WO2024030399A2 - Utilisation d'un modulateur allostérique positif de gaba-a pour la réduction de l'hypersensibilité tactile - Google Patents

Utilisation d'un modulateur allostérique positif de gaba-a pour la réduction de l'hypersensibilité tactile Download PDF

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WO2024030399A2
WO2024030399A2 PCT/US2023/029165 US2023029165W WO2024030399A2 WO 2024030399 A2 WO2024030399 A2 WO 2024030399A2 US 2023029165 W US2023029165 W US 2023029165W WO 2024030399 A2 WO2024030399 A2 WO 2024030399A2
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compound
subject
syndrome
tactile
pain
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PCT/US2023/029165
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English (en)
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WO2024030399A3 (fr
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James C. Barrow
Anne Christine BRIDEAU
Ingrid Buchler
David GINTY
Yifang Huang
Lauren OREFICE
Pankaj Jay Pasricha
Michael Poslusney
Original Assignee
Lab1636, Llc
Lieber Institute, Inc.
The Johns Hopkins University
Deerfield Discovery And Development, Llc
B2B Therapeutics Corp.
Galium Biosciences, Llc
Bluefield Innovations, Llc
President And Fellows Of Harvard College
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Publication of WO2024030399A2 publication Critical patent/WO2024030399A2/fr
Publication of WO2024030399A3 publication Critical patent/WO2024030399A3/fr

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    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam

Definitions

  • ASD Autism spectrum disorder
  • Compound 1 8-chloro-6-(2-fluorophenyl)-4H-benzo[f]pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (Compound 1) is a recently discovered GABA-A PAM “Positive Allosteric Modulator” with low CNS exposure after oral or intravenous dosing.
  • compositions that comprise and/or deliver Compound 1 in the treatment of subjects (e.g., human subjects) suffering from or susceptible to a tactile dysfunction condition and/or from a disease, disorder or condition that may be associated with tactile dysfunction.
  • One aspect of the present disclosure features a method of reducing tactile dysfunction in a subject (e.g., a human) by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e.g., in an amount and for a duration - e.g., by administration of one or more doses) sufficient to reduce the tactile dysfunction.
  • a subject e.g., a human
  • a regimen e.g., in an amount and for a duration - e.g., by administration of one or more doses
  • such human subject has been diagnosed with Autism Spectrum Disorder (ASD), Rett syndrome (RTT), Phelan McDermid syndrome (PMS), or Fragile X syndrome.
  • the present disclosure features a method of reducing anxiety or social impairment in a subject (e.g., a human) by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e.g., in an amount and for a duration - e.g., by administration of one or more doses) sufficient to reduce the anxiety or social impairment.
  • a subject e.g., a human
  • a regimen e.g., in an amount and for a duration - e.g., by administration of one or more doses
  • such human subject has been diagnosed with ASD, RTT, PMS, or Fragile X syndrome
  • the present disclosure features a method of reducing touch over-reactivity and/or pain and/or mechanical allodynia in a subject (e.g., a human) by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e.g., in an amount and for a duration - e.g., by administration of one or more doses) sufficient to reduce the touch over-reactivity and/or pain and/or mechanical allodynia.
  • a regimen e.g., in an amount and for a duration - e.g., by administration of one or more doses
  • such human subject has been diagnosed with ASD, RTT, PMS, or Fragile X syndrome.
  • the present disclosure features a method of reducing tactile dysfunction in a subject (e.g., a human) diagnosed with Autism Spectrum Disorder (ASD), Rett syndrome (RTT), Phelan McDermid syndrome (PMS), or Fragile X syndrome by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e.g., in an amount and for a duration - e g., by administration of one or more doses) sufficient to reduce the tactile dysfunction.
  • a subject e.g., a human diagnosed with Autism Spectrum Disorder (ASD), Rett syndrome (RTT), Phelan McDermid syndrome (PMS), or Fragile X syndrome
  • the present disclosure features a method of reducing anxiety or social impairment in a subject (e.g., a human) diagnosed with ASD, RTT, PMS, or Fragile X syndrome by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e.g., in an amount and for a duration - e.g., by administration of one or more doses) sufficient to reduce the anxiety or social impairment.
  • a subject e.g., a human diagnosed with ASD, RTT, PMS, or Fragile X syndrome
  • a regimen e.g., in an amount and for a duration - e.g., by administration of one or more doses
  • the present disclosure features a method of reducing touch over-reactivity and/or pain and/or mechanical allodynia in a subject (e.g., a human) diagnosed with ASD, RTT, PMS, or Fragile X syndrome by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, for example according to a regimen (e g., in an amount and for a duration - e.g., by administration of one or more doses) sufficient to reduce the touch over-reactivity and/or pain and/or mechanical allodynia.
  • the touch overreactivity and/or pain is associated with a disease states selected from Sensory Processing Disorder (SPD) and fibromyalgia.
  • the mechanical allodynia is associated with nerve injury, shingles, diabetic neuropathy, chemotherapy-induced neuropathy, or a neuropathic pain state.
  • ASD Autism Spectrum Disorder
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders 5th edition
  • DSM-5 redefined the autism spectrum to encompass the prior (DSM-IV- TR) diagnosis of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified, childhood disintegrative disorder, and Rett syndrome.
