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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• non-opioid analgesics e.g., acetaminophen
• NSAIDs non-steroidal anti-inflammatory drugs
• opioid analgesics e.g., aspirin
• co-analgesics co-analgesics.
• Sodium channel blockers have been shown to be useful in the treatment of pain, including acute, chronic, inflammatory, and neuropathic pain (see, e.g., Wood, J.N., el al., J. Neurobiol (2004), 61(1), 55-71). Preclinical evidence demonstrates that sodium channel blockers can suppress neuronal firing in peripheral and central sensory neurons, and it is via this mechanism that they are considered to be useful for relieving pain.
• Compound A N- 14-(6-FI uoro-3.4-dihydro- 1 /-isoquinol in-2-yl)-2.6-dimethyl phenyl
• the present disclosure is directed to a method of treating pain in a subject (preferably, a mammal, such as a human) in need thereof, comprising administering a therapeutically effective amount of Compound A to the subject.
• a subject preferably, a mammal, such as a human
• the pain treated by the administration of Compound A is nociceptive pain, neuropathic pain, or a combination thereof.
• the pain treated by the administration of Compound A is nociceptive pain, such as radicular pain, somatic pain, visceral pain, soft tissue pain, inflammatory pain, post-operative pain, or a combination thereof, particularly post-operative pain.
• the method of treating pain comprising administering a therapeutically effective amount of Compound A further comprises enhancing the opening of a Kv7 potassium channel in the subject (e.g., human).
• the present disclosure is directed to a method of opening or enhancing the opening of a Kv7 potassium channel in a subject (preferably, a mammal, such as a human), comprising administering an effective amount of Compound A to the subject, wherein the subject is suffering from pain such as the various types of pain described herein, including nociceptive pain, neuropathic pain, or a combination thereof, particularly inflammatory pain.
• a subject preferably, a mammal, such as a human
• pain such as the various types of pain described herein, including nociceptive pain, neuropathic pain, or a combination thereof, particularly inflammatory pain.
• the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5.
• the opening or enhanced opening of one or more of the Kv7.2, Kv7.3, Kv7.4, or Kv7.5 potassium channels is selective over Kv7.1.
• the method comprises opening or enhanced opening of the Kv7.2/Kv7.3 (KCNQ2/3) potassium channel.
• the present disclosure provides a method of treating pain in a subject (preferably, a mammal, such as a human) in need thereof, wherein Compound A is administered (preferably orally) to the subject.
• the administration to the subject comprises a dose of 2 to 200 mg of Compound A per administration.
• the administration to the subject comprises a dose of 5-1000 mg per day.
• the administration to the subject comprises a dose of 0.05-20 mg/kg, such as 0.1- 10 mg/kg.
• Compound A is orally administered to the subject (preferably, a mammal, such as a human) from between about 30 minutes before to about 2 hours after eating a meal, for example, Compound A may be orally administered to the subject during a meal or within 15 minutes after eating a meal.
• the present disclosure provides a method of treating pain in a subject (preferably, a mammal, such as a human) in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject in combination with one or more additional analgesic agents, such as an opioid analgesic.
• a subject preferably, a mammal, such as a human
• administering e.g., orally
• a therapeutically effective amount of Compound A to the subject in combination with one or more additional analgesic agents, such as an opioid analgesic.
• the present disclosure provides a method of reducing the dose (e.g., a maintenance dose) of an opioid analgesic administered to a subject (preferably, a mammal, such as a human) in need thereof comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject, for example, whereby the effective amount of Compound A reduces the dose of the opioid analgesic needed to achieve pain relief in the subject.
• Compound A is a small molecule currently being developed for the treatment of seizure disorders, and its use as a potassium channel modulator is disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593 as well as U.S. Application Serial Nos. 16/409,684 and 16/410,851, the disclosures of which are hereby incorporated by reference in their entireties.
• FIG. 1 shows results of the acetic acid induced mouse model of visceral pain showing nociceptive events (y-axis) and vehicle, 1 mg/kg, 3 mg/kg, and 10 mg/kg dosing of Compound A (x-axis) for Study 1 (top left), Study 2 (top right), the combination of Study 1 and Study 2 (bottom left), and PK/PD correlation (bottom right) showing a PK/PD correlation between Compound A concentrations in brain and plasma to the observed efficacy.
