New Directions for Treatment in ALS

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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

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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.
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Treatment Strategies

• Anti-glutamate
• Riluzole
• Gabapentin
• Topiramate
• Ceftriaxone

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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

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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

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Treatment Strategies

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

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Treatment Strategies

• Neurotrophic factors (subcutaneous)
• CNTF
• BDNF
• GDNF
• IGF-1 (Repeat study is on-going)
• Novel delivery techniques

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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

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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)

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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)

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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

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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.

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Manganoporphyrin

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

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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

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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

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New Treatment Strategies
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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.

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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. 20034158-61)
• No preliminary studies in rodents or primates.
• 9 patients direct injections of their own BM
  mesenchymal cells into the spinal cord. Claimed
  to notestabilization but eventually a few
  patients died without autopsy.

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Gene Therapy
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Retrograde Viral Delivery of IGF-1 Prolongs
Survival in a Mouse ALS Model (Brian K. et al.
Science 2003 301 839-842.)
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Exercise in ALS

• Little evidence, conflicting advice
• RCT (n25) - 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
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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
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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.