  • Autism spectrum disorders are typically characterized by social deficits and communication difficulties, stereotyped or repetitive behaviors and interests, and in some cases, cognitive delays.
  • an ASD is defined in the DSM-5 as exhibiting (i) deficits in social communication and interaction not caused by general developmental delays (must exhibit three criteria including deficits in social- emotional reciprocity, deficits in nonverbal communication, and deficits in creating and maintaining relationships appropriate to developmental level), (ii) demonstration of restricted and repetitive patterns of behavior, interest or activities (must exhibit two of the following four criteria: repetitive speech, repetitive motor movements or repetitive use of objects, adherence to routines, ritualized patterns of verbal or nonverbal, or strong resistance to change, fixated interests that are abnormally intense of focus, and over or under reactivity to sensory input or abnormal interest in sensory aspects of environment), (iii) symptoms must be present in early childhood, and (iv) symptoms collectively limit and hinder everyday functioning.
  • term “ASD” may be used herein to refer to or encompass Dravet’s syndrome and/or autistic-like behavior in non-human animals.
  • Rett syndrome refers to an X-linked disorder that affects approximately one in ten-thousand girls. Patients with Rett syndrome typically go through four stages: Stage I) Following a period of apparently normal development from birth, the child begins to display social and communication deficits, similar to those seen in other autism spectrum disorders, between six and eighteen months of age. The child shows delays in their developmental milestones, particularly for motor ability, such as sitting and crawling. Stage II) Beginning between one and four years of age, the child goes through a period of regression in which they lose speech and motor abilities, developing stereotypical midline hand movements and gait impairments. Breathing irregularities, including apnea and hyperventilation also develop during this stage.
  • Stage III Between age two and ten, the period of regression ends and symptoms plateau. Social and communication skills may show small improvements during this plateau period, which may last for most of the patients' lives.
  • Stage IV Motor ability and muscle deterioration continues. Many girls develop severe scoliosis and lose the ability to walk.
  • PMS Phelan McDermid syndrome
  • the terms “Phelan McDermid syndrome” or “PMS” refer to rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22ql3 region or a disease-causing mutation of the Shank3 gene.
  • PMS is generally thought to be characterized by neonatal hypotonia (low muscle tone in the newborn), normal growth, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. People who have PMS often show symptoms in very early childhood, sometimes at birth and within the first six months of life.
  • Fragile X syndrome refers to an X chromosome-linked condition that is characterized by a visible constriction near the end of the X chromosome, at locus q27.3 that causes intellectual disability, behavioral and learning challenges and various physical characteristics.
  • Fragile X syndrome is the most common inherited form of mental retardation and developmental disability. Males with Fragile X syndrome usually have mental retardation and often exhibit characteristic physical features and behavior. Fragile X syndrome is characterized by behavior similar to autism and attention deficit disorder, obsessive-compulsive tendencies, hyperactivity, slow development of motor skills and anxiety fear disorder. When these disabilities are severe and occur simultaneously, the condition is sometimes described as autism, and may be associated with any degree of intelligence.
  • Tactile dysfunction refers to exhibiting symptoms such as withdrawing when being touched, refusing to eat certain “textured” foods and/or to wear certain types of clothing, complaining about having hair or face washed, avoiding getting hands dirty (e.g. , glue, sand, mud, finger-paint), and using finger tips rather than whole hands to manipulate objects. Tactile dysfunction may lead to a misperception of touch and/or pain (hyper- or hyposensitive) and may lead to self-imposed isolation, general irritability, distractibility, and hyperactivity.
  • pain has its art-understood meaning.
  • pain is acute pain.
  • pain is chronic pain.
  • pain may be or comprise nociceptive pain (i.e., caused by tissue damage).
  • pain can be neuropathic pain (i.e., caused by nerve damage).
  • mechanical allodynia refers to a painful sensation resulting from exposure to an ordinarily innocuous stimulus (e g., light touch) - i.e., one that does not normally provoke pain.
  • an ordinarily innocuous stimulus e g., light touch
  • mechanical allodynia can result, for example, from physical trauma, nerve injury, shingles, diabetic neuropathy, chemotherapy-induced neuropathy, a neuropathic pain state, etc.
  • anxiety refers to emotions characterized by feelings of tension, concerned thoughts and physical changes like increased blood pressure. In some cases, anxiety can be characterized by having recurring intrusive thoughts or concerns, avoiding certain situations (e.g., social situations) out of worry, and physical symptoms such as sweating, trembling, dizziness, or a rapid heartbeat.
  • social impairment refers to a distinct dissociation from and lack of involvement in relations with other people. It can occur with various mental and developmental disorders, such as autism. In some cases, social impairment may occur when an individual acts in a less positive way or performs worse when they are around others as compared to when alone. Nonverbal behaviors associated with social impairment can include deficits in eye contact, facial expression, and gestures that are used to help regulate social interaction. Often there is a failure to develop age appropriate friendships. Alternatively or additionally, in some cases, social impairment can include a lack of spontaneous seeking to share achievements or interests with other individuals. A person with social impairment may exhibit a deficit in social reciprocity with individuals, decreased awareness of others, lack of empathy, and/or lack of awareness of the needs of others.
