Transcript orphan diseases - ALS Society of BC

Update on Current Drugs in
Development for ALS
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Dr. Angela Genge
Montreal Neurological Institute
&Hospital
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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
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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
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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
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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?
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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
‘Mild’
Where ‘mild’, ‘moderate’
and ‘severe’ are
composite health states
representing overall
disease status
‘Moderate’
‘Severe’
Death
• Estimating transition probabilities between
composite states, mortality, resource use,
costs, utilities.
• Developing model shell & model spec
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For Internal Use ONLY-Subject to Local Legal and Regulatory Approval
THANK YOU
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