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WO 2015/143447 A2 24 September 2015 (24.09.2015) P O P C T

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WO 2015/143447 A2 24 September 2015 (24.09.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/143447 A2 24 September 2015 (24.09.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/05 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 15/022058 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 23 March 2015 (23.03.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/968,595 2 1 March 2014 (21.03.2014) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: ALZHEON, INC.; I l l Speen Street, Suite GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 306, Framingham, MA 01701 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: TOLAR, Martin; c/o ALZHEON, INC., 111 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Speen Street, Suite 306, Framingham, Massachusetts LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 01701 (US). HEY, John; c/o ALZHEON, INC., 111 Speen SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Street, Suite 306, Framingham, Massachusetts 01701 (US). GW, KM, ML, MR, NE, SN, TD, TG). KOCIS, Petr; c/o ALZHEON, INC., I l l Speen Street, Suite 306, Framingham, Massachusetts 01701 (US). YU, Published: Jeremy; c/o ALZHEON, INC., I l l Speen Street, Suite — without international search report and to be republished 306, Framingham, Massachusetts 01701 (US). upon receipt of that report (Rule 48.2(g)) (74) Agents: TUSCAN, Michael S. et al; Cooley LLP, 1299 Pennsylvania Avenue, N.W., Suite 700, Washington, Dis trict of Columbia 20004-2400 (US). (54) Title: METHODS FOR TREATING NEUROLOGICAL DISORDERS Figure 1 :Tramiprosate Treatment of AD Patients Improves ADAS-Cog Score : " 0 13 26 39 52 65 78 " Weeks - (57) Abstract: Disclosed herein are methods and compositions for treating, ameliorating, and/or preventing Alzheimers disease in ApoE4-postitive patients using particular compounds and compositions thereof. METHODS FOR TREATING NEUROLOGICAL DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. provisional patent application no. U.S. 61/968,595, filed March 21, 2014, which is incorporated herein by reference. [0002] This application incorporates by reference for all purposes the contents of: U.S Application Publication Nos. 2008/0146642, filed October 12, 2007, 2009/0182056, filed January 30, 2009, and 2010/01 13591 filed November 5, 2009. BACKGROUND OF THE INVENTION [0003] Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. Prevalence of AD in the United States in 2000 was close to 4.5 Million. It was estimated that about one in ten individuals over 65 and nearly half of those over 85 are affected by Alzheimer's disease. Approximately 360,000 patients will be diagnosed with AD each year in the United States alone. [0004] Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years. [0005] Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and beta amyloid (or neuritic) plaques, comprised predominantly of an aggregate of a peptide fragment know as beta amyloid peptide Α β. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders. SUMMARY OF THE INVENTION [0006] The present disclosure is generally related to treatment of neurological disorders, particularly Alzheimer's disease in specific sub-populations that have one or more copies of the ApoE4 (or ε4) allele. [0007] L-Valyl-3-aminopropanesulfonate (Val-APS) is an orally available small molecule prodrug of tramiprosate with improved pharmaceutical properties. Tramiprosate was advanced to a -2,000 patient Phase 3 program which completed in 2007. However, the Val-APS prodrug demonstrates key advantages over tramiprosate including improved GI tolerability, reduced nausea & vomiting, and decreased inter-subject PK variability. In addition, administering the prodrug provides for once-daily dosing due to an advantageously extended ti/2 of 14.9 hours. Notably, oral administration of Val-APS provides a ~2-fold increase in plasma and brain exposure of tramiprosate in animals compared to tramiprosate administered at equimolar doses. Thus the present disclosure provides for administration of certain compounds including val-APS to ApoE4-postive patients for the treatment of Alzheimer's Disease. Val-APS: BRIEF DESCRIPTION OF FIGURES [0008] Figure 1 illustrates reduced ADAS-Cog score following treatment of Alzheimer's Disease patients with tramiprosate. At 26 weeks -1.25 (82%) P = 0.0219 for 100 mg BID, -1.03 (57%), P = 0.1 18 for 150 mg BID. At 52 weeks -2.03 (35%) P = 0.002 for 100 mg BID, -1.85 (32%), P = 0.006 for 150 mg BID. At 65 weeks -1.52 (22%) P = 0.024 for 100 mg BID, -1.90 (27%) P = 0.005 for 150 mg BID. At 78 weeks-1.90 (27%) P = 0.005 for 100 mg BID.-1.86 (21%) P = 0.028 for 150 mg BID. (n=599). Data derived from Caltagirone et ah, "The potential protective effect of tramiprosate (homotaurine) against Alzheimer's disease: a review," Aging Clin Exp Res. 2012 Dec;24(6):580-7. [0009] Figures 2 and 3 : Retrospective subgroup analysis in 599 ApoE4+ subjects using mixed effects repeated measures, covariate model (MERM) demonstrated a significant effect on both cognition and function utilizing ADAS-cog and CDR-SB. [0010] Figure 4 shows Brain exposure of tramiprosate after oral Val-APS (upper line) or tramiprosate (lower line). The AUC ratio of brain tramiprosate exposure due to Val-APS compared to tramiprosate is ~2.1 . [0011] Figure 5 shows Phase 1 SAD trial results in normal healthy elderly subjects demonstrating that oral Val-APS prodrug provides extended ti/2 of tramiprosate. [0012] Figure 6 shows Phase 1 SAD trial results in normal healthy elderly subjects showing reduced formation of metabolite NRM5074 following Val-APS administration [0013] Figure 7 shows a SAD study in normal HV demonstrating that orally administered Val- APS displays a reduction in PK variability superior to MR tablet or LF capsule tramiprosate. Val-APS loose filled capsule reduces PK variability by -50% and, furthermore, the terminal ti/2 is extended to 14.9 hours, allowing once-daily dosing. [0014] Figure 8 illustrates the advantageous effects of tramiprosate, the active agent of Val-APS, in certain sub-populations segregated based on Apo E4 status. The data established substantially improved ADAs-cog scores vs placebo over time. Data is presented at 13 weeks, 26 weeks, 39 weeks, 52 weeks, 65 weeks, and 78 weeks. The first column shows patients homozygous for ApoE4 ("ApoE4 +/+"), the second column shows combined data from ApoE4 heterozygous and homozygous patients "ApoE4 all-comers", the third column shows patients negative for ApoE4 (Non-ApoE4). ApoE4 prevalence correlates with improved cognition scores. DETAILED DESCRIPTION OF THE INVENTION Definitions [0015] The following definitions are used in connection with the disclosure: The term "subject," as used herein unless otherwise defined, is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon. In one embodiment, the subject is a human. [0016] The term "pharmaceutically acceptable salt," as used herein unless otherwise defined, is a salt of a basic group, such as an amino group, or of an acidic group, such as a carboxyl group, on the compounds disclosed herein. Illustrative salts of a basic group include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate (i.e., 1,1 '-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Illustrative salts of an acidic group include, but are not limited, to lithium, sodium, potassium, calclium, magnesium, aluminum, chromium, iron, copper, zinc, cadmium, ammonium, guanidinium, pyridinium, and organic ammonium salts. [0017] The terms "hydrate" and "solvate" as used herein and unless otherwise defined, describe a compound or salts thereof, which further include a stoichiometric or non-stoichiometric amount of water or other solvent bound by non-covalent intermolecular forces. [0018] An "effective amount" when used in connection with another therapeutic agent is an amount that is effective for treating or preventing a Condition in combination with a compound.
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