[go: up one dir, main page]

WO2025068765A1 - Méthode de traitement d'un trouble de stress post-traumatique - Google Patents

Méthode de traitement d'un trouble de stress post-traumatique Download PDF

Info

Publication number
WO2025068765A1
WO2025068765A1 PCT/IB2024/000517 IB2024000517W WO2025068765A1 WO 2025068765 A1 WO2025068765 A1 WO 2025068765A1 IB 2024000517 W IB2024000517 W IB 2024000517W WO 2025068765 A1 WO2025068765 A1 WO 2025068765A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
compound
formula
administered
ptsd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/000517
Other languages
English (en)
Inventor
Spyros PAPAPETROPOULOS
Elizabeth DOOLIN
Dharam Paul
Errol De Souza
Susan O'connor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bionomics Ltd
Original Assignee
Bionomics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bionomics Ltd filed Critical Bionomics Ltd
Publication of WO2025068765A1 publication Critical patent/WO2025068765A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • BNC210 has been described to function as an inhibitor alpha7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR). BNC210 compositions of the disclosure were identified as particularly effective for treating severe PTSD in female subjects.
  • 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.
  • the compound is administered in an amount effective to treat insomnia in the subject.
  • insomnia severity is reduced in the subject by at least two points on the insomnia severity scale (ISI score).
  • the compound is administered in an amount effective to treat depression in the subject.
  • the depression rating of the subject is reduced by at least two points on a Montgomery-Asberg Depression Rating Scale.
  • the compound is administered in an amount effective to reduce intrusive thoughts in the subject.
  • intrusive thoughts are reduced in the subject by at least two points on a CAPS-5 Criterion B Intrusion Severity Subscore scale.
  • the compound is administered in an amount effective to reduce negative alterations in cognitions and mood in the subject.
  • 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.
  • 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).
  • CGI-S score Clinician Global Impression Severity Scale
  • the observed score for the subject for CGI-S is reduced by at least 0.5.
  • 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).
  • PGI-S score Patient Global Impression Severity Scale
  • the observed score for the subject for PGI-S is reduced by at least 0.4.
  • 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.
  • the subject suffering from PTSD has experienced an Index Trauma Event less than ten years prior to the administration.
  • the CAPS-5 Total Severity Score of the subject is reduced by at least eight points within four weeks of treatment.
  • 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.
  • the compound is administered twice a day.
  • the compound is administered orally.
  • 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.
  • the compound is administered twice a day at 900 mg per dose.
  • the compound of formula (I) is administered as a pharmaceutical composition that includes between about 800mg and about 1000mg of the compound.
  • the pharmaceutical composition includes about 900 mg of the compound.
  • the composition includes a pharmaceutically acceptable carrier.
  • the Attorney Docket No.: 1011268.0011 compound is administered as a pharmaceutical composition in tablet form.
  • each tablet contains about 225 mg of the compound.
  • the compound of formula (I) is administered twice a day at 600 mg per dose.
  • the compound of formula (I) is administered twice a day at 450 mg per dose.
  • the compound of formula (I) is administered twice a day at a dose of at least 450 mg per dose.
  • 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.
  • the compound is administered as a pharmaceutical composition that includes about 600 mg of the compound and a pharmaceutically acceptable carrier.
  • the compound is administered as a pharmaceutical composition that includes 600 mg of the compound and a pharmaceutically acceptable carrier.
  • the compound is in tablet form.
  • each tablet administered to the subject contains about 200 mg of the compound.
  • liver function tests (LFTs) of the subject are assessed.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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 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.
  • 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).
  • 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.
  • the compound is administered at a dosage that achieves a compound plasma concentration of 25 mg.hr/L or more in the subject.
  • the effective amount of the compound of formula (I) is between about 450 mg and about 900 mg.
  • 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.
  • 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.
  • compositions with BNC210 at least one crystallisation inhibitor polymer and one or more excipients.
  • administer 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.
  • 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.
  • HPMC E15 LV a premium Attorney Docket No.: 1011268.0011 polymer of low viscosity grade of about 15cP (sold as METHCEL TM E15 Industrial LV from Dupont).
  • HPMC HPMC E15 LV
  • HPMC E15 LV a premium Attorney Docket No.: 1011268.0011 polymer of low viscosity grade of about 15cP (sold as METHCEL TM E15 Industrial LV from Dupont).
  • HPPMCAS 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.
  • HPMCAS 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.
  • Crosscarmellose 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
  • 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
  • PVP-VA 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.
  • Polectron 845 and Luviskol VA 281, Kolima 10, 35, Ganhon S 860, or Ganex E313, just to name a few are 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.
  • CAP also referred to as Cellacetate, Cellacefate, Celluloseacetate, 1,2- benzenedicarboxylate
  • CAP 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.
  • Soluplus TM is 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.
  • 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).
  • 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.
  • “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.
  • 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.
  • 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.
  • compositions or methods 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.
  • known or disclosed equivalents of any named essential element or step may be substituted for that element or step.
  • 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.
  • 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
  • oral administration for example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc, which may be
  • 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).
  • a human subject is an adult, adolescent, or pediatric subject.
  • a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein.
  • 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).
  • 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.
  • a subject is an individual to whom diagnosis and/or therapy is and/or has been administered.
  • 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.
  • the subject is a female human.
  • the subject is a male human.
  • the subject is an adult subject.
  • the subject is a pediatric subject.
  • treating refers 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.
  • 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).
  • 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.
  • phrases "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.
  • pharmaceutically-acceptable carrier 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.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • 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.
  • Pharmaceutically acceptable carriers include carriers for administration by injection.
  • 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- ⁇ sberg Depression Rating Scale (MADRS).
  • FIG. 3B shows improvement in sleep as measured by Insomnia Severity Index (ISI).
  • ISI Insomnia Severity Index
  • 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.
  • FIG. 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.
  • FIG. 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.
  • 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.
  • the tablet comprises at least one pharmaceutically acceptable polymer which is an at least one crystallisation inhibitor polymer.
  • 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%).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the formulation when presented as a tablet comprises about 900 mg of active ingredient.
  • the formulation when presented as a tablet comprises between about 800 mg to about 1000 mg of active ingredient.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • the crystallisation inhibitor polymer is HPMCAS-H.
  • the crystallisation inhibitor polymer is HPMCAS-M.
  • the crystallisation inhibitor polymer is HPMC E15 LV.
  • the crystallisation inhibitor polymer is HPMCAS-L.
  • the crystallisation inhibitor polymer is PVP-VA.
  • the solid dispersion formulations disclosed herein are produced by spray drying.
  • 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.
  • the spray drying solvent comprises dichloromethane.
  • the spray drying solvent comprises dichloromethane and methanol.
  • 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%.
  • the spray dried dispersion yield is from about 50 – 100%.
  • the solid dispersion formulations disclosed herein are produced by hot melt extrusion (HME).
  • 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 ⁇ - cellulose, obtained as a pulp from plant materials with mineral acids.
  • 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.
  • the tablet or pre-tabletting formulation comprises about 35% to about 55% (%wt/wt) of microcrystalline cellulose.
  • 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.
  • SSF sodium stearyl fumurate
  • 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.
  • 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.
  • 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.
  • PVA poly(vinyl alcohol)
  • the formulations also comprise a surfactant selected from SLS (sodium lauryl sulfate) or sorbates.
  • SLS sodium lauryl sulfate
  • 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).
  • 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.
  • Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless this exposure is work related.
  • 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.
  • 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).
  • 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:
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • BNC210 was dosed to subjects twice a day (BID) as a 900mg oral capsule.
  • BID twice a day
  • 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
  • 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).
  • 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).
  • CAPS-5 values were averaged over the duration of the treatment (Weeks 4, 8 and 12)
  • Intrusive thoughts FOG.4A
  • negative alterations in cognition and mood FOG.4B
  • 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).
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des méthodes thérapeutiques impliquant l'administration de BNC210 à un sujet en une quantité efficace pour réduire ou éliminer un trouble de stress post-traumatique (TSPT), ou un symptôme/métrique associé, chez un sujet traité.
PCT/IB2024/000517 2023-09-28 2024-09-25 Méthode de traitement d'un trouble de stress post-traumatique Pending WO2025068765A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363586149P 2023-09-28 2023-09-28
US63/586,149 2023-09-28

