WO2013010015A2 - Combination als therapy - Google Patents

Combination als therapy Download PDF

Info

Publication number
WO2013010015A2
WO2013010015A2 PCT/US2012/046523 US2012046523W WO2013010015A2 WO 2013010015 A2 WO2013010015 A2 WO 2013010015A2 US 2012046523 W US2012046523 W US 2012046523W WO 2013010015 A2 WO2013010015 A2 WO 2013010015A2
Authority
WO
WIPO (PCT)
Prior art keywords
riluzole
subject
administered
therapeutically effective
effective amount
Prior art date
Application number
PCT/US2012/046523
Other languages
English (en)
French (fr)
Other versions
WO2013010015A3 (en
Inventor
Jesse Cedarbaum
John Mao
Fady Malik
Andrew A. Wolff
Original Assignee
Cytokinetics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NZ619924A priority Critical patent/NZ619924B2/en
Priority to JP2014520335A priority patent/JP6145946B2/ja
Priority to CA2849213A priority patent/CA2849213A1/en
Priority to EA201490011A priority patent/EA028060B1/ru
Priority to KR1020147000783A priority patent/KR101951220B1/ko
Priority to AU2012281042A priority patent/AU2012281042B2/en
Priority to US14/131,649 priority patent/US10272082B2/en
Priority to EP12811325.5A priority patent/EP2731611B1/en
Priority to IN200DEN2014 priority patent/IN2014DN00200A/en
Application filed by Cytokinetics, Inc. filed Critical Cytokinetics, Inc.
Priority to PH1/2014/500094A priority patent/PH12014500094A1/en
Priority to MX2014000455A priority patent/MX2014000455A/es
Priority to CN201280034661.5A priority patent/CN104039148A/zh
Priority to BR112014000742A priority patent/BR112014000742A2/pt
Priority to HK14110537.3A priority patent/HK1197178A1/xx
Publication of WO2013010015A2 publication Critical patent/WO2013010015A2/en
Priority to IL230391A priority patent/IL230391B/en
Priority to ZA2014/00236A priority patent/ZA201400236B/en
Publication of WO2013010015A3 publication Critical patent/WO2013010015A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • ALS Amyotrophic lateral sclerosis
  • ALS is a degenerative and progressive disorder of the nervous system. ALS is characterized by progressive loss of motor neurons in the lateral column of the spinal cord and/or motor cortex. With progressive loss of motor neurons, the innervation to skeletal muscle is lost which results in an inability to ambulate, conduct daily activities and affects swallowing and breathing.
  • ALS is a rare and usually fatal disease; its progression can be variable but on average patients end up dying within 3 years of diagnosis. Most patients succumb to respiratory failure with broncho-pneumonia and pneumonia as the main causes of death. Treatment is supportive because no curative treatment exists.
  • Riluzole currently is the only drug approved to treat ALS. While the exact mechanism of action of riluzole is unknown, it is believed to act by inhibiting the deleterious effects of an overload of glutamic acid and other
  • 6-Ethynyl-1 -(pentan-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one is a selective activator of the fast skeletal muscle troponin complex, which sensitizes fast skeletal muscle to calcium and results in an amplification of the response to neuromuscular input, an increase in muscle power, and a decrease in the fatigability of muscle (see, e.g., U.S. Patent No. 7,598,248).
  • the use of CK-2017357 is being studied for use in the treatment of patients with ALS.
  • treatment with CK-2017357 may improve activities of daily living (such as ambulation, breathing and feeding), reduce hospitalizations, and possibly prolong the survival of patients with ALS.
  • CK-2017357 has been shown to be a mechanism-based inhibitor of human CYP1A2 in vitro, with a K
  • activation constant
  • ki n act maximum rate constant for inactivation
  • riluzole is primarily metabolized by CYP1A2 (see, e.g., Sanderink et al., J. Pharmacol. & Exp. Ther. (1997), 282(3): 1465-72).
  • a method for treating ALS in a subject comprising administering to the subject a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357.
  • riluzole exposure e.g., C max and/or AUC 24 h
  • riluzole exposure e.g., C ma x and/or AUC2 4 h
  • a method of increasing the exposure of riluzole e.g., Cmax and/or AUC 24 h
  • administering comprising administering to the subject a therapeutically effective amount of CK-2017357.
  • Also provided is a method for reducing the incidence and/or severity of adverse events in a subject treated with riluzole comprising administering to the subject treated with riluzole a therapeutically effective amount of CK-2017357.
  • composition comprising a
  • Figure 1 provides mean riluzole plasma concentration as a function of time for riluzole alone (50 mg single dose) and riluzole (50 mg single dose) and CK-2017357 (250 mg daily x 1 1 days in healthy subjects.
  • Figure 2 illustrates the effect of steady-state CK-2017357 on riluzole pharmacokinetics in healthy subjects.
  • Panel A provides Cmaxfor riluzole alone (50 mg single dose) and riluzole (50 mg single dose) + CK-2017357 (250 mg daily for 1 1 days).
  • Panel B provides AUC inf for riluzole alone (50 mg single dose) and riluzole (50 mg single dose) + CK-2017357 (250 mg daily for 1 1 days).
  • the figure shows that in healthy subjects, the inter-subject variability of C ma x of riluzole has been reduced through co-administration of CK-2017357.
  • Figure 3 provides mean riluzole plasma concentration as a function of time for 50 mg riluzole administered BID and CK-2017357 administered at either 250 or 500 mg single dose in ALS patients.
  • Figure 4 shows a study flow diagram for a clinical study investigating a twice-daily dose titration regimen of CK-2017357 in patients with ALS.
