for use of any of items 98 to 100, wherein n is 0 or 1.

[0852] 102. The CIC-1 inhibitor for use of any of items 93 to 101 , wherein the CIC-1 inhibitor is selected from the group consisting of:

[0853] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0854] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0855] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0856] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0857] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0858] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0859] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0860] (S)-2-(p-bromophenoxy)butyric acid;

[0861] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0862] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0863] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0864] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[0865] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0866] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0867] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;P7593PC00

[0868] 93

[0869] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0870] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0871] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0872] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0873] and

[0874] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0875] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0876] 103. The CIC-1 inhibitor for use of any of items 93 to 102, wherein the method further comprises administering to the subject a therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[0877] 104. The CIC-1 inhibitor for use of item 96 or 103, wherein the immunomodulating or immunosuppressive agent is selected form the group consisting of Efgartigimod such as Efgartigimod alfa (Vyvgart), Rozanolixizumab (Rystiggo), Nipocalimab (Imaavy), Batoclimab (HBM9161 / RVT-1401), IMVT-1402, ALXN 1830, M281, Orilanolimab (SYNT001),

[0878] 105. The CIC-1 inhibitor for use of any of items 93 to 104, wherein the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;

[0879] Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis.P7593PC00

[0880] 94

[0881] 106. The CIC-1 inhibitor for use of any of items 93 to 105, wherein the improvement in course and severity of a neuromuscular disease is determined by measuring one or more parameters before administration of the CIC-1 inhibitor, administering the CIC-1 inhibitor for a period of time, waiting for a period of time after stopping administration of the CIC-1 inhibitor, measuring the parameters that were measured before administration of the CIC-1 inhibitor, and comparing the effect on the parameters before administration of the CIC-1 inhibitor to after administration of the CIC-1 inhibitor.

[0882] 107. The CIC-1 inhibitor for use of any of items 93 to 106, wherein the improvement in course and severity of a neuromuscular disease is determined by:

[0883] identifying a subject in need thereof that suffers from one or more of: a neuromuscular disability, a neuromuscular disorder, or denervation, measuring one or more parameters before administration of the CIC-1 inhibitor,

[0884] administering the CIC-1 inhibitor for a period of time, and measuring the one or more parameters after a washout period.

[0885] 108. The CIC-1 inhibitor for use of item 107, wherein the washout period is any time or time range falling within a range of about 3 days to about six months.

[0886] 109. The CIC-1 inhibitor for use of any of items 93 to 106, wherein the improvement in course and severity of a neuromuscular disease is determined by:

[0887] identifying a subject in need thereof that suffers from one or more of: a neuromuscular disability, a neuromuscular disorder, or denervation, measuring one or more parameters before administration of the CIC-1 inhibitor,

[0888] administering the CIC-1 inhibitor for a period of time, and measuring the one or more parameters after stopping administration of the CIC-1 inhibitor for a period of time.

[0889] 110. The CIC-1 inhibitor for use of item 109, wherein the period of time after stopping the administration of the CIC-1 inhibitor is any time or time range falling within a range of about 3 days to about six months.

[0890] 111. The CIC-1 inhibitor for use of any of items 93 to 108, wherein the CIC-1 inhibitor is administered for a period of at least 21 days, such as at least 1 month, suchP7593PC00

[0891] 95

[0892] as at least 2 months, such as at least 3 months, such as at least 6 months, such as at least 12 months, such as at least 24 months.

[0893] 112. The CIC-1 inhibitor for use of any of items 105 to 109, wherein the period of time after stopping administration of the CIC-1 inhibitor is at least 6 half-lives of the compound, such as at least 9 half-lives, at least 12 half-lives.

[0894] 113. The CIC-1 inhibitor for use of any of items 105 to 109, wherein the period of time after stopping administration of the CIC-1 inhibitor is at least 3 days, such as at least 4 days, such as at least 5 days, such as at least 6 days, such as at least 7 days, such as at least 10 days, such as at least 14 days, such as at least 21 days, such as at least 28 days.

[0895] 114. The CIC-1 inhibitor for use of any of items 93 to 113, wherein the improvement in course and severity of a neuromuscular disease is determined by an improvement in skeletal muscle performance.

[0896] 115. The CIC-1 inhibitor for use of item 114, wherein skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction).

[0897] 116. The CIC-1 inhibitor for use of item 115, wherein muscle strength has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0898] 117. The CIC-1 inhibitor for use of item 115, wherein muscle strength has increased by between 10% and 400%, such as between 15% and 200%, such as between 20% and 100%.

[0899] 118. The CIC-1 inhibitor for use of item 115, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.P7593PC00

[0900] 96

[0901] 119. The CIC-1 inhibitor for use of item 115, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by between 10% and 400%, such as between 15% and 200%, such as between 20% and 100%.

[0902] 120. The CIC-1 inhibitor for use of any of items 115 to 119, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0903] 121. The CIC-1 inhibitor for use of any of items 115 to 119, wherein muscle strength determined by measuring grip strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0904] 122. The CIC-1 inhibitor for use of any of items 115 to 117, wherein muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.

[0905] 123. The CIC-1 inhibitor for use of any of items 115 to 117, wherein muscle strength determined by measuring knee flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0906] 124. The CIC-1 inhibitor for use of any of items 115 to 117, wherein muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by at least 0.25 kg, such as at least 0.50 kg, such as at least 0.75 kg, such as at least 1.0 kg, such as at least 1.25 kg, such as at least 1.5 kg, such as at least 1.75 kg, such as at least 2.0 kg, such as at least 2.5 kg, such as at least 3.0 kg.P7593PC00

[0907] 97

[0908] 125. The CIC-1 inhibitor for use of any of items 115 to 117, wherein muscle strength determined by measuring elbow flexor strength using a handheld dynamometer has increased by between 0.25 and 5.0 kg, such as between 0.25 and 4.0 kg, such as between 0.5 and 4.0 kg.

[0909] 126. The CIC-1 inhibitor for use of any of items 93 to 113, wherein the improvement in course and severity of a neuromuscular disease is determined by skeletal muscle fiber health.

[0910] 127. The CIC-1 inhibitor for use of item 126, wherein skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

[0911] 128. The CIC-1 inhibitor for use of item 127 wherein pulmonary function is determined by measuring forced vital capacity (FVC).

[0912] 129. The CIC-1 inhibitor for use of item 128, wherein the FVC has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0913] 130. The CIC-1 inhibitor for use of item 128, wherein the FVC has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0914] 131. The CIC-1 inhibitor for use of item 127, wherein the pulmonary function is determined by measuring forced expiratory volume in 1 second (FEV1).

[0915] 132. The CIC-1 inhibitor for use of item 131, wherein FEV1 has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0916] 133. The CIC-1 inhibitor for use of item 131, wherein FEV1 has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.P7593PC00

[0917] 98

[0918] 134. The CIC-1 inhibitor for use of item 127, wherein the pulmonary function is determined by measuring maximal inspiratory pressure (MIP).

[0919] 135. The CIC-1 inhibitor for use of item 134, wherein the MIP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0920] 136. The CIC-1 inhibitor for use of item 134, wherein the MIP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0921] 137. The CIC-1 inhibitor for use of item 127, wherein the pulmonary function is determined by measuring maximal expiratory pressure (MEP).

[0922] 138. The CIC-1 inhibitor for use of item 137, wherein the MEP has increased by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0923] 139. The CIC-1 inhibitor for use of item 137, wherein the MEP has increased by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0924] 140. The CIC-1 inhibitor for use of item 127, wherein blocking is determined using single fibre electromyography.

[0925] 141. The CIC-1 inhibitor for use of item 127, wherein blocking has been reduced by at least 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0926] 142. The CIC-1 inhibitor for use of item 127, wherein blocking has been reduced by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.P7593PC00

[0927] 99

[0928] 143. The CIC-1 inhibitor for use of item 127, wherein jitter is determined using single fibre electromyography.

[0929] 144. The CIC-1 inhibitor for use of item 127, wherein jitter has been reduced by at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%.

[0930] 145. The CIC-1 inhibitor for use of item 127, wherein jitter has been reduced by between 5% and 95%, such as between 5% and 80%, such as between 10% and 50%.

[0931] 146. The CIC-1 inhibitor for use of item 127, wherein jitter determined using single fibre electromyography has been reduced by at least 5 ps, such as at least 10 ps, such as at least 15 ps, such as at least 20 ps, such as at least 25 ps, such as at least 30 ps, such as at least 40 ps, such as at least 50 ps, such as at least 75 ps, such as at least 100 ps.

[0932] 147. The CIC-1 inhibitor for use of item 127, wherein jitter determined using single fibre electromyography has been reduced by between 5 ps and 200 ps, such as between 5 ps and 100 ps, such as between 10 ps and 50 ps.

[0933] 148. The CIC-1 inhibitor for use of any of items 93 to 113, wherein the improvement in course and severity of a neuromuscular disease is determined by reinnervation of muscle fibres.

[0934] 149. The CIC-1 inhibitor for use of item 148, wherein re-innervation comprises restoring at least 60% of a neuromuscular function.

[0935] 150. The CIC-1 inhibitor for use of item 148, wherein re-innervation comprises increasing an average percentage of fully innervated NMJs to at least 35%.

