WO2023178250A1 - Traitement de la sclérose tubéreuse avec du mirdametinib - Google Patents

Traitement de la sclérose tubéreuse avec du mirdametinib Download PDF

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Publication number
WO2023178250A1
WO2023178250A1 PCT/US2023/064545 US2023064545W WO2023178250A1 WO 2023178250 A1 WO2023178250 A1 WO 2023178250A1 US 2023064545 W US2023064545 W US 2023064545W WO 2023178250 A1 WO2023178250 A1 WO 2023178250A1
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mirdametinib
free base
patient
per day
administered
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PCT/US2023/064545
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English (en)
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Uchenna H ILOEJE
Abraham J LANGSETH
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SpringWorks Therapeutics Inc.
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Publication of WO2023178250A1 publication Critical patent/WO2023178250A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to a method for treating tuberous sclerosis or a symptom thereof (e.g., tuberous sclerosis-related epilepsy) comprising administering to a patient in need thereof mirdametinib or a pharmaceutically acceptable salt thereof.
  • a method for treating tuberous sclerosis or a symptom thereof comprising administering to a patient in need thereof mirdametinib or a pharmaceutically acceptable salt thereof.
  • Tuberous sclerosis complex also known as tuberous sclerosis, is a rare genetic disease that causes non-cancerous (benign) tumors to grow in the brain and several areas of the body, including the spinal cord, nerves, eyes, lung, heart, kidneys, and skin.
  • the name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which are affected by calcium with age and become hard or sclerotic.
  • TSC is a lifelong condition. Currently there is no cure for TSC, but some symptoms can be treated. The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Some people with TSC are able to lead independent, productive lives, while others have symptoms that can affect everyday life and even be life-threatening.
  • TSC TSC
  • Brain tumors The three types of brain lesions seen in TSC are: • Cortical tubers, for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain.
  • SEN Subependymal nodules
  • SEGA Subependymal giant-cell astrocytomas
  • tumors can form in the hearts of infants and young children with TSC (called rhabdomyomas) and in the eyes (called phakomas).
  • Other tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas.
  • Autism Spectrum Disorder There is a strong relationship between autism spectrum disorder and TSC. Many children with TSC develop autism spectrum disorder.
  • Mirdametinib is an allosteric, small molecule targeting mitogen-activated protein kinase kinase (MEK).
  • MEK mitogen-activated protein kinase kinase
  • the present invention relates to a method for treating tuberous sclerosis complex (TSC) in a human patient (e.g., a patient in need thereof) comprising administering (e.g., orally) to the patient mirdametinib or a pharmaceutically acceptable salt thereof.
  • a human patient e.g., a patient in need thereof
  • administering e.g., orally
  • the patient is a pediatric patient.
  • the patient may be concomitantly treated with (or administered) an anti-seizure medication.
  • TSC tuberous sclerosis complex
  • a human patient e.g., a patient in need thereof
  • the one or more symptoms associated with TSC include, but are not limited to, tumors (e.g., brain tumors, such as cortical tumors, subependymal nodules, or subependymal giant-cell astrocytomas), seizures, epilepsy (e.g., medically refractory epilepsy), cognitive difficulties, behavioral problems, autistic spectrum disorder, and any combination of any of the foregoing.
  • tumors e.g., brain tumors, such as cortical tumors, subependymal nodules, or subependymal giant-cell astrocytomas
  • seizures e.g., epilepsy (e.g., medically refractory epilepsy), cognitive difficulties, behavioral problems, autistic spectrum disorder, and any combination of any of the foregoing.
  • the present invention relates to a method for treating epilepsy (e.g., medically refractory epilepsy) associated with TSC in a patient (e.g., a patient in need thereof) comprising administering mirdametinib, or a pharmaceutically acceptable salt thereof, to the patient.
  • the patient is concomitantly treated with (or administered) one or more anti- seizure medications.
  • the anti-seizure medications can be administered separately or with the mirdametinib.
  • the patient has tuberous sclerosis complex (TSC) and medically refractory epilepsy.
  • TSC tuberous sclerosis complex
  • Another aspect is a method of treating medically refractory tuberous sclerosis- related epilepsy in a human patient in need thereof by administering an effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, (e.g., mirdametinib) to the patient.