• FIG. 2 shows results from the electronic von Frey test on non-lesion and lesion paws in groups of rats on Day 13, prior to treatment, showing force inducing paw-withdrawal (g) (y-axis) and the future treatment to be administered: vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• FIG. 3 shows results from the electronic von Frey test on lesioned paw (tactile allodynia evaluation on Day 14 and Day 18) in rats showing variation (delta from baseline) of force inducing paw- withdrawal (g) (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• NS Not Significant
• * p ⁇ 0.05
• ** p ⁇ 0.01;
• FIG. 4 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 14 at 2 h) in rats showing latency to the first paw-withdrawal (s) (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• Inter-group comparison versus vehicle (p.o.)):
• FIG. 5 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 14 at 2 h) in rats showing number of withdrawal responses (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• NS Not Significant
• * p ⁇ 0.05
• ** p ⁇ 0.01
• *** p ⁇ 0.001.
• FIG. 6 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 14 at 2 h) in rats showing total duration of withdrawal responses (s) (y- axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• Inter-group comparison (versus vehicle (p.o.)):
• FIG. 7 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 18 at 2 h) in rats showing latency to the first paw-withdrawal (s) (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• Inter-group comparison versus vehicle (p.o.)):
• FIG. 8 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 18 at 2 h) in rats showing number of withdrawal responses (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• NS Not Significant
• * p ⁇ 0.05
• ** p ⁇ 0.01
• *** p ⁇ 0.001.
• FIG. 9 shows results from the cold plate test on lesioned paw (thermal allodynia evaluation on Day 18 at 2 h) in rats showing total duration of withdrawal responses (s) (y- axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine p.o. dosing (x-axis).
• NS Not Significant
• * p ⁇ 0.05
• ** p ⁇ 0.01
• *** p ⁇ 0.001.
• the present disclosure relates to novel and improved methods and uses for Compound A, particularly for treatment of pain by administering Compound A to a subject (preferably, a mammal, such as a human) in need thereof by oral administration or by other routes.
• Compound A refers to the compound having the following formula: and having a chemical name of ,V-
• Kv7.2/Kv7.3 KCNQ2/3 opener
• Preparation of Compound A and its use as a Kv7.2/Kv7.3 (KCNQ2/3) opener is disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593 as well as U.S. Application Serial Nos. 16/409,684 and 16/410,851.
• Compound A potentiates and enhances opening of the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2/Kv7.3), which are important in controlling neuronal excitability.
• Compound A is used in the methods and uses described herein.
• Acute pain as used herein means pain that has a recent onset. Acute pain commonly declines over a short time (e.g., days, hours, or minutes) and follows injury to the body, and generally disappears when the bodily injury heals.
• “Breakthrough pain” as used herein means a transitory increase in pain above the baseline or background pain experienced by a patient.
• baseline pain means the pain that is experienced or reported by a patient as the average pain intensity experienced for 12 or more hours.
• Chronic pain as used herein means pain persisting for at least a week. Typically, chronic pain persists for three to six months or longer.
• administering Compound A refers to the simultaneous or sequential administration of Compound A with one or more additional therapeutic agents, such as one or more other pain treatments, regimens, or analgesic agents.
• administering Compound A in combination with another therapeutic agent means that Compound A may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms (e.g., as part of a multiple dosage regimen) or together in a single unit dosage form.
• the additional therapeutic agent and Compound A are administered sequentially, then this could be within a period of time up to 24 hours from the other, such 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours or less from the other.
• “Pain” as used herein refers to all categories of pain and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain, orofacial pain, bum pain, burning mouth syndrome, somatic pain, visceral pain, myofacial pain, dental pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and post-operative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain following stroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome and pain
• “Therapeutically effective amount” as used herein refers to an amount of Compound A that is sufficient to treat the stated disease, disorder, or condition or have the desired stated effect on the disease, disorder, or condition or one or more mechanisms underlying the disease, disorder, or condition in a subject.
• therapeutically effective amount refers an amount of Compound A which, upon administration to a subject, treats or ameliorates pain in the subject, or exhibits a detectable therapeutic effect in the subject that results in reduction in pain. Changes in pain experienced by a patient can be measured through the use of a pain rating scale, and such scales are used in daily clinical practice to measure pain intensity.
