MX2014000455A - Combination als therapy. - Google Patents

Abstract

Provided is 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. Also provided are methods of reducing the variability of riluzole exposure (e.g., Cmax and/or AUC24h) in a subject, methods of reducing the variability of riluzole exposure (e.g., Cmax and/or AUC24h) between two or more subjects, methods of decreasing the total daily dose of riluzole in a subject, methods of increasing the half-life of riluzole in a subject, methods for decreasing the frequency of riluzole dosing in the subject, and methods for reducing the incidence and/or severity of adverse events in a subject treated with riluzole.

Description

Combination Therapy for Amyotrophic Lateral Sclerosis This application claims the priority benefit of US Applications Nos. 61 / 507,381, filed July 13, 201 1, 61 / 637,770, filed on April 24, 2012, 61 / 544,533, filed on October 7. from 2011; 61 / 646,699, filed on May 14, 2012, and 61 / 637,759, filed on April 24, 2012, each of which is incorporated by reference for all purposes.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the nervous system. ALS is characterized by the progressive loss of motor neurons in the lateral column of the spinal cord and / or motor cortex. With the progressive loss of motor neurons, the innervation to the skeletal muscle is lost which results in the inability to wander, conduct daily activities and affect swallowing and breathing. ALS is a rare and usually fatal disease; Its progression may be variable, although on average patients die within 3 years of diagnosis. The majority of patients succumb to respiratory failure with bronchopneumonia and pneumonia being the main causes of death. The treatment is palliative because there is no curative treatment.

Currently, riluzole is the only drug approved to treat ALS. While the exact mechanism of action of riluzole is unknown, it is considered to act by inhibiting the harmful effects of an overload of glutamic acid and other neurotransmitters in the nervous system. central (see, for example, Couratier et al., NeuroReport (1994), 5 (8): 1012-14; Estevez et al., Eur. J. Pharmacol. (1995), 280 (1): 47-53; Rothstein et al., J. Neorochem. (1995), 65 (2): 643-51). Studies have shown that the serum and plasma concentrations of riluzole vary greatly from one person to another (see, for example, Groeneveld et al., J. Neurol, Sci. (2001), 191: 310-13). . Such variation can lead to difficulties in the determination and delivery of a therapeutically effective dose to a patient and can affect the incidence and severity of adverse events (see, for example, Groeneveld et al., Neurology (2003), 61: 1 41-43). 6-Ethynyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one (also known as CK-2017357 or CK-357) is a selective activator of the Rapid skeletal muscle troponin complex, which sensitizes rapid skeletal muscle to calcium and results in an amplification of the neuromuscular input response, an increase in muscle energy, and a decrease in muscle fatigue (see, for example, U.S. Patent No. 7,598,248). The use of CK-2017357 is being studied for use in the treatment of patients with ALS. By increasing the contraction force developed by fast skeletal muscle fibers in response to any level of neuronal input, treatment with CK-2017357 can improve activities of daily living (such as walking, breathing and feeding), reduce hospitalizations, and possibly prolong the survival of patients with ALS.

It has been shown that CK-2017357 is in inhibitor based on human CYP1A2 mechanism in vitro, with a Ki (inactivation constant) of 1 .9 μ? and kinact (maximum inactivation rate constant) of 0.031 min. "1 In humans, riluzole is metabolized primarily by CYP1A2 (see, for example, Sanderink et al., J. Pharmacol. &Exp. Ther. (1997). ), 282 (3): 1465-72) The ability of a number of other drugs to inhibit the metabolism of riluzole by human liver microsomes in vitro has been determined, although inhibition has been observed in certain cases (e.g. amitriptyline, diclofenac, diazepam, nicergoline, clomipramine, imipramine), the high concentrations required for inhibition make it unlikely that these drugs could alter riluzole concentrations if used in combination with riluzole in the clinical setting (see Bensimon et al., Expert Opin Drug Saf. (2004), 3 (6): 525-34).

A method for treating ALS in a subject is provided, which comprises administering to the subject a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357.

Also provided is a method for reducing the variation in riluzole exposure (eg, Cmax and / or AUC24h) in a subject, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

A method is also provided for reducing the variation in riluzole exposure (eg, Cmax and / or AUC24h) between two or more subjects, which comprises administering to subjects a therapeutically effective amount of CK-2017357.

