HOMOTAURINE INVESTIGATIONAL SUMMARY

Transcription

1 HOMOTAURINE INVESTIGATIONAL SUMMARY

2 Amyloid Precursor Protein (brain) Amyloid Aß Amyloid fibril Amyloid plaque action mechanism Aisen PS. Presented at: 9th International Geneva Springfield Symposium on Advances in Therapy. April 26. inhibits formation of toxic amyloid fibrils in vitro Brain cell damage/death Brain volume loss Memory Loss & Cognitive Decline Amyloid Aß protects against Aß-Induced Neurotoxicity in mouse hippocampal cells Aß 48 hours 24-hour incubation Amyloid Aß + Aisen PS. Presented at: 9th International Geneva Springfield Symposium on Advances in Therapy. April 26. Control Neurotoxicity Aß + 2 Propidium iodide staining (shows dead cells: red coloration)

3 Scapagnini G. Presented at: GerontoNet Symposium Roma Clinical Trials in the frail elderly person. November 29. GABA-Dependent Neuroprotective Effect of Apoptotic agents Ischemic stress Trophic deprivation MPTP MK81 STS GABA A Caspase 3/7 & 9 Neurotoxicity Scapagnini G. Presented at: GerontoNet Symposium Roma Clinical Trials in the frail elderly person. November 29. GABA-Independent Neuroprotective Activity of ERK1/2 Aß Aß action mechanism Biochemical analysis Western blot DNA fragmentation/condensation Hoechst assay Neurotoxicity 3

4 Gervais F. et al. Neurobiol Aging 27; 28(4): penetrates into the brain mouse study Plasma (1 mg/kg) Plasma (5 mg/kg) Brain (1 mg/kg) Brain (5 mg/kg) Mean (± SD) Brain and Plasma Concentration (µg eq/g) Time (h) preclinical Gervais F. et al. Neurobiol Aging 27; 28(4): Control (untreated) prevents Aß-Induced inhibition of Long-Term Potentiation (LTP) acsf Aß 1-42 Aß HT (25 µm) Aß HT (1 µm) (1 mg/kg/day) (8 weeks of treatment) Gervais F. et al. Neurobiol Aging 27; 28(4): Normalised fepsp amplitude LTP Induction reduces Amyloid deposition in happ transgenic mouse brain Rat Hippocampal Slice Time (min) P<.1 4 PRECLINICAL TOXICOLOGY/ PHARMACOKINETICS Safe & well tolerated upon chronic exposure (39 wks) Not mutagenic No effect on liver enzyme activity (CYP 45)

5 16 CLINICAL TRIALS INVOLVING > 2 SUBJECTS Studies N Population Duration Endpoints 1 Phase I 288 Healthy 7-1 days Safety / PK Phase II 58 3 months Amyloid Aβ CSF level Phase II Extension months Phase II Phase III North America (NA) Phase III NA Extension Phase III Europe 1 clinical Phase I studies 288 healthy subjects (74 elderly) exposed Safe & well tolerated in young & elderly No serious adverse events reported No effect on cardiac conduction (QTc) CSF Aß42 (pg/ml) change from baseline Aisen PS et al. Neurology 26; 67(1): Phase II: Dose-Dependent Decrease of Aß 42 Cerebrospinal (CSF) Levels in AD Patients Cerebral Amyloid Angiopathy 3 months 18 months 12 months 18 months Phase I: Safety Results Estimated fit with 95% confidence limits Neurological function Brain volume Brain volume r =.36 p =.41 clinical studies dose (mg BID) 5

6 clinical studies 6 NORTH AMERICAN PHASE III STUDY DESIGN 1,52 mild to moderate AD patients were given either placebo or homotaurine for 18 months /placebo administered as add-on to AChE inhibitors ± memantine was tested using the standard, validated ADAS-cog test every 3 months Brain Volume (hippocampus) was measured at baseline and after 18 months of treatment in a subset of patients Saumier D. et al. Domain-specific effects of tramiprosate in patients with mild-to-moderate s disease: ADAS-cog Subscale results from the Alphase study. J. Nutrition Health Aging 29; 13(9): ADAS-cog subtest Remembering Test Instructions Language Comprehension Spoken Language Ability Ideational Praxis Change in scores in 1 yr (1 mg homotaurine vs placebo) 66.7% better* 38.9% better 4.% better 33.% better *Statistically significant Gauthier S. et al. Effect of tramiprosate in patients with mild-to-moderate s disease: Exploratory analyses of the MRI subgroup of the Alphase study. J. Nutrition Health Aging 29; 13(6): Mean (95% Confidence Intervals) Effects of on specific types of cognitive performance Adjusted Least Square Mean Change in Hippocampal Volume From Baseline to Final Assessment 68% difference p-value =.35 Placebo 1 mg 15 mg Treatment Group Adjusted by Mixed Effects Model preserved by 68% brain volume vs control in ad patients

7 Sampalis J. Presented at: GerontoNet Symposium Roma Clinical Trials in the frail elderly person. November 29. reduces significantly cognitive decline in ad patients - APOE4+ Overall treatment effect: P =.25 Change in ADAS-Cog (Mean) (82%) P = (57%) P =.118 Placebo 1 MG BID 15 MG BID weeks -2.3 (35%) P = (32%) P = (22%) P = (27%) P = (21%) P = (12%) P =.265 Adjusted by Mixed Effects Repeated Measures Model PUBLICATIONS: STUDIES PERFORMED WITH HOMOTAURINE 1. Martineau E. et al. Investigation of the noncovalent interactions between anti-amyloid agents and amyloid beta peptides by ESI-MS. J Am Soc Mass Spectrom. 21 Sep;21(9): Epub 21 May Shitaka Y. et al. Progress in the development of anti amyloid drugs for treatment of s disease. Nippon Yakurigaku Zasshi. 21 Jul; 136(1): Gauthier S. et al. Effect of tramiprosate in patients with mild-to-moderate s disease: Exploratory analyses of the MRI subgroup of the Alphase study. J. Nutrition Health Aging 29; 13(6): Saumier D. et al. Domain-specific effects of tramiprosate in patients with mild-to-moderate s disease: ADAS-cog Subscale results from the Alphase study. J. Nutrition Health Aging 29; 13(9): Gervais F. et al. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 27; 28(4): Aisen PS. et al. A Phase II study targeting Amyloid ß with 3APS in mildto-moderate Disease. Neurology 26; 67, Greenberg SM. et al. A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Disease and Associated Disorders 26; 2(4): Kisilevsky R. et al. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for s disease. Nature Med 1995; 1: Aisen P. et al. Tramiprosate in mild-to-moderate s disease: a randomized, double-blind, placebo controlled, multicenter study. Submitted to J. Amer. Geriatry and Gerontology (under review). clinical studies 7