• VAS Visual Analog Scale
• GRS Graphic Rating Scale
• SDS Simple Descriptor Scale
• NRS Numerical Rating Scale
• FSS Faces Rating Scale
• Treatment refers to therapeutic applications associated with administering Compound A that ameliorate the indicated disease, disorder, or condition (e.g., pain) or one or more underlying mechanisms of said disease, disorder, or condition, including slowing or stopping progression of the disease, disorder, or condition or one or more of the underlying mechanisms in a subject.
• Treatment refers to therapeutic applications to slow or stop the increase of pain (i.e., to stabilize the level of pain) and/or reduction or elimination of pain.
• the treatment of pain comprising the administration of Compound A is accompanied by an alteration of the cellular activity of one or more Kv7 potassium channels (e.g., Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5, particularly Kv7.2 and/or Kv7.3, optionally over Kv7.1) toward a normal level that would be observed in the absence of the pain.
• Kv7 potassium channels e.g., Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5, particularly Kv7.2 and/or Kv7.3, optionally over Kv7.1
• Under fed conditions refers to the condition of having consumed food during the time period between from about 4 hours prior to the oral administration of an effective amount (e.g. , within the therapeutically effective dose range) of Compound A to about 4 hours after the administration of Compound A.
• the food may be a solid, liquid, or mixture of solid and liquid food with sufficient bulk and fat content that it is not rapidly dissolved and absorbed in the stomach. In some instances, the food is a meal, such as breakfast, lunch, dinner or, alternatively, baby food (e.g., formula or breast milk).
• the therapeutically effective amount of Compound A may be orally administered to the subject, for example, between about 30 minutes before to about 2 hours after eating a meal, most advantageously, Compound A is orally administered during a meal or within 15 minutes after eating a meal.
• Under fasted conditions refers to the condition of not having consumed food during the time period between from at least 4 hours prior to the oral administration of a therapeutically effective amount of Compound A to about 4 hours after administration of Compound A.
• the present disclosure is directed to a method of treating pain in a subject (preferably, a mammal, such as a human) in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject.
• a subject preferably, a mammal, such as a human
• administering e.g., orally
• the pain treated by administering Compound A is nociceptive pain, neuropathic pain, or a combination thereof.
• the pain is nociceptive pain, such as radicular pain, somatic pain, visceral pain, soft tissue pain, inflammatory pain, or a combination thereof, particularly inflammatory pain, including inflammatory pain associated with an inflammatory disease or condition, such as organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et ak, J. Mol, Cell Cardiol.
• Compound A can also be used to treat pain associated with an inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
• an inflammatory disease can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
• the pain is neuropathic pain, including neuropathic pain selected from pain associated with spinal cord injury, spinal or brain stroke, multiple sclerosis, cancer, shingles, post-herpetic neuralgia, erythromelalgia (including inherited erythromelalgia), chemotherapy -induced neuropathy, oxaliplatin-induced neuropathy, trigeminal neuralgia, phantom pain, phantom limb pain, radiculopathy, complex regional pain syndrome, causalgia, reflex sympathetic dystrophy, lower back pain, peripheral nerve trauma, herpes virus infection, diabetes mellitus, diabetic neuropathy, plexus avulsion, neuroma, limb amputation, vasculitis, chronic alcoholism, human immunodeficiency virus (HIV) infection, uremia, vitamin deficiency, pelvic pain, or a combination thereof.
• the neuropathic pain is chronic neuropathic pain, such as pain resulting from injury to the
• the neuropathic pain is selected from pain associated with spinal cord injury, spinal or brain stroke, post-herpetic neuralgia, erythromelalgia (including inherited erythromelalgia), trigeminal neuralgia, radiculopathy, complex regional pain syndrome, causalgia, reflex sympathetic dystrophy, peripheral nerve trauma, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, or a combination thereof.
• the neuropathic pain is selected from pain associated with shingles, multiple sclerosis, cancer, chemotherapy-induced neuropathy, oxaliplatin-induced neuropathy, herpes virus infection, diabetes mellitus, human immunodeficiency virus (HIV) infection, hypothyroidism, uremia, or a combination thereof, particularly pain associated with multiple sclerosis or cancer.
• the neuropathic pain is selected from pain associated with shingles or herpes virus infection.
• the neuropathic pain is selected from pain associated with cancer, chemotherapy -induced neuropathy, or oxaliplatin-induced neuropathy.
• the neuropathic pain is selected from pain associated with phantom pain, phantom limb pain, lower back pain, limb amputation, chronic alcoholism, vitamin deficiency, pelvic pain, or a combination thereof, particularly phantom pain, phantom limb pain, or pain associated with limb amputation.