[0936] 151. The CIC-1 inhibitor for use of item 148, wherein re-innervation comprises increasing an average percentage of partially innervated fibers to at least 60%.

[0937] 152. The CIC-1 inhibitor for use of any of items 93 to 113, wherein the improvement in course and severity of a neuromuscular disease is determined by immune system modulation.P7593PC00

[0938] 100

[0939] 153. The CIC-1 inhibitor for use of item 152, wherein immune system modulation is determined by a reduction in total IgG levels.

[0940] 154. The CIC-1 inhibitor for use of any of items 93 to 153, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent and a composition comprising a CIC-1 inhibitor.

[0941] 155. A CIC-1 inhibitor for use in a method for providing re-innervation and / or innervation to a subject in need thereof, wherein the method comprises administering to the subject a composition comprising a therapeutically effective amount of a CIC-1 inhibitor.

[0942] 156. The CIC-1 inhibitor for use of item 155, wherein the CIC-1 inhibitor is of Formula (I):

[0943]

[0944] Formula (I)

[0945] wherein:

[0946] - R1is selected from the group consisting of Cl and Br;

[0947] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[0948] - R3is selected from the group consisting of deuterium, Cl and F;

[0949] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl;P7593PC00

[0950] 101

[0951] - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[0952] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;

[0953] - R8is independently selected from the group consisting of deuterium, F and OMe;

[0954] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[0955] - n is an integer 0, 1, 2, or 3;

[0956] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0957] 157. The CIC-1 inhibitor for use of item 156, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5- yl and 1,2-oxazol-3-yl.

[0958] 158. The CIC-1 inhibitor for use of any of items 156 or 157, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[0959] 159. The CIC-1 inhibitor for use of any of items 156 to 158, wherein n is 0 or 1.

[0960] 160. The CIC-1 inhibitor for use of item 155, wherein the CIC-1 inhibitor is selected from the group consisting of:

[0961] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[0962] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[0963] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[0964] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[0965] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[0966] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[0967] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[0968] (S)-2-(p-bromophenoxy)butyric acid;P7593PC00

[0969] 102

[0970] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[0971] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0972] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[0973] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[0974] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[0975] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0976] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[0977] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0978] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[0979] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;

[0980] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0981] and

[0982] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[0983] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0984] 161. The CIC-1 inhibitor for use of any of items 156 to 160, wherein providing the reinnervation comprises improving a neuromuscular junction (NMJ) function in the subject.

[0985] 162. The CIC-1 inhibitor for use of any of items 156 to 161, wherein providing the reinnervation comprises restoring at least 60% of a neuromuscular function in the subject.

[0986] 163. The CIC-1 inhibitor for use of any of items 156 to 161, wherein providing the reinnervation comprises increasing an average percentage of partially innervated NMJs to at least 60%.

[0987] 164. The CIC-1 inhibitor for use of any of items 156 to 161, wherein providing the reinnervation comprises increasing an average percentage of fully innervated NMJs to at least 35%.

[0988] 165. The CIC-1 inhibitor for use of any of items 156 to 161, wherein providing the reinnervation comprises increasing an average percentage of partially innervated fibers to at least 60%.P7593PC00

[0989] 103

[0990] 166. The CIC-1 inhibitor for use of any of items 156 to 161, wherein providing the reinnervation comprises increasing an average percentage of fully innervated fibers in the subject to at least 35%.

[0991] 167. The CIC-1 inhibitor for use of any of items 156 to 166, wherein providing the reinnervation comprises reducing endplate fragmentation in the subject.

[0992] 168. The CIC-1 inhibitor for use of any of items 156 to 167, wherein providing the reinnervation comprises reducing an average NMJ fragmentation in the subject to no greater than 10 fragments per NMJ that are above 1 pm2.

[0993] 169. The CIC-1 inhibitor for use of any of items 156 to 168, wherein providing the reinnervation comprises increasing an average fragment size of acetylcholine receptor (AChR) in the subject to at least 15 pm2of AChR per fragment.

[0994] 170. The CIC-1 inhibitor for use of any of items 156 to 169, wherein providing the reinnervation comprises increasing a co-localization between a nerve and an AChR in the subject.

[0995] 171. The CIC-1 inhibitor for use of any of items 156 to 170, wherein providing the reinnervation comprises increasing a cross-sectional area of a muscle fiber in the subject by at least 15%.

[0996] 172. The CIC-1 inhibitor for use of item 171, wherein the muscle fiber includes one or more members selected from a group consisting of a type Ila fiber, a type lib fiber, and a type x fiber.

[0997] 173. The CIC-1 inhibitor for use of any of items 156 to 172, wherein the method is used to provide re-innervation in one or more neuromuscular conditions selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChRAB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia;P7593PC00

[0998] 104

[0999] metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot- Marie-Tooth disease (CMT) including CMT type 1, CMT type 2 and CMT type 2D and multiple sclerosis.

[1000] 174. The CIC-1 inhibitor for use of any of items 156 to 173, wherein the method is used to prevent a neuromuscular condition in the subject.

[1001] 175. The CIC-1 inhibitor for use of any of items 156 to 174, wherein the method further comprises protecting the subject against a loss of body weight.

[1002] 176. The CIC-1 inhibitor for use of any of items 156 to 175, wherein the method further comprises increasing a survival rate of the subject.

[1003] 177. The CIC-1 inhibitor for use of any of items 156 to 176, wherein providing the reinnervation results in an improved pulmonary function in the subject.

[1004] 178. The CIC-1 inhibitor for use of any of items 156 to 177, wherein providing the reinnervation results in an improved gait of the subject.

[1005] 179. The CIC-1 inhibitor for use of any of items 156 to 178, wherein the composition is administered daily to the subject.

[1006] 180. The CIC-1 inhibitor for use of any of items 156 to 179, wherein the composition is administered to the subject for at least seven days.

[1007] 181. A CIC-1 inhibitor for use in a method for providing reinnervation in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising:

[1008] a first therapeutically effective amount of a CIC-1 inhibitor; and a second therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[1009] 182. The CIC-1 inhibitor for use of item 181 , wherein the immunomodulating or immunosuppressive agent comprises a neonatal Fc receptor (FcRn) blocker, such as selected from Efgartigimod alfa (Vyvgart), Rozanolixizumab (Rystiggo), Nipocalimab (Imaavy), Batoclimab (HBM9161 I RVT-1401), IMVT-1402, ALXN1830, M281, Orilanolimab and (SYNT001).P7593PC00

[1010] 105

[1011] 183. The CIC-1 inhibitor for use of item 181 or 182, wherein providing the reinnervation comprises improving a neuromuscular transmission of the subject by at least 10%.

[1012] 184. The CIC-1 inhibitor for use of any of items 181 to 183, wherein providing the reinnervation comprises improving a compound muscle action potential (CMAP) decrement measured at a frequency of about 50 Hz.

[1013] 185. The CIC-1 inhibitor for use of any of items 181 to 184, wherein providing the reinnervation comprises improving a grip strength of the subject by at least 5%.

[1014] 186. The CIC-1 inhibitor for use of any of items 181 to 185, wherein providing the reinnervation comprises restoring at least 5% of a grip strength of the subject.

[1015] 187. The CIC-1 inhibitor for use of any of items 181 to 186, wherein providing the reinnervation comprises reducing the level of Immunoglobulin G (IgG) of the subject.

[1016] 188. The CIC-1 inhibitor for use of any of items 181 to 187, wherein the method is used to provide re-innervation in one or more neuromuscular conditions selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChRAB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy; Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy; Duchenne muscular dystrophy; Lambert Eaton syndrome; critical illness myopathy; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; post-polio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis.

[1017] 189. A CIC-1 inhibitor for use in a method for providing re-innervation and / or innervation in a subject in need thereof, wherein the method comprises:P7593PC00

[1018] 106

[1019] administering to the subject a composition comprising a first therapeutically effective amount of a CIC-1 inhibitor and, optionally, a second therapeutically effective amount of an immunomodulating or immunosuppressive agent for a period of time;

[1020] terminating administration of the composition for a period of time, measuring one or more re-innervation parameters in the subject after the period of time following termination; and

[1021] beginning administration of the composition again when the one or more re-innervation parameters fall below a threshold, wherein the threshold is a set value of a re-innervation parameter; and

[1022] wherein the CIC-1 inhibitor has a half-life in humans of about 3 hours to about 7 hours.

