WO2015095549A1 - Dosage regimen for gabaa receptor subtype selective drug - Google Patents

Abstract

Disclosed is a method of treating in a subject a disorder of the central nervous or pain. The method comprises administering to the subject an amount in the range of 2 mg/day to 60 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof.

Description

DOSAGE REGIMEN FOR GABAA RECEPTOR SUBTYPE SELECTIVE DRUG

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Provisional Patent

Application No. 61/917,736, filed December 18, 2013, the contents of which are

incorporated herein by reference.

BACKGROUND

GABA_A receptors can possess one of a number of a subunits, including al, a2, a3 and a5. The pharmacological effects of activating a GABA_A receptor in the nervous system are believed to depend mainly on which type of a subunit the receptor contains. Several classes of widely used drugs target GABA_A receptors, including benzodiazepines such as diazepam (Valium). Benzodiazepines are used for the treatment of anxiety, spasticity, muscle tension, insomnia, acute alcohol withdrawal and seizures. Activation of al GABA_A receptors is believed to be mainly responsible for sedation and ataxia, which is a lack of muscle control during voluntary movements, associated with benzodiazepine use, and may also contribute to their amnesiac and habituating effects. Activation of a2, a3 and a5 GABA_A receptors is believed to cause other therapeutic effects of benzodiazepines, including anti-spasticity, muscle relaxation, anti-anxiety, anti-seizure and potentially anti-pain activities. Certain sleep agents, such as Zolpidem (Ambien®) and zaleplon (Sonata®) also target GABA_A receptors. These sleep agents activate l GABA_A receptors much more potently than the other a subtypes, which is believed to cause their pronounced sedative properties. Based on this clinical precedent as well as a variety of preclinical models, it is believed that a compound that activates a2, a3 and a5 GABA_A receptors but does not significantly activate al GABA_A receptors will have clinical effects similar in a number of important respects to benzodiazepines, including anti-spasticity, muscle relaxant, anti-seizure and potentially anti-pain effects, but without the strong sedative effects of benzodiazepines. Consequently, there has been considerable effort over a number of years to discover agents that selectively activate the GABA_A receptors, particularly at the a2 and a3 receptors.

Merck identified two structurally related compounds in particular that demonstrated desirable GABA_A receptor subtype selectivity in vitro: L-838417 and TPA023, whose structures are shown below.

L-838417: R¹ = Me; R² = F

TPA023: R¹ = Et; R² = H

In preclinical studies, TPA023 was found to be a non-sedating anxiolytic in rodents and primates with essentially no abuse potential in a primate. It was effective in rodent anxiolytic models without overt sedation at plasma levels that produced between 70 and 88% GABA_A receptor occupancy, as determined by Positron Emission Tomography (PET) imaging studies (Atack, J. R. et al., Journal of Pharmacology and Experimental Therapeutics, 2010, 332(1) 17-25). By comparison, the structurally related L-838417 exhibited similar receptor subtype selectivity as TPA023 and had more potent agonist activity for the a2 and a3 subunits. However, despite the attractive pharmacological profile of L-838417, it was not advanced into human clinical trials due to its poor bioavailability in animals. TPA023 was selected for further development due to its more favorable pharmacokinetic properties.

In normal human volunteers, it was reported that TPA023 was well-tolerated in single ascending doses (SAD) administered orally up to 2.0 mg. However, at 3.0 mg, dose-limiting adverse events observed were dizziness, altered perception and motor incoordination. (Atack, Advances in Pharmacology, 2009, Volume 57, 137-185). GABA_A receptor occupancies of TPA023 in the human brain of around 50%, as determined by PET imaging studies, were achieved at doses of 2 mg. The fact that TPA023 was not well-tolerated above 2 mg suggested that receptor occupancies above about 50% in humans could not be achieved for this class of drugs without significant undesirable side effects. Furthermore, the short half- life of TPA023 in young, healthy males of 3.3 to 5.2 hours, suggested that the drug might require repeated dosing during the day.

