Use of riluzole prodrugs to treat alzheimer's disease

Abstract

To provide novel compounds, pharmaceutical compositions and methods for the treatment of Alzheimer's disease which may provide benefits for patients afflicted with the Alzheimer's disease.SOLUTION: Provided is a method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a riluzole prodrug.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the use of prodrugs of riluzole for treating Alzheimer's disease.

Background Art

[0002] Alzheimer's disease is a progressive and fatal neurodegenerative dementia. It accounts for up to 80% of dementia cases. According to the Alzheimer's Association, approximately 5.5 million people in the United States had this disease in 2016, and with the aging of the population, it is expected to escalate rapidly in the coming years. In the postmortem brain tissue of Alzheimer's disease patients, a decrease in glutamate uptake transporters has been reported, and the level of decrease in glutamate transporters correlates with cognitive impairment, as well as markers of synaptic density and markers of neurodegeneration.

[0003] The mental and economic burden of AD on patients, families, and society is enormous and is predicted to increase exponentially as the median age of the population rises. The possibility of maintaining or improving the cognitive function of adults at high risk of cognitive decline due to AD clearly has important implications not only for the patients but also for the support systems that bear the long-term social and economic burden of caregiving.

[0004] Currently, there are medications approved as symptomatic treatments for AD, but they have a small magnitude of effect and generally limited clinical efficacy. There is an urgent need to find effective treatment methods that can halt the disease or reverse it before the advanced stage of AD. Treatment strategies aimed at restoring synaptic and extrasynaptic glutamate levels offer potential therapeutic benefits not only in synaptic neuroprotection but also in AD and cognition, providing the possibility of disease improvement. Considering that symptomatic and disease-modifying therapies have not advanced since 2003, it cannot be overstated how important clinical research targeting this preclinically validated synaptic target is.

[0005] The FDA initially approved riluzole (RILUTEK®) 50 mg twice daily (NDA#20-599) for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole is only indicated for ALS and has many undesirable properties that limit its clinical use.

[0006] The bioavailability of riluzole tablets is 60%, which is due to high first-pass metabolism in the liver. This is thought to be related to metabolism by the heterogeneously expressed CYP1A2 enzyme, which also explains the high PK variability associated with riluzole (Non-Patent Document 1). Furthermore, riluzole is associated with a decrease in exposure (i.e., a negative food effect) when taken with food, and as a result, patients are instructed to take riluzole within a 3-hour fasting period (1 hour before or 2 hours after a meal).

[0007] In addition, riluzole is administered twice daily and has a dose-dependent effect on liver function tests. The drug itself has other inherent limitations, such as very low solubility in water, low oral acceptability, pH-dependent chemical stability, and strong oral numbness when administered directly to the oral mucosa.

[0008] Accordingly, there is a need for novel compounds, pharmaceutical compositions, and methods for the treatment of Alzheimer's disease that can provide benefits to patients suffering from Alzheimer's disease.

PRIOR ART DOCUMENTS

NON-PATENT LITERATURE

[0009]

Non-Patent Literature 1

SUMMARY OF THE INVENTION

[0010] The present invention is directed to the treatment of Alzheimer's disease with prodrugs of riluzole. This may now enable the present invention to provide more effective AD treatment to patients. Patients may experience improved responses in one or more areas including, for example, overall survival, quality of life, overall efficacy, duration of efficacy, onset delay, or patient-reported outcomes.

[0011] In one aspect of the present invention, there is provided a method for treating Alzheimer's disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a riluzole prodrug.

[0012] In one aspect, the riluzole prodrug has the following formula:

CHEMICAL FORMULA

[0013] In one embodiment, the riluzole prodrug has the following formula:

Chemical formula

[0014] In one embodiment, the riluzole prodrug is administered to a patient at a dosage of about 100 - 400 mg / day.

[0015] In one embodiment, the riluzole prodrug is administered to a patient at a dosage of about 110, or 140, or 150, or 210, or 280, or 350 mg / day.

[0016] In one embodiment, the riluzole prodrug is administered to a patient once a day at a dosage of 280 mg.

[0017] In one embodiment, the riluzole prodrug is administered to a patient twice a day at a dosage of 140 mg.

[0018] In one embodiment, the riluzole prodrug is administered to a patient once a day.

[0019] In one embodiment, the riluzole prodrug is administered to a patient twice a day.

[0020] In one aspect, the riluzole prodrug is administered to a patient in the dosage form of a capsule.

[0021] In one aspect, the riluzole prodrug is administered to a patient in the dosage form of a tablet.

[0022] In one aspect, the riluzole prodrug is administered to a patient for a period of about 8 weeks to 48 weeks. In one aspect, the riluzole prodrug is administered to a patient for the period from the start of treatment until the patient's death.

[0023] In one aspect of the present invention, there is provided a method for improving the response in a patient suffering from AD, the method comprising administering an effective amount of a riluzole prodrug to a patient in need thereof.

[0024] In one aspect, the improved response is one or more of overall survival, quality of life, overall response rate, response duration, onset delay, or patient-reported outcome.

[0025] In one aspect of the present invention, there is provided a kit for treating a patient suffering from AD, (a) a riluzole prodrug; and (b) instructions for administering the riluzole prodrug in the method of the present invention A kit comprising the above is provided.

[0026] In an aspect of the present invention, as an active ingredient

Chemical formula

[0027] In an embodiment of the present invention, the capsule preparation contains about 40 to 50% of tolclofos-methyl, 15 to 20% of mannitol, 3 to 15% of microcrystalline cellulose, 3 to 15% of dicalcium phosphate, 5 to 10% of hydroxypropyl cellulose, 5 to 10% of crospovidone, 0.1 to 1% of colloidal silicon dioxide, and 0.1 to 1% of magnesium stearate. The percentages are expressed as weight percentages.