A method is also provided for increasing the exposure of riluzole (e.g., Cmax and / or AUC24h) in a subject comprising administering to the subject a therapeutically effective amount of CK-2017357.

A method is also provided for increasing the half-life of riluzole in a subject, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

A method for reducing the frequency of riluzole dosing in the subject is also provided, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

A method is also provided for reducing the total daily dose of riluzole in a subject, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

A method is also provided for reducing the incidence and / or severity of adverse events in a subject treated with riluzole, which comprises administering to the subject treated with riluzole a therapeutically effective amount of CK-2017357.

Also provided is a pharmaceutical composition comprising a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-20 7357.

A method for treating ALS in a subject is also provided, which comprises administering to the subject at least two daily doses of CK-2017357.

DESCRIPTION OF THE FIGURES Figure 1 provides the mean riluzole plasma concentration as a function of time for riluzole alone (50 mg single dose) and riluzole (50 mg mg individual dose) and CK-2017357 (250 mg daily x 11 days in healthy subjects.

Figure 2 illustrates the effect of steady state CK-2017357 on the pharmacokinetics of riluzole in healthy subjects. Panel A provides Cmax for riluzole alone (50 mg single dose) and riluzole (50 mg single dose) + CK-2017357 (250 mg daily for 1 1 day). Panel B provides AUC / nf for riluzole alone (50 mg single dose) and riluzole (50 mg single dose) + CK-2017357 (250 mg daily for 11 days). The figure shows that in healthy subjects, the inter-subject variation of Cmax of riluzole has been reduced through the co-administration of CK-2017357.

Figure 3 provides the mean concentration of riluzole plasma as a function of time for 50 mg of riluzole administered BID and CK-2017357 administered at 250 or 500 mg of single dose in patients with ALS.

Figure 4 shows a study flow chart for a clinical study investigating a twice-daily dose titration regimen of CK-2017357 in patients with ALS.

As used herein, the following abbreviations, words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

As used herein, AUC2 h is the area under the plasma-time concentration curve from hour 0 to the last measurable plasma concentration (eg, 24 hours), calculated by the linear trapezoidal rule.

As used herein, ALS or amyotrophic lateral sclerosis refers to the motor neuron disease commonly known as Lou Gehrig's Disease, and in certain embodiments, amyotrophic lateral sclerosis with initial bulbar involvement or the bulbar form of the disease, and in certain modalities, ALS "of beginning in extremities".

As used herein, QD refers to once a day.

As used herein, IDB refers to twice a day.

As used herein, Cmax refers to maximum plasma concentration.

As used herein, fm refers to the metabolized fraction.

A method for treating ALS in a subject is provided, which comprises administering to the subject a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357.

In certain modalities, the administration of riluzole in combination with CK-2017357 extends the survival and / or time to the tracheostomy.

In certain embodiments, the therapeutically effective amount of riluzole administered in combination with CK-2017357 is a lower dose than the therapeutically effective amount of riluzole when administered individually (ie, without CK-2017357 treatment). In certain embodiments, both the therapeutically effective amount of riluzole and the therapeutically effective amount of CK-2017357 when administered in combination are lower than the therapeutically effective amount of riluzole and the therapeutically effective amount of CK-2017357 when each is administered from individual way.

In certain modalities, the administration of riluzole is BID. In certain embodiments, the administration of riluzole is QD.

In certain modalities, the administration of CK-2017357 is BID. In certain modalities, the administration is QD.

In certain modalities, the administration of riluzole is QD and the administration of CK-2017357 is BID. In certain modalities, the administration of riluzole is BID and the administration of CK-2017357 is BID.

In certain modalities, the administration of riluzole is QD and the administration of CK-2017357 is QD. In certain modalities, the administration of riluzole is BID and the administration of CK-2017357 is QD.

In certain modalities, CK-2017357 is administered in two or more doses at different times (for example, once in the morning and once in the evening). In certain modalities, CK-2017357 is administered in two or more equal doses. In certain modalities, CK-2017357 is administered in two or more different doses. In certain embodiments, the dose of CK-2107357 is titrated over time to a different (eg, higher) daily dose level.

