HOMOTAURINE INVESTIGATIONAL SUMMARY

HOMOTAURINE INVESTIGATIONAL SUMMARY

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)

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

Gervais F. et al. Neurobiol Aging 27; 28(4):537-47. 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) 1 1 1.1.1 4 8 12 Time (h) 16 2 24 preclinical Gervais F. et al. Neurobiol Aging 27; 28(4):537-47. Control (untreated) prevents Aß-Induced inhibition of Long-Term Potentiation (LTP) acsf Aß 1-42 Aß 1-42 + HT (25 µm) Aß 1-42 + HT (1 µm) (1 mg/kg/day) (8 weeks of treatment) Gervais F. et al. Neurobiol Aging 27; 28(4):537-47. Normalised fepsp amplitude 3 28 26 24 22 2 18 16 14 12 1 8 LTP Induction reduces Amyloid deposition in happ transgenic mouse brain Rat Hippocampal Slice 2 4 6 8 1 12 14 16 18 2 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)

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 42 41 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):1757-63. Phase II: Dose-Dependent Decrease of Aß 42 Cerebrospinal (CSF) Levels in AD Patients 15 1 5-5 -1-15 24 1.52 738 975 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 -2-25 5 1 15 dose (mg BID) 5

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): 88-12. 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): 55-7. Mean (95% Confidence Intervals) 6 4 2-2 -4-6 -8 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

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) -1-2 -3-4 -5-6 -7-8 -9-1 -1.25 (82%) P =.219-1.3 (57%) P =.118 Placebo 1 MG BID 15 MG BID 13 26 39 52 65 78 weeks -2.3 (35%) P =.2-1.85 (32%) P =.6-1.52 (22%) P =.24-1.9 (27%) P =.5-1.86 (21%) P =.28-1.2 (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):156-14. Epub 21 May 31 2. Shitaka Y. et al. Progress in the development of anti amyloid drugs for treatment of s disease. Nippon Yakurigaku Zasshi. 21 Jul; 136(1):15-2. 3. 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):55-7. 4. 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):88-12. 5. Gervais F. et al. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 27; 28(4):537-547. 6. Aisen PS. et al. A Phase II study targeting Amyloid ß with 3APS in mildto-moderate Disease. Neurology 26; 67, 1757-63. 7. Greenberg SM. et al. A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Disease and Associated Disorders 26; 2(4):269-274. 8. Kisilevsky R. et al. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for s disease. Nature Med 1995; 1:143-8. 9. 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