[0028] In an embodiment of the present invention, the capsule preparation contains about 70 to 280 mg of tolclofos-methyl, preferably 140 mg of tolclofos-methyl, 60 to 90 mg of mannitol, 30 to 60 mg of microcrystalline cellulose, 5 to 20 mg of dicalcium phosphate, 5 to 10 mg of hydroxypropyl cellulose, 5 to 20 mg of crospovidone, 0.5 to 5 mg of colloidal silicon dioxide, and 0.5 to 5 mg of magnesium stearate.

Mode for Carrying Out the Invention

[0029] Detailed Description of the Invention The following detailed description is provided to assist those skilled in the art in practicing the present invention. Those skilled in the art can make changes and modifications to the embodiments described herein without departing from the spirit or scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this disclosure belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0030] As used in the present application, unless explicitly defined herein, each of the following terms shall have the meanings described below. Further definitions are set forth throughout the present application. If a term is not specifically defined herein, that term shall be given the meaning recognized by those skilled in the art in connection with its use in the description of the present invention.

[0031] The articles "a" and "an" mean one or more (i.e., at least one) of the grammatical objects of the article, unless the context clearly indicates otherwise. For example, "an element" means one element or more than one element.

[0032] The term "about" means a value or composition that is within the tolerance range of a specific value or composition determined by those skilled in the art, which depends in part on how the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, "about" can mean within one standard deviation or more than one standard deviation according to the practice in the relevant technical field. Alternatively, "about" can mean a range up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any numerical value between 2.7 mg and 3.3 mg (in the case of 10%), or between 2.4 mg and 3.6 mg (in the case of 20%). Further, especially with respect to biological systems or processes, this term can mean a value up to one order of magnitude or up to five times. When a specific value or composition is described in the present application and the claims, unless otherwise specified, the meaning of "about" should be assumed to be within the tolerance range of that specific value or composition.

[0033] The term "administer" means physically introducing a composition containing a therapeutic agent into a subject using any of various methods and delivery systems known to those skilled in the art. Representative routes of administration of riluzole prodrugs include, for example, oral administration by means of capsules or tablets. Also, administration can be carried out, for example, once, multiple times, and / or over one or more extended periods, and can be a subtherapeutic dose, i.e., a dose below the therapeutically effective amount or therapeutic dose.

[0034] The term "AUC" (area under the curve) refers to the total amount of drug absorbed or exposed to the subject. Generally, AUC can be obtained from a mathematical method in a plot of the drug concentration in the subject over time until the concentration becomes negligible. Also, the term "AUC" (area under the curve) may refer to a partial AUC over a specified time interval.

[0035] The term "Cmax" refers to the maximum concentration of the drug contained in the blood, serum, specified compartment or test site of the subject between the first dose and the second dose. Also, the term "Cmax" may refer to the dose-normalized ratio if specified.

[0036] The term "dose interval" refers to the time elapsed during multiple administrations of the formulations disclosed herein to the subject. Thus, the dose interval can be expressed as a range.

[0037] The term "dose frequency" refers to the frequency of administering the dose of the formulations disclosed herein within a predetermined time. The dose frequency can be expressed as the number of administrations per given time, for example, once a week or once every two weeks.

[0038] The term "effective amount" refers to an amount sufficient to produce the intended result. The effective amount varies depending on the subject to be treated, the condition, the severity of the disease, and the mode of administration, and can be routinely determined by those skilled in the art.

[0039] The terms "in combination with" and "in conjunction with" refer to administering another treatment modality in addition to a certain treatment modality. Thus, "in combination with" or "in conjunction with" means administering another treatment modality before, during, or after administering a certain treatment modality to the subject.

[0040] The term "pharmaceutically acceptable salt" refers to a salt form of one or more of the compounds or prodrugs described herein that is presented to enhance the solubility of the compound in the gastric or digestive juices of the patient's gastrointestinal tract in order to promote dissolution and to enhance the bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Among the numerous acids and bases well known in the pharmaceutical art, preferred salts include alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, and ammonium salts.

[0041] The term "prodrug" refers to a precursor of a drug that can be administered in a modified or less active form. A prodrug can be converted to the active drug form by hydrolysis or other metabolic pathways in a physiological environment. Discussions on prodrugs are published in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.

[0042] The terms "subject" and "patient" refer to a human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0043] The terms "therapeutically effective amount," "therapeutically effective dose," and "therapeutically effective dosage" of an agent (often referred to herein as "drug") refer to the amount of the agent that, when used alone or in combination with other agents, protects a subject from the onset of a disease or promotes the regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods of the disease, or the prevention of disorders or disabilities resulting from the disease. The therapeutically effective amount of an agent can be evaluated using various methods known to those of skill in the art, for example, in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0044] The term "Tmax" refers to the time or period at which the maximum concentration (Cmax) is reached in the blood, serum, a specified compartment, or the test site of a subject after administration of a drug.

[0045] The term "treatment" means the treatment of a condition or disease in a subject and can include the following: (i) preventing a disease or condition from occurring in a subject who may have a predisposition to the disease but has not yet been diagnosed with the disease; (ii) inhibiting a disease or condition, i.e., arresting its onset; relieving a disease or condition, i.e., causing regression of the condition; or (iii) ameliorating or relieving a condition caused by a disease, i.e., the symptoms of the disease. Treatment can be used in combination with or alone in addition to other standard therapies. Treatment or "therapy" of a subject includes any type of intervention or process performed on the subject or administration of an agent to the subject for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of symptoms, complications or conditions associated with the disease, or biochemical markers.

[0046] Riluzole is currently marketed as RILUTEK® (riluzole) and is available from Sanofi-Aventis (Bridgewater, NJ) and has the following structure.