[1023] 190. A method for providing re-innervation and / or innervation to a subject in need thereof comprising:

[1024] - providing an at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or an at least 35% improvement in the subject’s average percentage of fully innervated NMJs by:

[1025] - administering a composition containing a therapeutically effective amount of a CIC-1 inhibitor; and

[1026] - obtaining an at least 65% improvement in the NMJ’s ability to induce muscle contraction after the administering when compared to the NMJ’s ability to induce muscle contraction before the administering by monitoring the NMJ’s ability to induce muscle contraction during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1027] 191. The method of item 190, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1028] - obtaining an at least 60% improvement in the NMJ’s average percentage of partially innervated fibers after the administering when compared to the NMJ’s average percentage of partially innervated fibers before the administering by monitoring the NMJ’s average percentage ofP7593PC00

[1029] 107

[1030] partially innervated fibers during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1031] 192. The method of item 190 or 191, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1032] - obtaining an at least 35% improvement in the NMJ’s average percentage of fully innervated fibers after the administering when compared to the NMJ’s average percentage of fully innervated fibers before the administering by monitoring the NMJ’s average percentage of fully innervated fibers during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1033] 193. The method of any one of items 190-192, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1034] - obtaining a reduction in the subject’s average NMJ fragmentation of no more than 10 fragments per NMJ that are above 1 pm2after the administering by monitoring the average NMJ fragmentation during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1035] 194. The method of any one of items 190-193, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1036] - obtaining an increase in the subject’s average fragment size of AChR of at least 15 pm2of AChR per fragment after the administering by monitoring the average fragment size of AChR during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.P7593PC00

[1037] 108

[1038] 195. The method of any one of items 190-194, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1039] - obtaining an increase in the subject’s cross-sectional area of a muscle fiber of at least 15% after the administering when compared to the cross- sectional area of the muscle fiber before the administering by monitoring the cross-sectional area of the muscle fiber during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1040] 196. The method of any one of items 190-195, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1041] - obtaining an increase in neuromuscular transmission in the subject of at least 10% after the administering when compared to the neuromuscular transmission in the subject before the administering by monitoring neuromuscular transmission in the subject during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1042] 197. The method of any one of items 190-196, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1043] - obtaining an at least 5% improvement in the subject’s grip strength after the administering when compared to the subject’s grip strength before the administering by monitoring the subject’s grip strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1044] 198. The method of any one of items 190-197, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:P7593PC00

[1045] 109

[1046] - restoring at least 5% of the subject’s grip strength after the administering by monitoring the subject’s grip strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1047] 199. The method of any one of items 190-198, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1048] - obtaining an increase in the subject’s muscle strength by at least 0.10 kg after the administering when compared to the subject’s muscle strength before the administering by monitoring the subject’s muscle strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1049] 200. The method of any one of items 190-199, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1050] - obtaining an increase in the subject’s muscle force by at least 3.0 newtons after the administering when compared to the subject’s muscle force before the administering by monitoring the subject’s muscle force during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1051] 201. The method of any one of items 190-200, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1052] - obtaining an at least 5% increase in the subject’s muscle strength after the administering when compared to the subject’s muscle strength before the administering by monitoring the subject’s muscle strength during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.P7593PC00

[1053] 110

[1054] 202. The method of any one of items 190-201 , wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1055] - obtaining an improvement in the subject’s forced vital capacity (FVC) of at least 5% after the administering when compared to the subject’s FVC before the administering by monitoring the subject’s FVC during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1056] 203. The method of any one of items 190-202, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1057] - obtaining an improvement in the subject’s forced expiratory volume in 1 second (FEV1) of at least 5% after the administering when compared to the subject’s FEV1 before the administering by monitoring the subject’s FEV1 during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1058] 204. The method of any one of items 190-203, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1059] - obtaining an improvement in the subject’s maximal inspiratory pressure (MIP) of at least 5% after the administering when compared to the subject’s MIP before the administering by monitoring the subject’s MIP during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1060] 205. The method of any one of items 190-204, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:P7593PC00

[1061] 111

[1062] - obtaining an improvement in the subject’s maximal expiratory pressure (MEP) of at least 5% after the administering when compared to the subject’s MEP before the administering by monitoring the subject’s MEP during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1063] 206. The method of any one of items 190-205, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1064] - obtaining a reduction in blocking in the NMJs of at least 5% after the administering when compared to a degree of blocking in the NMJs before the administering by monitoring blocking in the NMJs during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1065] 207. The method of any one of items 190-206, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1066] - obtaining a reduction in jitter of at least 5% after the administering when compared to a degree of jitter presented by the subject before the administering by monitoring jitter during the administering and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1067] 208. The method of any one of items 190-207, wherein providing the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1068] - reducing jitter in the subject to no more than 30 ps, no more than 25 ps, no more than 20 ps, no more than 15 ps or no more than 10 ps after the administering.

[1069] 209. The method of item 190, wherein the providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the atP7593PC00

[1070] 112

[1071] least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1072] - obtaining a reduction in blocking in the NMJs of at least 5% after the administering when compared to a degree of blocking in the NMJs before the administering by measuring blocking in the NMJs during the administering with single fibre electromyography (sfEMG) and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition; and

[1073] - obtaining a reduction in jitter of at least 5% after the administering when compared to a degree of jitter presented by the subject before the administering by measuring jitter during the administering with sfEMG and optionally increasing or decreasing the therapeutically effective amount of a CIC-1 inhibitor in the composition.

[1074] 210. The method according to item 209, wherein the providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1075] - reducing jitter in the subject to no more than 30 ps, no more than 25 ps, no more than 20 ps, no more than 15 ps or no more than 10 ps after the administering by measuring jitter during the administering with sfEMG.

[1076] 211. The method of any one of items 190-210, comprising administering to the subject in need thereof a therapeutically effective amount of an immunomodulating or immunosuppressive agent.

[1077] 212. The method of any one of item 190-211, wherein the providing of the at least 60% improvement in the subject’s average percentage of partially innervated NMJs and / or the at least 35% improvement in the subject’s average percentage of fully innervated NMJs further comprises:

[1078] - detecting a disease modifying effect in the subject during the administering by subjecting the subject to one or more MRI techniques.

[1079] 213. The method of item 212, wherein the disease modifying effect is a change in muscle architecture selected from: increased number of neuron connections with a muscle tissue, increased muscle volume, increased muscle fiber length,P7593PC00

[1080] 113

[1081] increased muscle pennation angle, increased physiological cross-sectional area (PCSA), and longer axons in motor neurons.

[1082] 214. The method of any one of item 190-213, wherein the CIC-1 inhibitor is of Formula (I):

[1083]

[1084] Formula (I)

[1085] wherein:

[1086] - R1is selected from the group consisting of Cl and Br;

[1087] - R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;

[1088] - R3is selected from the group consisting of deuterium, Cl and F;

[1089] - R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;

[1090] - R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;P7593PC00

[1091] 114

[1092] - R8is independently selected from the group consisting of deuterium, F and OMe;

[1093] - R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and

[1094] - n is an integer 0, 1, 2, or 3;

[1095] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[1096] 215. The method of item 214, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5-yl and 1,2- oxazol-3-yl.

[1097] 216. The method of item 214 or 215, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

[1098] 217. The method of any one of items 214 to 216, wherein n is 0 or 1.

[1099] 218. The method of item 214, wherein the CIC-1 inhibitor is selected from the group consisting of:

[1100] (S)-2-(p-bromophenoxy)-3-methylbutyric acid;

[1101] (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;

[1102] (R)-2-(p-bromophenoxy)-3-fluoropropionic acid;

[1103] (S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;

[1104] (S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;

[1105] (S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;

[1106] (S)-2-(4-bromo-2-fluorophenoxy)butyric acid;

[1107] (S)-2-(p-bromophenoxy)butyric acid;

[1108] (R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;

[1109] (S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;

[1110] (S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;

[1111] (S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;

[1112] (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;

[1113] (R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[1114] (S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;

[1115] (R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[1116] (S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;

[1117] (S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;P7593PC00

[1118] 115

[1119] (R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[1120] and

[1121] (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;

[1122] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[1123] 219. The method of any one of items 190 to 218, wherein the administering of the CIC-1 inhibitor occurs over a period of at least 21 days, such as at least 1 month, such as at least 2 months, such as at least 3 months, such as at least 6 months, such as at least 12 months, such as at least 24 months.

[1124] Examples

[1125] Described below are three sets of pre-clinical data demonstrating the diseasemodifying effects of compositions containing CIC-1 inhibitors. Specifically, the diseasemodifying effects of the composition disclosed herein have been demonstrated in three different preclinical models where animals have been repeatedly treated with the compositions for 7 to 60 days.

[1126] Example 1: Effect of CIC-1 inhibition on re-innervation confirmed in nerve crush model

[1127] FIG. 1 shows a graphical representation of the nerve crush model used in this example. The effect of accelerated re-innervation was examined in three treatment groups: rats without injury or treatment (sham), nerve crush rat models treated with NMD712, a CIC-1 inhibitor, and nerve crush rat models treated with vehicle only, respectively. NMD712 was administered once daily at a dosage of 50 mg / kg per os (p.o.) for 56 days from day 3 (after a CatWalk test) to day 58. The results of these treatments are shown in FIG. 2, FIG. 28, FIG 29 and FIG. 30. Changes in the Sciatic Functional Index were recorded and used to determine improvements in accelerated re-innervation. These changes were determined by using a CatWalk XT 10.6 gait analysis tool (FIG. 3). The data gathered from this experiment demonstrated thatP7593PC00

[1128] 116

[1129] NMD712-treated rats showed a faster recovery compared to vehicle-treated rats, and by the end of the treatment, at least 60% of a neuromuscular function was restored for NMD712-treated rats, whereas only less than 50% of a neuromuscular function was restored for vehicle-treated rats.

