1. 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

2. “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.”

4. Treatment Strategies Anti-glutamate Riluzole Gabapentin Topiramate
Ceftriaxone

5. 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 mos survival benefit
Registry Data (UK, IR, Italy, Holland, UW) -- 4 to 16mos increased survival

6. 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

7. Treatment Strategies Anti-oxidants Vitamin E - 2 large trials negative
Creatine - 3 negative trials
Edaravone (small phase 2)
Manganese-porphyrin (phase I)
CoQ10

8. Treatment Strategies Neurotrophic factors (subcutaneous)
CNTF
BDNF
GDNF
IGF-1 (Repeat study is on-going)
Novel delivery techniques

9. 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

10. Treatment Strategies Anti-apoptotic agents Preserve cAMP and cGMP
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)

11. 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)

12. 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

13. 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.

14. Manganoporphyrin Novel antioxidant (AEOLUS)
38% increase survival in SOD1 mouse
Phase I, subcutaneous injections
Single doses well tolerated
Multi-dose study underway

15. 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

16. 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

17. New Treatment Strategies

18. 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.

19. 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.

20. Gene Therapy

21. Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS Model (Brian K. et al. Science 2003; 301: )

22. 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

23. 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

24. 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.