Advances in ALS Therapy:

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• Advances in ALS Therapy
• A Brave New World

ASENT 2008
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The hallmark of ALS is muscle denervation and
wasting

• Survival 2-5 years
• Loss of neurons in the brain and spinal cord in
  the motor pathways
  
• 10-18 ALS familial
• SOD1 mutations -20 of familial ALS
• Dynactin, VAPB, Sentaxin, TDP43

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There are multiple targets for ALS treatment.
Familial ALS
Sporadic ALS
Cures/ Medicines

Neuroprotection Anti-excitoxicity mito
function Ca buffering Augment Transport
Protein inactivation
Apoptosis
Gene Inactivation
?
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Successes for ALS

• Improved understanding of disease
• One approved drug, riluzole
• Many tried, several in development
• Improved symptomatic care
• Longer survival
• Trial experience
• Hope
• Change in mind set (incremental gains)

Lacomblez et al., 1996
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Success Improvements in symptomatic care

• Exercise improved function
• Drory et al, J Neurol Sci, 2002
• Dal Bello-Haas V, et al. Neurology 2007
• Early G-tube improved survival
• Early non-invasive ventilation
• improved survival, FVC, cognition, QOL

Desport et al, Neurology, 1999
Heiman-Pattersen et al
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Survival has improved in placebo arms of clinical
trials
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25 unique therapeutic approaches have been tried

• Anti-glutamate
• Riluzole
• Talampanel
• Gabapentin
• Topiramate
• Dextromethorphan
• ONO-2506
• Valproic acid
• Growth factors
• BDNF-IT and SC
• CNTF
• IGF-1
• Xaliproden
• G-CSF

• Antioxidants/bioenergetics
• Creatine (5 and 10 g)
• Vitamin E
• Selegiline
• Acetylcysteine
• Anti-inflammatory
• Celecoxib
• Minocycline
• Anti-apoptotic
• TCH386
• Pentoxyfilline
• Tamoxifen
• Lithium
• Calcium channel blockade
• Nimodipine
• Verapamil

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Several agents worse than placebo

• ONO-2506
• Topiramate
• CNTF
• Minocycline
• Pentoxyfilline
• TCH386

Importance of trial participation and placebo
cohorts
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Only a few really convincing

• Riluzole TCH386

TCH 346 failed in ALS but was a well designed
and conducted study
placebo
2.5 mg
7.5 mg
1.0 mg
15 mg
Neurology 2007 69776-784.
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Lessons learned from failed trials

• Predictive ability of pre-clinical models not yet
  known (Not a go no go assay)
  
• Study Design
• Sample Size
• Dosage Selection
• Drug Delivery and Pharmacodynamics
• Study Conduct

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Trials with too few participants

• Dextromethorphan
• Creatine (5 g)
• Selegiline
• Acetylcysteine
• Nimodipine
• Verapamil

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ALS Trial Challenges Sample size

• Heterogenity of features is high
• ALSFRS_R - Drops on average one unit per month

Sample Size for ALSFRS-R(90 power, 5 p 1 year,
2 arms)
30 (1.0 ?0.7) 356 patients
40 (1.0 ?0.6) 200 patients
http//hedwig.mgh.harvard.edu/biostatistics/soft
ware
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Sample Size for Survival One Year Placebo
Rate75 (90 power , 5 p)
http//hedwig.mgh.harvard.edu/sample_size/size.htm
l
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Trials with inadequate dosing information
Picking the right dosage is one of biggest
challenges

• ? Too high
• Topiramate
• Minocycline
• ? Too low
• Creatine
• Celebrex
• Unknown (only one dosage tested)
• Pentoxyfilline
• ONO-2506

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Several clinical challenges impact study conduct.

• Delay in diagnosis starting late already
• Restrictive inclusion criteria
• Drug interactions/off label use
• Study retention
• Low enrollment

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FVC
Survival
ALSFRS_R
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Participation in ALS clinical trials is low.

• Enrollment slow
• Average 2 people/site/month
• SD1.9, range 0.1-7.5
• Duke University and MGH
• 9.9 enrolled in a clinical trial _at_ Duke
• 7.4 enrolled in a clinical trial _at_ MGH
• Possible reasons
• lack of information _at_ multiple levels
• Travel, burden

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Early Drug Discontinuation in ALS Clinical
Trials 1996 - 2007
Courtesy of Kevin Boylan and Swati Aggarwal
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New Approaches to ALS Treatment

Current
Upcoming

• IGF-1 (3)
• Ceftriaxone
• Arimoclomol
• Thalidomide
• Copaxone
• ONO-2506 (2)
• Memantine
• Diaphragm pacing
• MCI-186

• Antisense oligonucleotide SOD1
• Talampanal
• Trophos
• R Pramipexole (KNS-760704 )
• Lithium

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Summary of Prospects

• New concepts are emerging in the understanding of
  ALS and its possible treatment
  
• (novel drugs, gene and protein therapy, RNAi stem
  cells).
  
• At present, a record number of ALS therapeutic
  modalities are in trial or ready for trial.
  
• New approaches needed to facilitate translation
• Dosage/PK/PK studies
• Biomarkers of efficacy
• Proof of Concept phase 2 trials

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Collaborators

• Preclinical Studies
• Robert Brown
• Jeffrey Rothstein
• Tim Miller
• Don Cleveland
• Bob Ferrante
• Terry Heiman Patterson

• Clinical Studies
• Jeremy Shefner
• David Schoenfeld
• Tim Miller
• Northeast ALS Consortium