In certain embodiments, the individual daily dose of 50 mg riluzole is administered in combination with a therapeutically effective amount of CK-2017357. In certain embodiments, a single daily dose of 50 mg of riluzole is administered in combination with a total daily dose of between approximately 125 mg and 2000 mg of CK-2017357. In certain embodiments, 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.

In certain embodiments, a twice daily dose of 25 mg riluzole is administered in combination with a therapeutically effective amount of CK-2017357. In certain embodiments, a 25 mg twice daily dose of riluzole is administered in combination with a total daily dose of between approximately 125 mg and 2000 mg of CK-2017357. In certain embodiments, a 25 mg twice daily dose of riluzole is administered in combination with a total daily dose of 125, 250, 375, or 500 mg of CK-2017357.

In certain embodiments, an individual daily dose of 25 mg riluzole is administered in combination with a therapeutically effective amount of CK-2017357. In certain embodiments, a single daily dose of 25 mg of riluzole is administered in combination with a total daily dose of between approximately 125 mg and 2000 mg of CK-2017357. In certain 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.

In certain embodiments, a twice daily dose of 12.5 mg of riluzole is administered in combination with a therapeutically effective amount of CK-2017357. In certain embodiments, a dose of twice a day 12.5 mg of riluzole is administered in combination with a total daily dose of between approximately 125 mg and 2000 mg of CK-2017357. In certain modalities, a dose of twice daily 12.5 mg of riluzole is administered in combination with 125, 250, 375, or 500 mg of CK-2017357.

A method for increasing the half-life of riluzole in a subject is also described, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

Also, a method for reducing the frequency of dosing riluzole in a subject (eg, twice a day to once a day) or reducing the dosage of riluzole administered to the subject (eg, 200 mg daily) is disclosed. to 100 mg daily, or 100 mg daily to 50 mg daily, or 50 mg daily to 25 mg daily).

A method is also described for reducing the inter-subject variation of riluzole exposure (eg, Cmax and / or AUC24h) between two or more subjects, which comprises administering to subjects a therapeutically effective amount of CK-2017357.

Also disclosed is a method for reducing intra-subject exposure variation of riluzole (eg, Cmax and / or AUC24h), which comprises administering to the subject a therapeutically effective amount of CK-2017357.

A method for reducing the incidence and / or severity of adverse events in a subject treated with riluzole, which comprises administering to the subject a therapeutically effective amount of CK-2017357, is likewise described. In certain modalities, the adverse event is an adverse event related to CNS (see, for example, Mashiro et al., Anesthesia &Analgesia (2007), 104: 1415-21).

In certain modalities, CK-2017357 is administered to the subject concurrently with the administration of riluzole, that is, CK-2017357 and riluzole are administered simultaneously, essentially simultaneously or within the same treatment protocol. In certain cases of concurrent administration, the administration of CK-2017357 and riluzole starts and ends at the same time (that is, on the same day or within the same treatment protocol). In other cases of concurrent administration, only one of CK-2017357 and nluzol is administered during a first period, followed by co-administration of CK-2017357 and riluzole for a second period. For example, the subject can receive riluzole for a first period, then receive both CK-2017357 and riluzole for a second period. The administration of either CK-2017357 or riluzole may continue later for a third period. In another example, the subject can receive CK-2017357 during a first period, then receive both CK-2017357 and riluzole for a second period. The administration of either CK-2017357 or riluzole may continue later for a third period. In other cases of concurrent administration, CK-2017357 and riluzole are co-administered for a third period, followed by administration only of one of CK-2017357 and riluzole for a second period. For example, the subject can receive both CK-2017357 and riluzole during a first period, and then receive CK-2017357 during a second period. In another example, the subject can receive both CK-2017357 and riluzole during a first period, and then receive riluzole during a second period. In all cases, alternate administration can 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 experienced physician after evaluation of the patient's condition.

In certain modalities, riluzole and CK-2017357 are administered sequentially. In certain cases of sequential administration, CK-2017357 is administered to the subject after the administration of riluzole has ended. The administration of CK-2017357 can start immediately after the completion of the administration of riluzole, or there can be an interval (for example, one day, one week, one month, six months, one year, etc.) between the end of the administration of riluzole and the beginning of the administration of CK-2017357. In other cases of sequential administration, riluzole is administered to the subject after the administration of CK-2017357 has ended. The administration of riluzole can start immediately after the termination of the administration of CK-2017357, or there can be an interval (for example, a day, a week, a month, six months, a year, etc.) between the end of the administration of CK-2017357 and the initiation of administration of riluzole. In each case, alternate administration may be repeated during an individual 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 experienced physician after the evaluation of the patient's condition.