Chemical formula

[0047] A specific preferred riluzole prodrug for use in accordance with the present invention has the structure:

Chemical formula

[0048] Trolyzole, which is a particularly preferred riluzole prodrug, has the following formula:

Chemical formula

[0049] Riluzole prodrugs are described, for example, in U.S. Patent No. 9,725,427, issued August 8, 2017, U.S. Patent Application No. 14 / 410,647, filed December 23, 2014, U.S. Patent Application No. 15 / 549,154, filed August 5, 2017, PCT Application No. PCT / US2016 / 019773, filed February 26, 2016, and PCT Application No. PCT / US2016 / 019787, filed February 26, 2016.

[0050] Riluzole prodrugs may exist as isotopically labeled forms of the compounds described herein. Isotopically labeled compounds have the structures shown by the formulas described herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2H (deuterium, D), 3 H (tritium), n C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 Examples include, but are not limited to, S, Cl, and I. Various isotopically labeled compounds of the present disclosure, for example, 3 H, 13 C and 14 compounds incorporated with radioisotopes such as C are provided. Such isotopically labeled compounds are useful for detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including metabolic studies, kinetic studies, and tissue distribution assays of drugs or substrates, or for radioactive treatment of subjects (e.g., humans). Also, for the isotopically labeled compounds described herein, pharmaceutically acceptable salts or hydrates may be provided in some cases.

[0051] In some variations, the compounds disclosed herein may be varied such that 1 to “n” hydrogens bonded to carbon atoms are replaced with deuterium (where “n” is the number of hydrogens in the molecule). Such compounds can exhibit increased resistance to metabolism and are thus useful for increasing the half-life of the compound when administered to a subject. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524 - 527 (1984). Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogens are replaced with deuterium.

[0052] The deuterium-labeled or substituted therapeutic compounds of the present disclosure can improve the drug metabolism and pharmacokinetics (DMPK) properties related to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can result in therapeutic advantages due to improved metabolic stability, such as an increase in the in vivo half-life, a decrease in the required dose, and / or an improvement in the therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds of the present disclosure can generally be prepared by carrying out procedures known to those skilled in the art by using isotope-labeled reagents that are readily available instead of non-isotope-labeled reagents. Deuterium in this context is understood to be regarded as a substituent of the compounds provided herein.

[0053] The concentration of such heavier isotopes (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds of the present disclosure, atoms not specifically designated as a particular isotope are meant to represent the stable isotopes of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen with its natural abundance isotope composition.

[0054] The riluzole prodrugs of the present invention can be administered orally, sublingually, intranasally, buccally, subcutaneously, or by other suitable delivery means.

[0055] The dosage of the riluzole prodrug to be administered can vary depending on the subject being treated, including age, gender, weight, and general health. In this regard, the exact amount of the agent for administration is at the discretion of the practitioner. When determining the effective amount of the riluzole prodrug to be administered in the treatment or alleviation of conditions related to symptoms and disorders, the physician can evaluate clinical factors including the severity of the symptoms or the progression of the disorder. The effective amount of treatment varies depending on the subject or condition being treated, the severity of the affliction, and the method of administration, and can be routinely determined by those skilled in the art.

[0056] The riluzole prodrug for treating AD or symptoms can be administered in an effective dose for treating AD with an acceptable amount of side effects, if any, for the specific patient being treated. Typical dosing frequencies of the riluzole prodrug include once a day, twice a day, three times a day, four times a day, every other day, once a week, twice a week, three times a week, four times a week, once every two weeks, and once or twice a month, etc. Examples of dosages include about 400 mg / day or less, about 300 mg / day or less, about 150 mg / day or less, about 100 mg / day or less, about 70 mg / day or less, about 60 mg / day or less, about 50 mg / day or less, about 42.5 mg / day or less, about 37.5 mg / day or less, about 35 mg / day or less, about 20 mg / day or less, about 17.5 mg / day or less, about 15 mg / day or less, about 10 mg / day or less, about 5 mg / day or less, or about 1 mg / day or less. In one aspect, the riluzole prodrug is administered to a patient at a dosage of about 110, or 140, or 150, or 210, or 280, or 350 mg per day. In one aspect, the riluzole prodrug is administered to a patient once a day at a dosage of 280 mg. In another aspect, the riluzole prodrug is administered to a patient twice a day at a dosage of 140 mg.

[0057] The pharmaceutical composition of the present invention containing the riluzole prodrug typically also includes other pharmaceutically acceptable carriers and / or excipients such as binders, lubricants, diluents, coating agents, disintegrants, barrier layer components, lubricants, colorants, solubility enhancers, gelling agents, fillers, proteins, coenzymes, emulsifiers, solubilizers, suspending agents, and mixtures thereof. Those skilled in the art will know what other pharmaceutically acceptable carriers and / or excipients can be included in the formulations according to the present invention. The selection of excipients will depend on the properties of the composition and the nature of the other pharmacologically active compounds in the formulation. Suitable excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill) and have been utilized to obtain novel sublingual formulations with unexpected properties.

[0058] Examples of pharmaceutically acceptable carriers that can be used in preparing the pharmaceutical composition of the present invention include saccharides including lactose, sucrose, mannitol or sorbitol; starches such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, pyrogen-free water, and fillers such as cellulose preparations such as combinations thereof, but are not limited thereto. If necessary, a disintegrant may also be combined. Exemplary disintegrants may be crosslinked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate, but are not limited thereto. The composition can be prepared by any of the methods of pharmacy, but all methods include the step of associating one or more chemical agents as described above with a carrier constituting one or more required components. Generally, the pharmaceutical composition of the present invention can be manufactured by conventional methods known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, enclosing, freeze-drying processes, and the like.