[1130] As shown in FIG. 30, at 20 days post-injury, no effect of dosing was observed. At 63 days post injury, a main effect of dosing was observed, favouring an overall higher muscle mass in the crushed legs of NMD712-dosed animals closer to that of the sham animals, when compared to vehicles (p<0.01 ) . For the tibialis anterior, the average muscle mass of the crushed legs in NMD712-dosed and vehicle-dosed animals was 88 % and 80 %, respectively, of that in sham-crushed legs in sham animals. For the extensor digitorum longus, the same was 95 % and 86 %, and for the soleus, 87 % and 78 % in NMD712- and vehicle-dosed animals, respectively. When compared to sham controls, muscle mass of three muscle types in the hindlimb was 8-9% greater at 9 weeks (63 days) post injury in animals receiving CIC-1 inhibitor, compared to vehicle treatment. This data suggests recovery of myofiber mass induced by neurogenic atrophy.

[1131] These studies confirm accelerated neuromuscular recovery by CIC-1 inhibition following nerve crush and expand on molecular profiling to evaluate neurotrophic signalling and disease-modifying effect.

[1132] Understanding immunohistochemical data showing re-innervation

[1133] The results of the above experiment prompted further investigation into possible mechanisms on how CIC-1 inhibition prompted re-innervation. One possible mechanistic pathway is depicted in FIG. 4, which shows how CIC-1 inhibition promotes a re-innervation process from a denervated NMJ to a partially innervated NMJ to a (fully) innervated NMJ on a continuous scale. This schematic is consistent with confocal microscopy images taken during the above experiment (see FIG. 5). These images show regions corresponding to acetylcholine receptors (AChRs) in muscle fibers on the post-synaptic side and motoneurons overlapping with the AChRs in muscle fibers.P7593PC00

[1134] 117

[1135] Pre-liminary analysis indicate that CIC-1 inhibition enhances re-innervation

[1136] The effect that CIC-1 inhibition has on nerve re-innervation was further investigated by removing the gastrocnemius muscle from rats treated with either NMD712 or vehicle and assessing the state of the NMJs in the collected muscle tissue (see FIG. 6).

[1137] Specifically, the gastrocnemius muscle of nerve crush rat models was harvested 20 days after injury, after 18 days of dosing. The muscle samples were then analyzed by scoring of NMJ innervation status. Initial investigations by immunohistochemical analysis of the NMJ in the collected muscle tissue showed more fibers that are partially innervated in NMD712 group, which suggests that NMD712 accelerated re-innervation following treatment for 18 days (FIG. 7A, 7B and 8). As shown in FIGS. 7A and 7B, the percentage of partially innervated NMJs and / or fibers was increased to at least 60% (up to 85%) for NMD712-treated rats, whereas the percentage of partially innervated NMJs and / or fibers for vehicle-treated rats was below 50%. Prior to unblinding, weak immunostaining and a low number of endplates were observed in gastrocnemius tissue sections from one rat in the NMD712 group, and the data were not deemed representative. Innervation status data from this animal were therefore excluded, resulting in sample sizes of n = 5 for vehicle and n = 4 for NMD712 (FIG. 7B).

[1138] Reduction of polyinnervation after motor nerve injury

[1139] During reinnervation, intramuscular axons sprout within close proximity to their endplate targets to reinnervate multiple muscle fibers, forming larger motor units. While this ensures synapse formation, innervation of a single endplate by multiple motor neurons, termed polyinnervation, can also occur in parallel. This is considered maladaptive as a single muscle fiber controlled by multiple motor neurons firing asynchronous is not a physiological advantage. Polyinnervation of endplates during reinnervation has been argued to be transient, and removal of polyinnervation (termed synaptic pruning or elimination) is considered the final maturation step in the reinnervation process. However, multiple studies suggest that it can persist as a more chronic feature following reinnervation. The proportion of polyinnervated NMJs during reinnervation has been reported to be negatively associated with motor function.

[1140] Moreover, decreasing the proportion of polyinnervated NMJs during reinnervation, through various interventions, has likewise been associated with a better recovery of neuromuscular function.P7593PC00

[1141] 118

[1142] The presence of polyinnervated endplates in vehicle- and NMD712-dosed rats 9 weeks after crush were analysed. L4 lumbrical muscle were harvested 9-weeks after nerve crush and analysed by immunohistochemistry. For each image acquired, the z-stack was thoroughly run through to find polyinnervated NMJs. Image acquisition and analyses were performed blinded. The images were analysed as:

[1143] Polyinnervation fraction = total number of NMJs relative to number of polyinnervated NMJs per image / field of view.

[1144] A statistically significant difference was noted between groups, with 20% polyinnervated NMJs per field of view found in the vehicle treated group compared to 11% in the NMD712 treated group (FIG. 31). The lower prevalence of polyinnervated endplates within analysed regions of NMD712-dosed muscles, compared to vehicle, indicates a more mature reinnervation status 9 weeks after nerve crush.

[1145] Neurotrophin-4 (NT-4) protein expression

[1146] NT-4 is muscle-derived and activity-sensitive neurotrophic factor. The role of NT-4 involves signalling for motor neuron growth and remodelling, ensuring maintenance of synaptic connections and therefore helps preserve neuromuscular integrity between adult motor neurons and muscle fibers (Zhan etal, 2003; Funakoshi et al, 1995).

[1147] Moreover, NT-4 is important for axonal regrowth following peripheral nerve injury (English etal, 2005; English etal, 2011)

[1148] Protein expression of Neurotrophin-4 (NT-4) was investigated by Western Blot from sham rats and from vehicle- and NMD712-dosed rats 9 weeks after crush in gastrocnemius muscle. There was a statistically significant increase in NT-4 expression in the NMD712 treated group compared to sham treated animals and a 43% greater mean NT-4 expression compared to vehicle (p=0.085).

[1149] This data suggests that NMD712 promotes neurotrophic signalling through a signalling cascade involving NT-4, providing a molecular explanation of the accelerated recovery of neuromuscular function by NMD712 following sciatic nerve injury.

[1150] In conclusion, CIC-1 inhibition showed a disease-modifying effect in a rat model for investigation of re-innervation process. CIC-1 inhibition treatment of sciatic nerve crush model showed an accelerated re-innervation process after nerve crush. FunctionalP7593PC00

[1151] 119

[1152] nerve indexes (e.g., sciatic and peroneal) were assessed through gait function, and faster recovery was observed among NMD712-treated animals. Immunohistochemistry data showed earlier and more pronounced re-innervation after 20 days of treatment using NMD712.

[1153] Example 2: CIC-1 inhibition enhances re-innervation in CMT type 2D mice CIC-1 inhibition’s effect on re-innervation was next examined in CMT type 2D mice (heterozygous GarsAETAQ / +, where there is a deletion of 12 nucleotides in exon 8 in the Gars gene) and the homozygous Gars+I+mice were used as healthy wild type (WT) controls (see FIG. 9). CIC-1 inhibitor NMD712 (80 mg / kg p.o.) or vehicle (sterile water) were administered for 7 days (afternoon on day 1, morning and afternoon on days 2 and 3, and morning on days 4 to 7) in the NMD712 and vehicle treatment groups before NMJ innervation was evaluated. The homozygous Gars+I+mice were not dosed. The results of this experiment showed that repeated dosing of CIC-1 inhibitor NMD712 improved NMJ transmission (CMAP, as described in further detail below) and motor nerve function, which indicates the disease-modifying effect of CIC-1 inhibitors (see FIG. 10-11).

[1154] The NMJ morphology of innervation for the above experiment was assessed using immunohistochemistry (IHC) and confocal microscopy on plantaris muscle from the CMT type 2D mice. Immunohistochemical analysis of NMJ in CMT type 2D mice indicated disease modification as a result of treatment using a CIC-1 inhibitor (FIGS.

[1155] 10-11). As shown in FIG. 10, the percentage of fully innervated NMJs and / or fibers was increased to at least 35% (up to 65%, with an average of 50%) for NMD712-treated mice, whereas the percentage of fully innervated NMJs and / or fibers for vehicle-treated mice was on average below 40%.

[1156] The progress of normalized grip strength (GS) by body weight (BW) was also measured in CMT type 2D mice treated with NMD712 or vehicle (FIG. 25). In this experiment, grip strength of healthy WT mice, vehicle-treated CMT type 2D mice and NMD712-treated CMT type 2D mice was measured over a period of 7-days. The WT mice showed stable GS, and the vehicle group showed some increase to 111.5 % on study day 7. However, the group treated with NMD712 increased GS to 128.9 % on day 7.P7593PC00

[1157] 120

[1158] The decrement of compound muscle action potential (CMAP) was next investigated in CMT type 2D mice treated with NMD712 or vehicle. CMAP decrement of healthy wildtype mice, vehicle-treated CMT type 2D mice and NMD712-treated CMT type 2D mice was assessed for 7 days following treatment. CMAP decrement difference was calculated as the % difference between T1 and T10 (the first and 10thstimuli). The CMAP decrement difference between the three treatment groups at different detection frequencies can be seen in FIG. 26A and FIG. 26B. NMD712 improved CMAP decrement as the study progressed (FIG. 26A), and on study day 7 there was a significant difference between the NMD712 dosed group and the vehicle dosed group at 20 Hz, 30 Hz, 40 Hz and 50 Hz (FIG. 26B). A 2-way ANOVA with uncorrected Fisher’s LSD post-hoc test was used to determine statistical significance between the treatment groups. *p=0.0106 on day 7 (FIG. 26A). A 2-way ANOVA with uncorrected Fisher’s LSD post-hoc test for multiple comparison between NMD712 group and vehicle group, * p< 0.05 (FIG. 26B).