In certain embodiments, CK-2017357 and riluzole are administered in an individual pharmaceutical composition. The individual pharmaceutical composition can be administered through any of the accepted modes of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal , rectal, or intraocular. In certain embodiments, the individual pharmaceutical composition is administered orally. In certain embodiments, the individual pharmaceutical composition is formulated to administer both CK-2017357 and riluzole at the same time or speed. In certain embodiments, the individual pharmaceutical composition is formulated to administer both CK-2017357 and riluzole at different times or speeds. For example, the individual pharmaceutical composition can supply riluzole at a lower speed than CK-2017357, or CK-2017357 at a lower speed than riluzole. In another example, the individual pharmaceutical composition can supply CK-2017357 followed first by riluzole (ie, delayed release of riluzole), or riluzole followed first by CK-2017357 (ie, delayed release of CK-2017357).

In certain embodiments, CK-2017357 and riluzole are administered in separate pharmaceutical compositions. Each agent can, due to the different physical and chemical characteristics, be managed through different routes. For example, one agent can be administered orally, while the other is administered intravenously. Alternatively, each agent can be administered by the same route. For example, both CK-2017357 and riluzole can be administered orally (ie, in the form of two separate pills or capsules). The determination of the mode of administration and the convenience of administration, in the same pharmaceutical composition (if possible) is within the knowledge of the experienced physician. The initial administration can be done according to the established protocols known in the art, and then, based on the observed effects, the dosage, modes of administration and administration schedules can be modified by the experienced physician.

A method for treating ALS is also provided by administering to a patient at least two doses of CK-2017357. In certain modalities, two doses of CK-2017357 are administered at different times (for example, once in the morning and once in the evening). In certain embodiments, 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 less approximately 500 mg. In certain embodiments, 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. In certain embodiments, at least two of the doses are equal to or greater than about 25 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. In certain embodiments, CK-2017357 is administered in two or more equal doses (eg, two equal doses of 125 mg or two equal doses of 250 mg). In certain embodiments, CK-2017357 is administered in two or more different doses (eg, 125 mg / 250 mg or 250 mg / 125 mg). In certain embodiments, the dose of CK-2107357 is titrated with the passage of time for a different (eg, higher) daily dose level.

Administration of CK-2017357 can be through any of the accepted modes of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. In certain modalities, CK-2017357 is administered orally. In other modalities, CK-2017357 is administered intravenously. In other modalities, CK-2017357 is administered within the lungs by inhalation or spraying a dehydrated powder, suspension, solution or aerosol comprising CK-2017357.

The pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. CK-2017357 may also be administered in sined or controlled release dosage forms, which include depot injections, osmotic pumps, pills, transdermal patches (including electrotransport), and the like, for prolonged and / or timed administration, by pulses to a predetermined speed. In certain embodiments, the compositions are provided in unit dosage forms suitable for individual administration of a precise dose.

CK-2017357 can be administered either alone or in combination with a vehicle, conventional pharmaceutical excipient or the like (eg, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin , sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH regulating agents, and the like (eg, sodium acetate, sodium citrate, sodium derivatives). cyclodextrin, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% up to 95% or, in certain embodiments, approximately 0.5% to 50% by weight of CK-2017357. The actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

In certain embodiments, the compositions will take the form of a pill or tablet and therefore the composition may contain, together 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, acacia gum, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In certain embodiments of a solid dosage form, a powder, marum, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.

The liquid pharmaceutically administrable compositions can, for example, be prepared by means of dissolution, dispersion, etcetera. The active ingredient and optional pharmaceutical adjuvants in a vehicle (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectable compositions may 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 said parenteral compositions depends on the specific nature of the compound, as well as the activity of CK-2017357 and the needs of the subject. In certain modalities, percentages may be used of active ingredient from 0.01% to 10% in solution, and may be higher if the composition is a solid that will be diluted subsequently.