  • the patient’s epilepsy has failed to be adequately controlled by two different anti- seizure medications.
  • the patient’s epilepsy failed to be adequately controlled with two anti-seizure medications and the patient has at least 8 seizures in the 28 days preceding treatment with mirdametinib, or a pharmaceutically acceptable salt thereof.
  • the patient may be treated concomitantly with one or more anti-seizure medications.
  • a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof is administered.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/m 2 to about 10 mg/m 2 per day based on mirdametinib free base.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg/m 2 to about 10 mg/m 2 based on mirdametinib free base. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mirdametinib free base.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily. [0024] In one embodiment, 1 mg/m 2 is orally administered twice daily to the patient. In another embodiment, 2 mg/m 2 is orally administered twice daily to the patient. In yet another embodiment, 3 mg/m 2 is orally administered twice daily to the patient.
  • the patient is initially orally administered 4 mg mirdametinib twice daily (i.e., a total of 8 mg daily).
  • the patient is initially orally administered 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the patient is initially orally administered 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the patient is initially orally administered 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the patient is initially orally administered 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the patient is initially orally administered 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the dose administered is reduced due to an adverse event, wherein the dose is reduced as follows:
  • the adverse event resulting in the dose reduction is acneiform.
  • the method comprises orally administering 1 mg mirdametinib twice daily (i.e., a total of 2 mg daily).
  • the maximum oral daily dose administered to the patient is 4 mg mirdametinib twice daily (i.e., a total of 8 mg daily).
  • about 2 mg/m 2 mirdametinib is orally administered to the patient twice daily.
  • the mirdametinib is administered for the first three weeks and discontinued for the last one week.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof exhibits high blood-brain-barrier penetration.
  • the patient is a human.
  • the human has an age of > 2 and ⁇ 25.
  • the human has had no prior exposure to MEK inhibitors.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is dispersible in a potable liquid or orodispersible in a patient’s saliva. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally as a solid dosage form. In some embodiments of any of the methods described herein, the solid dosage form is a tablet or capsule. In some embodiments of any of the methods described herein, the solid dosage form is a capsule.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat tuberous sclerosis complex. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy to treat one or more symptoms associate with tuberous sclerosis complex. [0039] In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient (e.g., one or more anti-seizure medications) and/or surgery to treat tuberous sclerosis complex.
  • another active ingredient e.g., one or more anti-seizure medications
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient (e.g., one or more anti-seizure medications) and/or surgery to treat one or more symptoms associated with tuberous sclerosis complex.
  • another active ingredient e.g., one or more anti-seizure medications
  • mirdametinib refers to the single enantiomer N-(( R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • mg/m 2 refers to the dose in milligrams per m 2 body surface area of the patient.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse e.g., cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • patient and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the patient is a human patient, such as a pediatric patient.
  • the term "pediatric” refers to a human subject under the age of 21 years at the time of treatment.
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); young children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • neonates from birth through the first 28 days of life
  • infants 29 days of age to less than two years of age
  • young children two years of age to less than 12 years of age
  • adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman R E Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996
  • Rudolph A M et al. Rudolph's Pediatrics, 21st Ed.
  • the pediatric patient is 2 to 8 years of age, 2 to 7 years of age, 2 to 6 years of age or 2 to 5 years of age. Younger pediatric patients in particular, such as neonates, infants and young children, can have difficulty swallowing whole capsules or tablets.
  • the term “dispersible” as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) which disintegrates and/or dissolves when combined with water or another potable liquid (e.g., a non-water beverage), or a subject’s own saliva when placed in the subject’s mouth, with or without the addition of agitation or temperature modification.
  • the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid.
  • Such disintegration or dissolution need not be complete.
  • a dispersible tablet may dissolve almost entirely, but some undissolved particulate matter may remain.
  • orodispersible refers to a composition which is capable of dissolving or disintegrating in a subject’s mouth (i.e., dissolving or disintegrating in a subject’s saliva) if administered orally, without a requirement of first dissolving or disintegrating in a separate container.