[0059] In one aspect of the present invention, the riluzole prodrug is provided in the form of an orally disintegrating or dispersing tablet (ODT) for sublingual administration. Generally, excipients including mannitol and gelatin are formulated, solubilized with water, degassed, and then mixed with the active pharmaceutical ingredient (API) that has been separately pulverized. The particle size (D50) of the API is preferably less than about 2 microns. This mixture is lyophilized by instant freezing and then freeze-dried. The effective amount of the riluzole prodrug for a sublingual formulation useful in the present invention to achieve a therapeutically effective amount may be less than the effective amount of the drug administered orally. For example, the effective amount of the sublingual formulation of the riluzole prodrug may be about 1 to 95%, preferably 50 to 90%, more preferably 70 to 85%, and most preferably about 80% of the effective amount of the drug administered orally in a conventional tablet or capsule. In one aspect of the present invention, it is prepared in an ODT dosage form as described in U.S. Patent No. 9,192,580, issued November 24, 2015. The ODT dosage form is further described in British Patent No. 1,548,022 to Gregory et al. using fish gelatin as a carrier. The fish gelatin suitable for use in the present invention is commercially available.

[0060] Typically, the ODT dosage form disintegrates or disperses within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds, and particularly within 2 to 8 seconds after being contacted with a fluid. The fluid is preferably the fluid found in the oral cavity, i.e., saliva, as in the case of oral administration.

[0061] The ODT composition according to the present invention may also contain, in addition to the active ingredient, a dried fish gelatin carrier, other matrix formers and secondary components. Matrix formers suitable for use in the present invention include materials derived from animal or vegetable proteins, such as other gelatins, dextrins and soybean, wheat and psyllium seed proteins; gums such as acacia, guar, agar and xanthan; polysaccharides; alginates; carboxymethylcellulose; carrageenan; dextran; pectin; synthetic polymers such as polyvinylpyrrolidone; and polypeptide / protein or polysaccharide complexes such as gelatin-acacia complexes.

[0062] Other materials that can be further incorporated into the ODT composition of the present invention include saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate; and amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. One or more matrix formers can be incorporated into the solution or suspension before solidification (freezing). The matrix former can be present in addition to or excluding the surfactant. The matrix former can not only form a matrix but also help maintain the dispersibility of the active ingredient in the solution of the suspension. This is particularly effective in the case of active drugs that need to be suspended rather than dissolved because they are not sufficiently soluble in water. Secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, flavoring and odor-masking agents, pH adjusters, sweeteners or taste-masking agents can also be incorporated into the fast-dissolving composition. Suitable colorants include iron oxides in red, black and yellow, and FD&C dyes such as FD&C Blue No.2 and FD&C Red No.40 available from Ellis & Everard. Suitable flavoring and odor-masking agents include flavors of mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape and combinations thereof. Suitable pH adjusters include edible acids and bases such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweeteners include, for example, sucralose, aspartame, acesulfame K and thaumatin. Suitable taste-masking agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents or microencapsulated active substances.

[0063] In a preferred embodiment of the present invention, the ODT composition comprises about 50 to 70 wt% of a riluzole prodrug, about 10 to 30 wt% of fish gelatin, about 10 to 20 wt% of one or more fillers, and 0.1 to 5.0 wt% of one or more flavoring and odor-masking agents.

[0064] Other ODT preparation methods can be used without limitation, and detailed descriptions of its general methods are disclosed, for example, in U.S. Patent Nos. 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105; 7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and 8,313,768.

[0065] In a preferred embodiment of the present invention, as the active ingredient

Chemical formula

[0066] Kits containing a therapeutic rilzole prodrug (e.g., trololazole) are also within the scope of the present invention. The kit typically includes a label and instructions for use indicating the intended use of the contents of the kit. The term "label" includes written or recorded materials provided on or with the kit or attached to the kit.

Examples

[0067] The following examples illustrate the present invention and do not limit the scope of the present invention.

[0068] Example 1 A clinical trial is conducted using the following parameters. For further information, see ClinicalTrials.gov Identifier NCT03605667, www.clinicaltrials.gov.

[0069] Test content Summary: In preclinical models, riluzole, an active metabolite of BHV-4157, has been shown to protect against AD-related pathologies and cognitive impairment. A gradual dose increase to 280 mg of BHV-4157, or placebo, is administered orally once a day. The treatment period is 48 weeks. There is also a screening period of up to 42 days and a post-treatment observation period of 4 weeks.

[0070] [Table 1]

[0071] Test design [Table 2]

[0072] Arms and interventions [Table 3]

[0073] Outcome measures Primary outcome measure: 1. Change from baseline to week 48 in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) between the BHV-4157 treatment group and the placebo group [Timeframe: from baseline to week 48] Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) ADAS-Cog11 assesses memory (word recall, word recognition), logical thinking (following commands), language (naming, comprehension), orientation, ideational praxis (putting a letter in an envelope), and constructional praxis (copying geometric figures). An assessment of spoken language, language comprehension, anomia, and the ability to remember test instructions is also obtained. The test is scored by the number of errors, with higher scores indicating lower performance and greater impairment. Scores can range from 0 (best) to 70 (worse).

[0074] Eligibility Criteria

Table 4

[0075] Criteria Key Inclusion Criteria for Important Test Subjects: · From 50 to 85 years old (including the boundaries) at the time of screening · Diagnosed as having a high likelihood of Alzheimer's dementia: Central clinical criteria according to the NIA / Alzheimer's Association Guidelines. · Living in the community (including living assistance facilities, excluding long-term care facilities). · Able to walk, or able to walk using assistive devices such as a cane or walker. · Participants must have a test partner who communicates frequently (about 3 to 4 times or more per week), attends all clinic visits, and can assist in complying with the test procedures. · A brain MRI scan within 6 months of screening that is consistent with the diagnosis of Alzheimer's disease. · Participants must have been treated with a stable dosing regimen of an FDA-approved AD treatment (acetylcholinesterase inhibitor (AchEI) and / or memantine) for at least 3 months prior to screening. Participants should be expected to maintain a stable dosing regimen of these agents during the study period. · Participants who have not been treated with these therapies at screening because they are contraindicated or have previously failed treatment with these therapies will also be eligible for the study if they are not expected to receive treatment with these therapies during the study period.