  • blood brain barrier and “BBB” refer to a transvascular permeability barrier that tightly controls entry of substances into the brain. Capillaries that perfuse the brain are lined with special endothelial cells that lack fenestrations and are sealed by endothelial tight junctions; this tight endothelium provides a physical barrier that together with metabolic barriers forms the basis of the BBB.
  • a relevant model is a blood brain barrier penetration model.
  • an appropriate reference is a GABAA PAM compound whose performance in the relevant model is already known.
  • a relevant reference is a known, BBB-permeant compound such as for example a brain-penetrating GABAA PAM. See, for example, Groeneveld et al Drug Discov Today Technol 20:27, 2016.
  • permeability may be assessed, for example, using NeuroCArt as described by Goreneveld et al.
  • a composition or compound is considered to have “reduced permeability” (or “low permeability”) if it is determined to have reduced CNS exposure, e.g., as described herein.
  • a compound is considered to have “reduced” CNS exposure and or penetration if it is determined to have decreased (e.g., by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) performance in a relevant assay (e.g., that assesses ability to cross the blood brain barrier) relative to an appropriate control.
  • a relevant assay e.g., that assesses ability to cross the blood brain barrier
  • the term “reducing” refers to decreasing (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or about 100%) one or more side effects and/or symptoms (e.g. , tactile sensitivity, social impairment, or anxiety) of patients diagnosed with ASD, RTT, PMS, or Fragile X syndrome.
  • side effects and/or symptoms e.g. , tactile sensitivity, social impairment, or anxiety
  • treatment refers to one or more of reducing or decreasing frequency and/or intensity of one or more characteristics or side effects (e.g., one or more of tactile dysfunction, anxiety, and social impairment) of a particular disease, disorder, condition, or state, (e.g., of ASD, RTT, PMS, and/or Fragile X syndrome), to delaying onset thereof, and/or to decreasing risk of progression thereto or thereof (e.g. , by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or about 100%) a particular disease or condition.
  • characteristics or side effects e.g., one or more of tactile dysfunction, anxiety, and social impairment
  • a particular disease, disorder, condition, or state e.g., of ASD, RTT, PMS, and/or Fragile X syndrome
  • a particular disease, disorder, condition, or state e.
  • treatment may achieve such reduction relative to an appropriate reference or control (e.g., absence of treatment, presence of a reference treatment with known outcome) in a particular individual or test system, or in a population thereof.
  • treatment involves administration according to a dosing regimen that has been established (e.g., by statistically significant correlation) to achieve beneficial effect in a relevant population or system.
  • the terms “effective amount” or “therapeutically effective amount” refers to an amount sufficient to produce a desired result, for example, reducing (e.g. , by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) tactile dysfunction, social impairment, or anxiety in a subject upon administration of a composition containing a compound described herein.
  • a desired result may be assessed with respect to levels, symptoms, side effects, etc., as applicable, in a subject or population that has not received an administration, or has received a reference (e g., control) administration, or has received a prior administration, and/or may be assessed relative to a control or baseline average.
  • an “effective amount” may be included in a single dose; more commonly, however, an “effective amount” is achieved through administration of two or more doses, e.g., according to a dosing regimen (e.g., that has been established, for example by statistically significant correlation, to achieve the relevant desired result in a relevant subject or population).
  • a dosing regimen e.g., that has been established, for example by statistically significant correlation, to achieve the relevant desired result in a relevant subject or population.
  • the term “subject,” refers to an animal which may, in some embodiments, be a mammal. In many embodiments, a subject is a human. In some embodiments, a subject may display, or have been determined to be at risk of displaying, one or more symptoms or side effects (e g , one or more of tactile dysfunction, anxiety, and social impairment) of a particular disease, disorder, condition, or state, (e.g., of ASD, RTT, PMS, and/or Fragile X syndrome). In some embodiments, a subject may have been diagnosed with a particular disease, disorder, condition, or state, (e.g., of ASD, RTT, PMS, and/or Fragile X syndrome).
  • a particular disease, disorder, condition, or state e.g., of ASD, RTT, PMS, and/or Fragile X syndrome.
  • a subject may have been determined to be at risk of (e.g., via genetic assessment, observation of certain symptoms or side effects, administration of one or more standard tests or assessments, etc.) a particular disease, disorder, condition, or state, (e.g., of ASD, RTT, PMS, and/or Fragile X syndrome).
  • a subject may be or have been diagnosed, or determined to be at risk of, a relevant disease, disorder, or condition, for example, by virtue of having been subjected to one or more standard tests, or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • a subject is a human. In certain embodiments, a subject is an adult.
  • a subject is an adolescent. In some embodiments, a subject is a child. In certain embodiments, a child is less than 12 years of age. In certain embodiments, a child is less than 10 years of age. In certain embodiments, a child is less than 8 years of age. In certain embodiments, a child is less than 6 years of age. In certain embodiments, a child is less than 4 years of age. In certain embodiments, a child is less than 2 years of age. In certain embodiments, a child is 2-4 years of age. In certain embodiments, a child is 4-6 years of age. In certain embodiments, a child is 6-8 years of age. In certain embodiments, a child is 8-10 years of age.