[1159] The difference in CMAP decrement at 50 Hz in the three treatment groups at 3-days post treatment and 7-days post treatment can be seen in FIG. 27. A one-way ANOVA with uncorrected Fisher’s LSD post-hoc test was used to determine statistical significance between baseline, study day 3, and study day 7. Mean ± SEM, n=7.

[1160] *p=0.0213 between baseline and study day 7 for NMD712 treated group. No significant difference in vehicle group.

[1161] Neuromuscular transmission failure was also investigated looking at the failure of quantal release at the neuromuscular synapse (see Spaulding et al, 2016). At an excitation frequency of 120 Hz, there were fewer release failures (also referred to herein as nerve excitation failures (NEFs)) in the NMD712 treated group compared to the vehicle group (FIG. 33). The data suggest presynaptic dysfunction in CMT2D mice, and that NMD712 treatment improved these parameters significantly at 120 Hz.

[1162] In conclusion, CIC-1 inhibition showed a disease modifying effect in a genetic axonal neuropathic model. CIC-1 inhibition treatment in a CMT 2D mouse model and functional studies in living animals also showed an increased rate of weight gain and improved muscle force, as well as an improved motor nerve function (i.e. , fewer release failures (nerve excitation failures). Immunohistochemistry studies showed improved muscle fiber innervation.P7593PC00

[1163] 121

[1164] Example 3: CIC-1 inhibition shows disease-modifying effect in muscle-specific kinase myasthenia gravis (MuSK-MG) animals

[1165] Next CIC-1 inhibition’s ability to promote disease-modifying effects in a muscle-specific kinase myasthenia gravis (MuSK-MG) rat model was investigated. Muscle specific kinase myasthenia gravis (MuSK-MG) is a subtype of generalized MG with pathogenic antibodies against MuSK instead of acetylcholine receptors. This subgroup accounts for about 5-8 % of patients with MG with disease symptoms being very similar to general MG. However, in MuSK MG patients, mainly the facial-bulbar muscles are affected, and patients display high frequency of respiratory crisis with the need of assisted ventilation (see Rodolico etal, 2020). Existing treatment for this subgroup is limited, and the majority of MuSK-MG patients are refractory to treatment. Thus, a pre-clinical study in a rat model of MuSK MG was conducted to investigate the effect of CIC-1 inhibitor treatment on disease out-come including disease modifying effects.

[1166] The employed model in this experiment was an acute rat model of muscle-specific-kinase myasthenia gravis (MuSK MG) (FIG. 12). In this study, twenty Lewis rats were immunized with an antigen (N-MuSK 60) against MuSK. Disease symptoms (e.g. weight loss, muscle weakness and affected pulmonary function) started approximately 18-20 days after immunization. Rats were dosed for 14 days with either vehicle or NMD712 (50 mg / kg p.o.) starting at day 18 post immunization and ending at day 32 post immunization. The rats did not exhibit any adverse reactions to the administered compound, nor any signs of muscle stiffness. Rats dosed with NMD712 displayed reduced Compound Muscle Action Potentials (CMAP) decrement at all tested frequencies, improved pulmonary function and improved performance on gait analysis. Following the in-life part of the study ( / .e., 32 days post-immunization), including a 14-day dosing period, rats were euthanized in CO2 and muscle samples dissected and prepared for immunohistochemistry for neuromuscular junction (NMJ) integrity investigation (FIG. 13).

[1167] Methods

[1168] The rat model of MuSK MG

[1169] An anti-muscle specific kinase (MuSK) myasthenia gravis (MG) rat model was established at NMD Pharma. 20 Lewis rats, seven weeks old, were anesthetized and immunized with an antigen; a splicing variant of mouse MuSK, termed N-MuSK 60,P7593PC00

[1170] 122

[1171] initially discovered and described (see Richman etal, 2012). For the present study, N-MuSK 60 was manufactured by Bioneer A / S (Horsholm, Denmark). An emulsion of 150 pL was injected s.c. at the base of the tail by multiple injections dispersed over the area above the tail base. The rats were immunized with either 15 pg per rat MuSK antigen (N-MuSK 60) or no antigen (sham-immunization). Within 2 hours post-immunization, all rats received one s.c. injection of 1.88 pg pertussis vaccine.

[1172] In-life part of study

[1173] Twenty rats were actively immunized with a MuSK antigen (N-MuSK 60) and six rats were inactively immunized (sham). Following immunization, the rats were monitored for disease symptoms. To this end, bodyweight, compound muscle action potentials (CMAP) and pulmonary function by unrestrained whole body plethysmography (WBP) were monitored before and during the 14-day dosing period. At day 18 postimmunization, the twenty rats receiving antigen were stratified into 2 groups and per orally dosed (once daily, 5 ml / kg) of either vehicle (sterile water) or NMD712 (50 mg / kg). Rats were dosed for 14 days. The sham group was not dosed, and the study was blinded.

[1174] Following the in-life part of the study (=32 days post-immunization) N=5 vehicle-dosed and n=6 NMD712-dosed rats were selected for further analysis of neuromuscular junction morphology, innervation status, and muscle fiber size by immunohistochemistry. The selection was conducted to obtain a sample population representative of the two dosing groups. For the vehicle-dosed rats, n=3 of the selected animals was terminated based on humane endpoints, and the remaining n=2 was terminated by planned euthanization following 14 days of dosing. For the NMD712-dosed animals, n=1 was terminated based on humane endpoints, and n=5 was terminated as planned following 14 days of dosing. N=3 of the latter exhibited a disease score remission within the dosing period, meaning their disease score moved from 2 to 0 in the days before the termination. This phenomenon only occurred in the NMD712-dosed group.

[1175] Muscle sample harvesting and cryosectioning

[1176] Immediately after euthanization with an overdose of CO2, plantaris muscles were excised from both rat hindlimbs, rinsed in phosphate-buffered saline (PBS), gently blotted dry, and prepared for embedding in optimal cutting temperature (O.C.T.)P7593PC00

[1177] 123

[1178] medium. The right plantaris muscle was embedded full length in O.C.T. in a cryomold. For the left plantaris, the proximal and distal thirds were removed, leaving the mid-belly, which was then placed on the flat surface of a 5-mL syringe pestle and embedded in O.C.T. All preparations were snap-frozen in liquid nitrogen-cooled isopentane and stored at -70 °C until further processing.

[1179] The embedded samples were cryosectioned for histological analysis. The right plantaris was sectioned longitudinally at 20 pm thickness in serial, with four sections (80 pm apart in tissue depth) placed on each slide. The left plantaris was sectioned transversely at 10 pm, with two serial sections per slide.

[1180] Immunohistochemistry for visualization of plantaris NMJs

[1181] Antibody-based neuromuscular junction labeling included pre-synaptic markers of neurofilament M (mouse anti-NF-M, dilution 1:100) and synaptic vesicle glycoprotein 2A (mouse anti-SV2, dilution 1 :50) the post-synaptic marker of acetylcholine receptors (AChR) with alpha-bungarotoxin (a-BTX-Alexa flour555, dilution 1:250). Slides containing longitudinal plantaris cryosections were thawed at room temperature (RT) for 5-10 minutes, fixed in 4% paraformaldehyde (PFA) for 10 minutes, then washed in PBS. Tissue was permeabilized in PBS + 0.1% Triton X- 100 (PBST) and subsequently outlined with an immuno pen. After a 30-minute block in 10% donkey serum in PBST, primary antibodies (diluted in 10% donkey serum in PBST) were applied overnight at 4 °C. The following day, slides were washed in PBST and incubated for 2-4 hours at RT in the dark with donkey-anti-rabbit / mouse / rat secondary antibodies (1:1000) and alphabungarotoxin diluted in PBST. Samples were then washed, stained with Hoechst (1:5000 in PBS) for 10 minutes, washed again in PBS, and mounted with Dako mounting medium. Coverslips were sealed with nail polish once dry and stored at 4 °C in the dark.

[1182] Immunohistochemistry for visualization of plantaris muscle fiber area and fiber types Laminin was used as a marker of muscle fiber borders, and myosin heavy chain isoforms 7 and 2 were used as markers of type I slow-oxidative and Ila fast-oxidative fiber types, respectively. Transverse plantaris cryosections were thawed and air-dried at RT for 30-45 minutes. An immuno pen was used to encircle the sections, followed by rehydration in PBS + 0.05% Triton X-100 (PBST) for 10 minutes. Tissue was then blocked for 1 hour at RT in PBS containing 10% goat serum and 0.05% Triton X-100.P7593PC00

[1183] 124

[1184] Primary antibody mixtures (anti-laminin 1:200, anti-MYH2 1:500, and anti-MYH71:100 in PBST + 10% Goat serum block) were applied for 2 hours at RT in the dark, followed by three 5-minute washes in PBST. Secondary antibody mixtures (anti-rabbit alexa-fluor488, anti-mouse alexa-fluor594, and anti-mouse alexa-fluor488, all 1:250 dilution) were then incubated for 1 hour at RT in the dark. After three final washes in PBST, slides were briefly dried and mounted in antifade medium without DAPI, allowed to set for 24 hours at RT, and then sealed with nail polish. Slides were stored at 4 °C in the dark.