  • the terms “treat,” “treated,” and “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • those in need of treatment include those already diagnosed with or suspected of having the disorder.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • therapeutically effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a subject is successfully "treated” for a tumor, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor; a reduction in the volume of the tumor, improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • a subject is successfully "treated” for cancer, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor; a reduction in the number of or complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer, reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable salts refers to the relatively non- toxic, inorganic and organic acid addition salts of mirdametinib. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include, but are not limited to, the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts. See, e.g., Berge etal., " Pharmaceutical Salts”, J. Pharm. Set, 66, 1-19, 1977.
  • the pharmaceutically acceptable salts of mirdametinib also include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as, e.g., hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isothionic.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • TSC tuberous sclerosis complex
  • TSC tuberous sclerosis complex
  • a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof is administered.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/m 2 to about 10 mg/m 2 per day based on mirdametinib free base, about 1.5 mg/m 2 to about 9.5 mg/m 2 per day based on mirdametinib free base, about 2 mg/m 2 to about 9 mg/m 2 per day based on mirdametinib free base, about 2.5 mg/m 2 to about 8.5 mg/m 2 per day based on mirdametinib free base, about 3 mg/m 2 to about 8 mg/m 2 per day based on mirdametinib free base, about 3.5 mg/m 2 to about 7.5 mg/m 2 per day based on mirdametinib free base, about 4 mg/m 2 to about 7 mg/m 2 per day based on mirdametinib free base, about 4.5 mg/m 2 to about 6.5 mg/
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/m 2 per day based on mirdametinib free base, about 1.5 mg/m 2 per day based on mirdametinib free base, about 2 mg/m 2 per day based on mirdametinib free base, about 2.5 mg/m 2 per day based on mirdametinib free base, about 3 mg/m 2 per day based on mirdametinib free base, about 3.5 mg/m 2 per day based on mirdametinib free base, about 4 mg/m 2 per day based on mirdametinib free base, about 4.5 mg/m 2 per day based on mirdametinib free base, about 5 mg/m 2 per day based on mirdametinib free base, about 5.5 mg/m 2 per day based on mirdametinib free base, about 6 mg/
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg to about 20 mg per day based on mirdametinib free base, about 1.5 mg to about 19.5 mg per day based on mirdametinib free base, about 2 mg to about 19 mg per day based on mirdametinib free base, about 2.5 mg to about 18.5 mg per day based on mirdametinib free base, about 3 mg to about 18 mg per day based on mirdametinib free base, about 3.5 mg to about 17.5 mg per day based on mirdametinib free base, about 4 mg to about 17 mg per day based on mirdametinib free base, about 4.5 mg to about 16.5 mg per day based on mirdametinib free base, about 5 mg to about 16 mg per day based on mirdametinib free base, about 5.5 mg to about 15.5 mg per day
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg per day based on mirdametinib free base, about 1.5 mg per day based on mirdametinib free base, about 2 mg per day based on mirdametinib free base, about 2.5 mg per day based on mirdametinib free base, about 3 mg per day based on mirdametinib free base, about 3.5 mg per day based on mirdametinib free base, about 4 mg per day based on mirdametinib free base, about
  • mirdametinib free base about 5 mg per day based on mirdametinib free base, about 5.5 mg per day based on mirdametinib free base, about 6 mg per day based on mirdametinib free base, about 6.5 mg per day based on mirdametinib free base, about 7 mg per day based on mirdametinib free base, about 7.5 mg per day based on mirdametinib free base, about 8 mg per day based on mirdametinib free base, about 8.5 mg per day based on mirdametinib free base, about 9 mg per day based on mirdametinib free base, about 9.5 mg per day based on mirdametinib free base, about 10 mg per day based on mirdametinib free base, about 10.5 mg per day based on mirdametinib free base, about 11 mg per day based on mirdametinib
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg/m 2 to about 10 mg/m 2 based on mirdametinib free base, about 0.5 mg/m 2 to about 9.5 mg/m 2 based on mirdametinib free base, about 1 mg/m 2 to about 9 mg/m 2 based on mirdametinib free base, about 1.5 mg/m 2 to about 8.5 mg/m 2 based on mirdametinib free base, about 2 mg/m 2 to about 8 mg/m 2 based on mirdametinib free base, about 2.5 mg/m 2 to about 7.5 mg/m 2 based on mirdametinib free base, about 3 mg/m 2 to about 7 mg/m 2 based on mirdametinib free base, about 3.5 mg/m 2 to about 6.5 mg/m 2 based on mirdametin
