Method of treating post-traumatic stress disorder

Abstract

This disclosure provides therapeutic methods involving administration of BNC210 to a subject in an amount effective to reduce or eliminate post-traumatic stress disorder (PTSD), or an associated symptom / metric, in a treated subject.

Description

[0001] Attorney Docket No.: 1011268.0011 METHOD OF TREATING POST-TRAUMATIC STRESS DISORDER CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of and priority to U.S. Provisional Patent Application No.63 / 586,149, filed on September 28, 2023, the contents of which are incorporated by reference in their entiriety herein. FIELD OF THE INVENTION This disclosure relates generally to methods for treating post-traumatic stress disorder (PTSD). BACKGROUND OF THE INVENTION The U.S. National Comorbidity Survey Replication (NCS-R) estimated the 12-month prevalence of post-traumatic stress disorder (PTSD) among adult Americans to be 3.5%. Of these cases, 36.6% are considered to be severe based on the symptoms. The overall lifetime prevalence of PTSD in the USA is estimated to be 8 to 9%, costing about $8 billion, and is twice as common in women as in men. The 12-month prevalence was found to be 1.8% among men and 5.2% among women (National Institute of Mental Health, 2010). In adolescents (aged 13-18 years old) this prevalence is about 4%. As a result of such high prevalence, a large number of people are being treated every year with a 12-month treatment seeking rate of 49.9% in the USA, with about 42% of these patients receiving minimally adequate treatment. Current treatment options listed as having “significant” or “some” benefit in the “Post- Traumatic Stress Disorder Pocket Guide”, 2013 (Pocket Guide) include both psychotherapies (e.g., “cognitive”, “exposure” therapies) and pharmacotherapies. With respect to pharmacotherapies, monotherapies with antidepressants, especially selective serotonin or serotonin / norepinephrine reuptake inhibitors, have shown efficacy in randomized controlled trials; with only sertraline and paroxetine being approved by the Food and Drug Administration (FDA) for the treatment of PTSD. Although benzodiazepines, atypical antipsychotics, anticonvulsants have been also examined, these agents have not shown consistent efficacy, and are not currently on the recommended drug list in the aforementioned guideline. Combination of exposure therapy and paroxetine has been reported to produce no additional therapeutic efficacy compared to exposure therapy only. Additional treatments and investigational new drugs (IND) continue to undergo clinical trial Attorney Docket No.: 1011268.0011 evaluations as either monotherapies or as augmentation strategies to existing forms of PTSD treatment. A need exists for improved therapeutics and treatment regimens for PTSD. BRIEF SUMMARY OF THE INVENTION The instant disclosure relates, at least in part, to identification of BNC210 as a compound capable of treating PTSD in a subject with surprising efficacy, particularly for treating subjects having severe PTSD, and for reducing / ameliorating certain symptoms associated with PTSD (e.g., insomnia, depressive thoughts, other cognitive symptoms). Without wishing to be bound by theory, BNC210 has been described to function as an inhibitor alpha7 nicotinic acetylcholine receptor (α7 nAChR). BNC210 compositions of the disclosure were identified as particularly effective for treating severe PTSD in female subjects. In one aspect, the disclosure provides a method of treating post-traumatic stress disorder (PTSD) in a subject, the method involving administering the compound of formula (I): or a salt, or prodrug of PTSD in the subject by at least five points as measured by CAPS-5 total symptom severity score. In one embodiment, the compound is administered in an amount effective to treat insomnia in the subject. Optionally, insomnia severity is reduced in the subject by at least two points on the insomnia severity scale (ISI score). In another embodiment, the compound is administered in an amount effective to treat depression in the subject. Optionally, the depression rating of the subject is reduced by at least two points on a Montgomery-Asberg Depression Rating Scale. In certain embodiments, the compound is administered in an amount effective to reduce intrusive thoughts in the subject. Optionally, intrusive thoughts are reduced in the subject by at least two points on a CAPS-5 Criterion B Intrusion Severity Subscore scale. In some embodiments, the compound is administered in an amount effective to reduce negative alterations in cognitions and mood in the subject. Optionally, negative alterations in Attorney Docket No.: 1011268.0011 cognitions and mood in the subject are reduced by at least two points on a CAPS-5 Criterion D Severity Subscore scale. In an embodiment, the compound is administered in an amount effective to reduce an observed score for the subject on a Clinician Global Impression Severity Scale (CGI-S score). Optionally, the observed score for the subject for CGI-S is reduced by at least 0.5. In one embodiment, the compound is administered in an amount effective to reduce an observed score for the subject on a Patient Global Impression Severity Scale (PGI-S score). Optionally, the observed score for the subject for PGI-S is reduced by at least 0.4. In another embodiment, the subject suffering from PTSD has a CAPS-5 Severity Score of at least 35, for example, at least 40, at least 41, at least 42, at least 43, at least 45, or more. In certain embodiments, the subject suffering from PTSD has experienced an Index Trauma Event less than ten years prior to the administration. In some embodiments, the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within four weeks of treatment. In one embodiment, the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within eight weeks of treatment. In another embodiment, the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within twelve weeks of treatment. In certain embodiments, the compound is administered twice a day. Optionally, the compound is administered orally. Optionally, by tablet. In some embodiments, the compound of formula (I) is administered at a dosage that achieves a plasma concentration of 25 mg.hr / L or more in the subject. In some embodiments, the compound of formula (I) is administered at a dosage that achieves a plasma concentration of 40 mg.hr / L or more in the subject. In certain embodiments, the compound is administered twice a day at 450 mg per dose. In some embodiments, the compound is administered twice a day at 900 mg per dose. In certain embodiments, the compound of formula (I) is administered as a pharmaceutical composition that includes between about 800mg and about 1000mg of the compound. Optionally, the pharmaceutical composition includes about 900 mg of the compound. Optionally, the composition includes a pharmaceutically acceptable carrier. In a related embodiment, the Attorney Docket No.: 1011268.0011 compound is administered as a pharmaceutical composition in tablet form. Optionally, each tablet contains about 225 mg of the compound. In certain embodiments, the compound of formula (I) is administered twice a day at 600 mg per dose. In other embodiments, the compound of formula (I) is administered twice a day at 450 mg per dose. In still another embodiment, the compound of formula (I) is administered twice a day at a dose of at least 450 mg per dose. In a related embodiment, the compound is administered as a pharmaceutical composition that includes between about 450 mg and about 700 mg of the compound and a pharmaceutically acceptable carrier. Optionally, the compound is administered as a pharmaceutical composition that includes about 600 mg of the compound and a pharmaceutically acceptable carrier. Optionally, the compound is administered as a pharmaceutical composition that includes 600 mg of the compound and a pharmaceutically acceptable carrier. Optionally the compound is in tablet form. Optionally, each tablet administered to the subject contains about 200 mg of the compound. In another embodiment, liver function tests (LFTs) of the subject are assessed. Optionally, the assessed LFTs are selected from alkaline phosphatase activity, aspartate aminotransferase [AST] activity, alanine aminotransferase [ALT] activity, gamma-glutamyl transferase activity, and / or total bilirubin. In a further embodiment, LFTs of the subject administered the compound of formula (I) are approximately equivalent to LFTs of a control subject not administered the compound of formula (I), or are approximately equivalent to an appropriate control value. In certain embodiments, the pharmaceutical composition administered with between about 450 mg and about 700 mg of the compound of formula (I) is as effective a treatment for PTSD in the subject as a pharmaceutical composition having between about 800 mg and about 1000 mg of the compound of formula (I). Optionally, LFTs in the subject administered about 450 mg to about 700 mg of the compound of formula (I) are approximately equivalent to LFTs of a control subject not administered the compound of formula (I). Optionally, LFTs in the subject administered about 450 mg to about 700 mg of the compound of formula (I) show better liver function in the subject than in an appropriate comparison subject administered about 800 mg to about 1000 mg of the compound of formula (I). Attorney Docket No.: 1011268.0011 In certain embodiments, the severity of PTSD in the subject is reduced as compared to a starting value, as compared to an absolute value, and / or as compared to a placebo-treated control subject. In some embodiments, the subject is female. Another aspect of the disclosure provides a method of treating depression in a subject in need thereof, the method involving administering the compound of formula (I): or a salt, or prodrug in the subject by at least two points on the An additional aspect of the disclosure provides a method of treating insomnia in a subject in need thereof, the method involving administering the compound of formula (I): or a salt, or prodrug in the subject by at least two points on the insomnia severity scale (ISI score). In one embodiment, the subject suffers from PTSD. A further aspect of the disclosure provides a method of treating severe PTSD in a subject, the method involving administering the compound of formula (I): Attorney Docket