  • a child is greater than 12 years of age.
  • a subject is elderly.
  • a human subject is considered to be elderly if aged more than about 60, 65, 70, 75, 80, or 85 years.
  • the term “pharmaceutical composition,” refers to a composition that comprises and/or delivers a compound described herein (and/or, in some embodiments, a therapeutically active metabolite thereof) formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal; often a pharmaceutical composition described herein comprises its active agent (e.g., the compound) in a particular salt form (e g., a pharmaceutically acceptable salt form).
  • a pharmaceutical composition may be formulated (e.g., may have a form and/or may include particular excipient(s) appropriate for) administration by a particular route - for example for oral administration (e.g. , a tablet, capsule, caplet, gelcap, syrup or other drinkable liquid); for topical administration (e.g., as a cream, gel, lotion, or ointment); for parenteral (e.g., intravenous) administration (e g., as a sterile solution free of particulate emboli and in a solvent system suitable for parenteral use); or otherwise as described herein and/or understood by those skilled in the art.
  • oral administration e.g. , a tablet, capsule, caplet, gelcap, syrup or other drinkable liquid
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • parenteral (e.g., intravenous) administration e.g., as a sterile solution free of particulate emb
  • a pharmaceutically acceptable excipient refers to an ingredient in a pharmaceutical composition that is understood or considered not to be pharmaceutically “active”.
  • a pharmaceutically acceptable excipient or carrier is or comprises one or more ingredients (e.g., a vehicle capable of suspending or dissolving the active agent) other than a compound described herein and having the properties of being nontoxic and non-inflammatory in a patient.
  • excipients may include one or more of, for example: anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • anti adherents for example: anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene, calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E,
  • salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • salts e.g., salt forms
  • Salts of a carboxylate may include representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • isotopes of compounds described herein may be prepared and/or utilized in accordance with the present invention.
  • “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei.
  • isotopes of hydrogen include tritium and deuterium.
  • an isotopic substitution e.g., substitution of hydrogen with deuterium
  • pharmaceutically active compounds are often utilized (e.g., administered) in a prodrug form - e.g., in a form that converts to the active form after administration to a subject.
  • pharmaceutically active compounds e.g., Compound 1
  • a pharmaceutical composition that is administered to a subject includes a prodrug form of a relevant compound (e.g., Compound 1).
  • a relevant compound e.g., Compound 1
  • a prodrug form of a compound of interest includes at least one moiety attached to the compound of interest by a bond that is relatively labile under physiological conditions.
  • a prodrug moiety is attached by an ester linkage.
  • a prodrug of Compound 1 may have one of the following structures:
  • a dosing regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
  • Compound 1 may be provided and/or utilized in salt form.
  • Figure 1 depicts effects of 4 hours pre-treatment with 3 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 2 depicts effects of 0.5 hour pre-treatment with 10 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 3 depicts effects of 0.5 hour pre-treatment with 10 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 4 depicts effects of 4 hours pre-treatment with 3 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 5 depicts effects of 4 hours pre-treatment with 10 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 6 depicts effects of 0.5 hour pre-treatment with 3 mg/kg Compound 1 on tactile PPI in Phelan McDermid syndrome model in Male Shank3 heterozygous mice.
  • Figure 7 depicts effects of 0.5 hour pre-treatment with 3 mg/kg Compound 1 on tactile PPI in C57B1/6 wild type mice.
  • Figure 8 depicts effects of 0.5 hour pre-treatment with 10 mg/kg Compound 1 on tactile PPI in C57B1/6 wild type mice.
  • Figure 9 depicts effects of 0.5 hour pre-treatment with 30 mg/kg Compound 1 on tactile PPI in C57B1/6 wild type mice.
  • the present disclosure documents the surprising particular usefulness of Compound 1 in relieving touch hypersensitivity, and teaches the particular use of this compound in a variety of contexts including, for example, to treat one or more diseases, disorders or conditions (or features thereof) that may be associated with tactile dysfunction.
  • tactile dysfunction refers to exhibiting symptoms such as withdrawing when being touched, refusing to eat certain “textured” foods and/or to wear certain types of clothing, complaining about having hair or face washed, avoiding getting hands dirty (e.g. , glue, sand, mud, finger-paint), and using finger tips rather than whole hands to manipulate objects.
  • symptoms such as withdrawing when being touched, refusing to eat certain “textured” foods and/or to wear certain types of clothing, complaining about having hair or face washed, avoiding getting hands dirty (e.g. , glue, sand, mud, finger-paint), and using finger tips rather than whole hands to manipulate objects.
  • tactile dysfunction e.g., to misperception of touch and/or pain (hyper- or hyposensitive)
  • various contexts for example, in subjects diagnosed with one or more diseases, disorders or conditions as described herein and/or in subjects suffering from idiopathic tactile dysfunction, and will appreciate the applicability of provided technologies to contexts when reduction of tactile sensitivity (e.g., hyperreactivity) may be desirable.
  • tactile sensitivity e.g., hyperreactivity
  • a majority of ASD patients (60.9%) report altered tactile sensitivity in both glabrous (smooth) and hairy skin, and altered sensitivity to vibration and thermal pain.