  • AUC 24h is the area under the plasma concentration- time curve from hour 0 to the last measurable plasma concentration (e.g., 24 hours), calculated by the linear trapezoidal rule.
  • ALS or amyotrophic lateral sclerosis refers to the motor neuron disease commonly known as Lou Gehrig's Disease, and in some embodiments, amyotrophic lateral sclerosis with early bulbar involvement or the bulbar form of the disease, and in some embodiments, "limb-onset" ALS.
  • QD refers to once a day.
  • BID refers to twice a day.
  • C max refers to maximum plasma concentration
  • fm refers to fraction metabolized
  • a method for treating ALS in a subject comprising administering to the subject a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357.
  • administering the riluzole in combination with CK-2017357 extends survival and/or time to tracheostomy.
  • the therapeutically effective amount of riluzole administered in combination with CK-2017357 is a smaller dose than the therapeutically effective amount of riluzole when administered singly (i.e., without CK-2017357 treatment). In some embodiments, both the therapeutically effective amount of riluzole and the therapeutically effective amount of CK-2017357 when administered in combination are smaller doses than the therapeutically effective amount of riluzole and the therapeutically effective amount of CK-2017357 when each is administered singly.
  • the administration of riluzole is BID. In some embodiments, the administration of riluzole is QD.
  • the administration of CK-2017357 is BID. In some embodiments, the administration is QD.
  • the administration of riluzole is QD and the administration of CK-2017357 is BID. In some embodiments, the administration of riluzole is BID and the administration of CK-2017357 is BID. [033] In some embodiments, the administration of riluzole is QD and the administration of CK-2017357 is QD. In some embodiments, the administration of riluzole is BID and the administration of CK-2017357 is QD.
  • the CK-2017357 is administered in two or more doses at different times (e.g., once in the morning and once in the evening). In some embodiments, the CK-2017357 is administered in two or more equal doses. In some embodiments, the CK-2017357 is administered in two or more different doses. In some embodiments, the dose of CK-2107357 is titrated over time to a different (e.g., higher) daily dose level.
  • single daily dose of 50 mg riluzole is
  • CK- 2017357 administered in combination with a therapeutically effective amount of CK- 2017357.
  • a single daily dose of 50 mg riluzole is administered in combination with a total daily dose of between about 125 mg and 2000 mg of CK-2017357.
  • a single daily dose of 50 mg riluzole is administered in combination with a total daily dose of 125, 250, 375, or 500 mg of CK-2017357.
  • a twice daily dose of 25 mg riluzole is
  • a twice daily dose of 25 mg riluzole is
  • a twice daily dose of 25 mg riluzole is administered in combination with a total daily dose of 125, 250, 375, or 500 mg of CK-2017357.
  • a single daily dose of 25 mg riluzole is administered in combination with a therapeutically effective amount of CK- 2017357. In some embodiments, a single daily dose of 25 mg riluzole is administered in combination with a total daily dose of between about 125 mg and 2000 mg of CK-2017357. In some embodiments, a single daily dose of 25 mg riluzole is administered in combination with a total daily dose of 125, 250, 375, or 500 mg of CK-2017357.
  • a twice daily dose of 12.5 mg riluzole is administered in combination with a therapeutically effective amount of CK- 2017357. In some embodiments, a twice daily dose of 12.5 mg riluzole is administered in combination with a total daily dose of between about 125 mg and 2000 mg of CK-2017357. In some embodiments, a twice daily dose of 12.5 mg riluzole is administered in combination with 125, 250, 375, or 500 mg of CK- 2017357.
  • riluzole exposure e.g., C max and/or AUC 24h
  • riluzole exposure e.g., C max and/or AUC 24h
  • the adverse event is a CNS-related adverse event (see, e.g., Mashiro et al., Anesthesia & Analgesia (2007), 104:1415-21 ).
  • CK-2017357 is administered to the subject concurrently with riluzole administration, i.e., CK-2017357 and riluzole are administered simultaneously, essentially simultaneously or within the same treatment protocol.
  • concurrent administration i.e., CK-2017357 and riluzole are administered simultaneously, essentially simultaneously or within the same treatment protocol.
  • administration of CK-2017357 and riluzole begin and end at the same time (i.e., on the same day or within the same treatment protocol).
  • only one of CK-2017357 and riluzole is administered for a first period of time, followed by co-administration of the CK-2017357 and riluzole for a second period of time.
  • the subject may receive riluzole for a first period of time, then receive both CK-2017357 and riluzole for a second period of time.
  • Administration of either CK-2017357 or riluzole may then continue for a third period of time.
  • the subject may receive CK-2017357 for a first period of time, then receive both CK-2017357 and riluzole for a second period of time. Administration of either CK-2017357 or riluzole may then continue for a third period of time.
  • CK-2017357 and riluzole are co-administered for a first period of time, followed by administration of only one of CK-2017357 and riluzole for a second period of time.
  • the subject may receive both CK-2017357 and riluzole for a first period of time, then receive CK-2017357 for a second period of time.
  • the subject may receive both CK-2017357 and riluzole for a first period of time, then receive riluzole for a second period of time.