Deuterium substituted analogs of L-838417 were described in US patents 8,003,646 and 8,399,467. These analogs were previously reported to have improved bioavailability and metabolic stability in animal models compared to L-838417. See

http://www.concertpharma.com/Neuroscience2011.htm. Spasticity is a chronic condition characterized by involuntary tightness, stiffness or contraction of muscles that occurs in patients who have damage to the brain or spinal cord. Spasticity can result from a wide range of disorders, including multiple sclerosis, spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis, stroke and hereditary spastic paraplegia. Symptoms can range from mild muscle tightness to more severe symptoms, including crippling and painful inability to move limbs that can result in disability and diminished quality of life. The American Association of Neurological Surgeons estimated in 2006 that there were 12 million patients suffering from spasticity worldwide. GABA_A receptor modulators, though limited by severe side effects, can be broadly effective for the treatment of spasticity. For example, diazepam has demonstrated clinical efficacy as an anti- spasticity agent in patients with spinal cord injury, multiple sclerosis, cerebral palsy and stroke. The leading oral drugs for spasticity, baclofen and tizanidine, are also highly sedating.

Furthermore, these drugs have short half-lives and require multiple dosing per day.

SUMMARY OF THE INVENTION

It has now been found that very high GABA_A receptor occupancy levels of Compound

(I) (also referred to herein as CTP-354), a deuterated analog of L-838417, can be achieved in humans using certain dosage regimens that do not cause dose-limiting adverse events in humans (Example 2). High brain GABA_A receptor occupancy levels were achieved with Compound (I) at doses that were well-tolerated in a Phase 1 clinical trials. In a Phase 1 imaging study, Compound (I) produced much higher levels of GABA_A receptor occupancy than benzodiazepines without causing substantial sedation (Example 3) and, therefore, may provide similar clinical efficacy against spasticity without the dose-limiting effects of benzodiazepines .

Compound (I) It has also been found that the receptor occupancy is sufficiently long-lasting with the disclosed dosing regimen (e.g., receptor occupancies at around 50% at twenty-four hours - see Example 3) to permit once a day dosing. These data support once daily dosing of

Compound (I) at low doses. Based on these discoveries, novel dosing regimens using

Compound (I) for treating a disorder of the central nervous system or pain in a subject are disclosed herein.

A first embodiment of the invention is a method of treating a disorder of the central nervous system, such as anxiety or spasticity, or pain. The method comprises administering to a subject an amount of Compound (I) or a pharmaceutically acceptable salt thereof in the ranges of 2 mg/day to 40 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 18 mg/day; 2 mg/day to 16 mg/day; 2 mg/day to 12 mg/day; 2 mg/day to 8 mg/day; 2 mg/day to 4 mg/day; 4 mg/day to 40 mg/day; 4 mg/day to 20 mg/day; 4 mg/day to 18 mg/day; 4 mg/day to 16 mg/day; 4 mg/day to 12 mg/day; 4 mg/day to 8 mg/day; 8 mg/day to 40 mg/day; 8 mg/day to 20 mg/day; 8 mg/day to 18 mg/day; 8 mg/day to 16 mg/day; or 8 mg/day to 12 mg/day.

Alternatively, 2 mg/day; 4 mg/day; 8 mg/day; 16 mg/day; 18 mg/day; 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject. Alternatively, 2 mg/day; 4 mg/day; 6 mg/day; 8 mg/day; 12 mg/day; 16 mg/day; 18 mg/day; 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject. Alternatively, 2 mg/day; 6 mg/day; or 12 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject. Preferably, Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day at any of the foregoing dosages. Preferably, Compound (I) or a pharmaceutically acceptable salt thereof is administered orally at any of the foregoing dosages. More preferably, Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day and orally at any of the foregoing dosages.

A second embodiment is Compound (I) or a pharmaceutically acceptable salt thereof for treating in a subject a disorder of the central nervous system, such as anxiety or spasticity, or pain. The compound may be administered at the dosing regimens disclosed herein.

A third embodiment of the invention is the use of Compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with a disorder of the central nervous system, such as anxiety or spasticity, or pain. The compound may be administered at the dosing regimens disclosed herein. Another embodiment of the invention relates to a method of modulating/activating in the brain of a subject a2 and a3 subtypes of the GABA_A receptor, the method comprising administering to the subject a daily dose of Compound (I) or a pharmaceutically acceptable salt thereof according to one of the dosage regimens described herein, e.g., in the range of 2 mg to 60 mg.