• the pain treated by administering a therapeutically effective amount of Compound A to the subject is acute pain.
• the pain is chronic pain.
• Such administration may be, e.g., by oral, sublingual, buccal, occur, otic, vaginal, rectal, cutaneous, topical, or transdermal administration; by intravenous, intramuscular, intrathecal, or subcutaneous injection; or by implantation.
• the pain treated by administering a therapeutically effective amount of Compound A to the subject is mild, moderate, or severe pain.
• the pain is moderate or severe pain, or moderate to severe pain.
• Such administration may be, e.g., by oral, sublingual, buccal, occur, otic, vaginal, rectal, cutaneous, topical, or transdermal administration; by intravenous, intramuscular, intrathecal, or subcutaneous injection; or by implantation.
• the pain treated by administering (e.g., orally) a therapeutically effective amount of Compound A to the subject is associated with a disease state or other condition, such as cancer pain, rheumatic pain, arthritic pain, bone pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, pain associated with a periodontal disease (including gingivitis and periodontitis), or a combination thereof.
• the pain is of tumor origin. In other embodiments, the pain is of non-tumor origin.
• the pain is associated with a migraine, including migraine without aura (“common migraine”), migraine with aura (“classic migraine”), migraine without headache, basilar migraine, familial hemiplegic migraine, migrainous infarction, migraine with prolonged aura, or a combination thereof.
• the pain treated by administering e.g., orally
• a therapeutically effective amount of Compound A to the subject is breakthrough pain.
• the method of treating pain by administering a therapeutically effective amount of Compound A comprises enhancing the opening of a Kv7 potassium channel in the subject (preferably, a mammal, such as a human).
• the present disclosure provides a method or use comprising opening or enhancing the opening of a Kv7 potassium channel, such as the Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5 potassium channel, particularly the Kv7.2/Kv7.3 (KCNQ2/3) potassium channel in a subject in need thereof by administering an effective amount of Compound A.
• a Kv7 potassium channel such as the Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5 potassium channel, particularly the Kv7.2/Kv7.3 (KCNQ2/3) potassium channel in a subject in need thereof by administering an effective amount of Compound A.
• the subject suffers from pain, such as the types of pain described herein, including neuropathic pain or nociceptive pain, such as inflammatory pain.
• the method or use described herein comprises selectively opening or enhancing the opening of a Kv7 potassium channel, such as one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.1.
• the method or use is selective for Kv7.2, over Kv7.1.
• the method or use is selective for Kv7.3, over Kv7.1.
• the method or use is selective for Kv7.4, over Kv7.1.
• the method or use is selective for Kv7.5, over Kv7.1.
• the method or use is selective for Kv7.2 and Kv7.3, over Kv7.1.
• the method or use is selective for Kv7.2 and Kv7.3 over other Kv7 potassium channels.
• the method or use is selective for Kv7.2 and Kv7.3 over Kv7.4 and Kv7.5.
• parenteral administration routes include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques or by implantation.
• Compound A can be administered by injection, such as by intravenous, intramuscular, intrathecal, or subcutaneous injection.
• the above-discussed doses of Compound A are intended for oral administration and can be converted to doses suitable for parenteral administration, including administration by injection, by reducing the oral dose, for example by about half.
• compositions suitable for administration of Compound A include sublingual and buccal (e.g., with a film or other composition that dissolves in the mouth under the tongue or on the inside of the cheek), ocular (e.g., eye drops), otic (e.g., by ear drops), oral or nasal inhalation (e.g., by insufflation or nebulization), cutaneous or topical (e.g., by creams or lotions), or transdermal (e.g., by skin patches).
• enteral administration routes can be used for Compound A, including vaginal and rectal (e.g., by ointment, suppository, enema).
• the presently described methods and uses involving administering Compound A for treating pain may also include administering Compound A in combination with one or more additional therapeutic agents, such as one or more other pain treatments, regimens, or analgesic agents.
• additional therapeutic agents such as one or more other pain treatments, regimens, or analgesic agents.
• the present disclosure provides a method of treating pain in a subject (e.g., a human) in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject in combination with one or more additional analgesic agents.
• the one or more additional analgesic agents include opioid analgesics, such as opioid agonists, mixed agonist-antagonists, or partial agonists including but not limited to alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl-thiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone
• opioid analgesics
• the additional analgesic agent includes an opioid agonist, such as buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol including mixtures of any of the foregoing and pharmaceutically acceptable salts of any of the foregoing.
