Transcript AAN Kickoff Seminar Treatment of ALS PHARMACOTHERAPY IN ALS

New Directions for
Treatment in ALS
Robert G. Miller, M.D.
Forbes Norris MDA/ALS Research Center
California Pacific Medical Center
San Francisco, CA
May 6, 2006
“CONSIDER THE WONDERS OF THE
HUMAN BRAIN ~ IT WORKS FROM
THE MOMENT YOU ARE BORN AND
NEVER STOPS UNTIL YOU GET UP TO
SPEAK IN PUBLIC.”
Treatment Strategies
Anti-glutamate
 Riluzole
 Gabapentin
 Topiramate
 Ceftriaxone
Riluzole
 AAN Practice Advisory - Neurology 1997
 Approved in Canada 2000 (U.S., Europe 1996)
 National Institute for Clinical Effectiveness (NICE)
 systematic review 4 trials
 approved in U.K. (2001)
Cochrane Review 2005 - 2-3 mos survival benefit
 Registry Data (UK, IR, Italy, Holland, UW) -- 4 to
16mos increased survival
Implications for Practice
 Proven efficacy - modest effect size
 Generally safe and well tolerated
 Expensive ($10,000 US/yr)
 Provides hope - none before
 Education - adjustment/perception
Treatment Strategies
 Anti-oxidants
– Vitamin E - 2 large trials negative
– Creatine - 3 negative trials
– Edaravone (small phase 2)
– Manganese-porphyrin (phase I)
– CoQ10
Treatment Strategies
 Neurotrophic factors (subcutaneous)
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CNTF
BDNF
GDNF
IGF-1 (Repeat study is on-going)
 Novel delivery techniques
Anti-inflammatory
 Immunosuppressive agents - negative trials
(cytoxan, XRT, Plasma Exchange)
 COX-2 inhibitors
– Celecoxib - large trial negative in 2004
 Anti-microglial agents
– Minocycline - enrollment complete
Treatment Strategies
 Anti-apoptotic agents
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Indinavir (small phase II) - negative
TCH 346 (Novartis)
Minocycline
Methyl-cobalamin
 Preserve cAMP and cGMP
– Pentoxyfilline (ExonHit)
 Astrocyte modulator
– Ono-2506 (Ono)
 Protein kinase C inhibitor
– Tamoxifen
 Hyperbaric oxygen therapy (small phase I)
CURRENT and UPCOMING
MAJOR TRIALS
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IGF-I (NIH– GLALS, USA) -- enrolled
Minocycline (NIH– WALS/Columbia, USA) -- enrolled
CoQ10 (NIH– Columbia, USA) – enrolled Stage I (120 pts)
Manganese-porphyrin (Aeolus, USA) – phase I, in progress
Arimoclomol (NEALS) --enrolling
Ceftriaxone (NIH funded) – phase II study (high throughput
screening)--launch mid 2006
 Respiratory and nutritional treatment in ALS (NIH– Univ
of Kentucky, USA) --- phase II study (in progress)
 Multi Drug Combination Trial - summer 2006 (ALSA,
CUMC)
Ceftriaxone clinical trial in patients with
ALS
NINDS funded
Phase I- III
– 60 subjects – PK and safety study
– 600 subjects – efficacy study
FDA Requirement for additional animal toxicology
Enrollment planned for summer 2006
Northeast ALS Consortium (NEALS)
– 46 centers US and Canada
Coenzyme Q10
Encouraging results in Parkinsonism
Stage 1 – compare 1800 & 2700mg/day
Stage 2 – compare best dose to placebo
Phase II, 20 sites, 10 months
NIH funding, PI-Petra Kaufman, Columbia Univ.
Manganoporphyrin
Novel antioxidant (AEOLUS)
38% increase survival in SOD1 mouse
Phase I, subcutaneous injections
Single doses well tolerated
Multi-dose study underway
IGF-1
 Growth factor nourishing muscle, nerve
 Positive study in US, 1997
 Negative study in Europe (Mayo, Eric
Sorensen, M.D.)
 NIH funding
 24 months, muscle strength
Combination Drug Trial
 2 arms (60 patients each), 6 months, selection trial
 Minocycline 200/d, creatine 20/d vs. celecoxib 800/d,
creatine 20/d
 Safety with riluzole
 Design Phase III trial
 PI Paul Gordon, Columbia
New Treatment Strategies
Stem Cell Therapy
 Appel S, et al. A small clinical trial with allogeneic
hematopoietic stem cell (from HLA-matched siblings)
transplantation in 6 patients. (Reported at the 15th
International ALS/MND Symposium, Philadelphia, Nov 2004)
– 2 died, 1 progressed, 1 experienced a slowing of
progression, and 1 had an unexpectedly stable course.
– 17% to 25% of total DNA in CNS was donor-derived,
although only 1% was donor-derived DNA in the motor
cortex.
– Unusually high numbers of CD68+ cells were found in the
CNS, suggesting a neuroinflammation induced by
chemokine signaling.
Stem Cell Therapy (cont'd)
 Mazzini L, et al. Stem cell therapy in amyotrophic
lateral sclerosis: a methodological approach in
humans. (Amyotroph Lateral Scler Other Motor Neuron
Disord. 2003;4:158-61)
– No preliminary studies in rodents or primates.
– 9 patients direct injections of their own BM mesenchymal
cells into the spinal cord. Claimed to note“stabilization”
but eventually a few patients died without autopsy.
Gene Therapy
Retrograde Viral Delivery of IGF-1 Prolongs
Survival in a Mouse ALS Model
(Brian K. et al. Science 2003; 301: 839-842.)
Exercise in ALS
 Little evidence, conflicting advice
 RCT (n=25) - slower decline ALSFRS,
Ashworth at 3 mos, trend at 6 mos
 Transgenic SOD1 mice treadmill 10 wks vs no
exercise - prolonged survival
 Worse high intensity exercise
Drory 2001, Kirkinezos 2003, Mahoney, 2004
Exercise and Insulin-like Growth
Factor-1
 Comparison of exercise (0,2,6,12hr/day) and gene
therapy (AAV-IGF-1) in ALS mouse
 Prolonged survival (30-40d) and functionality with
exercise (6,12h) and also with IGF-1
 Remarkable synergistic effect with both exercise
and IGF-1 on survival (83 days!) and functionality
 Emerging evidence about exercise in ALS
Kaspar, May 2005
Summary and Conclusions
 Unprecedented number of clinical trials in ALS at
one time
 Marked diversity in technology and targeting
different disease mechanisms.
 We will have more clinical trials in ALS in the next
few years.
 Partnerships between NIH, ALSA, MDA and
corporate sector are forming
 New national ALS research group formed
 We need to improve patient access issues and the
efficiency of clinical trials.