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg/m 2 based on mirdametinib free base, about 0.2 mg/m 2 based on mirdametinib free base, about 0.3 mg/m 2 based on mirdametinib free base, about 0.4 mg/m 2 based on mirdametinib free base, about 0.5 mg/m 2 based on mirdametinib free base, about 1 mg/m 2 based on mirdametinib free base, about 1.5 mg/m 2 based on mirdametinib free base, about 2 mg/m 2 based on mirdametinib free base, about 2.5 mg/m 2 based on mirdametinib free base, about 3 mg/m 2 based on mirdametinib free base, about 3.5 mg/m 2 based on mirdametinib free base
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mirdametinib free base, about 0.5 mg to about 9.5 mg based on mirdametinib free base, about 1 mg to about 9 mg based on mirdametinib free base, about 1.5 mg to about 8.5 mg based on mirdametinib free base, about 2 mg to about 8 mg based on mirdametinib free base, about 2.5 mg to about 7.5 mg based on mirdametinib free base, about 3 mg to about 7 mg based on mirdametinib free base, about 3.5 mg to about 6.5 mg based on mirdametinib free base, about 4 mg to about 6 mg based on mirdametinib free base, or about 4.5 mg to about 5.5 mg based on mirdametinib free base.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg based on mirdametinib free base, about 0.2 mg based on mirdametinib free base, about 0.3 mg based on mirdametinib free base, about 0.4 mg based on mirdametinib free base, about 0.5 mg based on mirdametinib free base, about 1 mg based on mirdametinib free base, about 1.5 mg based on mirdametinib free base, about 2 mg based on mirdametinib free base, about 2.5 mg based on mirdametinib free base, about 3 mg based on mirdametinib free base, about 3.5 mg based on mirdametinib free base, about 4 mg based on mirdametinib free base, about 4.5 mg based on mirdametinib free base
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered one, two, three, or four times per day. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 0.5 mg/m 2 to about 10 mg/m 2 based on mirdametinib free base, about 1 mg/m 2 to about 9.5 mg/m 2 based on mirdametinib free base, about 1.5 mg/m 2 to about 9 mg/m 2 based on mirdametinib free base, about 2 mg/m 2 to about 8.5 mg/m 2 based on mirdametinib free base, about 2.5 mg/m 2 to about 8 mg/m 2 based on mirdametinib free base, about 3 mg/m 2 to about 7.5 mg/m 2 based on mirdametinib free base, about 3.5 mg/m 2 to about 7 mg/m 2 based on mirdametinib free base, about 4 mg/m 2 to about 6.5 mg/m 2 based on mirdametinib free
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 0.5 mg/m 2 based on mirdametinib free base, about 1 mg/m 2 based on mirdametinib free base, about 1.5 mg/m 2 based on mirdametinib free base, about 2 mg/m 2 based on mirdametinib free base, about 2.5 mg/m 2 based on mirdametinib free base, about 3 mg/m 2 based on mirdametinib free base, about 3.5 mg/m 2 based on mirdametinib free base, about 4 mg/m 2 based on mirdametinib free base, about 4.5 mg/m 2 based on mirdametinib free base, about 5 mg/m 2 based on mirdametinib free base, about 5.5 mg/m 2 based on mirdametinib free base, about 6 mg
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 0.5 mg to about 10 mg based on mirdametinib free base, about 1 mg to about 9.5 mg based on mirdametinib free base, about 1.5 mg to about 9 mg based on mirdametinib free base, about 2 mg to about 8.5 mg based on mirdametinib free base, about 2.5 mg to about 8 mg based on mirdametinib free base, about 3 mg to about 7.5 mg based on mirdametinib free base, about 3.5 mg to about 7 mg based on mirdametinib free base, about 4 mg to about 6.5 mg based on mirdametinib free base, about
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 0.5 mg based on mirdametinib free base, about 1 mg based on mirdametinib free base, about 1.5 mg based on mirdametinib free base, about 2 mg based on mirdametinib free base, about
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a total daily dose that does not exceed about 10 mg/m 2 based on mirdametinib free base, about 9.5 mg/m 2 based on mirdametinib free base, about 9 mg/m 2 based on mirdametinib free base, about 8.5 mg/m 2 based on mirdametinib free base, about 8 mg/m 2 based on mirdametinib free base, about 7.5 mg/m 2 based on mirdametinib free base, about 7 mg/m 2 based on mirdametinib free base, about 6.5 mg/m 2 based on mirdametinib free base, about 6 mg/m 2 based on mirdametinib free base, about 5.5 mg/m 2 based on mirdametinib free base, about 5 mg/m 2 based on mirdamet
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in a total daily dose that does not exceed about 20 mg based on mirdametinib free base, about 19.5 mg based on mirdametinib free base, about 19 mg based on mirdametinib free base, about 18.5 mg based on mirdametinib free base, about 18 mg based on mirdametinib free base, about 17.5 mg based on mirdametinib free base, about 17 mg based on mirdametinib free base, about 16.5 mg based on mirdametinib free base, about 16 mg based on mirdametinib free base, about 15.5 mg based on mirdametinib free base, about 15 mg based on mirdametinib free base, about 14.5 mg based on mirdametinib free base, about 14 mg based on mirdametin
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as mirdametinib free base.