Publications (1)

Publication Number Publication Date
WO2025068765A1 true WO2025068765A1 (fr) 2025-04-03

Family

ID=95202410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/000517 Pending WO2025068765A1 (fr) 2023-09-28 2024-09-25 Méthode de traitement d'un trouble de stress post-traumatique

Country Status (1)

Country Link
WO (1) WO2025068765A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021056048A1 (fr) * 2019-09-23 2021-04-01 Bionomics Limited Formulations thérapeutiques et leurs utilisations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021056048A1 (fr) * 2019-09-23 2021-04-01 Bionomics Limited Formulations thérapeutiques et leurs utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIONOMICS LIMITED: "A Phase 2b Study of BNC210 Tablet Formulation in Adults With PostTraumatic Stress Disorder (PTSD) (ATTUNE) - NCT04951076", CLINICAL TRIALS, CLINICALTRIALS.GOV, 17 August 2023 (2023-08-17), XP093302016, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT04951076?intr=BNC210&rank=3> *
BIONOMICS LIMITED: "Phase II Study of BNC210 in PTSD (RESTORE) - NCT02933606", CLINICAL TRIALS, CLINICALTRIALS.GOV, 23 February 2023 (2023-02-23), XP093302018, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT02933606?intr=BNC210&rank=5> *

Similar Documents

Publication Publication Date Title
US11607389B2 (en) Delayed release deferiprone tablets and methods of using the same
AU2015336463B2 (en) Compositions and methods for treating insomnia
EP4142764A1 (fr) Méthodes d&#39;utilisation de modulateurs de canaux calciques de type t
US20100256088A1 (en) Low dose therapy for treating viral infections
WO2025068765A1 (fr) Méthode de traitement d&#39;un trouble de stress post-traumatique
CN101677960A (zh) 美金刚胺的药物组合物
AU2023435173A1 (en) Method of treating social anxiety disorder with bnc210
KR101151342B1 (ko) 에페리손 함유 필름코팅정제, 및 이의 제조방법
EA042135B1 (ru) Таблетка деферипрона с отсроченным высвобождением и способ ее изготовления
HK40030435B (en) Delayed release deferiprone tablets and methods of using the same
HK40030435A (en) Delayed release deferiprone tablets and methods of using the same
HK40017808A (en) Methods of treating seizure disorders
KR20130106023A (ko) 에페리손 함유 필름코팅정제, 및 이의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24871125

Country of ref document: EP

Kind code of ref document: A1