Yet another embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and between 2 mg to 40 mg; 2 mg to 20 mg; 2 mg to 18 mg; 2 mg to 16 mg; 2 mg to 12 mg; 2 mg to 8 mg; 2 mg to 4 mg; 4 mg to 40 mg; 4 mg to 20 mg; 4 mg to 18 mg; 4 mg to 16 mg; 4 mg to 12 mg; 4 mg to 8 mg; 8 mg to 40 mg; 8 mg to 20 mg; 8 mg to 18 mg; 8 mg to 16 mg; or 8 mg to 12 mg of Compound (I) or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition comprises 2 mg; 4 mg; 8 mg; 16 mg; 18 mg; 20 mg or 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition comprises 2 mg; 4 mg; 6 mg; 8 mg; 12 mg; 16 mg; 18 mg; 20 mg or 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing a comparison of the plasma levels in ng/mL of

Compound (I) and L-838417 over time after oral administration of 1 mg/mL in a rat pharmacokinetic study.

Figure 2 is a graph showing the plasma concentrations in ng/mL over time in hours from a single ascending dose study in humans with Compound (I).

Figure 3 comprises brain images obtained from PET scans of two subjects in a Phase 1 imaging study with Compound (I). The first row of images were baseline scans obtained after injection with positron emitting flumazenil; the second row of images were obtained immediately after injection with positron emitting flumazenil, which was given five hours after a single oral dose of 20 mg of Compound (I); and the third row of images were obtained immediately after injection with positron emitting flumazenil, which was given twenty-four hours after the single oral dose of 20 mg of Compound (I).

Figure 4 is a graph showing the relationship between plasma concentration and brain

GABA_A receptor occupancy for Compound (I) in the first part of the imaging study described in Example 3. Figure 5 shows the steady- state Day 10 plasma concentration vs. time profile and the Day 1-10 Chough (C₂4hr) plasma concentration vs. time profile.

DETAILED DESCRIPTION OF THE INVENTION

This invention in one embodiment relates to Compound (I) or a pharmaceutically acceptable salt thereof; and certain pharmaceutical compositions comprising Compound (I) or a pharmaceutically acceptable salt thereof and methods of use thereof involving certain dosing regimens. The pharmaceutical compositions and dosing regimens are useful for treating diseases or disorders that can be treated by GABA_A receptor agonists. In particular, Compound (I) and pharmaceutically acceptable salts thereof and the pharmaceutical compositions and methods are useful for treating diseases and disorders that can be treated by compounds that more selectively activate the a2 and/or a3 subunits of the GABA_A receptor rather than the l subunit.

The pharmaceutical compositions comprise a pharmaceutically acceptable carrier and Compound (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. Compound (I) is

Each position that is specifically designated as "D" has deuterium at an abundance that is at least 5500 times the natural abundance of deuterium, which is about 0.015%, or at least 82.5% incorporation of deuterium. Preferably, each position that is specifically designated as "D" has deuterium incorporation of at least 90%, more preferably of at least 95%, and even more preferably of at least 99%. Each position that is specifically designated as "H" in Compound (I) refers to hydrogen at its natural isotopic abundance. Except for the deuterium atoms, all atoms of Compound (I) are present at their natural isotopic abundance.

Compound (I) has been disclosed in US patent 8,003,646 and US patent 8,399,467. The dosing regimens of Compound (I) or a pharmaceutically acceptable salt thereof are useful for treating various central nervous system disorders. In particular, the dosing regimens of Compound (I) are useful for treating spasticity, pain and anxiety. The dosing regimens of Compound (I) are also useful for treating fibromyalgia; epilepsy; obsessive- compulsive disorder; stress disorders (e.g., post-traumatic and acute stress disorder);

neuroses; convulsions; depressive disorders or bipolar disorders (e.g., single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders); organophosphate (OP) nerve agent-induced seizures and neuronal damage;

emesis; and cyclothymic disorder. Compound (I) or pharmaceutically acceptable salts thereof may also be used as a protectant against nerve-gas (agent) exposure and disorders associated with exposure to nerve gas as well as a treatment for such disorders. In one aspect, the disorders disclosed herein are treatable by the dosage regimen disclosed herein.

Examples of types of pain that are treatable by the disclosed dosing regimen with Compound (I) or a pharmaceutically acceptable salt thereof include neuropathic pain, inflammatory pain, migraine pain, and pain related to spasticity.

Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia, nerve injuries after surgery, pain following paraplegia, hypersensitivity to non-painful stimuli (allodynia), e.g. after surgery or during migraine attacks, spontaneous pain, hyperalgesia, diffuse muscle tenderness of myofacial syndromes, sensory abnormalities of the gastrointestinal tract, e.g. in irritable bowel disease, or chest pain and a large proportion of back pain. Cancer pain and AIDS- associated pain also qualify as neuropathic pain.

Inflammatory pain is triggered by nerve endings that become irritated when surrounded by inflamed tissue. Inflammatory pain is most commonly associated with conditions such as trauma, osteoarthritis, rheumatoid arthritis, post surgery recovery and some forms of cancer pain.

Migraine-associated pain attacks affect about 10 to 20% of the middle European population. Pain attacks are believed to originate from the sensitization of meningeal nociceptors by neuropeptides and/or their excitation by dilated meningeal blood vessels.

Examples of spasticity that may be treated by the Compound (I) dosing regimens disclosed herein include spasticity associated with multiple sclerosis and spinal cord injury. Other examples of spasticity include spasticity associated with stroke, cerebral palsy, traumatic brain injury, amyotrophic lateral sclerosis (ALS), or other neurodegenerative conditions or diseases.

Examples of anxiety disorders that may be treated by the Compound (I) dosing regimens disclosed herein include general anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, substance-induced anxiety disorder and phobias such as animal phobias or social phobias).

This invention also relates to a method of treating a disorder of the central nervous system, such as anxiety or spasticity, or pain, comprising administering to the subject an amount of Compound I or a pharmaceutically acceptable salt thereof in the range of 2 mg/day to 40 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 18 mg/day; 2 mg/day to 16 mg/day; 2 mg/day to 12 mg/day; 2 mg/day to 8 mg/day; 2 mg/day to 4 mg/day; 4 mg/day to 40 mg/day; 4 mg/day to 20 mg/day; 4 mg/day to 18 mg/day; 4 mg/day to 16 mg/day; 4 mg/day to 12 mg/day; 4 mg/day to 8 mg/day; 8 mg/day to 40 mg/day; 8 mg/day to 20 mg/day; 8 mg/day to 18 mg/day; 8 mg/day to 16 mg/day; or 8 mg/day to 12 mg/day. Alternatively, 2 mg/day; 4 mg/day; 8 mg/day; 16 mg/day; 18 mg/day; 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof are administered to the subject. Preferably,

Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day at any of the foregoing dosages. Preferably, Compound (I) or a pharmaceutically acceptable salt thereof is administered orally at any of the foregoing dosages. More preferably,

Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day and orally at any of the foregoing dosages.

Further disorders treatable by the disclosed dosage regimen with Compound (I) or a pharmaceutically acceptable salt thereof include emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss.

The disclosed dosage regimen with Compound (I) or a pharmaceutically acceptable salt thereof may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.

Compound (I) can be prepared according to procedures disclosed in U.S. Patent No. 8,003,646 and 8,399,467.

Pharmaceutically acceptable salts of Compound (I) can also be used with the disclosed dosage regimens. A salt of the compound represented by Structural Formula (I) is formed between an acid and a basic group of the compound, such as an amino functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,

monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta.- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

Compound (I) or pharmaceutically acceptable salts therein is preferably administered orally according to the disclosed dosage regimen. Suitable formulations for this route of administration are described in U.S. Patent No. 8,003,646.

A "subject" as used herein is a primate, preferably a human.

"Treating a subject with a disease or disorder" refers to ameliorating or improving a clinical symptom or indicator associated with the disease or disorder. The invention is illustrated by the following examples, which are not intended to be limiting in any way.

EXPERIMENTAL

Example 1 - Plasma Levels of Compound (I) in Male Sprague Dawley Rats

Compound (I) and L-838417 were orally dosed at 1 mg/kg in eight male Sprague- Dawley rats. The plasma levels of Compound (I) were significantly greater than those of L- 838417. The maximum observed peak plasma concentration for Compound (I) was 4.8 times higher than that of L-838417 and the total exposure to Compound (I) was three times higher as compared to L-838417. The results are shown in Figure 1. The corresponding study in humans showed that Compound (I) has a longer half-life in humans than it does in rats (see Figure 3 and Example 3).