No.: 1011268.0011 (I) or a salt, or prodrug thereof, in an amount effective to reduce the severity of PTSD in the subject by at least five points on the CAPS-5 total symptom severity score. Another aspect of the disclosure provides a method for treating post-traumatic stress disorder (PTSD) in a subject, the method involving administering the compound of formula (I) or a salt, or prodrug thereof, in an amount effective to reduce the severity of PTSD in the subject by at least five points on the CAPS-5 total symptom severity score, where the effective amount of the compound of formula (I) does not significantly modulate liver function tests (LFTs) performed upon the subject, as compared to an appropriate control. In one embodiment, the compound is administered at a dosage that achieves a compound plasma concentration of 25 mg.hr / L or more in the subject. In certain embodiments, the effective amount of the compound of formula (I) is between about 450 mg and about 900 mg. In another embodiment, the effective amount of the compound of formula (I) is between about 450 mg and about 675 mg. In yet another embodiment, the effective amount of the compound of formula (I) is approximately 600 mg BID. In another embodiment, liver damage in the subject is reduced or eliminated, as compared to an appropriate comparison test subject or to a comparison population of test subjects administered the compound of formula (I) at approximately 900 mg BID. Definitions That the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. For the purposes of the present disclosure, the following terms are defined below. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". Attorney Docket No.: 1011268.0011 The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. The term “at least” prior to a number or series of numbers is understood to include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. “BNC210” refers to compound of formula (I) as depicted below: This compound and PCT / AU2007 / 001566 (WO 2008 / 046135) the entire contents being incorporated herein by reference. "Excipients" are pharmaceutically inactive substances that serve as the vehicle or medium for a drug or other active substances, the “crystallisation inhibitor polymers” described herein are separate from the use of the term “excipients” as used herein. Accordingly, the disclosure, in certain embodiments, contemplates compositions with BNC210, at least one crystallisation inhibitor polymer and one or more excipients. The terms “administer”, “administering” or “administration” in reference to a compound, composition or formulation of the disclosure means introducing the compound into the system of the animal in need of treatment. When a compound of the disclosure is provided in combination with one or more other active agents, “administration” and its variants are each understood to include concurrent and / or sequential introduction of the compound and the other active agents. "HPMC" is the excipient hydroxypropyl methylcellulose, also known as hypromellose. It is a semisynthetic, inert, viscoelastic polymer. It is a non-ionic, hydrophilic derivative of cellulose ether and is stable over pH range 3 – 11. One preferred example is HPMC E15 LV, a premium Attorney Docket No.: 1011268.0011 polymer of low viscosity grade of about 15cP (sold as METHCELTME15 Industrial LV from Dupont). “HPMCAS” is the excipient hydroxypropyl methylcellulose acetate succinate (or hypermellose acetate succinate) and is primarily used for enteric coating materials for both regular enteric coating and sustained release formulations with various contents of acetyl and succinoyl groups in the polymer. There are several types of HPMCAS, which dissolve at different pH levels. Type L HPMCAS represents polymer with high ratio of succinoyl substituting to acetyl substitution (S / A ratio) while type H with low S / A ratio and type M with medium S / A ratio with a higher S / A ratio. Type L HPMCAS dissolves at lower pH (≥ 5.5), compared with pH ≥ 6.0 for type M and pH ≥ 6.8 for type H. "Cellulose-microcrystalline" is an excipient and is often referred to as refined wood pulp, often used as a texturiser, an anti-caking agent, suspending agent and adsorbent. Often sold as microcrystalline cellulose under the tradename Avicel PH-105. “Croscarmellose sodium” or “sodium croscarmellose” is an internally linked sodium salt of carboxymethylcellulose and is used as a superdisintergrant. It is sold by, inter alia, FMC Biopolymer under the tradename of Ac-Di-Sol SD 711. “Colloidal Silica” (also silicon dioxide or colloidal silicon dioxide) is used in tablet preparations as an anti-caking agent, adsorbent, disintergrant or a glidant to allow improved flowability when tablets are processed. It is sold by, inter alia, Cabot under the tradename Cab-O- Sil MP. “Sodium stearyl fumurate” (also known as sodium monostearyl fumurate or sodium monooctadecyl fumurate) is a water-soluble lubricant for aiding tablet compression. It is sold by, inter alia, JRS Pharma under the tradename Pruv SSF. “PVP-VA” (also PVP / VA copolymer or Poly(l-vinylpyrrolidone-co-vinyl) Acetate, or Copovidone, or PVP VA64) is a vinylpyrrolidone-vinyl acetate copolymer (vinyl acetate-vinyl pyrrolidone copolymer) of random linear arrangement produced by the free radical polymerisation of the monomers in ratios varying from 70:30 to 30:70 vinyl acetate to vinyl pyrrolidone. Also known under the tradenames Polectron 845 and Luviskol VA 281, Kolima 10, 35, Ganhon S 860, or Ganex E313, just to name a few. Attorney Docket No.: 1011268.0011 “CAP” (also referred to as Cellacetate, Cellacefate, Celluloseacetate, 1,2- benzenedicarboxylate) is a cellulose acetate phthalate polymer which is insoluble in water, alcohols, hydrocarbons and chlorinate hydrocarbons. Often used as an enteric coating material. “Eudragit” is the common tradename of copolymers derived from esters of acrylic and methacrylic acids containing ratio ranges from two to three methacrylate monomers, such as metharylic acid, methacrylic acid esters and dimethylaminomethyl methacrylate. SoluplusTMis a polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer (PCL-PVAc-PEG), available from BASF. It is a water soluble copolymer with average molecular weight ranging from 90,000 to 140,000 g / mol, and is capable of solubilizing poorly water soluble drugs. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity). A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method "consisting essentially of" (or which "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel Attorney Docket No.: 1011268.0011 characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of" (or "consists of") the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step. As used herein, the term “pharmaceutical composition” refers to a composition in which an active agent (e.g., a compound of formula (I) as disclosed herein) is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., in a solid form or a liquid form), and / or may be specifically adapted for, for example: oral administration (for example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc, which may be formulated specifically for example for buccal, sublingual,or systemic absorption); parenteral administration (for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation, etc); topical application (for example, as a cream, ointment, patch or spray applied for example to skin, lungs, or oral cavity); intravaginal or intrarectal administration (for example, as a pessary, suppository, cream, or foam); ocular administration; nasal or pulmonary administration, etc. As used herein, the term “subject” refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog). In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein. In some embodiments, a subject is susceptible to a disease, disorder, or condition; in some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing the disease, disorder or condition Attorney Docket No.: 1011268.0011 (e.g., PTSD). In some embodiments, a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered. In an embodiment, the subject is a human, such as a human being treated or assessed for a disease or disorder that would benefit from administration of a compound of formula (I); a human at risk for a disease or disorder that would benefit from administration of a compound of formula (I); a human having a disease or disorder that would benefit from administration of a compound of formula (I); or human being treated for a disease or disorder that would benefit from administration of a compound of formula (I) as described herein. In some embodiments, the subject is a female human. In other embodiments, the subject is a male human. In one embodiment, the subject is an adult subject. In another embodiment, the subject is a pediatric subject. As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result, such as reducing at least one sign or symptom of PTSD in a subject. Treatment also includes a reduction of one or more sign or symptoms associated with PTSD. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. "Therapeutically effective amount," as used herein, is intended to include the amount of a composition of the instant disclosure that, when administered to a subject having PTSD, is sufficient to effect treatment of PTSD (e.g., by diminishing, ameliorating, or maintaining the existing disorder or one or more symptoms of disorder). The "therapeutically effective amount" may vary depending on the agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. As used herein, the phrase "liver function tests" (abbreviated as "LFTs") refers to a series or panel of liver enzyme and / or other liver marker evaluations that can be used to assess the functionality of the liver of a subject, before, during and / or after treatment with an agent as described herein, or in the absence of treatment with such agent(s). Commonly used "liver function tests" include detection of alkaline phosphatase activity, aspartate aminotransferase [AST] activity, alanine aminotransferase [ALT] activity, and / or gamma-glutamyl transferase activity, as well as Attorney Docket No.: 1011268.0011 detection of total bilirubin, though other art-recognized means for assessing liver function can also be included in the range of "liver function tests" contemplated for the instant disclosure. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Such carriers are known in the art. Pharmaceutically acceptable carriers include carriers for administration by injection. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description, given by way of example, but not intended to limit the disclosure solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings. FIG.1 shows a pharmacometrics (PMX) analysis of target exposure which revealed that subjects that achieved BNC210 exposure (AUC90) values (plasma concentration) of >25 mg.hr / L were most responsive to BNC210 treatment of PTSD (as assessed by CAPS-5 score). A 900 mg dosage (b.i.d.) of BNC210 tablets was therefore selected for the Phase 2b clinical trial examining the efficacy of BNC210 for treatment of PTSD. FIG.2 shows that BNC210 administration to clinical trial subjects having PTSD achieved clear differentiation from placebo over twelve weeks, as assessed by measurement of CAPS-5 total symptom severity score. Clinically meaningful treatment effects were therefore observed, with efficacies higher than approved treatments. mITT population refers to Mixed Model for Repeated Measures (MMRM) with multiple imputation. * indicates p<0.05. FIGs. 3A and 3B show that BNC210 treatment resulted in improvements in both depression and sleep in subjects having PTSD. FIG. 3A shows improvement in depression as Attorney Docket No.: 1011268.0011 measured by Montgomery-Åsberg Depression Rating Scale (MADRS). FIG. 3B shows improvement in sleep as measured by Insomnia Severity Index (ISI). mITT population refers to MMRM (on observed data). * indicates p<0.05. FIGs. 4A and 4B show that BNC210 treatment resulted in improvements in intrusive thoughts, mood and cognition in BNC210-treated subjects. Such symptoms have been considered the most difficult to treat in PTSD subjects. FIG. 4A shows reduction of intrusive thoughts in treated subjects, as assessed by Criterion B: Intrusion. FIG.4B shows improvement of mood and cognition, as assessed by Criterion D: Negative alterations in cognitions and mood. mITT population refers to MMRM (on observed data). * indicates p<0.05; ** indicates p<0.01. FIGs. 5A and 5B show that BNC210 treatment resulted in improved Clinician (CGI-S) and Patient (PGI-S) Global Impression Severity Scales. FIG.5A shows a significant improvement in Clinician Global Impression Severity Scale (CGI-S) in BNC210-treated subjects. FIG. 5B shows an improvement in Patient Global Impression Severity Scale (PGI-S) in treated subjects. mITT population refers to MMRM with multiple imputation for CGI-S and with observed data for PGI-S. *p indicates <0.05. FIGs. 6A and 6B show the results of a CAPS-5 total symptom severity score subgroup analyses, in which it was shown that BNC210 treatment resulted in significant improvements for subjects having baseline CAPS-5 Severity (≥40 points) and an index trauma event that occurred within the past ten years. FIG.6A shows that CAPS-S total symptom severity score was reduced in BNC210-dosed subjects that entered the clinical trial with severe PTSD (a baseline CAPS-5 severity score ≥40 points). FIG. 6B shows that CAPS-S total symptom severity score was significantly reduced in BNC210-dosed subjects that entered the clinical trial having had an index trauma event within the past ten years. mITT population: MMRM (on observed data). * indicates p<0.05; ** indicates p<0.01. The present disclosure is further illustrated by the following detailed description. DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates, at least in some aspects, to identification of BNC210 compositions as unexpectedly effective for treatment of a subject having PTSD, particularly for a subject having severe PTSD. Attorney Docket No.: 1011268.0011 The Tablet The present disclosure is predicated on the effective administration of a solid dosage formulation of compound of formula (I) and specifically tablet formulations comprising said solid dispersion. The present disclosure also provides solid dosage formulations and specifically tablet formulations comprising said solid dispersion which are prepared by dry granulation and compression. In certain embodiments the tablet comprises at least one pharmaceutically acceptable polymer which is an at least one crystallisation inhibitor polymer. In a further embodiment the tablet comprises the solid dispersion with an effective amount of (i) a compound of formula (I) or a salt or prodrug thereof, and (ii) an amount of at least one crystallisation inhibitor polymer wherein the ratio of (i):(ii) is from about 10:90 to about 80:20 (wt / wt%). During preformulation studies the inventors noted that compounds of formula (I) displayed a high melting point, poor in vitro solubility of the crystalline form of compound I (which is thermodynamically stable form and observed when the amorphous form of compound I is exposed to water / moisture), and low oral exposure which increased with the addition of 0.5% HPMC to suspension formulations and depend upon fed / fasted state of subject. In this regard it was observed that there was a need to develop an alternative formulation for further development focusing on preventing (or at least substantially minimising) the formation of poorly soluble crystalline forms, reducing the food effect and increasing oral exposure. Solid dispersion technologies, such as hot melt extrusion (HME) and spray drying, lipid formulations and nanosizing were considered as approaches to overcome these formulation deficiencies. Considering the targeted dose of the compound and good solubility in mixture of dichloromethane (DCM) and methanol, it was recognised by the inventors that compounds of formula (I) may be suitable for spray drying. The undesirable drug / drug interactions which lead to crystallisation have been shown to be avoided when certain crystallisation inhibitor polymers are used in spray-dried amorphous solid dispersions of the drug (compound of formula (I)) which can be used, for instance, in the preparation of tablets. The preferred ratio of compounds of formula (I):polymer are discussed below, and can lead to advantageously high loading of the API in a subsequent tablet formulation. These resultant tablet Attorney Docket No.: 1011268.0011 formulations are shown to display good in vivo solubility and avoid or at least minimise any adverse food effect. In other embodiments the invention involves the administration of a tablet (or multiple tablets, e.g., for tablets containing 225 mg of the compound of formula (I), four (4) tablets can be administered to achieve a 900 mg dose) comprising: (i) 900 mg of a compound of formula (I): or a salt, or optionally dispersed a a acceptable polymer. In other embodiments, the disclosure involves the administration of a tablet (or multiple tablets) comprising: (ii) 900 mg of a compound of formula (I): or a salt, or (iii) a crystallization inhibitor polymer. In other embodiments the invention involves the administration of a tablet (or multiple tablets, e.g., for tablets containing 200 mg of the compound of formula (I), three (3) tablets can be administered to achieve a 600 mg dose) comprising: (iv) 600 mg of a compound of formula (I): Attorney Docket No.: 1011268.0011 or a salt, or optionally dispersed acceptable polymer. In other embodiments, the disclosure involves the administration of a tablet (or multiple tablets) comprising: (v) 600 mg of a compound of formula (I): or a salt, or (vi) a crystallization inhibitor polymer. Without wishing to be bound by theory, certain aspects of the disclosure contemplate that administration of 600 mg of a compound of formula (I) to a subject (e.g., three tablets of 200 mg compound each) is likely to exert therapeutic benefit to the subject for treatment of PTSD, yet is less likely to cause liver function issues (e.g., as evaluated by LFTs) in the subject than administration of 900 mg of a compound of formula (I) to subjects (e.g., four tablets of 225 mg compound each) is sometimes observed to cause. It is specifically contemplated that in circumstances where approximately equivalent therapeutic benefit is observed at both 600 mg BID and 900 mg BID doses, the 600 mg BID dosage is preferred, as the lower dosage is less likely to induce liver damage (as measured by assessment of LFTs). In some aspects, BNC210 is administered to a subject at sufficient dosage to achieve a plasma concentration in the subject of about 25 mg.hr / L or greater. Monitoring of BNC210 plasma concentration in a subject can be performed by art-recognized methods. Optionally, BNC210 can be dosed in tablet form to achieve a plasma concentration in a treated subject of about 20 mg.hr / L Attorney Docket No.: 1011268.0011 or greater, about 25 mg.hr / L or greater, about 30 mg.hr / L or greater, about 35 mg.hr / L or greater, or about 40 mg.hr / L or greater. In related embodiments, BNC210 can be dosed in tablet form to achieve a plasma concentration in a treated subject of about 25 mg.hr / L to about 75 mg.hr / L, optionally about 30 mg.hr / L to about 60 mg.hr / L optionally about 40 mg.hr / L to about 55 mg.hr / L. It is specifically contemplated that tablet forms of BNC210 as described herein and as available in the art are likely capable of achieving BNC210 plasma concentration levels at lower BNC210 doses than at 900 mg tablets b.i.d., as such 900 mg b.i.d. tablet doses exhibited a range of BNC210 plasma concentrations herein in treated subjects of 24 mg.hr / L to 57 mg.hr / L, with most observed BNC210 plasma concentrations in treated subjects measured at about 42 mg.hr / L to about 57 mg.hr / L. It is therefore contemplated, e.g., that BNC210600 mg tablet formulations b.i.d., taken without food, would be capable of achieving sufficient plasma concentrations of BNC210 in treated subjects (e.g., about 20 mg.hr / L or greater, about 25 mg.hr / L or greater) to be therapeutically effective. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. For the purposes of the present disclosure, the following terms are defined below. In the present formulation, the main active ingredient is the compound of formula (I), or a salt or prodrug thereof. The amount of the compound of formula (I) included in the formulation is effective to provide a therapeutic plasma concentration in a subject for up to 24 h. In an embodiment, the formulation when presented as a tablet comprises about 900 mg of active ingredient. In an embodiment, the formulation when presented as a tablet comprises between about 800 mg to about 1000 mg of active ingredient. It will be appreciated that the solid dispersion formulation as disclosed herein comprises only the compound of formula (I) and the at least one pharmaceutically acceptable polymer or at least one crystallisation inhibitor polymer. This solid dispersion will be ultimately mixed with further excipients prior to tablet formation and such formulations (i.e., solid-dispersion and added excipients) are referred to herein as a pre-tabletting formulations. In certain embodiments, the tablet formulation of the present disclosure will also comprise of a combination of formulation excipients which allows for immediate release of the active ingredient throughout the gastrointestinal tract. This can be achieved via a rapid dissolution controlled process, by swelling under the influence of a media and erosion of the matrix to release Attorney Docket No.: 1011268.0011 the active ingredient. In certain embodiments the formulations disclosed herein are immediate release formulations, for instance displaying about 70% dissolution in the first 15 minutes. The solid dispersion, pre-tableting and tablet formulations discussed herein comprise an effective amount of a compound of formula (I) dispersed within a polymer matrix formed by at least one pharmaceutically acceptable polymer or crystallization inhibitor polymer (used interchangeably) to ensure retention of the compound of formula (I) in substantially amorphous form. In certain embodiments the ratio of (i):(ii) is about 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, and about 80:20 wt / wt%. In certain embodiments the crystallisation inhibitor polymer is a polymer excipient selected from the group consisting of HPMCAS-M, HPMCAS-H, HPMCAS-L, PVP-VA, HPMC (for instance HPMC EI5LV) and Soluplus. In certain embodiments the crystallisation inhibitor polymer is HPMCAS-H. In certain embodiments the crystallisation inhibitor polymer is HPMCAS-M. In certain embodiments the crystallisation inhibitor polymer is HPMC E15 LV. In certain embodiments the crystallisation inhibitor polymer is HPMCAS-L. In certain embodiments the crystallisation inhibitor polymer is PVP-VA. In an embodiment, the solid dispersion formulations disclosed herein are produced by spray drying. In an embodiment, the total weight of solids (wt% total solids) in the spray dried solution is between 2 – 15% wt, such as between about 2 - 10% wt. In certain embodiments the spray drying solvent comprises dichloromethane. In certain embodiments the spray drying solvent comprises dichloromethane and methanol. In certain embodiments the spray drying solvent comprises dichloromethane and methanol in a weight to weight ratio of about 90:10 to 60:10 such as about 85:15, 80:20, 75:25, 70:30, and about 65:35 wt / wt%. In certain embodiments the spray dried dispersion yield is from about 50 – 100%. In an embodiment the solid dispersion formulations disclosed herein are produced by hot melt extrusion (HME). In certain embodiments the extrudate is produced at a temperature of about 160-190˚C. The pre-tabletting and tablet formulation may also comprise microcrystalline cellulose which is known in the art to be purified, partly depolymerised cellulose prepared by treating α- cellulose, obtained as a pulp from plant materials with mineral acids. In an embodiment, the tablet Attorney Docket No.: 1011268.0011 formulation or pre-tabletting formulation comprises between about 10% to about 60% (%wt / wt, based on total weight of the tablet) of microcrystalline cellulose. In another embodiment, the tablet or pre-tabletting formulation comprises about 35% to about 55% (%wt / wt) of microcrystalline cellulose. In another embodiment, the pre-tabletting and tablet formulation comprises about 40% to about 50% (%wt / wt) of microcrystalline cellulose. In an embodiment, the pre-tabletting and tablet formulation comprises between about 0.2% to about 2% (%wt / wt, based on total weight of the tablet) of sodium stearyl fumurate (SSF). In another embodiment, the pre-tabletting and tablet formulation comprises about 0.3% to 1.5% (%wt / wt) of SSF. In another embodiment, the pre-tabletting and tablet formulation comprises about 0.5% to 1% (%wt / wt) of SSF. In another embodiment, the formulation comprises about 0.5% to 0.8% (%wt / wt) of SSF. In other embodiments, the pre-tabletting and tablet formulation comprises about 0.8% to 2.5% (%wt / wt), based on total weight of the tablet, of croscarmellose sodium. In another embodiment, the pre-tabletting and tablet formulation comprises about 1% to 2% (%wt / wt) of croscarmellose sodium. In another embodiment, the pre-tabletting and tablet formulation comprises about 1.2% to 1.8% (%wt / wt) of croscarmellose sodium. In other embodiments, the pre-tabletting and tablet formulation comprises between about 0.5% to about 2% (%wt / wt, based on total weight of ferrous sulphate) of colloidal silica. In another embodiment, the pre-tabletting and tablet formulation comprises about 0.7% to about 1.5% (%wt / wt) of colloidal silica. In another embodiment, the formulation comprises about 0.9% to about 1.3% (%wt / wt) of colloidal silica. In certain embodiments the tablet formulation involves a coated tablet. Accordingly, the coating ingredients may comprise a polymer, plasticiser and pigment mixed together and dispersed finely as a film over the tablet to protect the tablet, maintain the shape of the tablet, aid in swallowing and for a lustre appearance. In the above formulations, poly(vinyl alcohol) (PVA) based coating formulations are used. In other embodiments and to further aid in solubility, the formulations also comprise a surfactant selected from SLS (sodium lauryl sulfate) or sorbates. When added the surfactant is included in an amount of less than 5% (wt / wt of the total formulation), such as about 4%, about 3%, about 2%, about 1% or less than about 1%. The surfactant can be added either at the solid dispersion or tabletting stage. Attorney Docket No.: 1011268.0011 PTSD Assessment Criteria Disorders disclosed herein are classified according to criteria listed in the Diagnostic and Statistical Manual of Mental Disorders Version 5 (DSM-5), International Statistical Classification of Diseases and Related Health Problems version 10, ICD-10, or both. DSM-5 Diagnostic Criteria for PTSD include the following (applied to adults, adolescents, and children older than 6 years. For children 6 years and younger, the DSM-5 section titled “Posttraumatic Stress Disorder for Children 6 Years and Younger” applies). A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways: 1. Directly experiencing the traumatic event(s). 2. Witnessing, in person, the event(s) as it occurred to others. 3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened death of a family member or friend, the event(s) must have been violent or accidental. 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first responders collecting human remains; police officers repeatedly exposed to details of child abuse). Note: Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless this exposure is work related. B. Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). Note: In children older than 6 years, repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed. 2. Recurrent distressing dreams in which the content and / or affect of the dream are related to the traumatic event(s). Note: In children, there may be frightening dreams without recognizable content. Attorney Docket No.: 1011268.0011 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings.) Note: In children, trauma-specific reenactment may occur in play. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). 5. Marked physiological reactions to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred, as evidenced by one or both of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). 2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). D. Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia, and not to other factors such as head injury, alcohol, or drugs). 2. Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., “I am bad,” “No one can be trusted,” “The world is completely dangerous,” “My whole nervous system is permanently ruined”). 3. Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the individual to blame himself / herself or others. Attorney Docket No.: 1011268.0011 4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame). 5. Markedly diminished interest or participation in significant activities. 6. Feelings of detachment or estrangement from others. 7. Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving feelings). E. Marked alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Irritable behavior and angry outbursts (with little or no provocation), typically expressed as verbal or physical aggression toward people or objects. 2. Reckless or self-destructive behavior. 3. Hypervigilance. 4. Exaggerated startle response. 5. Problems with concentration. 6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). F. Duration of the disturbance (Criteria B, C, D and E) is more than 1 month. G. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. H. The disturbance is not attributable to the physiological effects of a substance (e.g., medication, alcohol) or another medical condition. Specify whether: With dissociative symptoms: The individual’s symptoms meet the criteria for posttraumatic stress disorder, and in addition, in response to the stressor, the individual experiences persistent or recurrent symptoms of either of the following: Attorney Docket No.: 1011268.0011 1. Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside observer of, one’s mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of self or body or of time moving slowly). 2. Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual is experienced as unreal, dreamlike, distant, or distorted). Note: To use this subtype, the dissociative symptoms must not be attributable to the physiological effects of a substance (e.g., blackouts, behavior during alcohol intoxication) or another medical condition (e.g., complex partial seizures). Specify whether: With delayed expression: If the full diagnostic criteria are not met until at least 6 months after the event (although the onset and expression of some symptoms may be immediate). A sample form in use for PTSD assessment is reproduced below:

[0002] Attorney Docket No.: 1011268.0011 For the above- on measure on a at all; 1=A little bit; 2=Moderately; 3=Quite a bit, and 4=Extremely). The total score can range from 0 to 36 with higher scores indicating greater severity of posttraumatic stress disorder. In certain Attorney Docket No.: 1011268.0011 embodiments, such values from 0 to 36 are point scores for PTSD assessment. The clinician is asked to review the score on each item of the measure during the clinical interview and indicate the raw score for each item in the section provided for “Clinician Use.” The raw scores on the 9 items should be summed to obtain a total raw score. In addition, the clinician is asked to calculate and use the average total score. The average total score reduces the overall score to a 5-point scale, which allows the clinician to think of the severity of the individual’s posttraumatic stress disorder in terms of none (0), mild (1), moderate (2), severe (3), or extreme (4). The use of the average total score was found to be reliable, easy to use, and clinically useful to the clinicians in the DSM-5 Field Trials. The average total score is calculated by dividing the raw total score by number of items in the measure (i.e., 9). Methods of Treatment Certain aspects of the instant disclosure relate to administration of BNC210 to a subject, to treat PTSD, or to treat symptoms of or associated with PTSD, in such a subject. Such treatment is generally by oral delivery, with the BNC210 active agent formulated as a tablet. (E.g., to administer a dose of 900 mg of BNC210, two tablets containing 450 mg of BNC210 may be administered to a subject, with common dosing at 900 mg noted as twice a day (BID).) In certain embodiments, the disclosure involves the administration of a tablet comprising a compound of formula (I): or a salt, or prodrug optionally dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer. In other embodiments, the disclosure involves the administration of a tablet comprising: (i) 900 mg of a compound of formula (I): Attorney Docket No.: 1011268.0011 or a salt, or inhibitor polymer. In certain severity scores are reduced by administration of a BNC210 composition of the disclosure. In such embodiments, severity scores can be reduced by measured point values – e.g., the severity of the disorder and / or a symptom of the disorder can be reduced via administration of a BNC210 composition such that severity declines by at least one point, at least two points, at least three points, at least four points, at least five points, at least six points, at least seven points, at least eight points, at least nine points, at least ten points, at least eleven points, at least twelve points, at least thirteen points, at least fourteen points, at least fifteen points, at least sixteen points, at least seventeen points, at least eighteen points, at least nineteen points, at least twenty points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points, at least 26 points, at least 27 points, at least 28 points, at least 29 points, at least 30 points, or more. In some embodiments, the observed reduction in disorder and / or symptom severity can be expressed as a percent reduction – e.g., severity is reduced by at least 5%, 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%, or more. Such reductions (whether by observed point score or % reduction, or by other criteria) can be measured relative to a starting value for the subject, relative to an absolute value, and / or relative to an appropriate control (e.g., a placebo-treated subject or group). INCORPORATION BY REFERENCE All publications, patent applications, patents, and other references mentioned herein, including GenBank Accession Numbers, are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Attorney Docket No.: 1011268.0011 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described herein. This present disclosure is further illustrated by the following examples which should not be construed as limiting the scope or content of the disclosure in any way. The entire contents of all references, patents and published patent applications cited throughout this application, as well as the informal Sequence Listing and Figures, are hereby incorporated herein by reference. EXAMPLES Example 1: Phase 2b Clinical Trial Design A phase 2b clinical trial examining the efficacy of BNC210 for treatment of PTSD was was conducted in a total of 34 sites in the United States and the United Kingdom, with 212 initially enrolled patients, randomized 1:1 to receive either twice daily 900 mg BNC210 as a monotherapy (n=106) or placebo (n=106) for 12 weeks, with 123 patients (60%) having completed the trial through the follow-up visit. The study employed the following criteria: Outpatient dosing: BNC210 was dosed to subjects twice a day (BID) as a 900mg oral capsule. Follow-up monitoring occurred at 4 weeks, 8 weeks and 12 weeks, after initiation of BNC210 (or placebo in control group). N=212. KEY INCLUSION CRITERIA • Females and males (18 – 75 years) • Current PTSD diagnosis, with a CAPS-5 Score of ≥30 at Screening and Baseline and no >25% decrease in Score from Screening to Baseline • CAPS-5 ≥ 30 (Screening & Baseline) & ≤ 25% decrease Screening to Baseline • Index trauma event must have occurred in adulthood (i.e., when participant was ≥18 years of age) KEY EXCLUSION CRITERIA • Complex PTSD Attorney Docket No.: 1011268.0011 • MADRS score ≥35 • Antidepressants, benzodiazepines, other psychotropics (Antidepressant use within 30 days, benzodiazepines within 90 days, other psychotropics within 5 days of screening) • Bipolar, borderline personality disorder, other psychotic disorders, TBI • History of seizure disorders, uncontrolled sleep apnea or severe neurologic disease • Moderate or severe substance use disorder in the last 12 months • Less than 6 months since index trauma event occurred • Current and ongoing exposure to the trauma that caused the PTSD • Bipolar, Borderline Personality and other psychotic disorders • Moderate to severe traumatic brain injury • Increased risk of suicide • Failed more than three trials of antidepressants for PTSD treatment • Concurrent trauma-based psychotherapy (e.g. CBT, EMDR) Primary Endpoint: CAPS-5 Total Symptom Severity Scores in change from Baseline to Week 12 compared to placebo Secondary Endpoints: Change from Baseline to Week 12 compared to placebo in: Depression (MADRS), sleep (ISI), CAPS-5 symptom clusters, PTSD-checklist (PCL-5), anxiety (HAM-A), CGI, PGI, and disability (SDS); Safety & tolerability endpoints (CGI-S / I = Clinical Global Impression – Severity / Improvement Scales; CAPS-5 = Clinician Administered PTSD Scale for DSM-5; HAM-A = Hamilton Anxiety rating Scale; ISI = Insomnia Severity Index; MADRS = Montgomery-Asberg Depression Rating Scale; PCL-5 = PTSD Checklist for DSM-5; PGI-S / I = Patient Global Impression – Severity / Improvement Scales; SDS = Sheehan Disability Scale) Attorney Docket No.: 1011268.0011 Table 1. Efficacy Schedule of Assessments Modality Scale Purpose Time Points Primary Endpoint: The difference between BNC210 and placebo in change from Baseline to Week 12 in CAPS-5 Total Symptom Severity Scores Key Secondary Endpoints: (1) The difference between BNC210 and placebo in change from Baseline to Week 12 in Clinical Global Impression – Severity Scale (CGI-S) (2) Sheehan Disability Scale (SDS) Attorney Docket No.: 1011268.0011 Other Secondary Endpoints – CAPS-5: (1) The difference between BNC210 and placebo in change from Baseline to Week 12 in symptom cluster severity scores for CAPS-5: (a) Criterion B: Intrusion (b) Criterion C: Avoidance (c) Criterion D: Negative Alterations in Cognition and Mood (d) Criterion E: Arousal and Reactivity (2) Proportion of participants who achieve a) ≥30% improvement, or b) ≥50% improvement on CAPS-5 Total Symptom Severity Scores (3) Proportion of participants who achieve remission in PTSD symptoms with a score of ≤11 on CAPS-5 Total Symptom Severity Scores Secondary Endpoints – Other Scales: (1) The difference between BNC210 and placebo in Week 12 scores in Clinical Global Impression – Improvement Scale (CGI-I) (2) The difference between BNC210 and placebo in change from Baseline to Week 12 in: (a) Hamilton Anxiety Rating Scale (HAM-A) (b) Montgomery-Åsberg Depression Rating Scale (MADRS) (c) PTSD Checklist for DSM-5 (PCL-5) (d) Patient Global Impression – Severity and Improvement Scales (PGI-S / I) (e) Insomnia Severity Index (ISI) Safety Endpoints: Change from baseline to Week 12 in vital signs, electrocardiogram (ECG), hematology and blood chemistry, urinalysis, physical examination, and Columbia Suicide Severity Rating Scale (C-SSRS). Reporting of continuous Adverse Events (AE). Tabulated setup and results of phase IIb clinical trials is provided below. Table 2. Statistical Efficacy Outputs – Primary and Key Secondary Endpoint Analysis Statistical method Population Table # Attorney Docket No.: 1011268.0011 CAPS-5 CFB to Week 12 in Total Symptom MMRM with MI mITT 14.2.1.1 Severity Scores p p p achieve remission in PTSD symptoms with a score of <11 on Total Symptom Severity Scores CGI-S CFB to Week 12 in score MMRM with MI mITT 14.2.2.1 p p Table 3. Statistical Efficacy Outputs – Secondary & Exploratory Endpoint Analysis Statistical Population Table # method CGI-I Difference between mean endpoint scores at ANCOVA mITT 14.2.6.1 Week 12 HAM-A CFB to Week 12 in Total Score MMRM mITT 14.2.7.1 Attorney Docket No.: 1011268.0011 PCL-5 CFB to Week 12 in Total Score mITT 14.2.9.1 PGI-S CFB to Week 12 in Score MMRM mITT 14.2.10.1 PGI-I Difference between mean endpoint scores at ANCOVA mITT 14.2.11.1 Week 12 ISI CFB to Week 12 in