The pharmaceutical compositions of CK-2017357 can also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In certain embodiments, the particles of the pharmaceutical composition have diameters 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 an individual 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 pharmacokinetic properties (PK) of an individual dose of riluzole in healthy subjects. On Day 1, 12 subjects (7 men and 5 women) received an individual oral dose of 50 mg riluzole. On Day 6, all subjects started a period of 11 days of oral dosing with 250 mg CK-2017357 QD (until Day 16). On Day 13, 11 of the 12 subjects received another individual oral dose of 50 mg riluzole. After each dose of riluzole, the plasma samples were collected in pre-doses, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post -dose. The plasma concentrations of riluzole were determined using a validated HPLC / MS / MS method with a quantification range of 5.00 to 2,000 ng / mL. The samples were analyzed using an aliquot volume of 50.0 pL and an extraction procedure by protein precipitation followed by HPLC / MS / MS. Concentrations of riluzole were calculated with a linear regression of 1 / x2 over a concentration range of 5.00 to 2,000 using riluzole-13C, 15N2 as an internal standard. Separately, another set of plasma samples was collected at pre-dose of CK-2017357 on days 1 1, 12, and 13. These plasma samples were analyzed using a validated LC / MS / MS method for CK- levels. 20 7357 in order to determine the obtaining of the stable-state pharmacokinetic properties of CK-2017357.

The plasma concentration data of riluzole were analyzed through non-compartmental methods to determine the 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 in order to calculate the descriptive statistics and non-compartmental analyzes. The summary PK parameters of riluzole are presented in Tables 1A and 1B below.

Table 1A: Summary pharmacokinetic parameters of riluzole in healthy subjects The extension of the drug-drug interaction was evaluated by comparing the values AUCjnf of Period 1 (riluzole alone) with the values of Period 2 (riluzole + CK-2017357). The results are presented in Table 2 below. The half-time plasma concentration profiles are presented graphically in Figure 1, and the Cmax and AUC¡nf data for Periods 1 and 2 were plotted in Figure 2.

Table 2: Individual and Summary of Increase AUC injections of riluzole presence of stable-state CK-2015375 (250mg) in healthy subjects AUCinf AUCinf Increase in Patient Period 1 Period 2 x-times (hr * ng / ml) (hr * ng / ml) 1 1335.38 2 813.03 1622.66 2.00 3 619.77 1931.23 3.12 4 162.75 1951.67 11.99 5 883.12 2608.46 2.95 6 1189.32 4361.09 3.67 7 1674.53 3577.29 2.14 8 1263.88 7018.50 5.55 9 630.27 2635.93 4.18 10 573.21 2559.42 4.47 1 1 378.92 1412.02 3.73 12 612.18 2540.58 4.15 N 12 11 1 1 Mean 844.70 2929.00 4.36 SD 440.32 1600.93 2.73 Min 162.75 1412.02 2.00 Median 721.65 2559.42 3.73 Max 1674.53 7018.50 11.99 CV% 52.1 54.7 62.7 This study showed that stable-state CK-2017357 (250mg) raised the mean Cmax of riluzole approximately 1.7-fold, and its AUCinf average approximately 4.4-fold compared to riluzole alone. The mean t 2 of riluzole was increased from 8.0 hours to 15.5 hours in the presence of stable-state CK-2017357. As illustrated in Figure 2, the co-administration of CK-2017357 generally reduced the inter-subject variation of the pharmacokinetic properties of riluzole in these healthy subjects.

Example 2: Drug-drug interaction (DDI) between riluzole and CK-2017357 in patients with ALS This was a cross-over study of three periods, controlled with placebo. Each patient received 50 mg of riluzole BID and individual doses of placebo, 250 mg CK-2017357, and 500 mg CK-2017357 in random order, separated by 6-10 days. PK samples were collected in duplicate from each patient in the clinical study. A set was analyzed for CK-2017357, and the another analyzed for riluzole using a validated LC / MS / MS method. The riluzole exposure (AUC2 h) was calculated for each patient and each treatment of CK-2015357 (placebo, 250 mg, and 500 mg). The AUC-x fold increase in riluzole during the CK-2017357 placebo period was used to determine the extent of the drug-drug interaction.