[0076] Key Exclusion Criteria: · Liver dysfunction defined as severe liver dysfunction with a Child-Pugh classification of A or above. · Other neurodegenerative diseases and causes of dementia including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy body dementia), PSP (progressive supranuclear palsy), AIDS (acquired immunodeficiency syndrome) or NPH (normal pressure hydrocephalus). · History of a major depressive episode within the past 6 months prior to screening. · Insulin-dependent diabetes or uncontrolled diabetes with an HbA1c value > 8.0%. · Cancer or malignancy within the past 3 years (except for patients who have received treatment with a curative potential with no signs of recurrence for over 3 years). Patients with stable prostate cancer or non-melanoma skin cancer are not excluded. · Participating in a clinical trial for another investigational agent and having taken the study medication at least once within 12 weeks prior to screening (except when it has been confirmed that only placebo has been taken). The end of a previous trial is defined as the last dosing day of the study drug.

[0077] Example 2 The clinical trial will be conducted with the following parameters.

[0078] Test Summary

Table 5-1

Table 5-2

Table 5-3

Table 5-4

[0079] List of Abbreviations

Table 6-1

Table 6-2

[0080] 1 Test Design This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group comparative trial in patients with mild to moderate Alzheimer's disease.

[0081] Participants are randomized to one of two groups: BHV-4157 280 mg or placebo. Based on the evidence summarized in Section 1.8, a treatment dose of 280 mg of BHV-4157 was selected for evaluation in the current trial. The treatment period is 48 weeks (12 months). There is a maximum screening period of 42 days and a post-treatment observation period of 4 weeks.

[0082] A sentinel cohort of 50 participants randomized first in each arm will undergo an interim analysis for futility when they have received treatment in the trial for more than 24 weeks (analysis of completers only). The interim analysis is based on changes in two measures, the surrogate primary endpoint (ADAS-Cog11) and hippocampal volume change, from baseline to week 24.

[0083] 2 Objectives 2.1 Primary Objective The primary objective is to evaluate the efficacy of BHV-4157 as measured by ADAS-Cog11.

[0084] 2.2 Secondary Objectives The secondary objectives are to evaluate the efficacy, safety, and tolerability of BHV-4157 as outlined below.

[0085] 2.2.1 Efficacy The efficacy of BHV-4157 is evaluated by the following metrics: · Total CDR-Box (important secondary objective), · Volume MRI (Quarc bilateral hippocampal volume, bilateral lateral ventricles, and total brain volume), · Neuropsychiatric Inventory (NPI), · Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living (ADCS-ADL), · Neuropsychological test battery (Craft Story 21 recall (immediate and delayed), Benson Figures (copy and delayed recall), Multilingual Naming Test (MINT), Letter and Category Fluency, Trail Making Tests A and B, Digit Span forward and backward), · Mini-Mental State Examination (MMSE), and · Montreal Cognitive Assessment (MoCA).

[0086] 2.2.2 Safety and Tolerability The safety and tolerability of BHV-4157 are evaluated by the following metrics: · Mortality rate, · Incidence of severe adverse events, · Adverse events, · Clinical safety laboratory, · Vital signs, · Physical examinations, · ECG, and · Use of concomitant medications.

[0087] 3 Endpoints 3.1 Primary Endpoints The primary efficacy endpoint is the within-participant change in ADAS-Cog11 from baseline to week 48, compared between the treatment group and the placebo group.

[0088] 3.2 Secondary Endpoints The secondary endpoints measure the efficacy, safety, and tolerability of BHV-4157, as outlined below.

[0089] 3.2.1 Efficacy The efficacy of BHV-4157 is evaluated by the within-participant change in the following from baseline to week 48, compared between the treatment group and the placebo group: · Total CDR-Box (key secondary endpoint), · Volumetric MRI (Quarc bilateral hippocampal volume, bilateral lateral ventricles, and total brain volume) · Neuropsychiatric Inventory (NPI) score · Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score · Neuropsychological test battery scores (Craft Story 21 recall (immediate and delayed), Benson Figures (copy and delayed recall), Multilingual Naming Test (MINT), Letter and Category Fluency, Trail Making Tests A and B, Digit Span Forward and Backward), · Mini-Mental State Examination (MMSE) score, and · Montreal Cognitive Assessment (MoCA) score.

[0090] 3.2.2 Safety and Tolerability The following safety and tolerability metrics are evaluated for differences between the treatment group and the placebo group: · Occurrence of death events, · Occurrence of serious adverse events (SAEs), · Occurrence of adverse events (AEs), · Clinical laboratory tests, · Vital signs, · Physical examinations, · ECG, and · Use of concomitant medications.

[0091] 4 Study Drug 4.1 Study Medication The study medication is provided as one of the following: · BHV-4157, one or two capsules (size 1) of 140 mg each, depending on the assigned dose · One or two capsules of matching placebo Study drug capsules must not be opened. The study medication is stored safely at the study site according to the conditions described on the label, distinct from other medications. The study medication may not be used for purposes other than this study.

[0092] 4.2 Blinding This is a double-blind placebo-controlled trial. Treatments are blinded to participants and study personnel throughout the study. Treatment blinding is maintained by the use of matching placebo medications. Only in case of an emergency, if it is essential for the clinical management or well-being of the participant to know whether the participant received the investigational drug, the study responsible physician may unblind the participant's treatment assignment. The procedure for emergency unblinding is initiated by contacting the ADCS Medical Monitor.