  • alternate administration may be repeated during a single treatment protocol. The determination of the order of administration and the number of repetitions of administration of each therapy during a treatment protocol is within the knowledge of the skilled physician after evaluation of the condition of the patient.
  • riluzole and CK-2017357 are administered sequentially. In some instances of sequential administration, CK-2017357 is administered to the subject after riluzole administration has ended.
  • administration of CK-2017357 may begin immediately following termination of riluzole administration, or there may be a time interval (e.g., one day, one week, one month, six months, one year, etc.) between the end of riluzole administration and the beginning of CK-2017357 administration. In other instances of sequential administration, riluzole is administered to the subject after CK-2017357
  • administration has ended.
  • the administration of riluzole may begin immediately following termination of CK-2017357 administration, or there may be a time interval (e.g., one day, one week, one month, six months, one year, etc.) between the end of CK-2017357 administration and the beginning of riluzole
  • CK-2017357 and riluzole are administered in a single pharmaceutical composition.
  • the single pharmaceutical composition may be administered via any of the accepted modes of administration for therapeutic agents including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally,
  • the single pharmaceutical composition is administered orally. In some embodiments, the single pharmaceutical composition is formulated to administer both CK-2017357 and riluzole at the same time or rate. In some embodiments, the single pharmaceutical composition is formulated to administer both CK-2017357 and riluzole at different times or rates. For example, the single pharmaceutical composition may deliver riluzole at a slower rate the CK- 2017357, or CK-2017357 at a slower rate than riluzole.
  • the single pharmaceutical composition may deliver CK-2017357 first followed by riluzole (i.e., delayed release of riluzole), or riluzole first followed by CK-2017357 (i.e., delayed release of CK-2017357).
  • CK-2017357 and riluzole are administered in separate pharmaceutical compositions.
  • Each agent may, because of different physical and chemical characteristics, be administered by different routes. For example, one agent can be administered orally, while the other is administered intravenously. Alternatively, each agent may be administered by the same route. For example, both CK-2017357 and riluzole may be administered orally (i.e., in the form of two separate pills or capsules).
  • the determination of the mode of administration and the advisability of administration, in the same pharmaceutical composition is within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • a method for treating ALS by administering to a patient at least two doses daily of CK-2017357.
  • two doses of CK-2017357 are administered at different times (e.g., once in the morning and once in the evening).
  • the total daily dose is at least about 250 mg, or at least about 300 mg, or at least about 350 mg, or at least about 400 mg, or at least about 450 mg, or at least about 500 mg.
  • at least one of the doses is equal to or greater than about 125 mg, or equal to or greater than about 150 mg, or equal to or greater than about 200 mg, or equal to or greater than about 250 mg.
  • the doses are equal to or greater than about 125 mg, or equal to or greater than about 150 mg, or equal to or greater than about 200 mg, or equal to or greater than about 250 mg.
  • the CK-2017357 is administered in two or more equal doses (e.g., two equal doses of 125 mg or two equal doses of 250 mg).
  • the CK-2017357 is administered in two or more different doses (e.g., 125mg/250mg or 250mg/125mg).
  • the dose of CK-2107357 is titrated over time to a different (e.g., higher) daily dose level.
  • Administration of CK-2017357 can be via any of the accepted modes of administration for therapeutic agents including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarily, vaginally, rectally, or intraocularly.
  • CK-2017357 is administered orally.
  • CK-2017357 is administered intravenously.
  • CK-2017357 is administered intravenously.
  • CK-2017357 is administered into the lungs by inhalation or spraying of a dry powder, suspension, solution or aerosol comprising CK- 2017357.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like.
  • CK-2017357 can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • CK-2017357 can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the pharmaceutical composition will contain about 0.005% to 95% or, in certain embodiments, about 0.5% to 50% by weight of CK-2017357.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's
  • the compositions will take the form of a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. the active ingredient and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of CK-2017357 contained in such parenteral compositions is dependent on the specific nature of the compound, as well as the activity of CK-2017357 and the needs of the subject. In some embodiments, percentages of active ingredient of 0.01 % to 10% in solution are employable, and may be higher if the composition is
  • compositions of CK-2017357 may also be provided.
  • the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
  • Example 1 Effect of multiple daily doses of CK-2017357 on the PK of a single dose of riluzole in healthy subjects
  • the primary objective of this study was to evaluate the effect of multiple daily doses of CK-2017357 on the pharmacokinetics (PK) of a single dose of riluzole in healthy subjects.