  • the present invention relates to a method for treating tuberous sclerosis complex (TSC) in a patient (e.g., a patient in need thereof) comprising administering mirdametinib free base to the patient.
  • TSC tuberous sclerosis complex
  • a therapeutically effective amount of mirdametinib free base is administered.
  • the mirdametinib free base is administered in an amount of about 1 mg/m 2 to about 10 mg/m 2 per day, about 1.5 mg/m 2 to about 9.5 mg/m 2 per day, about 2 mg/m 2 to about 9 mg/m 2 per day, about 2.5 mg/m 2 to about 8.5 mg/m 2 per day, about 3 mg/m 2 to about 8 mg/m 2 per day, about 3.5 mg/m 2 to about 7.5 mg/m 2 per day, about 4 mg/m 2 to about 7 mg/m 2 per day, about 4.5 mg/m 2 to about 6.5 mg/m 2 per day, or about 5 mg/m 2 to about 6 mg/m 2 per day.
  • any of the per day about 1.5 mg/m 2 per day, about 2 mg/m 2 per day, about 2.5 mg/m 2 per day, about 3 mg/m 2 per day, about 3.5 mg/m 2 per day, about 4 mg/m 2 per day, about 4.5 mg/m 2 per day, about 5 mg/m 2 per day, about 5.5 mg/m 2 per day, about 6 mg/m 2 per day, about 6.5 mg/m 2 per day, about 7 mg/m 2 per day, about 7.5 mg/m 2 per day, about 8 mg/m 2 per day, about 8.5 mg/m 2 per day, about 9 mg/m 2 per day, about 9.5 mg/m 2 per day, or about 10 mg/m 2 per day.
  • the mirdametinib free base is administered in an amount of about 1 mg to about 20 mg per day, about
  • the mirdametinib free base is administered in an amount of about 1 mg per day, about 1.5 mg per day, about 2 mg per day, about 2.5 mg per day, about 3 mg per day, about 3.5 mg per day, about 4 mg per day, about 4.5 mg per day, about 5 mg per day, about 5.5 mg per day, about 6 mg per day, about 6.5 mg per day, about 7 mg per day, about 7.5 mg per day, about 8 mg per day, about 8.5 mg per day, about 9 mg per day, about 9.5 mg per day, about 10 mg per day, about 10.5 mg per day, about 11 mg per day, about 11.5 mg per day, about 12 mg per day, about 12.5 mg per day, about 13 mg per day, about 13.5 mg per day, about 14 mg per day, about 14.5 mg per day, about 15 mg per day, about 15.5 mg per day, about 16 mg per day, about 16.5 mg per day, about 17 mg per day, about 17.5 mg per day, about 18 mg per day, about
  • the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg/m 2 to about 10 mg/m 2 , about 0.5 mg/m 2 to about 9.5 mg/m 2 , about 1 mg/m 2 to about 9 mg/m 2 , about 1.5 mg/m 2 to about 8.5 mg/m 2 , about 2 mg/m 2 to about 8 mg/m 2 , about 2.5 mg/m 2 to about 7.5 mg/m 2 , about 3 mg/m 2 to about 7 mg/m 2 , about 3.5 mg/m 2 to about 6.5 mg/m 2 , about 4 mg/m 2 to about 6 mg/m 2 , or about 4.5 mg/m 2 to about 5.5 mg/m 2 .