Total Score MMRM mITT 14.2.12.1 CAPS-5 CFB to Week 12 in Total mITT 14.2.5.1 • By gender • By degree of severity (Baseline CAPS-5 <40, ≥ 40) • By time since index trauma event (≤10 years, > 10 years) ANCOVA = Analysis of Covariance; CFB = change from Baseline; MMRM = mixed model for repeated measures Statistical Methods: The primary efficacy analysis compared BNC210 and placebo using the contrast (difference in least squares [LS] means) between treatment groups through to Week 12. Significance tests were based on the LS means using a 2-sided significance level (2-sided 95% CIs). The primary efficacy endpoint was analyzed in the mITT population using a restricted maximum likelihood (REML)-based Mixed Model for Repeated Measures (MMRM) model with multiple imputation (MI) methods to impute missing CAPS-5 scores. Supportive analyses were performed using no MI on the mITT and PP populations. The MMRM model included fixed effects for treatment, visit, interaction between treatment and visit, center, and covariate for baseline score, using an unstructured covariance structure. Table 4. Subject Disposition Disposition BNC210900 Placebo Overall Attorney Docket No.: 1011268.0011 Safety Population* 105 104 209 Modified Intent to Treat (mITT) 89 93 182 Population** Completed Through to End of 57 66 123 Treatment Discontinued Study Early 48 38 * Safety population includes all participants who receive any amount of the study intervention. ** mITT population includes all randomized participants who receive any amount of study drug and have at least one post-baseline primary efficacy assessment (CAPS-5). Table 5. Subject Demographics Demographics- Randomized BNC210900 Placebo Overall Population mg n / mITT Population) Category BNC210900 mg Placebo Overall Attorney Docket No.: 1011268.0011 PCL-5 Total Score – Mean (min, 49.3 (18, 80) 49.8 (23, 74) 49.5 (18, 80) max) SAF pop mITT pop 49.8 (18, 80) 49.9 (23, 74) 49.9 (18, CGI-S Total Score – Mean (min, 4.7 (4, 6) 4.7 (4, 6) 4.7 (4, 6) max) SAF pop 4.7 (4, 6) 6) 4.7 (4, 6) PGI-S Total Score – Mean (min, 4.7 4.5 6) 4.6 (2, 6) max) SAF pop mITT pop 4.7 (3, 6) 4.6 (2, 6) 4.6 (2, 6) MADRS Total Score – Mean 21.9 (6, 37) 22.4 (3,41) 22.1 (3, (min, max) SAF pop mITT pop 21.9 (6, 37) 22.3 (3, 41) 22.1 (3, HAM-A Total Score – Mean 18.5 (5, 37) 19.5 (5, 41) 19.0 (5, (min, max) SAF pop mITT pop 18.7 (5, 37) 18.9 (5, 36) 18.8 (5, SDS Total Score – Mean (min, 19.5 (8, 30) 19.5 (4, 30) 19.5 (4, max) SAF pop mITT pop 19.5 (9, 30) 19.7 (4, 30) 19.6 (4, (SAF Population / mITT Population) SAF Population mITT Population Attorney Docket No.: 1011268.0011 Exposure to toxic substance 0 0 0 0 0 0 Physical assault 23 19 42 20 15 35 Example 2: Phase 2b Clinical Trial of BNC210 for Treatment of PTSD Yielded Positive Topline Data A pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed upon previously obtained lower-dose (e.g., 600 mg b.i.d., 300 mg b.i.d., or 150 mg b.i.d. liquid suspensions) BNC210 clinical data, to evaluate the exposure-response relationship for CAPS-5 Total Severity Score as a continuous direct effect. The PK model developed for such BNC210 liquid suspensions with time-varying bioavailability (FreI) indicated that higher doses were associated with a decreasing FreI over time such that after ~3 months of treatment at 600 mg b.i.d., the achieved exposure was only 60% higher than at 150 mg b.i.d. Modelled exposure (AUC) values in the PTSD patients were also observed to be only ~60% of those achieved with BNC210 in a previous healthy volunteer Multiple Ascending Dose study using the same doses and formulation. An inhibitory Emax model, which included estimates of interindividual variability, produced the best PD model fit and established an exposure-response relationship for CAPS-5 Total Severity scores (p- value<0.01), where higher AUC values were related to a larger effect. The model showed that the Attorney Docket No.: 1011268.0011 AUC90 (90% of the maximal blood concentration) was achieved at ~25 mg.hr / L BNC210 plasma concentration with a predicted change from placebo of ~7.5 points on the CAPS-5 scale. Exposure- response modelling therefore indicated the potential for BNC210 to have benefit in PTSD provided that adequate blood levels of BNC210 could be achieved (~25 mg.hr / L). Pharmacometric modelling showed that exposure from the BNC210 liquid suspension formulation study was insufficient to achieve efficacy in the PTSD study [600 mg b.i.d, mean AUC at steady state was 14.3 mg.hr / L (SD 5.4)], and it was considered that the reduced drug exposure observed in the lower dose BNC210 PTSD study might be attributable in part to the liquid suspension of BNC210 being highly dependent on administration with food to achieve maximum absorption. A solid dose (tablet) formulation of BNC210 at 900 mg was therefore identified as a preferred dose to employ for PTSD treatment in a Phase 2b clinical trial, as such dosage was predicted to overcome the apparent under-exposure to BNC210 observed at such lower doses (FIG.1). Indeed, such 900 mg b.i.d. solid dose (tablet) formulations of BNC210 were observed to overcome the food effect and exhibited dose linear exposure. Performance of the double-blind, placebo-controlled Phase 2b clinical trial described herein with the solid dose (tablet) formulation of BNC210 at 900 mg b.i.d. achieved exposures in subjects (from 24 to 57 mg.h / L BNC210 plasma concentrations, predominantly BNC210 plasma concentrations in the range of about 42 to 57 mg.h / L) that were generally much higher than the target steady state concentration value of 25 mg.h / L (FIG.1). This double-blind, placebo-controlled Phase 2b clinical trial resulted in positive topline data, with BNC210 administration to subjects with PTSD having demonstrated broad benefits in such PTSD patients. BNC210 treatment specifically led to a broad and clinically meaningful reduction in total PTSD symptom severity over 12 weeks (FIG.2). A statistically significant change in Clinician- Administered PTSD Scale for DSM-5 (CAPS-5) score was observed at Week 4 (p=0.015), at Week 8 (p=0.014), and at Week 12 (p=0.048). In a post-hoc analysis where CAPS-5 values were averaged over the duration of the treatment (Weeks 4, 8 and 12), a statistically significant improvement was also observed (p=0.014). Treatment with BNC210 also showed statistically significant improvement both in clinician-administered and patient self-reporting in two of the secondary endpoints of the trial. Specifically, BNC210 led to significant improvements at Week 12 in depressive symptoms (p=0.040; FIG. 3A) and sleep (p=0.041; FIG. 3B) as measured by Montgomery-Åsberg Attorney Docket No.: 1011268.0011 Depression Rating Scale (MADRS) and Insomnia Severity Index (ISI), respectively. Intrusive thoughts (FIG.4A) and negative alterations in cognition and mood (FIG.4B) were also reduced in subjects treated with BNC210. BNC210 showed encouraging signals and trends across visits in the other secondary endpoints including the clinician and patient global impression - symptom severity (CGI-S (FIG. 5A), PGI-S (FIG.5B)) and the Sheehan Disability Scale (SDS). High levels of BNC210 therapeutic efficacy were observed in subjects that entered the clinical trial with severe PTSD (based upon a baseline CAPS-5 severity score equal to or greater than 40 points; FIG.6A), as well as in PTSD subjects for whom less than ten years had elapsed since an index trauma event (ITE; FIG. 6B); however, these results were not elevated at a statistically significant level as compared to placebo. The Phase 2b trial therefore delivered an overall positive dataset in an indication with high unmet need and no new medications approved for decades. Treatment with 900 mg twice daily BNC210 also had a favorable safety and tolerability profile (see below Tables 20-22). The most common (>5% of subjects in each group) reported adverse events, included headache, nausea and fatigue, which were consistent with previous studies with BNC210. A hepatic enzyme increase was observed in 14 (13.3%) patients treated with BNC210 vs 2 (0.19%) in the placebo group; the abnormal results were not associated with hepatic injury and in most cases were resolved without drug discontinuation. Example 3: Endpoint Tables The following endpoint tables show the results of respective analyses performed upon observed Phase 2b data. Table 8. CAPS-5 Total Score – MMRM (mITT Population) Attorney Docket No.: 1011268.0011 Week 4 Mean 28.7 -13.6 31.3 -9.5 28.7 -13.6 31.3 -9.5 Table 9. CAPS-5 Symptom Cluster Scores – MMRM Observed Data (mITT Population) Category CAPS-5 Criterion BNC210900 mg Attorney Docket No.: 1011268.0011 C - Avoidance -0.17 (0.5612) D - Negative Alterations in Cognitions -2.05 & Mood E - Arousal & Reactivity -0.79 Week 8 LS Mean Difference from B - Intrusion -1.35 Placebo (p-value) C - Avoidance -0.65 D - Negative Alterations in Cognitions -1.79 & Mood E - Arousal & Reactivity -0.83 Week 12 LS Mean Difference from B - Intrusion -1.33 (0.0467) Placebo (p-value) C - Avoidance -0.49 (0.1673) p p - Table 10. CAPS-5 Total Score by Gender – MMRM Observed Data (mITT Population) Males Females Category BNC210900 mg Placebo BNC210900 mg Placebo Attorney Docket No.: 1011268.0011 P-value for Difference from Placebo 0.2627 0.0086 0 2 Table 11. CAPS-5 Total Score by Severity – MMRM Observed Data (mITT Population) Baseline CAPS-5 < 40 Baseline CAPS-5 ≥40 Category BNC210900 mg Placebo BNC210900 mg Placebo 4 Attorney Docket No.: 1011268.0011 LS Mean Difference from Placebo -5.82 -4.13 P-value for Difference from Placebo 0.0274 0.2082 6 64 a e . oa coe y e ce au a e – se e aa (mITT Population) Index Trauma Event ≤10 years Index Trauma Event >10 years