• the additional analgesic agent is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HC1.
• the one or more additional analgesic agents include non-opioid treatments, such as aspirin; acetaminophen; non-steroidal anti-inflammatory drugs (“NS AIDS”), e.g., ibuprofen, ketoprofen, naproxen, etc.; N-methyl-D-aspartate (NMD A) receptor antagonists, e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine; cyclooxygenase-2 inhibitors (“COX-II inhibitors”), such as celecoxib, rofecoxib, and etoricoxib; and/or glycine receptor antagonists.
• NPD A N-methyl-D-aspartate receptor antagonists
• COX-II inhibitors cyclooxygenase-2 inhibitors
• administering Compound A in combination with one or more additional analgesic agents permits a reduction in the dosage of the additional analgesic agent without a reduction in the level of pain relief or analgesic efficacy provided.
• the present disclosure provides a method of treating pain in a subject (e.g., a human) in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject in combination with an amount of one or more additional analgesic agents, wherein the amount of the additional analgesic agent is less than the amount of the additional analgesic agent that would be needed to achieve the same or a similar level of pain relief or analgesic efficacy in the absence of administering Compound A.
• the one or more additional analgesic agents is an opioid analgesic, such as buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol including mixtures of any of the foregoing and pharmaceutically acceptable salts of any of the foregoing.
• the additional analgesic agent is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HC1.
• the present disclosure provides a method of reducing the dose (e.g., maintenance dose) of an opioid analgesic administered to a subject (preferably, a mammal, such as a human) in need thereof comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject, for example, whereby the effective amount of Compound A offsets the reduction in the dose of the opioid analgesic such that the level of pain relief or analgesic efficacy experienced by the subject is maintained.
• a method of reducing the dose (e.g., maintenance dose) of an opioid analgesic administered to a subject preferably, a mammal, such as a human
• administering e.g., orally
• a therapeutically effective amount of Compound A offsets the reduction in the dose of the opioid analgesic such that the level of pain relief or analgesic efficacy experienced by the subject is maintained.
• the opioid analgesic is selected from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol, including mixtures of any of the foregoing and pharmaceutically acceptable salts of any of the foregoing.
• the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HC1.
• the present disclosure provides a method of reducing the dose (e.g., a maintenance dose) of an opioid analgesic administered to a subject (preferably, a mammal, such as a human) in need thereof comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject, for example, whereby the effective amount of Compound A reduces the dose of the opioid analgesic needed to achieve pain relief in the subject.
• the opioid analgesic is selected from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol, including mixtures of any of the foregoing and pharmaceutically acceptable salts of any of the foregoing.
• the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HC1.
• the methods and uses described herein such as the method of or use in treating pain in a subject (preferably, a mammal, such as a human) in need thereof, is achieved by administering (e.g., orally) a therapeutically effective amount of Compound A, such as from about 0.05 mg/kg to about 20 mg/kg, including from about 0.05 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 20 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 0.05 mg/kg to about 5 mg/kg, from about 0.1 mg/kg to about 5 mg/kg, from about 0.05 mg/kg to about 2 mg/kg, or from about 0.1 mg/kg to about 2 mg/kg.
• a therapeutically effective amount of Compound A such as from about 0.05 mg/kg to about 20 mg/kg, including from about 0.05 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 20 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about
• More specific representative amounts include 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg,
• the method or use includes administering (e.g., orally) 0.1-1 mg/kg of Compound A. In certain aspects, the method includes administering (e.g., orally) 0.2-0.5 mg/kg of Compound A.
• the method or use includes administering (e.g., orally) 0.05-20 mg/kg of Compound A. In certain aspects, the method includes administering (e.g., orally) 1-10 mg/kg of Compound A.
• the present disclosure provides a method of treating pain in a subject (preferably, a mammal, such as a human) in need thereof comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject, wherein the pain is nociceptive pain, such as those described herein, including inflammatory pain, and wherein Compound A is administered at a dose of 0.05-5 mg/kg to the subject, such as 0.1- 5 mg/kg, 0.05-2 mg/kg, or 0.1-2 mg/kg, including about 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.24 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.5 mg
• the present disclosure provides a method of treating pain in a subject (e.g., human) in need thereof comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject, wherein the pain is neuropathic pain, such as those described herein, and wherein Compound A is administered at a dose of 0.5-10 mg/kg to the subject, such as 0.5-8 mg/kg, 1-10 mg/kg, or 1-8 mg/kg, including about 0.5 mg/kg, 0.8 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3 mg/kg, 3.5 mg/kg,
• the methods and uses described herein such as the method of or use in treating pain in a subject (e.g., human) in need thereof, is achieved by administering (e.g., orally) a therapeutically effective amount of Compound A, such as 2 to 200 mg of Compound A in a single or multiple dosage units.