[1185] Analysis of plantaris NMJ morphology and innervation status

[1186] Before imaging, the IDs of the cryosections were blinded to the assessor. A Zeiss LSM800 laser scanning confocal microscope with a 40X oil objective (Bioimaging Core Facility, Health, Aarhus University, Denmark) was used to acquire z-stacks projections of en-face NMJs. Images were analyzed using Imaged software where endplates were manually traced according to AChR signal and AChR and nerve area measured. The number and size of AChR fragments were determined using “Analyze Particles” with a size from 1 pm2-infinity. Co-localization of AChR and nerve was calculated using the freely available plugin “Colocalization” and a ratio of 50%. Innervation degree was scored as innervated (pre-synapse signal of SV2 and NF-M occupies >90% of postsynapse AChR signal), partially innervated (pre-synapse overlays <90% to >10% of post-synapse), or denervated (pre-synapse occupies <10% of post-synapse. An average of 22.6 ± 2.4 NMJs in the vehicle group and 20.7 ± 4.1 NMJs in the NMD712 group was analyzed (mean ± SD).

[1187] Analysis of plantaris muscle fiber type-specific area

[1188] An inverted fluorescence microscope (Olympus CKX53) was used to visualize the stained muscle sections at 10x magnification, and multichannel (green and red) digital images were acquired with a mounted camera and acquisition software (Ocular 2.0). Image section filenames were blinded to the assessor before image analysis. A semiautomatic approach for muscle fiber border segmentation and fiber type determination (Smith L.R., Barton E.R., SMASH - semi-automatic muscle analysis using segmentation of histology: a MATLAB application. Skelet Muscle. 2014, 4, 21) was used to obtain muscle fiber areas of type I slow-oxidative (MYH7 positive), type Ila fast-oxidative (MYH2 positive), and type llb / x fast-glycolytic (non-positive / labelled) fibers. All acquired image sections were assessed for eligible fibers, meaning nonorthogonal cutP7593PC00

[1189] 125

[1190] fibers and fibers with poor sarcolemmal and morphological definition were excluded. The fiber area in an average of 796 ± 106 muscle fibers was obtained per sample (mean ± SD).

[1191] Results

[1192] NMJ morphology and innervation status

[1193] A hallmark trait of the MuSK-MG disease phenotype (Cole et al, 2008) on the microscopic level is fragmented and damaged NMJs in the affected skeletal muscles. Histologically, this is evidenced by fragmented and punctiform scattering of the AChR clusters, in contrast to the normal, healthy pretzel-like shape of the endplate. FIG. 15 depicts an example of such disease phenotype in especially the vehicle-dosed animals (upper row).

[1194] Morphological and functional analyses of the NMJs in plantaris muscles of both vehicle-dosed and NMD712-dosed MuSK-MG rats confirmed this disease phenotype. In FIG. 14, the effect that NMD712 has on the nerve health and innervation of NMJ in MuSK-MG rats is shown. Treatment of MuSK-MG animals with NMD712 increased the number of fibers that are fully innervated, from 21% in the vehicle-treated group to 46% in the NMD712-treated group; only amongst treated animals was a complete removal of symptoms seen (Score 2— > 0, gray squares). FIG. 15 depicts the immunohistochemical staining images of AChR, nerves and composites thereof for both the NMD712-treated and the vehicle-treated MuSK-MG rat groups. FIG. 16 depicts the fragmented neuromuscular junctions (NMJs) and average number of fragments per NMJ in both the NMD712-treated and the vehicle-treated MuSK-MG rat groups. White bars represent vehicle-dosed (n=5) and grey bars NMD712-dosed (n=6) MuSK-MG rats. Grey squares highlight rats exhibiting disease remission ( / .e., moving from disease score 2 back to 0), a phenomenon only occurring in the NMD712-dosed group. Bars are means ± SD. The P-values above bars are results from statistical testing by Student’s t-test in vehicle vs. NMD712 groups. P <0.05 was considered significant. While the included sample size was statistically underpowered to detect an effect of the NMD712-dosing on the NMJ damage and fragmentation, the average number of fragments per NMJ was approximately 65% greater on average in vehicle-versus NMD712-dosed rats (FIG. 16). Moreover, the average fragment area was concomitantly greater in NMD712-dosed rats by an average of 72% (FIG. 16). TheP7593PC00

[1195] 126

[1196] mean differences in favor of a healthier NMJ morphology of the NMD712-dosed group in both outcomes related to NMJ morphology were especially driven by the three animals undergoing disease remission (grey square points).

[1197] Concomitantly with the morphology analysis, the innervation status of each NMJ was categorized based on the overlap in pre- (nerve) and post-synaptic (AChRs) staining signal. The relative distribution of the innervation status is displayed in FIG. 14. Dosing with NMD712 improved the percentage of fully innervated NMJs from 21% in the vehicle group to 46%.

[1198] Muscle fiber size

[1199] Muscle atrophy is likewise considered a disease trait (Borges etal, 2020) in MuSK-MG, potentially induced by the combination of disuse through impaired NMJ transmission and a myopathic component by the loss of MuSK function. In MuSK-MG, especially slow-twitch type I muscle fibers are affected by atrophy. To evaluate the effect of NMD712 dosing on the mitigation of muscle atrophy in MuSK-MG rats, immunohistochemistry analysis of muscle fiber morphology in transverse plantaris muscle cryosections was conducted. Representative images of the immunohistochemical staining are presented in FIG. 18.

[1200] Using immunohistochemical techniques to visualize muscle fiber borders and fiber types in plantaris cryosections (FIG. 18), fiber-type specific cross-sectional areas were analyzed. Results are shown in FIG. 17A and FIG. 17B. On average, the mean fiber areas of the fast-oxidative type Ila and fast-glycolytic type llb / x were improved by 22% and 19%, respectively, in the plantaris muscle of NMD712-dosed MuSK-MG animals. For the slow-twitch type I muscle fibers, no effect of NMD712 dosing was observed. When all fiber types were pooled, the overall mean fiber area was 13% greater in the NMD712-dosed group. Accordingly, the NMD712-dosing mitigated plantaris muscle atrophy in MuSK-MG rats specifically in fast-twitch type II muscle fibers.

[1201] Conclusion: CIC-1 inhibition attenuates denervation in MuSK-MG animals

[1202] NMJ morphology of innervation from the MuSK-MG animals were assessed using immunohistochemistry (IHC) and confocal microscopy on plantaris muscle. Treatment of MuSK-MG animals with NMD712 increased the percentage of fully innervated fibers, from 21% in vehicle-treated group to 46% in the NMD712-treated group. A completeP7593PC00

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[1204] removal of symptoms (e.g., Score 2 ^ 0) was only observed amongst NMD712-treated animals (FIGS. 14 and 16). Additionally, NMD712 also reduced NMJ fragmentation and increases co-localization between nerves and AChRs (FIG. 16). As shown in FIG. 16, upon treatment using NMD712, the average fragment size of AChR was increased from approximately 12 pm2(up to 20 pm2) to approximately 22 pm2of AChR (up to 35 pm2) per fragment, and the average NMJ fragmentation that are above 1 pm2was reduced from approximately 13 fragments to approximately 8 fragments per NMJ.

[1205] The size of muscle fiber was assessed using IHC. Treatment of MuSK-MG animals with NMD712 improved plantaris muscle fiber cross-sectional area by 22% in type Ila, and 19% in type llb / x fibers. The heavily myopathy-affected type I fibers remain unaffected after up to 14 days of dosing. This increase in muscle fiber cross-sectional area can be interpreted as improved recovery of muscle mass.

[1206] Overall, CIC-1 inhibition showed a disease-modifying effect in a post-synaptic autoimmune disease. CIC-1 inhibition treatment of MuSK-MG rat model and functional studies thereof showed a reduced disease progression and increased survival.

[1207] Immunohistochemical studies showed decreased endplate fragmentation and larger endplate fragments. IHC data also showed improved innervation and better-maintained muscle fiber area.

[1208] Example 4: Combination treatment with CIC-1 inhibitors and neonatal Fc receptor (FcRn) blocker in preclinical MG model

[1209] Myasthenia gravis (MG) is an autoimmune disorder characterized by generalized muscle weakness due to autoantibodies causing dysfunction of the neuromuscular junction (NMJ). The EAMG model is an active immunization model in which an autoimmune response against the acetylcholine receptor at the NMJ is induced. This model is recognized as a translational disease model for evaluating the efficacy of treatments for MG (Losen et al, 2015). The aim of this study was to investigate the effect of chronic treatment with NMD712 alone, 1G3 (an FcRn blocker) alone or the two in combination in comparison to treatment with vehicle and positive control (Dexamethasone) on muscle function in an Experimental Autoimmune Myasthenia Gravis (EAMG) rat animal model. Muscle function in the MG rats was investigated by application of grip strength testing (FIG. 21) and compound muscle action potentialP7593PC00

[1210] 128

[1211] recordings, and immune response was assessed as total IgG concentration before and after treatment.