  • idiopathic or non-syndromic ASD pervasive developmental disorders that cause syndromic forms of ASD are also associated with disrupted somatosensation.
  • PMS Phelan McDermid Syndrome
  • Fragile X syndrome which are both highly associated with ASD and are caused by mutations in Shank3 and Fmrl, respectively.
  • tactile hypersensitivity is common in patients with Rett syndrome (RTT), which is caused by mutations in the X-linked methyl-CpG-binding protein 2 (Mecp2) gene.
  • RTT Rett syndrome
  • RTT Rett Syndrome
  • PMS Phelan McDermid syndrome
  • Mecp2, Shcmk3, and Gabrb3 function autonomously in peripheral somatosensory neurons for normal tactile behaviors.
  • ShankS mutant DRG neurons which are associated with PMS, on the other hand, exhibit hyperexcitability.
  • Such somatosensory deficits during development may contribute to aberrant social behaviors as well as anxiety -like behaviors in adulthood.
  • somatosensory neuron dysfunction underlies aberrant tactile perception in various disorders including, for example, ASD, RTT, PMS, and Fragile X syndrome, and/or that functional insufficiency of GABAA receptors, or hyperactivity of peripheral sensory neurons, cause tactile processing deficiency during development, which leads to anxiety-like behavior and social interaction deficits in adult mice.
  • peripheral sensory neurons represent exciting therapeutic targets for ASD, RTT, PMS, and Fragile X syndrome.
  • the present disclosure appreciates that deficits in peripheral sensory neurons, and not neurons in the brain, account for touch hypersensitivity in mouse models of ASD. Moreover, the present disclosure appreciates that touch hypersensitivity during development causes anxiety and social interaction deficits in adulthood.
  • the present disclosure specifically appreciates that Orefice et al (Cell 178:867, 2019-08-08) have proposed that “GABAAR agonists, GABA reuptake inhibitors, or GABAAR PAMS that are peripherally-restricted may reduce tactile overreactivity and improve brain microcircuit function and related ASD behaviors observed in certain patients with ASD, while minimizing or avoiding entirely potentially detrimental effects on brain development observed in clinical use of classical, FCA-approved GABAA drugs. .
  • Peripherally restricted methods for augmenting GABAAR signaling may also have applicability in other diseases and disorders in which touch over-reactivity is present, such as mechanical allodynia in neuropathic pain states, sensory processing disorder, and schizophrenia”.
  • Compound 1 is a recently discovered GABA-A positive allosteric modulator with low CNS exposure after oral or intravenous dosing.
  • the present disclosure provides an insight that Compound 1 might be both sufficiently peripherally restricted (and specific) and sufficiently effective in its GABAA modulation to usefully treat tactile dysfunction (e.g., touch hypersensitivity) and/or other disorders or conditions as discussed herein (e.g., as may be characterized by and/or arise from tactile dysfunction).
  • the present disclosure furthermore documents that Compound 1 displayed robust efficacy in a mouse model of touch hypersensitivity, and teaches that Compound 1 is an excellent compound for reducing tactile dysfunction in a human subject diagnosed with Autism Spectrum Disorder (ASD), Rett syndrome (RTT), Phelan McDermid syndrome (PMS), or Fragile X syndrome, and/or reducing anxiety or social impairment in a subject (e g., a human) diagnosed with ASD, RTT, PMS, or Fragile X syndrome and/or treating touch over-reactivity and/or pain and/or mechanical allodynia in a human subject.
  • ASSD Autism Spectrum Disorder
  • RTT Rett syndrome
  • PMS Phelan McDermid syndrome
  • Fragile X syndrome Fragile X syndrome
  • Compound 1 is administered to an appropriate subject in accordance with the present disclosure by administration of a pharmaceutical composition as described herein. In some embodiments, Compound 1 is administered according to a dosing regimen, e.g., involving administration of one or more unit doses (e g., unit dosage forms).
  • a dosing regimen e.g., involving administration of one or more unit doses (e g., unit dosage forms).
  • Compound 1 is utilized, and/or a pharmaceutical composition comprises and/or delivers Compound 1, in a particular form (e.g., salt form, solid form, etc.).
  • a pharmaceutical composition comprises and/or delivers Compound 1, in a particular form (e.g., salt form, solid form, etc.).
  • administration is oral and/or a pharmaceutical composition is formulated for oral administration (e.g., including one or more orally-acceptable carriers or excipients).
  • administration is via an immediate release formulation (e.g., an immediate release oral formulation). In some embodiments, administration is via an extended release formulation.
  • administration is via a pediatrically acceptable formulation such as, for example, a flavored liquid, or a solid or gel formulation that is or comprises small-sized particles (e.g., sprinkles).
  • a pediatrically acceptable formulation such as, for example, a flavored liquid, or a solid or gel formulation that is or comprises small-sized particles (e.g., sprinkles).
  • a composition that comprises or delivers Compound 1 in accordance with the present disclosure is characterized in that it shows efficacy in a mouse tactile PPI model as described herein (with dosing and/or route of administration adjusted appropriately to the mouse).
  • a composition that comprises or delivers Compound 1 in accordance with the present disclosure is characterized by low CNS exposure of Compound 1 upon administration of the composition to a subject (e.g., a human subject).