• a therapeutically effective amount of Compound A such as 2 to 200 mg of Compound A in a single or multiple dosage units.
• the method can include administering (e.g., orally), in a single or multiple dosage units, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about
• the method or use includes oral administration of 5 to 50 mg of Compound A in a single or multiple dosage units to a subject (e.g., a human). In some aspects, the method or use includes the oral administration of 10, 20, or 25 mg of Compound A in a single or multiple dosage units to a subject (e.g., a human). In some aspects, the method or use includes oral administration of 20 mg of Compound A in a single or multiple dosage units to a subject (e.g., a human).
• the methods and uses described herein such as the method of or use in treating pain in a subject (e.g., human) in need thereof, is achieved by administering (e.g., orally) at least 20 mg of Compound A, such as at least 25, 30, 35, 50, 75, or 100 mg of Compound A.
• the methods and uses described herein, such as the method of or use in treating pain in a subject in need thereof is achieved by administering (e.g., orally) at least 50 mg of Compound A per day, such as at least 60, 75, 85, 100, 125,
• Compound A 150, 175, or 200 mg of Compound A per day to a subject (e.g., a human).
• the methods and uses described herein such as the method of or use in treating pain in a subject (e.g., a human) in need thereof, is achieved by administering (e.g., orally) a therapeutically effective amount of Compound A per day, such as 5 to 1000 mg of Compound A per day, such as 5 to 500 mg or 5 to 250 mg of Compound A per day.
• a therapeutically effective amount of Compound A per day such as 5 to 1000 mg of Compound A per day, such as 5 to 500 mg or 5 to 250 mg of Compound A per day.
• the method or use can include administering (e.g., orally) about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about
• the method or use includes orally administering 10 to 200 mg of Compound A per day, such as 10, 15, 20, 25, 30, 35, or 40 mg to 75, 100, 125, 150, 175, or 200 mg of Compound A per day, including 20 to 150 mg per day to a subject (e.g., a human).
• the oral administration includes 50, 75, 100, or 125 mg of Compound A per day, such as 100 mg per day to a subject (e.g., a human).
• the above daily doses of Compound A are administered (e.g., orally) as multiple doses per day, such as in two, three, four, or five doses per day.
• a daily dose of 100 mg maybe administered in five 20 mg, four 25 mg, three 33.3 mg, or two 50 mg doses throughout the day.
• the above daily doses of Compound A are administered (e.g., orally) as a single dose.
• about 5, 10, 15, 20, 25, or 30 mg to about 50, 65, 75, 100, 125, or 150 mg of Compound A per day can be orally administered as a single dose, including 10-25 mg, 10-30 mg, and 10-40 mg per day as a single dose, such as 10-25 mg per day as a single dose.
• any of the doses of Compound A discussed in the preceding paragraphs may be included in a single unit dosage form or in multiple unit dosage forms, such as two, three, or four unit dosage forms.
• the methods and uses described herein for treating pain by administering include administering according to a 12-hour (i.e., twice-a-day), 24-hour (i.e., once-a-day), 48-hour (i.e., once-per-two-days), 72-hour, 96-hour, 5-day, 6-day, 1-week, or 2-week dosing regimen, particularly 12-hour, 24-hour, or 48-hour dosing regimens.
• Such regimens can involve administering any of the above-described doses or daily doses.
• the present disclosure provides methods of treating pain in a subject (e.g., a human) in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the subject according to 12-hour, 24- hour, 48-hour, 72-hour, 96-hour, 5-day, 6-day, 1-week, or 2-week intervals, particularly 12- hour, 24-hour, or 48-hour intervals, wherein the amount of Compound A corresponds to any of the above-described doses or daily doses.
• Compound A is orally administered to a human subject under fed conditions, e.g., from between about 30 minutes before to about 2 hour after eating a meal, including during a meal or within 15 minutes after eating a meal.
