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)
– – – – 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
– – – – 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
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.