[1212] Methods

[1213] To generate the EAMG model (Lazaridis etal, 2017), anaesthetized female Lewis rats were injected subcutaneously with an emulsion consisting of 1:1 Complete Freund’s Adjuvant and phosphate-buffered saline, and 80 pg of human AChR extracellular domain a fragments containing the immunogenic epitope. Three deposits were distributed between base of the tail, left hindleg, and right foreleg. Disease onset was typically 7 to 12 weeks after immunization. Animals were enrolled in 5 treatments groups (15-16 animals per group), 1) NMD712 alone (50 mg / kg, per oral, q.d.), 2) neonatal FcR (FcRn) blocker (1G3) (30 mg / kg, s.c., 3x / week), 3) the two above in combination, 4) Dexamethasone (1 mg / kg, s.c., 3x / week), or 5) vehicle, stratified based on e.g., in vivo measurement grip strength. During pre-dose testing (study day 0) and throughout the treatment schedule (study day 1-14), the animals were scored, monitored for clinical symptoms and weighed daily. Blood samples were collected prior to treatment (study day 0), and at termination on study day 14. The blood samples were used to determine IgG levels by enzyme-linked immunosorbent assay for quantitative detection of rat IgG total (Invitrogen Catalog Number 88-50490).

[1214] Results

[1215] As shown in FIG. 24, baseline serum IgG levels (study day 0) were comparable across all treatment groups, with no statistically significant differences observed. At termination, a significant increase in IgG levels was observed in the Vehicle-treated group compared to baseline values, consistent with the autoimmune response elicited by immunization. In contrast, both the FcRn (1G3)- and NMD712 & FcRn (1G3)-treated groups exhibited a marked reduction in total IgG levels, indicating the efficacy of FcRn blockade in potentially enhancing the clearance of IgG. However, a significant within-group reduction was only observed in the NMD712 & FcRn (1G3)-treated group.

[1216] Importantly, IgG levels at termination were significantly lower in the NMD712 & FcRn (1G3)-treated group compared to both the Vehicle- and NMD712-treated groups, highlighting the enhanced efficacy of the combined treatment. Similarly, the FcRn blocker (1G3)-treated group demonstrated significantly lower IgG levels at termination compared to the Vehicle-treated group.P7593PC00

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[1218] FIG. 24 shows the change in IgG from start to end of the treatment period in %. In the vehicle group the IgG concentration is 42 % larger at day 14 compared to day 0. This is a significant larger increase than in any of the other treatment groups. On the other hand, NMD712 alone or in combination with FcRn blocker (1G3) has significantly reduced IgG levels in plasma day 14, showing that NMD712 treatment alone modifies the immune response against theAChR in the model.

[1219] Treatment with CIC-1 inhibitor NMD712 only and NMD712 in combination with an FcRn blocker also significantly improved CMAP decrement and grip strength neuromuscular transmission compared to vehicle and FcRn blocker alone (FIG. 19, FIG, 20, FIG. 22 and FIG. 23). An improvement in CMAP decrement of at least 5% (up to 25%) was observed among rat models treated with i) NMD712 only and ii) a combination of NMD712 and FcRn blocker 1G3. When compared to vehicle-treated rat models, an improvement in grip strength of at least 10% was observed among rat models treated with a combination of NMD712 and FcRn blocker 1G3. While the use of Dexamethasone and / or FcRn blocker 1G3 only results in a reduction in IgG level of the subject, such reduction can be suppressed when NMD712 is administered.

[1220] Example 5: Phase HA Clinical Trial in Charcot-Marie Tooth Disease

[1221] A phase 2a, randomised, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of NMD670 ((2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid) over 21 days in ambulatory adult patients with Type 1 and Type 2 Charcot-Marie-Tooth (CMT) disease was run as described in Example 8 of WO 2024 / 180199. The study design is shown in FIG. 34.

[1222] The study has a 1 -sided alpha level of 10%, and therefore p values below 0.2 are considered statistically significant.

[1223] Protocol Amendments

[1224] In amendment 1, the following amendments of note were made:

[1225] • The Timed Up and Go test and 10MW / RT were moved from primary to secondary endpoints, and the hierarchisation of the primary endpoint, which now is confined to the 6-minute walk test, was removed as a consequence. The Timed Up and Go test is an individual item of the CMT-FOM. Because allP7593PC00

[1226] 130

[1227] individual items of the CMT-FOM will be tested as secondary endpoints, the Timed Up and Go test is not specifically mentioned in the Objectives and Endpoints table.

[1228] • The proportion of participants with a clinically meaningful change from baseline in 10MW / RT for NMD670 vs placebo was added as a secondary endpoint. • Exclusion Criterion 2 was updated to explain that assistive devices are not permitted for 4 weeks prior to screening or for the duration of the study.

[1229] Additionally, the criterion was updated to explain what daily use of assistive devices means.

[1230] Subject Disposition and CMT subtype

[1231] Of the 81 participants who were enrolled into the study, 42 were treated with NMD670 (41 completed treatment), 38 were treated with placebo (37 completed treatment) and 1 was randomised into the NMD670 group but not dosed. The demographics of the groups is given in table 1 and the CMT subtype of the 81 participants is given in table 2.

[1232] Table 1: Study demographics

[1233]

[1234] P7593PC00

[1235] 131

[1236] Table 2: CMT subtype

[1237]

[1238] Overall summary of adverse events

[1239] A summary of the adverse effects is given in table 3. NMD670 was safe and well tolerated. No SAEs or Adverse Events of Special Interest observed in patients on NMD670.

[1240] Table 3: summary of adverse events

[1241]

[1242] P7593PC00

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[1244]

[1245] Abbreviations: AE = adverse event; AESI = AE of special interest; IMP = investigational medicinal product; NA = not applicable; TEAE = treatment emergent AE

[1246] SAE: 1 event with placebo was reported as an SAE. The event was a bone contusion requiring hospitalization.

[1247] AESI: 1 event with placebo was reported as an AESI. The event was a lenticular opacities.

[1248] Results of CMT clinical trail

[1249] The CMT functional outcome measure (CMT-FOM) is a validated clinician-rated outcome measure that measures muscle strength and motor function. There was a numerically larger improvement in the NMD670 treatment group compared to the placebo group after both 7 and 21 days of treatment (FIG. 35).

[1250] However, a statistically significant effect (** p = 0.06) was seen in the CMT-FOM measure on day 28, which is 7 days after discontinuing treatment. This is surprising since until now the effects of CIC-1 inhibition have been considered to be exposure dependent. Example 6 and Figure 10 of WO 2024 / 068862 shows that the effect of CIC-1 inhibition is dose / exposure dependent - as dose is increased improvement in muscle function (force) increases. Ruijs et al (2024) discloses that NMD670 has a halflife in man of about 3.7 hours after 400mg BID dose on day 1 and 5.1 hours after 10 days of 400mg BID dosing. Plasma concentrations were <3% of Cmax after 24 hours and <0.2% after 48 hours meaning that there will be no compound present 7 days after discontinuing treatment. However, the drug treatment benefit on muscle strength and function did not disappear within one week of stopping treatment, suggesting that 21 days of dosing is enough to result in disease modifying effects in man.P7593PC00

[1251] 133

[1252] This disease modifying effect is also apparent in additional measures. Based on the published PK data for NMD670, there will be no accumulation of NMD670 between dosing days. Therefore, it would be expected that the increase in hand grip strength (force) after 21 days would be the same as after 7 days and would return back to baseline 7 days after discontinuing treatment. However, as shown in FIG. 36 and table 4, hand grip strength increased further on day 21 compared to day 7 and the improvement in hand grip strength was maintained on day 28, 7 days after discontinuing treatment. In comparison, there was no effect in the placebo group and the NMD670 group was statistically improved over the placebo group on days 21 and 28 (*** p < 0.05; **** p < 0.01).

[1253] Table 4: average hand grip strength at baseline (day 0), and days 7, 21 and 28

[1254]

[1255] *Change from baseline calculated using lease squares mean method

[1256] This same disease modifying effect was noted in the 9-hole peg test (FIG. 37) where the reduction in the time to complete the test increased numerically from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. In comparison, there was no effect in the placebo group and the NMD670 group was statistically significantly improved over the placebo group on days 7, 21 and 28 (* p < 0.2; ** p < 0.1).

[1257] This same disease modifying effect was noted in the patient reported outcome of the CMT health index (CMT-HI) total score (FIG. 38) where the patient reported score increased numerically from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28, the improvement was larger than -3.2 points for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein etal, 2024). In comparison, there was no change in effect in the placebo group from day 7 to day 21 or day 28 and the score did not reach the clinically meaningful level.

[1258] This same disease modifying effect was noted in the patient reported outcome of the CMT health index (CMT-HI) short form score (FIG. 39) where the patient reportedP7593PC00

[1259] 134

[1260] score increased numerically from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -2.8 points for the NMD670 group, which is considered to be a clinically meaningful change (Rehbein etal, 2024). In comparison, there was no change in effect in the placebo group from day 7 to day 21 or day 28 and the score did not reach the clinically meaningful level.

[1261] This same disease modifying effect was noted in the patient reported outcome of the CMT-HI hand / finger subscale score (FIG. 40) where the patient reported score increased numerically from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, the improvement was larger than -1.8 points with NMD670, which is considered to be a clinically meaningful change (Rehbein et al, 2024).

[1262] This same disease modifying effect was noted in the time to cover 10 metre walk / run test (FIG. 41) where the patient reported score increased numerically from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On day 28, there was a statistically significant (p < 0.2) improvement for the NMD670 group over the placebo group.

