1. Dr. Angela Genge Montreal Neurological Institute &Hospital Update on Current Drugs in Development for ALS _________________________ 1

2. ORPHAN DISEASES Legislation encouraging drug development in rare diseases has been present since 1983 A rare disease is defined as 5:10,000 The drug development path for rare diseases includes the following: Pre-review and advice prior to trials Ability to do one pivotal 2b/3 trial if granted orphan drug status Modeling of trial different with ability to treat much smaller numbers Patent protection, supplemented with market access exclusivity 2

3. Pitfalls for Pharma in ALS A primary outcome measure that has been positive in a clinical trial other than survival A biomarker that is validated, reliable, reproducible, changes over time AND correlates with relevant clinical changes Identification of patients early in their disease El Escorial criteria staging accepted by the community however would benefit from an update and correlation with new biomarker information No staging system, an important element for drugs in development 3

5. Cytokinetics Inc. – VITALITY-ALS Tirasemtiv- small molecule Activator of the fast skeletal muscle troponin Increases affinity of troponin C for Ca, slowing rate of calcium release Highly selective for fast skeletal muscle troponin No effect on cardiac muscle 5

6. GSK-Ozanezumab Phase 2B/3 study complete No significant positive effect of ozanezumab on primary outcome measures Anti NOGO-A monoclonal antibody Joint rank scale combining function with survival Similar results for secondary outcome measures 6

7. Cytokinetics Inc. – BENEFIT-ALS Phase 2B completed study Used ALSFRS as primary outcome measure 711 patients 3 months/12 weeks of dosing Negative for primary outcome measure HOWEVER statistically significant reduction in decline of SVC Other secondary endpoints demonstrated slowing of decline, including strength measures Well identified side effects and interactions with Riluzole 7

8. Cytokinetics Inc. – VITALITY-ALS Phase 3 study, multinational, multi-center 48 weeks of blinded dosing 2:1 dosing during blinded phase Innovative design with 2-week open-label lead-in phase, and 1:1 blinded 4-week withdrawal phase Primary outcome measure –percent predicted SVC Secondary outcomes –time to first event looking at sub-scores of ALSFRS, HHD, SNIP Also slow rate of decline of a composite of muscle strength 8

9. AB Sciences- Masitinib Targets microglia and mast cells Currently in clinical trial for indications in cancer Also being studied in SPMS and PPMS Tested in ALS models because of activation of glia by patients with ALS by PET imaging Masitinib has been shown to decrease microglia proliferation and astrocyte migration in SOD1 G93A rodents Also shown to reduce motor neuron death Evidence of decrease in gliosis and improved survival in rats, with exposure starting after onset of weakness 9

10. AB Sciences- Masitinib Phase 2B/3 study has started in Europe Will start at McGill in October 2:1 active compound to placebo Oral medication 48 weeks 381 patients Primary outcome measure is ALSFRS-R Respiratory function is secondary outcome measure 10

11. BIOGEN/ISIS- SOD1 ASO Inhibition of SOD1 in patients with ALS who have a mutation in their SOD1 gene SOD1 ASO extends survival in SOD1 G93A rat Delivery of ASO via intrathecal injection Study will be phase 1, SAD and MAD Select group of 17 ALS centers worldwide Primary outcome is safety and tolerability Will also look at levels of SOD1 protein in the CSF Exploratory outcome measures will include MUNIX, EIM, HHD, FVC 11

12. Stem Cell therapies NeuralStem complete- awaiting publication (see Jonathan Glass) Brainstorm- last patient to be treated in October 2015 Q therapeutics - Margakis and Glass to start in Q1 2016 All phase 1 - safety and tolerability 12

13. NEALS- Retigabine Phase 2 study pharmacodynamic study Not yet recruiting Dr Brian Wainger 13

14. NIALS Major issue of concentration of withaferin A in natural products Not clear when it will start Fortunately movement occurring on other fronts e.g. withanaloids 14

15. Treeway Therapeutics Protocol being developed by Dr. Van den Berg in the Netherlands 15

16. Pimozide project Funded by the Hudson grant of ALS Canada Currently in initial phases at University of Calgary Not yet fully enrolled Pimozide use based on the work of Dr. Pierre Drapeau Antipsychotic with activity against dopaminergic receptors in the central nervous system Safety and tolerability well known Current trial is for 20 patients Using electrophysiological criteria 16

17. Mitsubishi-Tanabe Edaravone is approved in Japan for the treatment of ALS Intravenous therapy originally developed for stroke 10 days on 20 days off Not yet in a trial in North America or Europe Free radical scavenger ALSFRS-R used as primary outcome 17

18. What’s next? Further monoclonal antibody therapies Possibly new formulations of growth factors HDAC’s Withanaloids Gene therapy 18

19. Needs Phase 1-PoC studies Biomarkers to be correlated both to molecules being tried and to disease markers Better diagnostic guidelines Clinical Trials Guidelines meeting upcoming Biomarker research being funded now throughout North America Staging 19

20. Disease states: Moving to Model Programming Phases 20 Estimating transition probabilities between composite states, mortality, resource use, costs, utilities. Developing model shell & model spec ‘Mild’‘Moderate’ ‘Severe’ Death Where ‘mild’, ‘moderate’ and ‘severe’ are composite health states representing overall disease status Strictly Confidential - Proprietary information of Novartis For Internal Use ONLY-Subject to Local Legal and Regulatory Approval

21. THANK YOU 21