Example 2 - Single Ascending Dose Clinical Trial

A randomized, double-blind, placebo-controlled, single ascending dose Phase 1 clinical trial in 71 healthy adult volunteers was carried out at a single center in the United States to assess the safety, tolerability and pharmacokinetics of Compound (I). Volunteers were randomized to receive Compound (I) or placebo in a three to one ratio with eight cohorts of eight volunteers each and one cohort of seven volunteers. Six volunteers in each cohort received a single dose of Compound (I) and the remaining subjects received placebo. Doses were administered in oral liquid suspensions ranging from 0.15 mg up to 60 mg.

In the clinical trial, Compound (I) was well-tolerated up to 60 mg, the highest dose tested. Higher doses were not tested after our concurrently conducted Phase 1 imaging study described in Example 3 indicated that high levels of GABA_A receptor occupancy could be achieved at doses lower than 60 mg.

Pharmacokinetic data from our single ascending dose trial indicated that Compound (I) was well-absorbed with low inter-subject variability and a long plasma half-life, potentially supporting once-daily dosing of the compound. The graph in Figure 2 shows the mean plasma concentration over time following administration of single ascending doses of Compound (I) in the six subjects in each cohort of the trial who received Compound (I). As illustrated in the graph in Figure 2, doses of Compound (II) of 20 mg and higher resulted in plasma concentrations in excess of 100 ng/mL, maintained for 24 hours following dosing. The Phase 1 imaging study described in Example 3 indicated that these plasma concentrations corresponded to brain GABA_A receptor occupancy of greater than 50%. The high GABA_A receptor occupancy of Compound (1) at well-tolerated doses supports its potential as a non-sedating oral treatment for spasticity.

Compound (I) was generally well tolerated in our Phase 1 single ascending dose trial. No serious adverse events were reported in the trial.

Example 3 - Phase 1 Imaging Study with Compound (I)

A Phase 1 imaging clinical trial using PET scanning to measure the extent to which Compound (I) binds to GABA_A receptors in the brain in healthy adult volunteers. For the first part of this imaging study, single doses of Compound (I) of 4 mg, 20 mg, 40 mg and 60 mg were evaluated in a total of nine healthy volunteers. These doses were selected because they did not produce dose-limiting side effects in the single ascending dose clinical trial and with the goal of providing a wide range of GABA_A receptor occupancy. The objectives in this study were to assess whether Compound (I) could provide similar or higher brain GABA_A receptor occupancy levels than those typically provided by benzodiazepines at doses that do not cause dose-limiting sedation; and to compare the relationship between Compound (I) plasma levels and GABA_A brain receptor occupancy.

Subjects lay supine on the PET imaging camera for administration of [ 18 F]-flumazenil and preparation for PET imaging. Subjects were injected at a target dose of 5 mCi (+ 0.5) by intravenous injection over approximately 3 minutes using an infusion pump. PET imaging commenced at the time injection begins.

Data acquisition and image reconstruction: PET imaging data was acquired using a Siemens HR+ camera at Molecular Neurolmaging. An initial transmission scan (up to 7 minutes) was performed to develop an attenuation correction map prior to dosing with [ 18 F]-flumazenil. 3D PET scans were acquired for 6 x 30 sec, 4 x 1 min, 4 x 2 min followed by 5 minute frames for a total imaging time of approximately 90 minutes. Images were reconstructed in a 128 x 128 matrix (zoom=2) with an iterative reconstruction algorithm (OSEM 4 iterations, 16 subsets) and a post hoc Gaussian filter = 5 mm. Random and scatter correction were applied and attenuation correction performed using the isotope transmission map.

In the first part of the imaging study, GABA_A receptor occupancies of between 34% to 82% were observed in subjects receiving Compound (I) at single doses of 4 mg, 20 mg, 40 mg and 60 mg. For each subject, a baseline scan was conducted in which a small amount of flumazenil, a radiolabeled, positron emitting benzodiazepine, was injected and the brain was imaged to show flumazenil binding to the GABA_A receptors. The subject was given a single oral dose of Compound (I) within two weeks of the baseline scan. Five hours after

Compound (I) dosing, the subject received another injection of radiolabeled flumazenil and the imaging was repeated to provide a second scan. Twenty-four hours after Compound (I) dosing, the subject received another injection of radiolabeled flumazenil and the imaging was repeated to provide a third scan.