  • PK pharmacokinetics
  • Plasma samples were collected at pre-dose, 0.5, 1 , 1 .5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post-dose.
  • Plasma concentrations of riluzole were determined using a validated HPLC/MS/MS method with a quantitation range of 5.00 to 2,000 ng/mL. Samples were analyzed using a 50.0 ⁇ _ aliquot volume and a protein-precipitation extraction procedure followed by HPLC/MS/MS. Riluzole concentrations were calculated with a 1/x 2 linear regression over a concentration range of 5.00 to 2,000 using riluzole- 13 C, 15 N 2 as an internal standard.
  • another set of plasma samples were collected at pre-dose of CK-2017357 on days 1 1 , 12, and 13.
  • Plasma concentration data of riluzole were analyzed by noncompartmental methods to determine pharmacokinetic parameters of riluzole.
  • Descriptive pharmacokinetic parameters such as Cmax, Tmax, AUC, t1/2, Cl/F, and V/F were calculated using Phoenix WinNonlin 6.1 (Pharsight, Mountain View, CA). All concentrations ⁇ LLOQ were set to zero for the purpose of calculating descriptive statistics and noncompartmental analysis.
  • Summary PK parameters of riluzole are presented in Tables 1 A and 1 B below. Table 1 A: Summary pharmacokinetic parameters of riluzole in healthy subjects
  • Table 1 B Summary pharmacokinetic parameters of riluzole + CK2017357 (250 mg QD) in healthy subjects
  • Example 2 Drug-drug interaction (DDI) between riluzole and CK-2017357 in ALS patients
  • Plasma concentrations of riluzole were determined using a validated HPLC/MS/MS method with a quantitation range of 5.00 to 2,000 ng/mL. Samples were analyzed using a 50.0 ⁇ aliquot volume and a protein-precipitation extraction procedure followed by HPLC/MS/MS. Riluzole concentrations were calculated with a 1/x 2 linear regression over a concentration range of 5.00 to 2,000 using hluzole- 13 C, 15 N 2 as an internal standard. Descriptive
  • pharmacokinetic parameters such as C max , T max , AUC, t 2 , Cl/F, and V/F were calculated using Phoenix WinNonlin 6.1 (Pharsight, Mountain View, CA). All concentrations ⁇ LLOQ were set to zero for the purpose of calculating descriptive statistics and noncompartmental analysis. Since the time of dosing for riluzole was not recorded, time elapsed was calculated based on nominal time points of CK-2017357, and used to calculate riluzole AUC 24 h.
  • Plasma levels of CK-2017357 achieved steady state by Day 8; levels four hours after dosing on Day 8 were approximately 70% higher than four hours after the first dose on Day 1 .
  • CK-2017357 C max increased proportionally by dose with no apparent effect of riluzole, as shown in Table 4.
  • CK-2017357 approximately doubled riluzole levels across all dose groups as shown in Table 5 below Adverse event frequencies were not altered by the presence of riluzole at any dose of CK-2017357.
  • CK-2017357 had predictable linear kinetics at the repeated doses used in the current study, reaching steady state within 1 week.
  • CK- 2017357 plasma levels were not affected by the presence of riluzole.
  • Riluzole levels were increased by CK-2017357 with plasma levels increasing approximately 2-fold across all dose levels of CK-2017357.
  • no adverse events were reported during this study attributable to higher riluzole levels with the daily riluzole dose reduced to 50 mg daily.
  • the CK-2017357 titration regimen was as follows: dosing initiated at 125 mg twice daily for 7 days (250 mg total daily dose); on Day 8, up titration to 125 mg in the morning and 250 mg in the evening (375 mg total daily dose); on Day 15, up titration to 250 mg twice daily (500 mg total daily dose) continued through the morning dose on Day 22. Patients who did not tolerate a dose escalation returned to the previous tolerated dose level and remained at that dose level to complete the study. Placebo patients underwent a similar dummy dose titration to maintain the blind.
  • Figure 4 illustrates the study design. [071] Twenty-seven patients were treated in this study. All six patients randomized to placebo completed three weeks of dosing.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychology (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2012/046523 2011-07-13 2012-07-12 Combination als therapy WO2013010015A2 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
IN200DEN2014 IN2014DN00200A (forum.php) 2011-07-13 2012-07-12
CA2849213A CA2849213A1 (en) 2011-07-13 2012-07-12 Combination of riluzole and ck-2017357 for treating als
PH1/2014/500094A PH12014500094A1 (en) 2011-07-13 2012-07-12 Combination als therapy
KR1020147000783A KR101951220B1 (ko) 2011-07-13 2012-07-12 조합 als 치료법
AU2012281042A AU2012281042B2 (en) 2011-07-13 2012-07-12 Combination ALS therapy
US14/131,649 US10272082B2 (en) 2011-07-13 2012-07-12 Combination ALS therapy
EP12811325.5A EP2731611B1 (en) 2011-07-13 2012-07-12 Combination therapie for als
NZ619924A NZ619924B2 (en) 2011-07-13 2012-07-12 Combination als therapy
EA201490011A EA028060B1 (ru) 2011-07-13 2012-07-12 Комбинированная терапия бокового амиотрофического склероза
JP2014520335A JP6145946B2 (ja) 2011-07-13 2012-07-12 併用ａｌｓ療法
MX2014000455A MX2014000455A (es) 2011-07-13 2012-07-12 Terapia de combinacion para esclerosis lateral amiotrofica.
CN201280034661.5A CN104039148A (zh) 2011-07-13 2012-07-12 组合als疗法
BR112014000742A BR112014000742A2 (pt) 2011-07-13 2012-07-12 terapia de combinação de als
HK14110537.3A HK1197178A1 (en) 2011-07-13 2012-07-12 Combination als therapy
IL230391A IL230391B (en) 2011-07-13 2014-01-09 Combination als therapy
ZA2014/00236A ZA201400236B (en) 2011-07-13 2014-01-10 Combination als therapy