[0093] 5 Patient Selection 5.1 Eligibility Criteria for Study Subjects Participants must meet all of the following eligibility criteria for study subjects in order to be enrolled: 1. Between 50 and 85 years old (inclusive) at screening 2. Diagnosed as likely to have Alzheimer's dementia: Central clinical criteria according to the NIA / Alzheimer's Association Guidelines. 3. Living in a local community (including living assistance facilities, excluding long-term nursing care facilities). 4. Able to walk independently or with the use of assistive devices such as a cane or walker. 5. Participants must have a study partner who can communicate frequently (about 3 - 4 times or more per week), attend all clinic visits, and assist in complying with the study procedures. 6. Women must have been continuously postmenopausal for at least 2 years or be surgically sterile (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months prior to screening. 7. Modified Hachinski score of 4 or less at screening. 8. MMSE score of 14 - 24 (including the border) at screening. 9. Brain MRI scan within 6 months of screening that is consistent with the diagnosis of Alzheimer's disease. 10. Body mass index (BMI) ≤ 35 kg / m 2 at screening. 11. Participants must not have been treated with a stable dosing regimen of an FDA-approved AD treatment drug (acetylcholinesterase inhibitor (AchEI) and / or memantine) for at least 3 months prior to screening. Participants are expected to maintain a stable dosing regimen of these drugs during the study period. a. Participants who are not being treated with these treatment drugs at screening because they are contraindicated or have previously failed treatment with these drugs, and who are not expected to receive treatment with these drugs during the study period, will be included in the study. 12. Reading, conversation, and comprehension skills in English or Spanish (for the patient and their study partner) to ensure compliance with cognitive tests and study visit procedures. 13. Provision of informed consent from the participant (or, if consent cannot be obtained, the legally authorized representative (LAR) of the participant) and the study partner.

[0094] 5.2 vMRI Evaluation Structural changes in the brain are seen with normal aging but are accelerated in neurodegenerative diseases including AD. Brain atrophy in AD results from the loss of neurons and synapses that begins in the olfactory cortex. Pathology then spreads throughout the limbic region of the temporal lobe, including the hippocampus. Subsequently, neuronal loss and atrophy are seen throughout the neocortical association areas of the temporal, parietal, and frontal lobes.

[0095] vMRI enables in vivo evaluation of brain structure volumes and provides measurements of atrophy rates. Results of vMRI studies suggest that atrophy patterns in AD, which reflect the pathological progression of AD, can be reliably detected and followed over time. In vMRI studies of AD, atrophy of the medial temporal lobe, including the hippocampus and olfactory cortex, has been reported for a long time. The volume of the hippocampus derived from MRI correlates with histological hippocampal volume as well as the degree of neuronal loss and AD pathology, and changes in the thickness of the olfactory cortex are considered to be an early and sensitive indicator of neurodegeneration associated with AD (Holland et al., 2009; Jack et al., 2004). Longitudinal MRI measurements of regional and whole-brain volume changes are valuable in complementing cognitive measures in that they are not affected by transient improvements in symptoms and also provide an initial indicator of the ability of a test drug to reach the target organ and affect AD-related atrophy.

[0096] Participants will undergo brain vMRI scans at screening, week 24, and week 48 to evaluate changes in brain volume that may be related to clinical changes resulting from treatment with BHV-4157.

[0097] Volume MRI scans will include a localizer scan, 3D T1-weighted sagittal acquisition (MPRAGE or IR-SPGR), T2-weighted FLAIR axial acquisition, and T2* gradient recalled echo axial acquisition * for susceptibility *Use the same imaging protocol, including gradient recalled echo axial acquisition and diffusion weighted axial acquisition for evaluating restricted diffusion.

[0098] The images are checked for image quality and compliance with the scan protocol. 3D T1-weighted data passing the quality check are corrected for spatial distortion and intensity variation. The screening and follow-up dataset for each participant are spatially registered to each other using rigid body registration followed by non-linear registration and neuroanatomical segmentation to quantify whole brain and subregional volume changes for each patient.

[0099] Based on the results of local MRI, the eligibility of each participant in the study is determined. The PI makes this decision after reviewing the MRI, signs and dates the local report to approve this review, and is responsible for confirming that the MRI results are consistent with AD and do not meet the exclusion criteria. The PI may consult freely with the local neuroradiologist, but a formal MRI reading by the neuroradiologist is not required. The ADCS Medical Safety team or the ADCS Imaging core can address questions regarding MRI eligibility. If any safety concerns are identified on this MRI, the PI needs to contact the participant's primary care physician and consult with the ADCS Medical Monitor, the ADCS Director, and the ADCS Imaging core.

[0100] Measure the whole brain volume (excluding the cerebellum), bilateral ventricular volumes, and bilateral hippocampal volumes. Use Quantitative anatomical regional change (Quarc) as a computerized MR image processing application. Details of the statistical calculations are described in the Statistical Analysis Plan (SAP).

[0101] If performed on the same day as a lumbar puncture, vMRI must be performed before the lumbar puncture. Otherwise, a window of at least 3 days is required between vMRI and lumbar puncture. A scanner that has passed the qualification procedure for this test is used. Participants must be scanned on the same scanner throughout the study.

[0102] Participants who are MRI - contraindicated at screening are considered ineligible to participate in this study. If participants have already been randomized, they can continue to participate in the study even if they become MRI - contraindicated during the study.

[0103] 5.3 Sub - study evaluation of CSF, serum, and plasma To measure biomarkers (Aβ42, Aβ42 / 40 ratio, total tau, p - tau, neurogranin, NfL, YKL - 40, VILIP, SNAP - 25, sTREM2), collect CSF, serum, and plasma at screening within 14 days before the first dose of the study drug and within 14 days before week 24 and week 48.

[0104] CSF samples need to be collected at the same time of day, either in the morning (between 8 and 10 am) or in the afternoon (between 1 and 3 pm). The first lumbar puncture must be performed before the start of the study drug. Plasma samples for PK need to be collected at the time of lumbar puncture. It is necessary to collect the dosing date and time on the day of lumbar puncture and the previous dosing day in the case report form for entry into the EDC system.

[0105] An estimated 100 participants (n = 50 active, n = 50 placebo) within the sentinel cohort that constitutes the test samples for futility analysis also have the opportunity to participate in the sub - study of CSF, serum, and plasma, with samples collected during the screening period and at week 24, and the third sample collection time point can be selected at week 48.