[1263] Improvements in muscle function were noted in both CMT Type 1, which is the demyelinating type of the disease and CMT Type 2, which is the axonal type of the disease. Specifically, hand grip force improved in both CMT Type 1 (FIG. 42) and CMT Type 2 (FIG. 43) patients from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On days 21 and 28, there was a statistically significant (** p < 0.1; *** p < 0.05) improvement for the NMD670 group over the placebo group for both CMT Type 1 and CMT Type 2 patients.

[1264] Time to complete the 9-hole peg test improved in both CMT Type 1 (FIG. 44) and CMT Type 2 (FIG. 45) patients from 7 days of treatment to 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. There were numerical improvements for the NMD670 group over the placebo group for both CMT Type 1 and CMT Type 2 patients.P7593PC00

[1265] 135

[1266] Improvement in the CMT-HI short form score was noted in CMT Type 1 (FIG. 46) and patients from 7 days of treatment to 21 days and was maintained on day 28, 7 days after discontinuing treatment. There were numerical improvements for the NMD670 group over the placebo group for CMT Type 1 patients. Improvement over baseline was also noted in CMT Type 2 (FIG. 47) after 21 days of treatment and was maintained on day 28, 7 days after discontinuing treatment. On days 7, 21 and 28, there was a statistically significant (** p < 0.1 ; *** p < 0.05) improvement for the NMD670 group over the placebo group for the CMT Type 2 patients.

[1267] Both groups increased the distance walked on days 7, 21 and 28 over baseline but no difference between groups was noted at any time point in the 6-minute walk test.

[1268] In conclusion, the data shows that even 7 days after discontinuing treatment, the effect of 21-days of treatment with a CIC-1 inhibitor (NMD670) maintained improvements in muscle function, such as muscle strength, motor function and patient reported disease burden. This is surprising since, based on published PK data on NMD670 in man, only trace amounts of NMD670 would be present after 24 hours. Therefore, this maintenance of improved muscle function 7 days after discontinuing treatment suggests CIC-1 inhibitors, such as NMD670, have disease modifying effects and suggests structural recovery at the neuromuscular junction, which can improve the course and reduce the severity of the disease burden in patients with Charcot-Marie-Tooth disease. It is also important to note that this improvement after discontinuing treatment was observed in two different disease types of CMT, both the demyelinating type of the disease (CMT Type 1 or CMT1) and the axonal type of the disease (CMT Type 2 or CMT2).

[1269] The foregoing has been a detailed description of illustrative embodiments of the disclosure. Various modifications and additions can be made without departing from the spirit and scope of this disclosure. Features of each of the various embodiments described above can be combined with features of other described embodiments as appropriate in order to provide a multiplicity of feature combinations in associated new embodiments. Furthermore, while the foregoing describes a number of separate embodiments, what has been described herein is merely illustrative of the disclosure of the principles of the present disclosure. Additionally, although particular methods herein can be illustrated and / or described as being performed in a specific order, the orderingP7593PC00

[1270] 136

[1271] is highly variable within ordinary skill to achieve methods, systems, and software according to the present disclosure. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this disclosure.

[1272] Exemplary embodiments have been disclosed above and illustrated in the accompanying drawings. It will be understood by those skilled in the art that various changes, omissions and additions can be made to that which is specifically disclosed herein without departing from the spirit and scope of the present disclosure.

[1273] References

[1274] Borges etal, 2020: Borges LS, Richman DP. Muscle-Specific Kinase Myasthenia Gravis. Front Immunol. 2020, 11, 707

[1275] Cole etal, 2008: Cole RN, Reddel SW, Gervasio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol. 2008 Jun;63(6):782-9.

[1276] English etal, 2005: English AW, Meador W, Carrasco DI. Neurotrophin-4 / 5 is required for the early growth of regenerating axons in peripheral nerves. Eur J Neurosci.

[1277] 2005 May;21(10):2624-34.

[1278] English etal, 2011: En...

Claims

P7593PC00139Claims1. A CIC-1 inhibitor for use as disease-modifying agent in a disease-modifying treatment of a neuromuscular disease.

2. The CIC-1 inhibitor for use of claim 1 , wherein the disease modifying treatment is determined by at least one disease modifying effect, and said disease modifying effect is determined by re-innervation of skeletal muscle fibres, improved nerve health, improved nerve performance, improved skeletal muscle fiber health, improved skeletal muscle performance and improved immune system modulation.

3. The CIC-1 inhibitor for use of any of claims 1 or 2, wherein the disease modifying effect is at least determined by improved skeletal muscle performance, and skeletal muscle performance is determined by measuring muscle strength such as hand grip strength, thigh strength (knee flexors), upper arm strength (elbow flexor and extension) and / or shoulder strength (shoulder abduction).

4. The CIC-1 inhibitor for use of any of claims 1 or 2, wherein the disease modifying effect is at least determined by improved skeletal muscle fiber health, and skeletal muscle fiber health is determined by measuring one or more parameters selected from the group consisting of compound muscle action potentials; muscle decrement; jitter; blocking; pulmonary function; and gait.

5. The CIC-1 inhibitor for use according to claim 4, wherein the disease modifying effect is an improvement in compound muscle action potential (CMAP) decrement.

6. The CIC-1 inhibitor for use according to claim 1 , wherein said use is in:a. promoting re-innervation of muscle fibres in the subject suffering from the neuromuscular disorder,b. improving nerve health in the subject suffering from the neuromuscular disorder,c. improving nerve performance in the subject suffering from the neuromuscular disorder,P7593PC00140d. improving muscle fiber health in the subject suffering from the neuromuscular disorder,e. improving muscle fiber performance in the subject suffering from the neuromuscular disorder, and / orf. modulating the immune system in the subject suffering from the neuromuscular disorder.

7. A CIC-1 inhibitor for use in a method of promoting re-innervation of muscle fibres in a subject suffering from a neuromuscular disorder.

8. The CIC-1 inhibitor for use of any of claims 1 to 7, wherein the CIC-1 inhibitor is of Formula (I):Formula (I)wherein:- R1is selected from the group consisting of Cl and Br;- R2is selected from the group consisting of H, deuterium, F, Cl, C3-4 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;- R3is selected from the group consisting of deuterium, Cl and F;- R4is selected from the group consisting of C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8and C3 alkynyl; - R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkylP7593PC00141optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R9;- R6is independently selected from the group consisting of deuterium and F; - R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;- R8is independently selected from the group consisting of deuterium, F and OMe;- R9is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and- n is an integer 0, 1, 2, or 3;or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

9. The CIC-1 inhibitor for use of claim 8, wherein R2is selected from the group consisting of H, F, cyclopropyl, cyclobutyl, -CF2-Me, -CF2-CH2Me, 1,2-oxazol-5- yl and 1,2-oxazol-3-yl.

10. The CIC-1 inhibitor for use of any of claims 8 to 9, wherein R4is selected from the group consisting of methyl, -CH2F, -CH2-OMe ethyl, -CH2-CCH and isopropyl.

11. The CIC-1 inhibitor for use of any of claims 8 to 10, wherein n is 0 or 1.

12. The CIC-1 inhibitor for use of claims 1 to 11 , wherein the CIC-1 inhibitor is selected from the group consisting of:(S)-2-(p-bromophenoxy)-3-methylbutyric acid;(S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;(R)-2-(p-bromophenoxy)-3-fluoropropionic acid;(S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-fluorophenoxy)butyric acid;(S)-2-(p-bromophenoxy)butyric acid;(R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;P7593PC00142(S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;(S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;(R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;(S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;(R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid;(S)-2-(4-bromo-2-cyclobutylphenoxy)-4-pentynoic acid;(R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (R)-2-[4-bromo-2-(1 , 1 -difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;and(S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

13. The CIC-1 inhibitor for use of any of claims 1 to 12, wherein the neuromuscular disease is selected from the group consisting of myasthenia gravis (MG) including autoimmune myasthenia gravis, congenital myasthenia gravis, and myasthenia gravis with anti-acetylcholine receptor antibodies (AChR AB+ MG); motor neuron disorders; X-linked spinal and bulbar muscular atrophy;Kennedy’s disorder; multifocal motor neuropathy; myotubular myopathy;Duchenne muscular dystrophy; Lambert Eaton syndrome; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); critical illness myopathy (CIM); reversal diabetic polyneuropathy; Guillain-Barre syndrome; poliomyelitis; postpolio syndrome; chronic fatigue syndrome; critical illness polyneuropathy; primary or secondary sarcopenia; metabolic myopathy; mitochondrial myopathy; periodic paralysis including hypokalemic periodic paralysis and hyperkalemic periodic paralysis; Charcot-Marie-Tooth disease (CMT) including, without limitation, CMT type 1, CMT type 2 and CMT type 2D; and multiple sclerosis.

14. The CIC-1 inhibitor for use of any of claims 1 to 13, wherein the CIC-1 inhibitor is co-administered with an immunomodulating or immunosuppressive agent.

15. The CIC-1 inhibitor for use of claim 14, wherein the neuromuscular disease is selected from the group consisting of autoimmune myasthenia gravis, AChRP7593PC00143antibody-positive myasthenia gravis, Lambert-Eaton syndrome, multifocal motor neuropathy, Guillain-Barre syndrome and multiple sclerosis.

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