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US201161507381P 2011-07-13 2011-07-13
US61/507,381 2011-07-13
US201161544533P 2011-10-07 2011-10-07
US61/544,533 2011-10-07
US201261637759P 2012-04-24 2012-04-24
US201261637770P 2012-04-24 2012-04-24
US61/637,759 2012-04-24
US61/637,770 2012-04-24
US201261646699P 2012-05-14 2012-05-14
US61/646,699 2012-05-14

Publications (2)

Publication Number Publication Date
WO2013010015A2 true WO2013010015A2 (en) 2013-01-17
WO2013010015A3 WO2013010015A3 (en) 2014-05-15

Family

ID=47506929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/046523 WO2013010015A2 (en) 2011-07-13 2012-07-12 Combination als therapy

Country Status (16)

Country Link
US (1) US10272082B2 (forum.php)
EP (1) EP2731611B1 (forum.php)
JP (2) JP6145946B2 (forum.php)
KR (1) KR101951220B1 (forum.php)
CN (2) CN104039148A (forum.php)
AU (2) AU2012281042B2 (forum.php)
BR (1) BR112014000742A2 (forum.php)
CA (1) CA2849213A1 (forum.php)
EA (2) EA028060B1 (forum.php)
HK (1) HK1197178A1 (forum.php)
IL (1) IL230391B (forum.php)
IN (1) IN2014DN00200A (forum.php)
PH (1) PH12014500094A1 (forum.php)
SG (1) SG10201605707UA (forum.php)
WO (1) WO2013010015A2 (forum.php)
ZA (1) ZA201400236B (forum.php)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015063318A1 (en) * 2013-11-04 2015-05-07 Ab Science Use of masitinib for treatment of amyotrophic lateral sclerosis
WO2015168064A1 (en) 2014-04-29 2015-11-05 Shefner Jeremy M Methods of reducing decline in vital capacity
WO2016081466A1 (en) * 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Sublingual administration of riluzole
WO2016081472A1 (en) * 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Sublingual formulation of riluzole
US10092564B2 (en) 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation
US10766899B2 (en) 2006-08-02 2020-09-08 Cytokinetics, Incorporated Methods for preparing substituted imidazo[4,5-b]pyrazines

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3072513A1 (en) * 2015-03-26 2016-09-28 Medday Biotin for treating Amyotrophic lateral sclerosis
EP4031135A4 (en) * 2019-09-20 2023-10-18 Icahn School of Medicine at Mount Sinai CONTROLLED RELEASE FORMULATIONS OF RILUZOLE AND USES THEREOF