[0003] Attorney Docket No.: 1011268.0011 LS Mean -18.25 -15.44 -25.32 -20.21 LS Mean Difference from Placebo -2.81 -5.11 . Population) Category BNC210900 mg (N=89) Placebo (N=93) W k 4 Results obtained for key secondary endpoints (CGI-S - Clinical Global Impression – Severity scale; SDS - Sheehan Disability Scale) are also tabulated below. Attorney Docket No.: 1011268.0011 Table 14. CGI-S Score – MMRM (mITT Population) MMRM with MI MMRM on Observed Data Category BNC210900 mg Placebo BNC210900 mg Placebo Table 15. SDS Score – MMRM (mITT Population) MMRM with MI MMRM on Observed Data B Attorney Docket No.: 1011268.0011 Mean 19.5 19.7 19.5 19.7 5 9 3 Table 16. HAM-A, MADRS, ISI Score – MMRM Observed Data (mITT Population) HAM-A MADRS ISI 5 Attorney Docket No.: 1011268.0011 LS Mean -0.99 -1.46 -2.03 Difference from Placebo 0 6 PCL-5 PGI-S

[0004] Attorney Docket No.: 1011268.0011 LS Mean Difference from Placebo -0.23 P-value for Difference from Placebo 0.1067 5 8 a e . -, - – serve aa (m opua on) CGI-I PGI-I Table 19. Preliminary Efficacy of BNC210 in the ATTUNE Phase 2b Study (pre-specified and post-hoc) No. subjects (BNC210 / Placebo); LS Mean difference from placebo (p-value) Attorney Docket No.: 1011268.0011 Week 4 Week 8 Week 12 Endpoint Summary of Main Efficacy Outcomes Observed: Clear evidence of effect shown by improvement compared to placebo from baseline through to Week 12 on all efficacy endpoints. Both treatment effect and effect sizes were higher than those observed previously for approved SSRIs. The primary endpoint of change in CAPS-5 total symptoms severity score from baseline to Week 12 was calculated with two methodologies: (a) Not including early termination (ET) CAPS-5 values narrowly missing statistical significance in the pre-specified primary endpoint due to drop out of study participants during this period leading to loss of statistical power (p=0.057). (b) LOCF - Including CAPS-5 values from 4 early termination visits that were considered as – only occurred between week 8 and week 12, where statistical significance was observed (p=0.037). When CAPS-5 values were averaged over the duration of the treatment (Weeks 4, 8 and 12), a statistically significant improvement was also observed (p=0.014). Attorney Docket No.: 1011268.0011 CAPS-5 symptom clusters: Intrusion and negative mood / cognitions were contributing to statistically significant results. Statistically significant findings were also seen in depressive symptoms and sleep. Trends and signals in multiple additional secondary endpoints were also not included in the topline. Safety and tolerability were also assessed, and results are tabulated below. Table 20. Adverse Event Summary Number of Subjects BNC210900 mg Placebo Overall p) Number of Subjects BNC210900 mg Placebo Overall Clinical chemistry, hematology, urinalysis - no clinically significant results deemed related to study drug, apart from the elevated liver enzyme(s). C-SSRS – 1 AE of suicidal ideation deemed possibly related to drug (for a subject on BNC210) Attorney Docket No.: 1011268.0011 Table 22. Summary of Subjects Reporting Elevated Liver Enzyme(s) Subject Peak LFT levels Normal Visit AE Relationship Subject Hepatologist ID Range Severity to Study Status Assessment ly ly ly ss Attorney Docket No.: 1011268.0011 Approx.4 [ALT 0-33 U / L] Early Probably 025-0006 ALT = 212 ; AST = 91 weeks of Mild Unrelated [AST 14-34 U / L] Terminated Related ly ly ss Discontinuations anticipated in PTSD. Abnormal liver enzyme test results were reported by 16 participants out of the 209 participants in the Safety Population – 14 of these received 900 mg BNC210 BID; 2 were on placebo. An expert hepatologist reviewed the findings during the study (blinded) and noted that although many of the abnormal liver enzyme results were probably attributable to study medication, these findings were not associated with hepatic functional impairment (i.e., no liver injury) and the subjects remained largely asymptomatic. In some participants, the elevated test results returned to baseline despite continued dosing, which is consistent with adaptation. 9 of the 14 participants on BNC210 continued the study and completed 12 weeks of treatment. The 2 on placebo were both discontinued. For those who withdrew from treatment, the elevated results resolved on cessation of medication. Attorney Docket No.: 1011268.0011 Overall, BNC210 exhibited a favorable profile, considering the high unmet need in PTSD for effective treatments. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