  • the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg/m 2 , about 0.2 mg/m 2 , about 0.3 mg/m 2 , about 0.4 mg/m 2 , about 0.5 mg/m 2 , about 1 mg/m 2 , about 1.5 mg/m 2 , about 2 mg/m 2 , about 2.5 mg/m 2 , about 3 mg/m 2 , about 3.5 mg/m 2 , about 4 mg/m 2 , about 4.5 mg/m 2 , about 5 mg/m 2 , about 5.5 mg/m 2 , about 6 mg/m 2 , about 6.5 mg/m 2 , about 7 mg/m 2 , about 7.5 mg/m 2 , about 8 mg/m 2 , about 8.5 mg/m 2 , about 9 mg/m 2 , about 9.5 mg/m 2 , or about 10 mg/m 2 .
  • the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg to about 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg, about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg, or about 4.5 mg to about 5.5 mg.
  • the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.
  • the mirdametinib free base is administered one, two, three, or four times per day. In some aspects, the mirdametinib free base is administered once daily. In some embodiments of any of the methods described herein, the mirdametinib free base is administered twice daily. In some embodiments of any of the methods described herein, the mirdametinib free base is administered three times daily. In some embodiments of any of the methods described herein, the mirdametinib free base is administered four times daily.
  • the mirdametinib free base is administered twice daily in an amount of about 0.5 mg/m 2 to about 10 mg/m 2 , about 1 mg/m 2 to about 9.5 mg/m 2 , about 1.5 mg/m 2 to about 9 mg/m 2 , about 2 mg/m 2 to about 8.5 mg/m 2 , about 2.5 mg/m 2 to about 8 mg/m 2 , about 3 mg/m 2 to about 7.5 mg/m 2 , about 3.5 mg/m 2 to about 7 mg/m 2 , about 4 mg/m 2 to about 6.5 mg/m 2 , about 4.5 mg/m 2 to about 6 mg/m 2 , or about 5 mg/m 2 to about 6 mg/m 2 .
  • the mirdametinib free base is administered twice daily in an amount of about 0.5 mg/m 2 , about 1 mg/m 2 , about 1.5 mg/m 2 , about 2 mg/m 2 , about 2.5 mg/m 2 , about 3 mg/m 2 , about 3.5 mg/m 2 , about 4 mg/m 2 , about 4.5 mg/m 2 , about 5 mg/m 2 , about 5.5 mg/m 2 , about 6 mg/m 2 , about 6.5 mg/m 2 , about 7 mg/m 2 , about 7.5 mg/m 2 , about 8 mg/m 2 , about 8.5 mg/m 2 , about 9 mg/m 2 , about 9.5 mg/m 2 , or about 10 mg/m 2 .
  • the mirdametinib free base is administered twice daily in an amount of about 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg, about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg to about 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg, about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, or about 5 mg to about 6 mg.
  • the mirdametinib free base is administered twice daily in an amount of about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.
  • the mirdametinib free base is administered in a total daily dose that does not exceed about 10 mg/m 2 , about 9.5 mg/m 2 , about 9 mg/m 2 , about 8.5 mg/m 2 , about 8 mg/m 2 , about 7.5 mg/m 2 , about 7 mg/m 2 , about 6.5 mg/m 2 , about 6 mg/m 2 , about 5.5 mg/m 2 , about 5 mg/m 2 , about 4.5 mg/m 2 , about 4 mg/m 2 , about 3.5 mg/m 2 , about 3 mg/m 2 , about 2.5 mg/m 2 , about 2 mg/m 2 , or about 1.5 mg/m 2 .
  • die mirdametinib free base is administered in a total daily dose that does not exceed about 20 mg, about 19.5 mg, about 19 mg, about 18.5 mg, about 18 mg, about 17.5 mg, about 17 mg, about 16.5 mg, about 16 mg, about 15.5 mg, about 15 mg, about 14.5 mg, about 14 mg, about 13.5 mg, about 13 mg, about 12.5 mg, about 12 mg, about 11.5 mg, about 11 mg, about 10.5 mg, about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof exhibits high blood-brain-barrier penetration.
  • the patient is a human.