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7598248B2 (en) 2006-08-02 2009-10-06 Cytokinetics, Inc. Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols, compositions thereof, and methods for their use
US20110014212A1 (en) 2006-08-02 2011-01-20 Aaron Hinken Certain Chemical Entities, Compositions and Methods

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3507866A (en) 1967-08-08 1970-04-21 Merck & Co Inc 1h - imidazo(4,5-b)pyrazin - 2 - one and processes for their preparation
BE788065A (fr) 1971-08-26 1973-02-26 Degussa Nouvelles aza-benzimidazoles et procede pour leur preparation
IT1156732B (it) 1978-05-10 1987-02-04 Roussel Maestretti Spa Derivati sostituiti dell'1,3-diidroimidazo(4,5-b)piridin-2-one e relativo procedimento di produzione
US4668686A (en) 1985-04-25 1987-05-26 Bristol-Myers Company Imidazoquinoline antithrombrogenic cardiotonic agents
US4775674A (en) 1986-05-23 1988-10-04 Bristol-Myers Company Imidazoquinolinylether derivatives useful as phosphodiesterase and blood aggregation inhibitors
US4943573A (en) 1989-11-01 1990-07-24 Bristol-Myers Squibb Company Imidazo[4,5-b]quinolinyloxyalkanoic acid amides with enhanced water solubility
US5354759A (en) 1991-09-12 1994-10-11 Fujisawa Pharmaceutical Co., Ltd. Angiotenin II antagonizing heterocyclic compounds
JPH0641135A (ja) 1992-07-21 1994-02-15 Nippon Soda Co Ltd イミダゾプテリジン誘導体及びその製造方法
US6162804A (en) 1997-09-26 2000-12-19 Merck & Co., Inc. Tyrosine kinase inhibitors
CA2333770A1 (en) 1998-06-04 1999-12-09 Abbott Laboratories Cell adhesion-inhibiting antinflammatory compounds
US6232320B1 (en) 1998-06-04 2001-05-15 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory compounds
SK286788B6 (sk) 1999-10-08 2009-05-07 Grnenthal Gmbh Bicyklické deriváty imidazo-3-yl-amínu, spôsob ich výroby, ich použitie a liečivá obsahujúce tieto látky
MXPA02002837A (es) 1999-10-08 2002-08-30 Gr Nenthal Gmbh Derivados biciclicos de imidazo-5-il-amina.
DE10050663A1 (de) 2000-10-13 2002-04-18 Gruenenthal Gmbh Verwendung von substituierten Imidazo[1,2-a]pyridin-, -pyrimidin- und pyrazin-3-yl-amin-Derivaten zur Herstellung von Medikamenten zur NOS-Inhibierung
US20030083318A1 (en) * 2001-10-25 2003-05-01 Jean-Pierre Julien Therapy for neurodegenerative diseases
US20040235801A1 (en) * 2001-10-25 2004-11-25 Jean-Pierre Julien Therapy for stroke
GB0206860D0 (en) 2002-03-22 2002-05-01 Glaxo Group Ltd Compounds
GB0212048D0 (en) 2002-05-24 2002-07-03 Merck Sharp & Dohme Therapeutic agents
AU2003294249A1 (en) 2002-11-08 2004-06-03 Trimeris, Inc. Hetero-substituted benzimidazole compounds and antiviral uses thereof
GB2400101A (en) 2003-03-28 2004-10-06 Biofocus Discovery Ltd Compounds capable of binding to the active site of protein kinases
JO2355B1 (en) 2003-04-15 2006-12-12 ميرك شارب اند دوم كوربوريشن Hereditary calcitonin polypeptide receptor antagonists
ATE461196T1 (de) 2003-06-26 2010-04-15 Merck Sharp & Dohme Benzodiazepin-cgrp-rezeptor-antagonisten
WO2005002520A2 (en) 2003-07-01 2005-01-13 Merck & Co., Inc. Ophthalmic compositions for treating ocular hypertension
JP2007515429A (ja) 2003-12-19 2007-06-14 エリクシアー ファーマシューティカルズ， インコーポレイテッド 障害を治療する方法
EP1715855A4 (en) 2004-01-29 2010-06-16 Elixir Pharmaceuticals Inc ANTIVIRAL DRUGS
WO2005108374A1 (en) 2004-04-29 2005-11-17 Fmc Corporation Insecticidal diazole and triazole derivatives
GB0420719D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
AU2005289644A1 (en) 2004-09-24 2006-04-06 Janssen Pharmaceutica, N.V. Imidazo{4,5-b}pyrazinone inhibitors of protein kinases
MY179032A (en) 2004-10-25 2020-10-26 Cancer Research Tech Ltd Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors
MX2007010068A (es) 2005-02-16 2007-10-10 Schering Corp Piperazino-piperidinas con actividad antagonista de cxcr3.
US7718657B2 (en) 2005-12-16 2010-05-18 Cytokinetics, Inc. Certain indanyl urea modulators of the cardiac sarcomere
US20090082370A1 (en) 2006-04-25 2009-03-26 Neil Thomas Thompson Pharmaceutical Combinations of PK Inhibitors and Other Active Agents
EP3719018B1 (en) 2006-04-25 2025-08-27 Astex Therapeutics Ltd Purine and deazapurine derivatives as pharmaceutical compounds
US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
US20100173930A1 (en) 2006-08-01 2010-07-08 Alex Muci Certain Chemical Entities, Compositions and Methods
CN101522681B (zh) * 2006-08-02 2012-10-03 赛特凯恩蒂克公司 特定的化学个体、组合物和方法
ATE543819T1 (de) 2006-10-19 2012-02-15 Signal Pharm Llc Heteroarylverbindungen, zusammensetzungen daraus und behandlungsverfahren damit
CL2007002994A1 (es) 2006-10-19 2008-02-08 Wyeth Corp Compuestos derivados heterociclicos que contienen sulfamoilo, inhibidores de hsp90; composicion farmaceutica; y uso para el tratamiento del cancer, tal como cancer de mama, de colon y prostata, entre otros.
WO2008075007A1 (en) 2006-12-21 2008-06-26 Cancer Research Technology Limited Morpholino-substituted bicycloheteroaryl compounds and their use as anti cancer agents
JP5491199B2 (ja) 2007-01-19 2014-05-14 アルデア バイオサイエンシズ，インコーポレイティド Ｍｅｋのインヒビター
WO2008121333A1 (en) 2007-03-30 2008-10-09 Cytokinetics, Incorporated Certain chemical entities, compositions and methods
EP2018854A1 (en) * 2007-07-27 2009-01-28 Merz Pharma GmbH & Co. KGaA Novel combinations of neramexane for the treatment of neurodegenerative disorders
CA2713864A1 (en) 2008-02-04 2009-08-13 Cytokinetics, Incorporated Certain chemical entities, compositions and methods
US7998976B2 (en) 2008-02-04 2011-08-16 Cytokinetics, Inc. Certain chemical entities, compositions and methods
CA2730473A1 (en) 2008-07-11 2010-01-14 Glaxo Group Limited Novel treatment
ES2554375T3 (es) 2008-11-25 2015-12-18 University Of Rochester Inhibidores de las MLK y métodos de uso
EP2228054A1 (en) * 2009-03-13 2010-09-15 ITALFARMACO S.p.A. Riluzole aqueous suspensions
CA2765876A1 (en) * 2009-06-19 2010-12-23 Knopp Neurosciences, Inc. Compositions and methods for treating amyotrophic lateral sclerosis
SG10201701101YA (en) 2012-04-02 2017-04-27 Cytokinetics Inc Methods for improving diaphragm function
EP2836590A4 (en) 2012-04-11 2016-04-13 Cytokinetics Inc METHOD FOR IMPROVING THE RESISTANCE TO SKELETON MUSCULAR FEEDING
PT3137622T (pt) 2014-04-29 2022-03-08 Cytokinetics Inc Métodos para reduzir o declínio da capacidade vital