• the above-discussed methods or uses of treating pain by administering a therapeutically effective amount of Compound A comprises oral administration of Compound A to a human subject under fed conditions, e.g., from between about 30 minutes before to about 2 hour after eating a meal, including during a meal or within 15 minutes after eating a meal.
• the oral administration of Compound A to a human subject under fed conditions significantly enhances the bioavailability and exposure of Compound A as compared to the oral administration of Compound A to the subject under fasted conditions.
• the oral administration of Compound A to a human subject under fed conditions increases one or more pharmacokinetic parameters for Compound A (e.g., Cmax, AUCmf, Tmax, t etc.) as compared to when the same amount of Compound A is orally administered to the subject under fasted conditions.
• one or more pharmacokinetic parameters for Compound A e.g., Cmax, AUCmf, Tmax, t etc.
• the methods and uses described herein administer Compound A in the form of a pharmaceutically acceptable oral composition that comprises Compound A and one or more pharmaceutically acceptable carriers or excipients.
• the amount of Compound A included in these compositions may correspond to one or more of the amounts described herein.
• the compositions are a unit dose.
• Examples of pharmaceutically acceptable oral compositions that comprise Compound A include solid formulations (such as tablets, capsules, lozenges, dragees, granules, powders, wafers, multi-particulates, and films), liquid formulations (such as aqueous solutions, elixirs, tinctures, slurries, suspensions, and dispersions), and aerosolized formulations (such as mists and sprays).
• a pharmaceutically acceptable oral composition of Compound A includes a pediatric suspension or granulate. All above- noted amounts of Compound A may be included in such formulations, e.g., a capsule comprising 5, 10, 15, 10, 25, 30, or 35 mg of Compound A.
• compositions suitable for parenteral administration of Compound A include sterile injectable solutions, suspensions, or dispersions, including aqueous or oleaginous preparations, particularly aqueous.
• Compound A is administered according to a method or use described herein in an injectable sterile aqueous formulation that includes a parenterally-acceptable diluent or solvent, such as water, Ringer’s solution, isotonic sodium chloride solution, buffered aqueous solutions, and aqueous solutions containing a miscible alcohol, such as 1,3-butanediol.
• a parenterally-acceptable diluent or solvent such as water, Ringer’s solution, isotonic sodium chloride solution, buffered aqueous solutions, and aqueous solutions containing a miscible alcohol, such as 1,3-butanediol.
• kits are provided for oral administration of Compound A for the treatment of pain. Such kits comprise a plurality of oral unit dosage forms of Compound A in combination with instructions for orally administering Compound A.
• Example 1 Acetic Acid Induced Mouse Model of Visceral Pain
• the acetic acid test was performed to assess the potential efficacy of Compound A in the acetic acid writhing (AAW) model of inflammatory pain.
• the AAW test was performed as described previously (Yeping Bi et ak, “Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice. ” Mol. Pain 2011, 7:84; Gabriela F.
• Pavao-de-Souza et ah “Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI3K and microglia in mice ” Pharmacol. Biochem. Behav. 101 (2012) 320-328; Kazufumi Hirano et ah, “Kv7.2- 7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin- induced visceral pain in mice.” Neurosci. Lett. 413 (2007) 159-162; Mosad A.
• acetic acid was injected intraperitoneally at 0.4% concentration in 6-7 week old CD1 mice. After the injection of acetic acid, animals were placed in a chamber and their subsequent writhing behavior was video recorded. A writhe is defined as contraction of abdominal muscles accompanied by elongation of the body and extension of hind limbs or rotation of the trunk. Writhes were counted between 5-15 min after the injection of acetic acid. [0079] Selection of Acetic Acid Dose: Based on the concentration response (0.2-0.8%) of acetic acid in CD1 mice, EC75 concentration (0.4%) was selected to produce optimal writhing response. Diclofenac was used as positive control in the acetic acid model.
• the first study shows a dose-responsive decrease in the number of nociceptive events was observed through the dose groups (vehicle, 1 mg/kg, 3 mg/kg, and 10 mg/kg Compound A).
• the second study shows a decrease in the number of nociceptive events at 10 mg/kg Compound A.
• a PK/PD correlation was shown between Compound A concentrations in brain and plasma to the observed efficacy (FIG.l, PK/PD Correlation).
• the EC 50 (effective concentration to give a 50% reduction in nociceptive events) was 0.25 mM and 0.4 mM in plasma and brain respectively.