The images obtained from the two subjects that received a single 20 mg dose of Compound (I) are shown in Figure 3. In the images:

• the baseline, or first, scans appear bright due to the presence of radiolabeled

flumazenil bound to the GABA_A receptors;

• the second and third scans are not as bright as the first scan due to the binding of Compound (I) to the subjects' GABA_A brain receptors, which prevents the radiolabeled flumazenil from binding; and

• the third scan is somewhat brighter than the second scan showing that after 24 hours less Compound (I) is bound to the GABA_A receptors than after five hours.

The scans obtained from the seven other patients in the first part of the imaging study were consistent with these scans from the subjects receiving the 20 mg dose, with GABA_A receptor occupancy levels increasing with dosing levels between 4 mg and 40 mg, but appearing not to increase significantly between 40 mg and 60 mg.

In the first part of the imaging study, quantitative measures of GABA_A receptor occupancy were obtained for the single doses of Compound (I) that were administered. A single 20 mg dose of Compound (I), a dose at which no sedative or other adverse events were reported in the study, provided GABA_A receptor occupancy levels, at both five hours and 24 hours following dosing, substantially in excess of the 10% to 25% occupancy levels at which benzodiazepines and related GABA_A receptor-binding sleep drugs become highly sedative. The table below shows the average GABA_A receptor occupancy at five hours and 24 hours after dosing in the first part of the imaging study.

The graph in Figure 4 shows the relationship between plasma concentration and brain

GABA_A receptor occupancy for Compound (I) in the first part of the imaging study. The 17 data points on the graph below each represent a single reading in a single subject. These include two readings for each subject, one at five hours and one at 24 hours following dosing, with the exception of one subject for whom we could not calculate receptor occupancy at five hours due to a computer error. The graph in Figure 4 shows how receptor occupancy increases with increasing plasma concentration. As illustrated in the graph, we observed that plasma concentrations in excess of 100 ng/mL resulted in GABAA receptor occupancy in excess of 50%. Combined with the pharmacokinetic data from the Phase 1 single ascending dose clinical trial of Compound (I), which indicated that doses of Compound (I) of 20 mg and higher resulted in plasma concentrations in excess of 100 ng/mL for 24 hours following dosing, Compound (I) appears to have therapeutic potential for the treatment of spasticity when administered once daily.

In the Phase 1 imaging study, no drug related adverse events were reported in volunteers receiving 4 mg or 20 mg of Compound (I). At 40 mg, two of three subjects reported mild to moderate dizziness, mild drowsiness and nausea and one subject each reported mild euphoria, loss of balance and lightheadedness. At 60 mg, adverse events included sedation and ataxia, both mild in one subject and both moderate in the other. One subject receiving 60 mg of Compound (I) reported mild lightheadedness, restlessness and irritability and the other reported mild dizziness. All adverse effects had resolved by the following day. Based on clinical studies of diazepam and other benzodiazepines, it appears that the high brain GABA_A receptor occupancy levels achieved by Compound (I) at doses that were well-tolerated in our Phase 1 clinical trials provide evidence of its therapeutic potential. In the Phase 1 imaging study, Compound (I) produced much higher levels of GABA_A receptor occupancy than benzodiazepines without causing substantial sedation and, therefore, may provide similar clinical efficacy against spasticity without the dose-limiting effects of benzodiazepines .

Example 4 - Multiple Dose Imaging Study with Compound (I)

Two healthy male human subjects were imaged with [i8F]-flumazenil over 90 min

(see Example 3 for imaging conditions), once at baseline and then at 5 hours and 48 hours post dosing (after the final dose) with 6 mg Compound (I) for 9 consecutive days as part of the multiple dose (MD) study. Reported adverse effects included blurred vision, dizziness, headache, somnolence, restlessness, insomnia, elevated liver enzymes (LFTs), and weight gain. Each event listed above occurred in one of the two subjects and all were considered mild in intensity.

Results of the percent receptor occupancy ( RO) were presented for each subject and plotted against the plasma concentration, along with the results from the single ascending dose (SAD) study (Example 2). Results from the SAD study were predictive of the receptor occupancy obtained for the MD study at their respective plasma concentration levels.

