Dr. Angela GengeMontreal Neurological Institute &Hospital

Update on Current Drugs in Development for ALS_________________________

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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NEALS- Retigabine

• Phase 2 study pharmacodynamic study• Not yet recruiting• Dr Brian Wainger

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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

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Treeway Therapeutics

• Protocol being developed by Dr. Van den Berg in the Netherlands

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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

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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

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What’s next?

• Further monoclonal antibody therapies• Possibly new formulations of growth factors• HDAC’s• Withanaloids• Gene therapy

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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

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Disease states: Moving to Model Programming Phases

• 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 NovartisFor Internal Use ONLY-Subject to Local Legal and Regulatory Approval

THANK YOU

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