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Clinical Trials in ALS

Clinical Trials in ALS. Robert G. Miller MD Director, Forbes Norris MDA/ALS Research Center California Pacific Medical Center San Francisco, CA. December, 2005. Conflict of Interest Disclosure (Robert G. Miller, M.D.) Since 2004. Research Grants: Novartis, Aeolus

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Clinical Trials in ALS

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  1. Clinical Trials in ALS Robert G. Miller MD Director, Forbes Norris MDA/ALS Research Center California Pacific Medical Center San Francisco, CA December, 2005

  2. Conflict of Interest Disclosure(Robert G. Miller, M.D.)Since 2004 • Research Grants: Novartis, Aeolus • Educational Grants: Aventis • Honorariafor consultation: Novartis, Pharmacyclics, Jazz Pharmaceuticals, Teva • No other financial relationship

  3. Summary • To discuss ALS disease mechanisms targeted in current treatment trials • To review recent clinical trial results • Upcoming clinical trials • New treatment strategies

  4. Cell Death Process in ALS Motoneurons SOD Mutations Virus Glutamate Excitotoxicity Mitochondrial dysfunction Oxidative injury Nitration, glycation Neurofilament abnormality Apoptosis Neurotrophic factor impairment DNA injury Aging Astrocyte Dysfunction Trace Metals Excessive Physical Activity Autoimmunity Inflammation Environmental Factors

  5. Treatment Strategies Anti-glutamate • Riluzole • Gabapentin • Topiramate • Ceftriaxone

  6. Evidence for Glutamate Excitotoxicity in ALS • Abnormal glutamate metabolism • Loss of glutamate transport protein • Motor neuron susceptibility to glutamate toxicity • Clinical efficacy of anti-glutamate agents

  7. 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 2003 • Registry Data (UK, IR, UW) - 8-16m increased survival

  8. 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

  9. Treatment Strategies • Anti-oxidants • Vitamin E - 2 large trials negative • Creatine - 2 negative trials, 2003,4 • Edaravone (small phase 2) • Manganese-porphyrin (phase I) • CoQ10

  10. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzoleGraf M, et al 2004 • A double blind, placebo-controlled, randomized, stratified, and parallel-group clinical trial. • 160 patients, all treated with riluzole, were randomly assigned to receive either Vitamin E (5000 mg per day) or placebo for 18 months. • The primary outcome: survival. • No significant difference between placebo and vitamin E. • Megadose vitamin E caused no significant side effects in this patient population.

  11. Neurotrophic Factors • Spectacular survival- promoting effects on motor neurons • Requiring a minute amount of protein • Mostly target-derived • Neuronal growth, differentiation, maturation, and regeneration/ repair

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

  13. INFLAMMATION MICROGLIA COX2 COX2 Prostaglandin E2 N Pro-inflammatory Cytokines Peripherin Cytochrome C CASPASE M Bax ROS Cell Deassembly N Pro-inflammatory Cytokines Chemokines IL-6, IL-1ß ICAM TNF-α MOTONEURON N N T-LYMPHOCYTE ASTROCYTE

  14. Anti-inflammatory • Immunosuppressive agents - negative trials (cytoxan, XRT, PE) • COX-2 inhibitors • Celecoxib - large trial negative in 2004 • Anti-microglial agents • Minocycline - enrolling

  15. Minocycline • Inhibits MAP Kinase (Caspase 1 and 3) • Neuroprotection in SOD mouse • High penetration into brain/cord • Well tolerated orally • Pilot trial UNM, CPMC Tikka et al, Brain 2002; 125:722

  16. Minocycline • Positive results in SOD1 mouse – 4 labs • Two Phase I/II trials complete; some toxicity with doses up to 400mg/day (esp GI) • Tolerability of higher doses, long dosing • NIH/MDA funding • Enrollment – widely available drug Gordon 2003

  17. CELL APOPTOSIS Mitochondria Death Signals Mitochondria Other pathways A Family of Caspase Proteins Endoplasmic reticulum

  18. 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)

  19. TCH-346 (Novartis) • 16 week lead-in phase (before randomize) • 52 week treatment phase • 5 groups (4 dose groups and placebo) • Over 500 patients (International) • Primary outcome: slope of the ALSFRSR • Secondary outcomes: time to event (death and tracheostomy), MMT, FVC, and Neuro-cognitive evaluation (selected sites) • There were no differences in groups