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7598248B2 (en) 2006-08-02 2009-10-06 Cytokinetics, Inc. Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols, compositions thereof, and methods for their use
US20110014212A1 (en) 2006-08-02 2011-01-20 Aaron Hinken Certain Chemical Entities, Compositions and Methods

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", MACK PUBLISHING COMPANY
BENSIMON ET AL., EXPERT OPIN. DRUG SAF., vol. 3, no. 6, 2004, pages 525 - 34
COURATIER ET AL., NEUROREPORT, vol. 5, no. 8, 1994, pages 1012 - 14
ESTEVEZ ET AL., EUR. J. PHARMACOL., vol. 280, no. 1, 1995, pages 47 - 53
GROENEVELD ET AL., J. NEUROL. SCI., vol. 191, 2001, pages 310 - 13
GROENEVELD ET AL., NEUROLOGY, vol. 61, 2003, pages 1141 - 43
MASHIRO ET AL., ANESTHESIA & ANALGESIA, vol. 104, 2007, pages 1415 - 21
ROTHSTEIN ET AL., J. NEOROCHEM., vol. 65, no. 2, 1995, pages 643 - 51
SANDERINK ET AL., J. PHARMACOL. & EXP. THER., vol. 282, no. 3, 1997, pages 1465 - 72
See also references of EP2731611A4