The plasma concentrations of riluzole were determined using a validated HPLC / MS / MS method with a quantification range of 5.00 to 2,000 ng / mL. The samples were analyzed using an aliquot volume of 50.0 μl and a protein precipitation extraction procedure followed by HPLC / MS / MS. Concentrations of riluzole were calculated with a linear regression of 1 / x2 over a concentration range of 5.00 to 2,000 using riluzole-13C, 15N2 as an internal standard. Descriptive pharmacokinetic parameters such as Cmax, Tmax, AUC, ti / 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 non-compartmental analysis. Since the dosing time of riluzole was not recorded, the time elapsed was calculated based on nominal time points of CK-2017357, and used to calculate AUC24H of riluzole.

The results of this experiment were summarized in Table 3 below and the plasma-time concentration profiles were presented in Figure 3.

Table 3: AUC24n of riluzole and increment of AUC24hr-fold individual and 41 1387.18 887.4 3869.44 0.64 2.79 42 536.67 1448.56 849.78 2.70 1.58 43 1379.36 N 39 38 40 37 36 Average 1775.54 3252.18 4025.65 2.10 2.57 SD 969.09 1462.15 1721.25 1.27 1.32 Min 307.49 887.4 830.83 0.64 0.78 Mediana 1460.67 31 18.31 3982.49 1.79 2.41 Max 4841.83 7371.82 9116.2 6.07 6.29 CV% 54.6 45 42 8 60.5 51.1 The analysis of AUC24h of riluzole after 50 mg BID showed a general tendency to increase the concentrations of riluzole in the active periods of CK-2017357 (250 and 500 mg vs. 0 mg). Compared with the placebo CK-2017357 period, AUC24 of riluzole medium increased approximately 2.1- and 2.6-fold for the dose of 250- and 500-mg CK-2017357, respectively. As illustrated in Figure 3, the average riluzole Cmax doubled in the presence of stable-state concentrations of CK-2017357.

Example 3: Pharmacokinetic and Interactive Effects of Rapid Skeletal Muscle Activator CK-2017357 and Riluzole The objective of this study was to determine the pharmacokinetic properties of repeated doses of CK-2017357 both in the presence and in absence of riluzole, and determine the effects of CK-2017357 in varying doses on serum levels of riluzole in plasma.

In this study, 49 patients with ALS were treated; 24 patients were not taking riluzole and the rest took a stable but reduced dose of riluzole (50 mg daily). Patients (n = out of / in riluzole) received individual daily doses of placebo (n = 6/7), 125, 250, or 375 mg of CK-357 (n = 6/6 for all 3 groups of CK-2017357) for 14 days. The levels of CK-2017357 and riluzole on Days 1, 2, 8 and 15.

Plasma levels of CK-2017357 reached steady state on Day 8; the levels four hours after dosing on Day 8 were of approximately 70% greater than four hours after the first dose on Day 1. The Cmax of CK-2017357 was increased proportionally by dose without apparent effect of riluzole, as shown in Table 4.

Table 4: Levels of Cm x of CK-2017357 with no riluzole CK-2017357 approximately doubled riluzole levels through of all the studio groups as shown in Table 5 below. The frequencies of adverse event were not altered by the presence of riluzole at any dose of CK-20 7357.

Table 5: Cmax levels of riluzole with various doses of CK-2017357 CK-2017357 had predictable linear kinetics in the repeated doses used in the current study, reaching stable state within 1 week. The plasma levels of CK-2017357 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. However, no adverse events were reported during this study attributable to higher levels of riluzole with the daily dose of riluzole reduced to 50 mg daily. These results suggest that CK-2017357 and riluzole can be safely supplied in combination.

Example 4: Investigation of Dosage Titration Regimen Twice a Day of CK-20 7357 in Patients with ALS In previous clinical trials, 1- (ethylpropyl) -6-ethynylimidazo [4,5-b] pyrazin-2-ol (CK-2017357) has been administered once a day in the morning. While there were patient improvements and overall researcher evaluations, muscle fatigue and lung function have been observed in these studies, dizziness has been an adverse dose-limiting event in both healthy volunteers and patients with ALS. This example examines whether the maximum tolerable total daily dose of CK-2017357 can be increased by dividing the daily dose into two portions (morning and evening), and initiating the treatment with a low dose and ascending dose adjustment up to a target of 250 mg twice a day.