  • the human has an age of > 2 and ⁇ 25 years. In some embodiments of any of the methods described herein, the human has an age of >2 and ⁇ 18 years.
  • the human has had no prior exposure to one or more MEK inhibitors. In some embodiments of any of the methods described herein, the human has not responded to prior treatment to one or more MEK inhibitors.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally as a solid dosage form. In some embodiments of any of the methods described herein, the solid dosage form is a tablet or capsule. In some embodiments of any of the methods described herein, the solid dosage form is a capsule. In some embodiments of any of the methods described herein, the mirdametinib, or a pharmaceutically acceptable salt thereof, is dispersible in a potable liquid or orodispersible in a patient’s saliva.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat tuberous sclerosis complex.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and/or surgery to treat tuberous sclerosis complex.
  • the patient is concomitantly administered one or more anti-seizure medications.
  • anti-seizure medications include aldehydes (e.g., paraldehyde), aromatic allylic alcohols (e.g., stiripentol), benzodiazepines (e.g., clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, and nimetazepam), barbiturates (e.g., phenobarbital, methylphenobarbital, and barbexaclone), bromides (e.g., potassium bromide), carbamates (e.g., felbamate), carboxamides (e.g., carbamazepine, oxcarbazepine, and eslicarbazepine acetate), fatty acids (e
  • the anti-seizure medication is a benzodiazepine, for example, midazolam. In other aspects, the anti-seizure medication is a barbiturate. In still other aspects, the anti-seizure medication is a hydantoin. In some aspects, the anti-seizure medication is paraldehyde. In other aspects, the anti-seizure medication is potassium bromide. In some aspects, the anti-seizure medication is a fatty acid. In other aspects, the anti- seizure medication is topiramate.
  • Example 1 Phase 1/2 Evaluation of Single Agent Mirdametinib (PD-0325901) a Brain- Penetrant MEK1/2 Inhibitor, for the Treatment of Children and Adults with Medically Refractory Tuberous Sclerosis-Related Epilepsy
  • Table 1 Study Summary of Phase 1/2 Evaluation of Single Agent Mirdametinib in Tuberous Sclerosis Complex (TSC) and Medically Refractory Epilepsy.

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Abstract

La présente invention concerne une méthode de traitement de la sclérose tubéreuse ou d'un symptôme de celle-ci (par exemple, l'épilepsie associée à la sclérose tubéreuse réfractaire au traitement médical), comprenant l'administration, chez un patient dont l'état le nécessite, de mirdametinib ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2023/064545 2022-03-17 2023-03-16 Traitement de la sclérose tubéreuse avec du mirdametinib WO2023178250A1 (fr)

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Citations (3)

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US20120207767A1 (en) * 2006-03-13 2012-08-16 Osi Pharmaceuticals, Llc. Combined Treatment with an EGFR Kinase Inhibitor and an Agent that Sensitizes Tumor Cells to the Effects of EGFR Kinase Inhibitors
US20120213778A1 (en) * 2000-12-08 2012-08-23 Luca Rastelli Method of detecting and treating tuberous sclerosis complex associated disorders
US20140128377A1 (en) * 2006-06-15 2014-05-08 Ucb Pharma Gmbh Methods of treating refractory repetitive seizures

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US20120213778A1 (en) * 2000-12-08 2012-08-23 Luca Rastelli Method of detecting and treating tuberous sclerosis complex associated disorders
US20120207767A1 (en) * 2006-03-13 2012-08-16 Osi Pharmaceuticals, Llc. Combined Treatment with an EGFR Kinase Inhibitor and an Agent that Sensitizes Tumor Cells to the Effects of EGFR Kinase Inhibitors
US20140128377A1 (en) * 2006-06-15 2014-05-08 Ucb Pharma Gmbh Methods of treating refractory repetitive seizures

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NGUYEN LENA H.; LEISER STEVEN C.; SONG DEKUN; BRUNNER DANIELA; ROBERDS STEVEN L.; WONG MICHAEL; BORDEY ANGELIQUE: "Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex", EPILEPSY RESEARCH, ELSEVIER SCIENCE PUBLISHERS , AMSTERDAM, NL, vol. 181, 18 February 2022 (2022-02-18), NL , XP086993394, ISSN: 0920-1211, DOI: 10.1016/j.eplepsyres.2022.106890 *

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