[0106] In addition to Sentinel sub-study participants, other consented study participants are approached to have blood drawn to provide serum and plasma biomarkers. For CSF, consented participants undergo lumbar puncture at screening and within 14 days prior to the first dose of study drug and within 14 days prior to Week 48 to measure CSF biomarkers.

[0107] Administration of antiplatelet and anticoagulant medications and lumbar puncture are described above in Prohibited Concomitant Medications. Participants taking anticoagulants or dual antiplatelet medications are excluded from the CSF sub-study.

[0108] Details of CSF sample collection are included in the Study Procedures Manual.

[0109] Unused portions of CSF can be transferred to the National Cell Repository for Alzheimer's Disease (NCRAD) for future research. Participants are given the option to consent to the retention of such samples and further investigation of the CSF.

[0110] 6 Study-Specific Measures 6.1 Cognitive Measures 6.1.1 Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) ADAS-Cog11 (Rosen, Mohs, & Davis, 1984) is a structured scale that evaluates memory (word recall, word recognition), logical thinking (execution of instructions), language (naming, comprehension), orientation, ideational praxis (putting a letter in an envelope), and constructional praxis (copying geometric figures). An evaluation of oral language, language comprehension, anomia, and the ability to remember test instructions is also obtained. The test is scored by the number of errors, with higher scores indicating lower performance and greater impairment. Scores can range from 0 (best) to 70 (worse).

[0111] 6.1.2 Mini-Mental State Examination (MMSE) The MMSE is a screening tool frequently used for Alzheimer's disease drug trials. The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, as well as the ability to make a sentence and copy two intersecting pentagons (Folstein, Folstein, & McHugh, 1975). Lower scores indicate more cognitive impairment. The highest (best) score is 30.

[0112] 6.1.3 Montreal Cognitive Assessment (MoCA) The MoCA is a brief mental status examination designed to be more sensitive than the MMSE to mild cognitive impairment and early dementia (Nasreddine et al., 2005). It evaluates a number of cognitive domains including attention and concentration, executive function, memory, language, visual construction skills, conceptual thinking, calculation, and orientation. Similar to the MMSE, the highest (best) score is 30. In this test, by administering both the MoCA and the MMSE, a comparison of their utility within the context of clinical trials is possible.

[0113] 6.1.4 Neuropsychological Test Battery (NTB) To more thoroughly evaluate cognitive function, a neuropsychological battery (Weintraub et al., 2009) from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (v3.0 - Form C2) is administered. This battery includes simple measures of attention, processing speed, executive function, episodic memory, and language. Exploratory analyses classify participants as typical (i.e., significant memory impairment) or atypical (i.e., relatively preserved memory) based on the performance pattern of the baseline neuropsychological test battery. As described in the manual for test administration and scoring (Version 3.0, March 2015), Form C2 of the NACC UDS battery includes the following measures:

[0114] 6.1.4.1 Craft Story 21 Recall (Immediate and Delayed) This is a measure of verbal episodic memory (Craft et al., 1996). Participants are read a short story and then asked to immediately recall it from memory. The primary measure of performance is the number of story units recalled. Delayed recall of the story is evaluated 20 minutes after immediate recall. Other neuropsychological measures are administered during the delay interval (range: 0 - 25 for each recall trial).

[0115] 6.1.4.2 Benson Figure Copying and Recall This test is a simplified version of the Rey-Osterrieth Complex Figure (Possin, Laluz, Alcantar, Miller, & Kramer, 2011). The purpose is to evaluate visual construction and visual memory functions. In this test, participants are presented with a figure composed of geometric shapes. Then, the participants are asked to reproduce (copy) the figure on the same page. The accuracy of each shape and its placement are recorded. The main performance measure is the total score for copying the figure (range: 0 - 17). Visual memory is evaluated by asking the participants to draw the figure again from memory on a blank page approximately 10 - 15 minutes after they have copied the figure. The accuracy of each shape and its placement are recorded. The main performance measure is the total score for the delayed drawing of the Benson figure (range: 0 - 17).

[0116] 6.1.4.3 Multilingual Item Naming Test (MINT) MINT is a test of visual confrontation naming (Ivanova, Salmon, & Gollan, 2013). Participants need to identify (i.e., name) line drawings of objects. If the initial response is incorrect, semantic and / or phonemic cues are provided as needed. If the participant names the item spontaneously after receiving a semantic cue, the item is counted as correct (range: 0 - 32).

[0117] 6.1.4.4 Trail Making Test (Tests A and B) The Trail Making Test is a test of processing speed and executive function. Trail A consists of 25 numbered circles from 1 to 25 distributed on a white paper. The participants are instructed to draw a line connecting the circles in ascending order as quickly as possible (maximum 150 seconds). Trail B consists of 25 circles containing numbers (1 - 13) or letters (A - L) randomly distributed across the page, and the participants are instructed to connect the circles alternately in ascending order (e.g., from 1 to A; from 2 to B). Performance is judged by the time taken to complete each trail. The time taken to complete Trail B adjusted by the time taken to complete Trail A to control for the sensorimotor demands of the task (maximum 300 seconds) is a sensitive indicator of executive function and working memory.

[0118] 6.1.4.5 Language Fluency - Category Fluency Category fluency assesses semantic memory and language fluency in which participants name as many different examples of a given semantic category as quickly as possible. The participants are given 60 seconds to name examples for each of two categories: animals and vegetables.

[0119] 6.1.4.6 Language Fluency - Phonemic Fluency Phonemic fluency is an indicator of word generation that can be sensitive to dysfunction in the dominant frontal lobe. The participants are given 60 seconds to name examples beginning with each of two letters, F and L.

[0120] 6.1.4.7 Digit Span Forward and Backward The digit span assesses two different working memory construct concepts: The forward digit span measures the ability to hold information for a very short time with the aim of accurately repeating it, while the backward digit span measures the ability not only to hold information but also to mentally manipulate the digits and recite them in reverse order. The digits for both the forward and backward span tests are presented in the order of the digit range from 2 to 9. Two trials are conducted for each sequence length. Two scores are reported for each task: the number of correct trials and the longest sequence correctly repeated before failing two consecutive trials of the same length.