For the previous SAD study, the ECso was estimated to be 94.4 + 7.0 ng/mL.

Considering both the SAD and MD studies, the ECso remains virtually unchanged at 95.0 + 5.8 ng/mL. Example 5 - Multiple Ascending Dose Clinical Trial with Compound (I)

Methodology: This was a randomized, 2-part study in healthy subjects. At least 3 subjects of each gender were enrolled into each dosing group.

Part A

• Subjects in Cohort 1 were randomized, 8 subjects to a 2 mg oral suspension dose of Compound (I) and 2 to matching placebo. Subjects were then dosed once daily (QD) for 10 days with double-blind suspension. • Following completion of Cohort 1 (and an acceptable safety/tolerability outcome), subjects in Cohort 2 were randomized, 8 subjects to a 6 mg oral suspension dose of Compound (I) and 2 to matching placebo. Subjects were then dosed QD for 10 days with double-blind suspension.

· Following completion of Cohort 2 (and an acceptable safety/tolerability outcome), subjects in Cohort 3 were randomized, 8 subjects to a 12 mg solid dose of Compound (I) and 2 to matching placebo. Subjects were then dosed QD for 10 days with double- blind capsules.

• Upon the completion of each of the first and second cohorts, there was a review of the safety and tolerability data performed by the Principal Investigator (PI) and Medical

Monitor to determine whether to escalate to the next dose. Upon determination of whether (or not) to dose the next subsequent cohort, data from the prior cohort could have been unblinded.

Part B

Part B randomized 12 new subjects, 4 subjects per sequence, into 1 of 3 treatment sequences. Subjects were then treated (in an open-label fashion) with a single 6 mg dose of suspension in a fasted state or 6 mg solid dose Compound (I) in a fasted or fed state. Note that Periods 1 and 2 were each followed by a washout period of at least 7 days. The effects of food (as compared to fasting) were assessed and a comparison between the suspension and the solid dose was assessed.

Number of patients (planned and analyzed):

A total of 42 subjects (30 subjects in Part A and 12 subjects in Part B) entered the study and received study treatment. All 42 subjects were included in the safety evaluation. All of the available data from the 36 subjects who received Compound (I) were included in the plasma PK analysis, including 24 subjects in Part A (8 per cohort) and 12 subjects in Part B (for each treatment). All of the available data for the 16 subjects who received Compound (I) in Cohorts 2 and 3 (8 subjects per cohort; Part A) were included in the urine PK analysis for Compound (I), with the exception of some excluded data for one subject (12 mg solid dose), who lost part of the void for the 0 to 6 hour urine collection interval on Day 1. Diagnosis and main criteria for inclusion:

Healthy adult females or males between 18 and 50 years of age, inclusive, weighing at least 50 kg, with a body mass index (BMI) within the range of 18 to 30 kg/m , inclusive.

Test product, dose and mode of administration, batch number:

The test products were Compound (I) Capsules, 6 mg (Lot no. Compound (I)-2014-

04) and Compound (I) Form 1 Drug Substance. In Part A, subjects randomized to receive active treatment were administered oral doses of 2 mg or 6 mg Compound (I) suspension or

12 mg solid dose QD for 10 days. In Part B, subjects were administered 3 doses of

Compound (I), either as a suspension or solid dose, with or without a high-fat meal.

Duration of treatment:

For Part A, subjects were treated with QD doses of Compound (I) or placebo for 10 days. The total duration (excluding the screening period) of participation in the study for each subject in Cohorts 1, 2, and 3 was approximately 2 weeks. For Part B, subjects were treated in 3 successive periods with a 7-day washout between periods. For each period, subjects were dosed with a single dose of Compound (I) (in either solid form or suspension), with or without food (according to their treatment sequence). The total duration (excluding the screening period) of participation in the study for each subject in (Part B) was approximately

4 weeks.

Reference therapy, dose and mode of administration:

The reference products were Placebo for Compound (I), 6 mg Capsule and

Ora-Blend^® Flavored Suspending Vehicle. In Part A, subjects randomized to receive placebo treatment were administered oral doses of Ora-Blend^® or placebo capsules QD for 10 days.

Results.