  • the present disclosure provides use of Compound 1 in (e.g., in the manufacture of a medicament for) reducing tactile dysfunction in a subject. In some embodiments, the present disclosure provides a use of Compound 1 (e.g., in the manufacture of a medicament for) reducing anxiety or social impairment in a subject. In some embodiments, the present disclosure provides use of Compound 1 in (e g., in the manufacture of a medicament for) treating touch over-reactivity and/or pain and/or mechanical allodynia in a human subject in need thereof.
  • the present disclosure provides use of Compound 1 as a reference for comparison of other GABAA modulators (e.g., GABAA PAMs), for example to establish a useful degree of modulation of touch hypersensitivity or other tactile dysfunction, a useful extent of efficacy in treatment of one or more diseases, disorders or conditions, a useful (limited) extent of CNS penetration or exposure, etc.
  • GABAA PAMs GABAA PAMs
  • the present disclosure provides use of Compound 1 for assessing peripheral restriction of one or more GABAA-associated phenomena or events.
  • pain that responds to treatment with Compound 1 is peripheral pain; tactile dysfunction that responds to exposure to Compound 1 is peripheral tactile dysfunction.
  • a subject suffering pain that does not respond to Compound 1 may require treatment with a CNS-active pain reliever.
  • Compound 1 may be used to characterize (e.g., diagnose) one or more aspects of a subject’s state, and appropriate treatment (e.g., central and/or peripheral, which may be or comprise treatment with Compound 1) may be administered accordingly.
  • appropriate treatment e.g., central and/or peripheral, which may be or comprise treatment with Compound 1.
  • a subject (or population of subjects) to whom Compound 1 (e.g., a composition that comprises or delivers Compound 1) is administered in accordance with the present disclosure is a subject (or population thereof) who is displaying or has displayed one or more features of tactile dysfunction (e.g., touch over-reactivity, pain, mechanical allodynia).
  • tactile hypersensitivity is associated with known genetic conditions.
  • such tactile hypersensitivity is idiopathic.
  • a subject (or population of subjects) to whom Compound 1 (e.g., a composition that comprises or delivers Compound 1) is administered in accordance with the present disclosure is a subject (or population thereof) who suffers from mechanical allodynia associated with physical trauma, nerve injury, shingles, diabetic neuropathy, chemotherapy-induced neuropathy or a neuropathic pain state.
  • a subject (or population of subjects) to whom Compound 1 (e.g., a composition that comprises or delivers Compound 1) is administered in accordance with the present disclosure is a subject (or population thereof) who suffers from or has been determined to be susceptible to (e.g., has been diagnosed with) one or more of Autism Spectrum Disorder (ASD), Rett syndrome (RTT), Phelan McDermid syndrome (PMS), or Fragile X syndrome.
  • ASD Autism Spectrum Disorder
  • RTT Rett syndrome
  • PMS Phelan McDermid syndrome
  • Fragile X syndrome Fragile X syndrome
  • a subject (or population of subjects) to whom Compound 1 (e.g., a composition that comprises or delivers Compound 1) is administered in accordance with the present disclosure is receiving or has recently received pain management therapy; in some embodiments, such pain management therapy may be or comprises administration of one or more of Acetaminophen, Alfentanil, Alprazolam, Amitriptyline, Amoxapine, Aspirin, Baclofen, Buprenorphine, Bupropion, Butorphanol, Carbamazepine, Celecoxib, Citalopram, Clomipramine, Clonazepam, Codeine, Desipramine, Desvenlafaxine, Diclofenac, Diflunisal, Doxepin, Duloxetine, Escital opram, Etodolac, Etoricoxib, Fenoprofen, Fentanyl, Fluoxetine, Flurbiprofen, Fluvoxamine, Gabapentin, Hydroco
  • a subject (or population of subjects) to whom Compound 1 (e.g., a composition that comprises or delivers Compound 1) is administered in accordance with the present disclosure is receiving pain management therapy at a lower level than that required for comparable pain reduction absent administration of Compound 1.
  • administration in accordance with the present disclosure e.g., of Compound 1 or a composition that comprises or delivers Compound 1, for example to a subject suffering from a disease, disorder or condition as described herein
  • administration in accordance with the present disclosure is or comprises oral administration.
  • an amount administered may be or comprise an amount of about 3 mg to about 1000 mg.
  • an amount administered e.g., in a single dose or in a daily dose or via a dosing regimen
  • the present invention provides methods of reducing tactile dysfunction, wherein the method comprises administering to a subject in need thereof about 0.1 mg to about 10,000 mg of Compound 1.
  • provided methods comprise an amount administered (e.g., in a single dose or in a daily dose or via a dosing regimen) of about 0.1 mg to about 9000 mg, about 0.1 mg to about 8000 mg, about 0.1 to about 7000 mg, about 0.1 mg to about 6000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 4000 mg, about 0.1 mg to about 3000 mg, about 0.1 mg to about 2000, about 0.1 mg to about 1000 mg, about 0.1 mg to about 900 mg, about 0.1 mg to about 800 mg, about 0.1 mg to about 700 mg , about 0.1 mg to about 600 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 400 mg, about 0.1 mg to about 300 mg, about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 400 mg, about 0.1 mg
  • provided methods comprise administering to a patient in need thereof Compound 1 or a composition that comprises or delivers Compound 1 in an amount that is equivalent to about 3 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 30 mg/kg in a mouse. In some embodiments, provided methods comprise administering to a patient in need thereof Compound 1 in an amount that is equivalent to about 100 mg/kg in a mouse. In some such embodiments, the amount of Compound 1 is about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 150 mg, or about 500 mg.