Attorney Docket No.: 1011268.0011 We claim:

1. A method of treating post-traumatic stress disorder (PTSD) in a subject, the method comprising administering the compound of formula (I): or a salt, or prodrug of PTSD in the subjectby at least five points on score.

2. The method of claim 1, wherein the compound is administered in an amount effective to treat insomnia in the subject, optionally wherein insomnia severity is reduced in the subject by at least two points on the insomnia severity scale (ISI score).

3. The method of claim 1 or claim 2, wherein the compound is administered in an amount effective to treat depression in the subject, optionally wherein the depression rating of the subject is reduced by at least two points on a Montgomery-Asberg Depression Rating Scale (MADRS).

4. The method of any one of the preceding claims, wherein the compound is administered in an amount effective to reduce intrusive thoughts in the subject, optionally wherein intrusive thoughts are reduced in the subject by at least two points on a CAPS-5 Criterion B Intrusion Severity Subscore scale.

5. The method of any one of the preceding claims, wherein the compound is administered in an amount effective to reduce negative alterations in cognitions and mood in the subject, optionally wherein negative alterations in cognitions and mood in the subject are reduced by at least two points on a CAPS-5 Criterion D Severity Subscore scale.

6. The method of any one of the preceding claims, wherein the compound is administered in an amount effective to reduce an observed score for the subject on a Clinician Global ImpressionAttorney Docket No.: 1011268.0011 Severity Scale (CGI-S score), optionally wherein the observed score for the subject for CGI-S is reduced by at least 0.

5.

7. The method of any one of the preceding claims, wherein the compound is administered in an amount effective to reduce an observed score for the subject on a Patient Global Impression Severity Scale (PGI-S score), optionally wherein the observed score for the subject for PGI-S is reduced by at least 0.

4.

8. The method of any one of the preceding claims, wherein the subject suffering from PTSD has a CAPS-5 Severity Score of at least 35, for example, at least 40, at least 41, at least 42, at least 43, at least 45, or more.

9. The method of any one of the preceding claims, wherein the subject suffering from PTSD has experienced an Index Trauma Event less than ten years prior to said administration.

10. The method of any one of the preceding claims, wherein the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within four weeks of treatment.

11. The method of any one of the preceding claims, wherein the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within eight weeks of treatment.

12. The method of any one of the preceding claims, wherein the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within twelve weeks of treatment.

13. The method of any one of the preceding claims, wherein the compound is administered twice a day.

14. The method of any one of the preceding claims, wherein the compound is administered at a dosage that achieves a compound plasma concentration (AUC90) of at least 25 mg.hr / L in the subject.

15. The method of any one of the preceding claims, wherein the compound is administered at a dosage that achieves a compound plasma concentration (AUC90) of at least 40 mg.hr / L in the subject.Attorney Docket No.: 1011268.0011 16. The method of any one of the preceding claims, wherein the compound is administered twice a day at 450 mg per dose.

17. The method of any one of the preceding claims, wherein the compound is administered twice a day at 900 mg per dose.

18. The method of any one of the preceding claims, wherein the compound is administered as a pharmaceutical composition comprising between about 800mg-1000mg of the compound of formula (I), optionally about 900 mg of the compound of formula (I), optionally 900 mg of the compound of formula (I), and a pharmaceutically acceptable carrier, optionally in tablet form, optionally wherein each tablet contains about 225 mg of the compound of formula (I).

19. The method of any one of claims 1-15, wherein the compound is administered twice a day at 600 mg per dose.

20. The method of any one of claims 1-15 and 19, wherein the compound is administered as a pharmaceutical composition comprising between about 450 mg-700 mg of the compound of formula (I), optionally about 600 mg of the compound of formula (I), optionally 600 mg of the compound of formula (I), and a pharmaceutically acceptable carrier, optionally in tablet form, optionally wherein each tablet contains about 200 mg of the compound of formula (I).

21. The method of any one of the preceding claims, wherein liver function tests (LFTs) of the subject are assessed, optionally wherein the assessed LFTs are selected from the group consisting of alkaline phosphatase activity, aspartate aminotransferase [AST] activity, alanine aminotransferase [ALT] activity, gamma-glutamyl transferase activity, and total bilirubin.

22. The method of any one of the preceding claims, wherein liver function tests (LFTs) of the subject administered the compound of formula (I) are approximately equivalent to LFTs of a control subject not administered the compound of formula (I), or as compared to an appropriate control value.

23. The method of claim 20, wherein said administered pharmaceutical composition comprising between about 450 mg-700 mg of the compound of formula (I) is as effective a treatment for PTSD in the subject as a pharmaceutical composition comprising between about 800Attorney Docket No.: 1011268.0011 mg-1000 mg of the compound of formula (I), optionally wherein LFTs in the subject administered about 450 mg-700 mg of the compound of formula (I) are approximately equivalent to LFTs of a control subject not administered the compound of formula (I), optionally wherein LFTs in the subject administered about 450 mg-700 mg of the compound of formula (I) show better liver function in the subject than in an appropriate comparison subject administered about 800 mg-1000 mg of the compound of formula (I).

24. The method of any one of the preceding claims, wherein the severity of PTSD in the subject is reduced as compared to a starting value, as compared to an absolute value, and / or as compared to a placebo-treated control subject.

25. The method of any one of the preceding claims, wherein the subject is female.

26. A method of treating depression in a subject in need thereof, the method comprising administering the compound of formula (I): or a salt, or prodrugin the subject by at least two points on the Montgomery-Asberg Depression Rating Scale (MADRS).

27. A method of treating insomnia in a subject in need thereof, the method comprising administering the compound of formula (I):Attorney Docket No.: 1011268.0011 or a salt, or prodrug thereof, in an amount effective to reduce insomnia in the subject by at least two points on the insomnia severity scale (ISI score).

28. The method of claim 26 or claim 27, wherein the subject suffers from PTSD.

29. A method of treating severe PTSD in a subject, the method comprising administering the compound of formula (I): or a salt, or prodrug of PTSD in the subjectby at least five points on symptom score.

30. The method of claim 29, wherein the subject is a female.

31. A method of treating post-traumatic stress disorder (PTSD) in a subject, the method comprising administering the compound of formula (I): or a salt, or prodrugof PTSD in the subject by at least five points on the CAPS-5 total symptom severity score, wherein the effective amount of the compound of formula (I) does not significantly modulate liver function tests (LFTs) administered to the subject, as compared to an appropriate control.

32. The method of claim 31, wherein the compound is administered at a dosage that achieves a compound plasma concentration of 25 mg.hr / L or more in the subject.Attorney Docket No.: 1011268.0011 33. The method of claim 31 or claim 32, wherein the effective amount of the compound of formula (I) is approximately 600 mg BID.

34. The method of any one of claims 31-33, wherein liver damage in the subject is reduced or eliminated, as compared to an appropriate comparison test subject or comparison population of test subjects administered the compound of formula (I) at approximately 900 mg BID.

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