Mean (%CV; =S) Day 1 and Steady State (Day 10) PK Parameters for

Miiltiple Ascending Doses of CTP-354

* ΤΚΜΧ is represented as median (mill, max); AUC_BB = AUC R = DaylO/Dayl

The steady- state Day 10 plasma concentration vs. time profile and the Day 1-10 Ct_rou_gh (C₂4hr) plasma concentration vs. time profile are shown in Figure 5.

Compound (I) demonstrated a favorable PK profile supporting once-daily dosing.

Compound (I) provided high and sustained brain GABA(A) receptor occupancy levels following both single and repeat doses. Treatment was generally well tolerated.

Transient mild to moderate somnolence and dizziness were reported in 13% of the Compound (I) treated subjects at doses > 6 mg. The long half-life of Compound (I) supports once-daily dosing of the drug. The C_max of Compound (I) increased dose-proportionally from 0.15 to 6 mg, and AUC (AUCo-₂₄hr and AUCo-₄8hr) increased dose-proportionally in the 0.15- 20 mg dose range. Both C_max and AUC increased less than dose-proportionally at the higher doses of Compound (I).

Steady state was reached at Day 5-7 for all three multiple ascending doses (MAD) (2, 6 and 12 mg). Accumulation of about 2-fold was observed for both C_max and AUC_tau at steady state (Day 10).

Steady state (Day 10) C_max and AUC_tau increased with dose but in a less than dose- proportional manner. Across all doses, plasma Ti_/2 was approximately 20 hours.

Similar exposure was observed under fed and fasted conditions, suggesting

Compound (I) may be dosed without regard to food.

Claims

is claimed is:

A method of treating a disorder of the central nervous system in a subject, comprising administering to the subject an amount in the range of 2 mg/day to 40 mg/day of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1, where the disorder of the central nervous system is anxiety, spasticity, or pain.

3. The method of Claim 1, wherein the disorder is anxiety.

4. The method of Claim 1, wherein disorder is spasticity.

5. The method of Claim 1, wherein the disorder is pain.

6. The method of Claim 1, wherein the disorder is neuropathic pain, inflammatory pain or migraine- associated pain.

7. The method of any one of Claims 1-6, comprising administering to the subject an amount in the range of 2 mg/day to 40 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 18 mg/day; 2 mg/day to 16 mg/day; 2 mg/day to 12 mg/day; 2 mg/day to 8 mg/day; 2 mg/day to 4 mg/day; 4 mg/day to 40 mg/day; 4 mg/day to 20 mg/day; 4 mg/day to 18 mg/day; 4 mg/day to 16 mg/day; 4 mg/day to 12 mg/day; 4 mg/day to 8 mg/day; 8 mg/day to 40 mg/day; 8 mg/day to 20 mg/day; 8 mg/day to 18 mg/day; 8 mg/day to

16 mg/day; or 8 mg/day to 12 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof.

8. The method of any one of Claims 1-6, comprising administering to the subject 2 mg/day, 4 mg/day, 8 mg/day, 16 mg/day, 18 mg/day, 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof. The method of any one of Claims 1-6, comprising administering to the subject an amount in the range of 2 mg/day to 16 mg/day of Compound (I) or a

pharmaceutically acceptable salt thereof.

10. The method of any one of Claims 1-6, comprising administering to the subject an amount in the range of 2 mg/day, 8 mg/day or 16 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof.

11. The method of any one of Claims 1-10, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once a day to the subject.

12. The method of any one of Claims 1-11, wherein the compound is administered orally.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and between of 2 mg to 40 mg; 2 mg to 20 mg; 2 mg to 18 mg; 2 mg to 16 mg; 2 mg to 12 mg; 2 mg to 8 mg; 2 mg to 4 mg; 4 mg to 40 mg; 4 mg to 20 mg; 4 mg to 18 mg; 4 mg to 16 mg; 4 mg to 12 mg; 4 mg to 8 mg; 8 mg to 40 mg; 8 mg to 20 mg; 8 mg to 18 mg; 8 mg to 16 mg; or 8 mg to 12 mg of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of Claim 13, comprising 2 mg; 4 mg; 8 mg; 16 mg;

18 mg; 20 mg; or 40 mg of the compound or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of Claim 13 or 14, wherein the pharmaceutical

composition is suitable for oral administration.