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10766899B2 (en) 2006-08-02 2020-09-08 Cytokinetics, Incorporated Methods for preparing substituted imidazo[4,5-b]pyrazines
WO2015063318A1 (en) * 2013-11-04 2015-05-07 Ab Science Use of masitinib for treatment of amyotrophic lateral sclerosis
WO2015168064A1 (en) 2014-04-29 2015-11-05 Shefner Jeremy M Methods of reducing decline in vital capacity
EP3137622A4 (en) * 2014-04-29 2018-01-10 Cytokinetics, Inc. Methods of reducing decline in vital capacity
WO2016081466A1 (en) * 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Sublingual administration of riluzole
WO2016081472A1 (en) * 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Sublingual formulation of riluzole
EP3616686A1 (en) * 2014-11-21 2020-03-04 Biohaven Pharmaceutical Holding Company Ltd. Sublingual formulation of riluzole
EA038518B1 (ru) * 2014-11-21 2021-09-09 Биохэйвен Фармасьютикал Холдинг Компани Лтд. Сублингвальный препарат рилузола
US11660267B2 (en) 2014-11-21 2023-05-30 Biohaven Therapeutics Ltd. Sublingual formulation of riluzole
KR20230135183A (ko) 2014-11-21 2023-09-22 바이오하벤 파마슈티컬 홀딩 컴퍼니 엘티디. 릴루졸의 설하 제제
US10092564B2 (en) 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation

Also Published As

Publication number Publication date
EA201490011A1 (ru) 2014-08-29
BR112014000742A2 (pt) 2016-08-23
CA2849213A1 (en) 2013-01-17
PH12014500094A1 (en) 2014-03-17
EP2731611A2 (en) 2014-05-21
EP2731611A4 (en) 2015-02-18
AU2012281042A1 (en) 2014-01-30
IL230391B (en) 2019-03-31
CN109316480A (zh) 2019-02-12
NZ619924A (en) 2016-02-26
EA201791043A1 (ru) 2017-09-29
ZA201400236B (en) 2014-10-29
HK1197178A1 (en) 2015-01-09
EP2731611B1 (en) 2019-09-18
CN104039148A (zh) 2014-09-10
US10272082B2 (en) 2019-04-30
KR20140074270A (ko) 2014-06-17
KR101951220B1 (ko) 2019-02-22
WO2013010015A3 (en) 2014-05-15
EA028060B1 (ru) 2017-10-31
JP6145946B2 (ja) 2017-06-14
US20140243344A1 (en) 2014-08-28
AU2012281042B2 (en) 2016-07-14
JP2014520856A (ja) 2014-08-25
AU2016244263A1 (en) 2016-11-03
SG10201605707UA (en) 2016-09-29
JP2017128610A (ja) 2017-07-27
IN2014DN00200A (forum.php) 2015-06-05

Similar Documents

Publication Publication Date Title
AU2012281042B2 (en) Combination ALS therapy
JP4938905B2 (ja) 選択的ｓ１ｐ１レセプターアゴニストの投与法
RU2221563C2 (ru) Фармацевтическая композиция для лечения болезни паркинсона и синдромов паркинсона, способ ее получения, способ лечения болезни паркинсона и синдромов паркинсона
EP4114466B1 (en) Treatment of pain and vasoconstriction
EP2646031B9 (en) Increasing drug bioavailability in naltrexone therapy
CA3075719A1 (en) Synthetic transdermal cannabidiol for the treatment of focal epilepsy in adults
US20200323817A1 (en) Methods and compositions for treatment of alzheimer's disease and other neurodegenerative disorders
JP2022518944A (ja) 肺動脈性肺高血圧症を治療するための投与レジメンおよび方法
JP2022543837A (ja) てんかん重積状態の治療に使用するためのガナキソロン
EP2768481A1 (en) Compositions for reduction of side effects
JP6420923B1 (ja) 医薬
NZ619924B2 (en) Combination als therapy
MX2014000455A (es) Terapia de combinacion para esclerosis lateral amiotrofica.
JP6860984B2 (ja) 脊髄小脳変性症における運動失調の治療剤の投与レジメン
US20230172895A1 (en) Methods of treating or preventing organophosphorus poisoning
TW201806599A (zh) 用於快速開始抗抑鬱作用之給藥方案
TW202506126A (zh) 發炎性腸道疾病之治療用醫藥組成物
WO2016208045A1 (ja) 脊髄小脳変性症における運動失調の治療剤の投与レジメン
Menezes et al. Experimental pharmacological agents in the management of Parkinson’s disease
CA2775061A1 (en) Methods and compositions for treatment of raynaud's phenomenon

Legal Events

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

Ref document number: 12811325

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2849213

Country of ref document: CA

Ref document number: 2014520335

Country of ref document: JP

Kind code of ref document: A

Ref document number: 20147000783

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2014/000455

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2012811325

Country of ref document: EP

Ref document number: 201490011

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 2012281042

Country of ref document: AU

Date of ref document: 20120712

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14131649

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014000742

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112014000742

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20140113