  • subjects receiving treatment with Compound 1 as described herein are monitored, for example, for changes (e.g., improvement) in one or more aspects of tactile dysfunction (e.g., touch hypersensitivity) and/or in one or more physical or behavioral symptoms, and/or for increase or decrease in experienced pain.
  • additional therapy is administered, and/or Compound 1 therapy is adjusted (e.g., increased, decreased, or terminated), responsive to such monitoring.
  • treatment with Compound 1 is initiated during a subject’s youth (e.g., when a subject is a baby or a child).
  • Compound 1 treatment is administered to a subject over a period of years, optionally with one or more breaks or rest periods during which Compound 1 therapy is not administered.
  • Step 1 ethyl l-(4-chlorophenyl)-5-methyl-lH-pyrazole-3-carboxylate
  • Step 3 ethyl 5-(bromomethyl)-l-(4-chloro-2-(2-fluorobenzoyl)phenyl)-lHpyrazole- 3 -carboxylate
  • Step 4 ethyl 8-chloro-6-(2-fluorophenyl)-4H-benzo[f]pyrazolo[l,5- a] [1 ,4]diazepine-2-carboxylate
  • Step 5 8-chloro-6-(2-fluorophenyl)-4H-benzo[f]pyrazolo[l,5-a][l,4]diazepine-2- carboxylic acid
  • Wistar rat brain (minus cerebellum) was used, with an incubation time of 60 minutes at 25°C and 50 mM phosphate buffer (pH 7.4) was used as incubation buffer.
  • IOUM of diazepam was used as the non-specific ligand, and 1 nM 3 H-flunitrazepam was used as the radio-ligand.
  • the binding Ki of Compound 1 in this assay was found to be 170 nM.
  • Equipment Amplifier; EPC- 10, HEKA Electronics;
  • Headstage Preamplifier EPC- 10, HEKA Electronics
  • Culture media The cells were continuously maintained in and passaged in sterile culture flasks containing a 1: 1 mixture of Dulbecco’s modified eagle medium and nutrient mixture D- MEM/F-12 (lx, liquid, with L-Glutamine) for Ltk cells or HAM/F-12 (lx, liquid, with L Glutamine) for CHO cells, supplemented with 10% fetal bovine serum and 1.0% Penicillin/Streptomycin solution.
  • D- MEM/F-12 lx, liquid, with L-Glutamine
  • HAM/F-12 lx, liquid, with L Glutamine
  • Antibiotics The complete medium as indicated above was supplemented with selected antibiotics:
  • GABAA alB2y2
  • Puromycin Puromycin
  • GABAA ot3B2y2
  • GABAA a5B2y2
  • the stock solution of GABA was prepared prior to the experimental start of the present study, stored frozen (-10°C to -30°C) until the day of experimentation. Shortly prior to the electrophysiological experiments frozen stock solution was thawed and diluted.
  • Negative control Two additional cells were treated with vehicle (0.1% DMSO) only instead of test item to show current run-down during the course of the experiment (time-matched).
  • Rat plasma protein binding (93.5 %), and rat brain homogenate binding (86.5 %) were determined by equilibrium dialysis.
  • Compound 1 was administered in a single IV dose (1 mg/kg) as a solution (5% DMSO in pH 8 phosphate buffer). Compound 1 did not readily cross the blood brain barrier following a single IV (1 mg/kg) dose with brain:plasma ratio of 0.018 observed one hour post administration. The ratio of unbound drug (brain: plasma) was 0.037.
  • Compound 1 was administered in single oral doses of 10 mg/kg and 100 mg/kg as solutions (5% DMSO in pH 8 phosphate buffer). Total brain levels of Compound 1 were measured 1 hour post administration as 176 ng/g at lOmg/kg and 2053 ng/g at 100 mg/kg. This results in a braimplasma ratio of 0.014 from the 10 mg/kg oral dose and 0.023 from the 100 mg/kg oral dose. The ratio of unbound drug (brain:plasma) was 0.029 from the 10 mg/kg oral dose and .048 from the 100 mg/kg oral dose.
  • the plasma:brain ratio of 0.0135 and 0.0162 for the 10 mg/kg and 100 mg/kg dose respectively was noted.
  • the ratio of unbound drug (braimplasma) at the 4 hr timepoint was 0.028 from the 10 mg/kg oral dose and .034 from the 100 mg/kg oral dose.
  • Plasma to brain ratios were measured 24 hours post administration with the 100 mg/kg dose and was 0.0172, giving a braimplasma unbound drug ratio of 0.035.
  • the change in braimplasma ratios of total and unbound drug changed little over the course of the study; 1, 4 and 24 hours post oral administration at either 10 mg/kg or 100 mg/kg.
  • the tactile prepulse inhibition (PPI) assay was adapted from methods published by Orefice et al., 2016 (Cell 166, 299-313).