Patients enrolled in this clinical study were randomized, double-blind, and placebo controlled. There was a 7-day stabilization period for riluzole at a reduced dose of 50 mg QD. Patients were randomized after 3: 1 for CK-2017357 or placebo for 14 days.

The dose adjustment regimen of CK-2017357 was as follows: dosing initiated at 125 mg twice daily for 7 days (250 mg total daily dose); on Day 8, up to dose adjustment at 125 mg in the morning and 250 mg at night (375 mg total daily dose); on Day 15, until dose adjustment to 250 mg twice daily (500 mg total daily dose) continued until the morning dose on Day 22. Patients who did not tolerate a dose escalation returned to the previous tolerated dose level and they were maintained at that dose level until the study was complete. Patients on placebo experienced a similar sham dose adjustment to maintain the blind design. Figure 4 illustrates the design of the study.

Twenty-seven patients were treated in this study. The six patients randomized to placebo completed three weeks of dosing. Of the 21 patients randomized to treatment with CK-2017357, 14 were switched to the highest total daily dose of 500 mg and completed three weeks of dosing. The adverse event emerging from the treatment most commonly reported was dizziness, which was moderate in 10 of the 12 patients in whom it occurred and only moderate in the other two. Dizziness was self-limited in 6 of 12 patients in whom it occurred. Trends were observed encouraging increases in the ALSFRS-R and MW registry in CK-2017357 in relation to placebo. Therefore, this study suggests that CK-2017357 administered in a dose adjustment regimen, twice a day is safe and well tolerated.

While the present invention has been described with reference to the specific embodiments described herein, those skilled in the art will understand that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, modifications may be made to adapt a particular situation, material, composition of matter and / or process to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (26)

CLAIMS.

1. 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 C-2017357.

2. The method according to claim 1, characterized in that the therapeutically effective amount of riluzole administered in combination with CK-2017357 is a lower dose than the therapeutically effective amount of riluzole when administered individually.

3. A method for reducing the exposure variation of riluzole in a subject, comprising administering to the subject a therapeutically effective amount of CK-2017357.

4. A method for reducing the total daily dose of riluzole in a subject, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

5. A method for increasing the half-life of riluzole in a subject, comprising administering to the subject a therapeutically effective amount of CK-2017357.

6. A method for reducing the dosing frequency of riluzole in a subject, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

7. The method according to claim 6, characterized in that the dosing frequency of riluzole changes from two or more doses per day to once a day.

8. A method for reducing the incidence or severity of adverse events in a subject treated with riluzole, which comprises administering to the subject a therapeutically effective amount of CK-2017357.

9. The method according to claim 8, characterized in that the adverse event is an adverse event related to the CNS.

10. The method according to any of claims 1 to 9, characterized in that riluzole is administered QD.

The method according to claim 10, characterized in that the CK-2017357 is administered QD.

12. The method according to claim 10, characterized in that the CK-2017357 is administered BID.

13. The method according to any of claims 1 to 9, characterized in that riluzole is administered BID.

14. The method according to claim 13, characterized in that the CK-2017357 is administered QD.

15. The method according to claim 3, characterized in that the CK-2017357 is administered BID.

16. The method according to any of claims 1 to 15, characterized in that the total daily dose of riluzole is selected from 25 mg and 50 mg.

17. The method according to any of claims 1 to 15, characterized in that the total daily dose of CK-2017357 is selected from 125 mg, 250 mg, 375 mg, and 500 mg.

18. The method according to any of claims 1 to 17, characterized in that riluzole is administered orally.

19. The method according to any of claims 1 to 18, characterized in that CK-2017357 is administered orally.

20. The method according to any of the claims 1-19, characterized in that riluzole and CK-2017357 are administered in separate pharmaceutical compositions.

21. The method according to any of claims 1 to 19, characterized in that riluzole and CK-2017357 are administered in an individual pharmaceutical composition.

22. A pharmaceutical composition comprising a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357.

23. A method for treating amyotrophic lateral sclerosis in a patient, comprising administering to the patient at least two daily doses of CK-2017357.

24. The method according to claim 23, characterized in that the total daily dose is at least about 250 mg.

25. The method according to claim 23, characterized in that at least one of the doses is equal to or greater than about 250 mg.

26. The method according to claim 25, characterized in that at least two of the doses are equal to or greater than about 250 mg.