[0121] 6.2 Behavioral and Functional Metrics 6.2.1 Clinical Dementia Rating (CDR) Scale - Sum of Boxes (SOB) The CDR-SOB (Hughes, Berg, Danziger, Coben, & Martin, 1982) is a valid composite assessment of cognition and daily function used in longitudinal AD studies that incorporates both informant input and direct performance evaluation. A semi-structured interview is used to evaluate three cognitive domains including memory, orientation, and judgment / problem-solving, and three daily function domains including community activities, home and hobbies, and self-care. There are five levels of impairment from no CDR = 0 to severe CDR = 3. The scores of the individual domains are added to calculate the total box score.

[0122] 6.2.2 ADCS - Activities of Daily Living (ADL) Scale The ADCS-ADL scale is a questionnaire developed by the ADCS to assess the functional performance of participants with AD (Galasko et al., 1997). The scores range from 0 to 75, with higher scores indicating better function.

[0123] 6.2.3 Neuropsychiatric Inventory (NPI) The NPI is a well - validated and reliable multi - item instrument for assessing the psychopathology of AD dementia based on interview results with a caregiver (Cummings, 1997). The NPI assesses both the frequency and severity of 10 neuropsychiatric symptom features, including delusions, hallucinations, agitation / aggression, dysphoria, anxiety, elation, apathy, disinhibition, irritability and lability, and abnormal motor behavior, and also assesses sleep disturbances and appetite / eating disorders. The frequency rating ranges from 1 (occasionally, less than once a week) to 4 (very frequently, more than once a day or continuously). The severity rating ranges from 1 (mild) to 3 (severe). The score for each subscale is the product of severity and frequency, and the total score is the sum of all subscales.

[0124] 6.3 Modified Hachinski This simple questionnaire, administered by a clinician, incorporates information on the medical history, cognitive symptoms, and characteristics of stroke reported by the caregiver as well as by neurological and neuroimaging examinations (Rosen, Terry, Fuld, Katzman, & Peck, 1980).

[0125] 6.4 Sheehan Suicide Tendency Scale (Sheehan STS) The Sheehan STS (S-STS) is a prospective patient-reported or clinician-administered assessment scale that includes 16 questions to track both suicidal ideation and suicidal behavior that occurred during treatment (Sheehan, Alphs, et al., 2014; Sheehan, Giddens, & Sheehan, 2014). The S-STS is filled out on a paper form in the field. At the screening visit, the recall period for filling out the S-STS is 12 months prior; at other visits, the recall period for filling out the S-STS is since the previous visit. Subjects with an S-STS score greater than 0 should be evaluated by the principal investigator of the clinical trial. If the principal investigator of the clinical trial determines that the subject is at risk of suicide or self-harm, appropriate measures must be taken to ensure the subject's safety and obtain a mental health evaluation. The subject must be immediately withdrawn from the trial. This event must be recorded as an AE or SAE determined by the principal investigator of the clinical trial and reported to the sponsor within 24 hours.

[0126] Example 3 Capsules containing 140 mg of trolizole for use in the tests described in Example 1 and Example 2 are prepared in the following proportions.

[0127] Composition of 140 mg trolizole capsules

Table 7

[0128] Throughout this application, various publications are referenced by author name and date, or patent number or patent publication number. To more fully describe the state of the art known to those of skill in the art at the time of the date of the invention described and claimed herein, the disclosures of these publications are hereby incorporated by reference in their entirety as part of this specification. However, the citation of a reference herein should not be construed as an admission that the reference is prior art to the present invention.

[0129] One of ordinary skill in the art will recognize many equivalents to the specific procedures described herein or will be able to ascertain such equivalents using only routine experimentation. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. For example, according to the present invention, it is contemplated that ataxia and other related disorders can be treated using a combination therapy using riluzole prodrugs and other therapeutic agents. Also, riluzole prodrugs other than those specifically disclosed in the description and examples herein can be used. Furthermore, specific items within a list of items, or subsets of items within a larger group of items, are intended to be combinable with other specific items, subsets of items, or larger groups of items, whether or not there is a specific disclosure herein that identifies such a combination.

Claims

1. 2. A method for treating Alzheimer's disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a riluzole prodrug.

2. A riluzole prodrug has the formula: 【Chemistry 1】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of 2. The method of claim 1, wherein the compound is:

3. A riluzole prodrug has the formula: 【Chemistry 2】 The method of claim 2, wherein

4. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient at a dosage of about 100-400 mg per day.

5. 5. The method of claim 4, wherein the riluzole prodrug is administered to the patient at a dosage of about 110, or 140, or 150, or 210, or 280, or 350 mg per day.

6. 6. The method of claim 5, wherein the riluzole prodrug is administered to the patient once daily at a dosage of 280 mg.

7. 7. The method of claim 6, wherein the riluzole prodrug is administered to the patient at a dosage of 140 mg twice daily.

8. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient once daily.

9. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient twice daily.

10. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient in the form of a capsule.

11. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient in tablet form.

12. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient for a period of about 8 weeks to about 48 weeks.

13. 10. The method of claim 1, wherein the riluzole prodrug is administered to the patient from the start of treatment until the death of the patient.

14. 2. A method for improving response in a patient suffering from Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a riluzole prodrug.

15. 15. The method of claim 14, wherein the improved response is one or more of overall survival, quality of life, overall response rate, duration of response, delay in onset or patient reported outcome.

16. 1. A kit for treating a patient suffering from Alzheimer's disease, comprising: (a) a riluzole prodrug; and (b) instructions for administering the riluzole prodrug in the method of any one of claims 1 to 15. Kit including:

17. The prodrug has the formula: 【Chemistry 3】 The kit according to claim 16, wherein

Images