• Dosing For efficacy testing, Compound A was dosed orally once a day for 5 consecutive days from Day 14-18. Animals were evaluated again for tactile and thermal allodynia on Day 14 and Day 18 two hours after the administration of Compound A. Morphine was used as positive control. Table 3 shows the body weight of the rats over the duration of testing.
• Results Tables 4-5 and FIG. 3 show the results of the tactile allodynia von Frey evaluation on Day 14 and Day 18. Compared to morphine, neither Compound A nor retigabine had much effect on the tactile allodynia endpoint. This was not surprising for the Kv7.2 mechanism (see Blackbum-Munro and Jensen, Eur J Pharmacol, 460(2-3): 109-116 (2003)).
• Results Tables 6-7 and FIGs. 4-9 show the results of the thermal allodynia von Frey evaluation on Day 14 and Day 18.
• FIGs. 7-9 show that at both 16 and 24 mg/kg, Compound A outperformed morphine (128 mg/kg) in the thermal allodynia endpoint.
• Example 3 Crossover Study with Pharmacokinetic Analysis [0088] The pharmacokinetics (PK), safety, and tolerability of single doses of Compound A in healthy right-handed male human subjects were investigated in a randomized, double-blind, placebo-controlled, transcranial magnetic stimulation (TMS) crossover study.
• PK pharmacokinetics
• TMS transcranial magnetic stimulation
• An objective of the study was to evaluate the safety, tolerability, and pharmacokinetics of single doses of Compound A in healthy male subjects.
• Subjects were screened within 27 days prior to entering the study on Day 1. For Period 1, subjects were admitted to the study unit and dosed on Day 1, and discharged on Day 2. For Period 2, following a washout of 6 days, the same subjects were again admitted to the study unit and dosed on Day 7, and discharged on Day 8. All subjects returned to the clinical unit for an outpatient visit on Day 14, and received a follow-up telephone call on Day 37.
• PK variables included maximal plasma concentration (C max ), time of maximal plasma concentration (T max ), terminal elimination half-life (ti / 2), elimination rate constant (lz), area under the curve from 0 to 24 h (AUCo- 24h ), area under the curve from time zero to the last quantifiable concentration (AUCo- tiast ), area under the curve from time zero to infinity (AUCo-i nf ), the percentage of AUC that is due to extrapolation from tlast to infinity (%AUC extrap ), apparent total body clearance following oral administration (CL/F), CL/F normalized by body weight, mean residence time from time zero to the last quantifiable concentration (MRTi ast ), mean residence time extrapolated to infinity (MRTinf), apparent volume of distribution during the terminal phase (Vz/F), and Vz/F normalized by body weight.
• C max maximal plasma concentration
• T max time of maximal plasma concentration
• T max terminal elimination half-life
• lz elimination rate constant
• PK parameters for this study were summarized in two ways. Firstly, PK parameters were calculated where possible using the PK samples collected during each 24 h sampling period for Period 1 and Period 2 separately. Secondly, PK parameters were determined using samples beyond the 24 h sampling period (i.e., from Day 7/8 and/or Day 14). For subjects who received Compound A in the first period, PK samples taken prior to placebo treatment provided additional PK timepoints at >24 h. For subjects who received Compound A in the second period, there was no >24 h PK timepoint until a Day 14 PK sample was added. Thus, subjects randomized to receive Compound A in the second period who were enrolled prior to implementation of the additional PK sample at Day 14 did not have PK data beyond 24 h.
• the full PK profile data set consists of the 16 subjects for whom PK samples were taken at >24 h post-dose. For discussion of the PK parameters below, the full PK profile data set was generally used, because it allowed more accurate estimation of PK parameters.
• the mean ⁇ SD plasma concentrations were 15.9 ⁇ 21.4 ng/mL, 30.2 ⁇ 21.1 ng/mL and 42.1 ⁇ 19.1 ng/mL, respectively.
• Vz/F mean normalized volume of distribution
• Compound A was slowly absorbed after a 20 mg oral dose with median peak plasma concentrations occurring approximately 8 hours after administration. Upon absorption, it distributed out of plasma into surrounding tissues and was slowly cleared from systemic circulation at rates well below hepatic blood flow, indicating minimal hepatic extraction (metabolism). It exhibited a mean half-life of 127 h (range 48.2-306 h) and mean residence time of 102 h (range 33-304 h) which may be an underestimation since a number of subjects had %AUC extrap values above 20% and as high as 40%.

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