  • the response of mice to tactile stimulus was measured using San Diego Instruments startle reflex system (SR-LABTM Startle Response System).
  • Tactile sensorimotor gating deficits were measured using a PPI assay where the pre-stimulus was an air puff (0.9 PSI or 0.6 PSI as specified below, 50 ms), administered to the back of the mouse to assess hairy skin sensitivity, followed by an acoustic startle stimulus (125 dB, 20 ms).
  • mice were group-housed in OPTIMice ventilated cages for the remainder of the study. Testing commenced at 8 weeks of age. All animals were examined and weighed prior to initiation of the study to assure adequate health and suitability and to minimize non-specific stress associated with manipulation. Mice were maintained on a 12/12 light/dark cycle. The room temperature was maintained between 20 and 23°C with a relative humidity maintained at approximately 50%. Chow and water were provided ad libitum for the duration of the study. Animals were randomly assigned across treatment groups and balanced by test chamber. The test was performed during the animal’s light cycle.
  • Compound 1 was evaluated at 3 and 10 mg/kg. Compound 1 was dissolved in 5% DMSO in Phosphate Buffer (pH 8) and administered p.o. at a dose volume of 10 ml/kg. Tactile PPI testing began at 30 minutes or 4 hours post-dose as indicated below.
  • Each experiment consisted of two sessions separated by 72 hours. A 1-week washout separated the start of each experiment. A crossover design was used within each experiment.
  • Experiments 1&2 used the same mice. Across the six (6) experiments, the following regimens were assessed: Experiments 1 & 2
  • Session a consisted of an acclimation phase followed by 2 blocks of trials.
  • the acclimation phase consisted of a 5-minute period during which constant background white noise (78 dB) was presented.
  • Block I consisted of 5 prepulse stimuli alone trials(i.e., air puff trials all of which were presented at either 0.6 PSI or 0.9 PSI, depending on the session).
  • Block II consisted of 5 pulse alone trials (i.e., acoustic startle stimuli trials, 125 dB, 20 ms), 10 prepul se+pulse trials, and 5 no stimulation trials which were presented in a pseudorandom order.
  • the prepulse intensity remained constant at either 0.6 or 0.9 PSI (20 ms) and the interstimulus interval (1ST) between prepulse and pulse varied from 250 ms (5 trials) to 500 ms (5 trials) in duration.
  • the intertrial intervals ranged between 10 to 50 seconds.
  • Whole body flinch, or startle reflex was quantified using an accelerometer sensor which measured the amplitude of movement of the animal within the cylindrical holder.
  • the air puff pressure was adjusted from 0.6 PSI to 0.9 PSI (or vice versa). The pressure of the air puff delivery in each test chamber was then checked for accuracy using a manometer.
  • Session b was run in the same manner described above.
  • the following measures were determined from the data obtained from the tactile PPI sessions: 1) response to the prepulse (air puff) alone as a percentage of the startle response); 2) response to the pulse (acoustic startle stimuli alone and 3) % pre-pulse inhibition.
  • the response to the prepulse alone was calculated using the formula: ((average startle response to prepulse alone trials in Block Vaverage startle response to pulse alone trials in Block II) - (average startle response to no stim trials in Block Il/average startle response to pulse alone trials in Block II))*100.
  • % pre-pulse inhibition was calculated using the formula: (l-(average startle response to the prepul se+pulse trials in Block Il/average startle response to pulse alone trials in Block II)* 100.
  • the data sets generated from each experiment were analyzed independently in the following manner: The startle response to air puff alone (i.e., the Block I trials) and the startle response to the pulse alone (in the Block II trials) were analyzed using a paired t-test. Prepulse inhibition of the startle response (i.e., Block II prepulse/pulse trials relative to Block II pulse alone trials) was evaluated using a two-way repeated measures ANOVA with factors of Treatment and ISI as the within subject measures. Bonferroni’s post-hoc comparisons were performed if appropriate. An effect was considered significant if p ⁇ 0.05.
  • Experiments 3-6 utilized a separate cohort of mice than was used in experiments 1&2, and in a different set of runs on a different month, again with 3mg/kg and 10 mg/kg of Compound 1 tested in the tactile PPI model in Male Shank3 heterozygous mice, with 0.6PSI and 0.9PSI air puffs, and with both 250ms and 500ms ISI.
  • the results of Experiments 3-6, are shown in Figures 3-6.
  • Experiments 7-9 tested 30-minutes pretreatment with 3 mg/kg, 10 mg/kg and 30 mg/kg of Compound 1 in C57B1/6 wild type mice, with 0.6 PSI and 0.9 PSI air puffs, and with both 250 ms and 500 ms ISI. The results of Experiments 7-9, are shown in Figures 7-9.

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Abstract

La présente invention concerne des procédés d'utilisation d'un composé modulateur de GABA-A particulier, comprenant en particulier des populations de patients et/ou pour des indications particulières (par exemple, des maladies, des troubles ou des états).
PCT/US2023/029165 2022-08-02 2023-08-01 Utilisation d'un modulateur allostérique positif de gaba-a pour la réduction de l'hypersensibilité tactile WO2024030399A2 (fr)

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