  20. Pentoxifylline: A phase II trialV. Meininger, et al. Reported at the 15th International ALS/MND Symposium, Nov 2004, Philadelphia • Increases intracellular cAMP • RCT to assess the efficacy (15% difference) of pentoxifylline 400 mg t.i.d. (or placebo) • 400 patients • The primary endpoint was 18-month survival rate • The secondary endpoints: ALSFRS, MMT • No benefit with drug treatment

  21. Tamoxifen, phase I/II studyBen R. Brooks, M.D. Univ of Wisconsin, reported at 2005 AAN meeting • Tamoxifen, anti-breast cancer agent, protein kinase C inhibitor • A patient with breast cancer and ALS who was treated with tamoxifen experienced marked slowing in progression of ALS • Abnormally activated protein kinase C in degenerating motor neurons • The drug was well tolerated but both sexes experienced hot flashes • Patients receiving 20 to 40 mg per day may have longer survival compared to patients receiving only 10 mg per day • A Phase III trial is required

  22. Symptomatic Treatment

  23. Treatment of Pseudobulbar Affect in ALS With DM/Q n=70 DM/Q bid (DM 30 mg/Q 30 mg) • Probable or definite ALS (≥2 months) • History of PBA • CNS-LS score ≥13 • HAM-D score ≤16 n=33 Randomize DM 30 mg bid N=140 n=37 Q 30 mg bid Primary outcome measure: Change from baseline in CNS-LS ALS=amyotrophic lateral sclerosis. CNS-LS=Center for Neurologic Study-Lability Scale. HAM-D=Hamilton DepressionRating Scale. Brooks BR, et al. Neurology. 2004;63:1364–1370.

  24. Plasma Concentration of DM 150 P < .0001 100 n=35 ng/mL 50 n=23 0 DM/Q DM Brooks BR, et al. Neurology. 2004;63:1364–1370

  25. Improvement of CNS-LS Score in ALS Patients DM/Q DM Q 0 2.5 Reduction in CNS-LS Score 5.0 7.5 P< .001 Brooks BR, et al. Neurology. 2004;63:1364–1370

  26. Quality of Life Scores(Visual scale) 30 P< .002 20 Change in QoL (VAS) 10 0 DM/Q DM Q Brooks BR, et al. Neurology. 2004;63:1364–1370

  27. Adverse Events (AEs) • Adverse events reported in 89% of DM/Q, 70% of DM, and 65% of Q patients • Events occurring at a significantly higher incidence in the DM/Q group compared to the DM- and Q-alone groups: • Nausea (33%) • Dizziness (20%) • Somnolence (13%) Brooks BR, et al. Neurology. 2004;63:1364–1370

  28. Bourke et al studied the benefits of non-invasive positive pressure ventilation (NIPPV) to 40 patients with ALS. • In RCT, 22 patients received NIPPV and 19 had standard care. • Patients with NIPPV survived significantly longer and had a better quality of life. 12/04 Phila.

  29. CURRENT and UPCOMING MAJOR TRIALS • IGF-I (NIH– GLALS, USA) -- enrolled • Minocycline (NIH– WALS/Columbia, USA) -- enrolling • CoQ10 (NIH– Columbia, USA) – enrolling • Manganese-porphyrin (Aeolus, USA) – phase I, in progress • Ceftriaxone (NIH funded) – phase II study (high throughput screening)--planned fall 2005 • Respiratory and nutritional treatment in ALS (NIH– Univ of Kentucky, USA) --- phase II study (early 2005) • Methyl-cobalamin (Aisai, in Europe) – phase I study

  30. Ceftriaxone treatment at disease onset increases survival of G93A SOD1 mice(preliminary analysis) 1.0 Ceftriaxone (200mg/kg/day 0.9 0.8 0.7 0.6 % Surviving Start Therapy 0.5 0.4 0.3 Saline control 0.2 0.1 0.0 80 85 90 95 100 105 110 115 120 125 130 135 140 Survival (Days)

  31. Ceftriaxone clinical trial in patients with ALS • NINDS funded • Phase I- III • 60 subjects – PK and safety study • 600 subjects – efficacy study • Efficient study design – to expedite drug development • FDA Requirement for additional animal toxicology • Enrollment planned for early 2006 • Northeast ALS Consortium (NEALS) • 46 centers US and Canada

  32. Sodium phenylbutrate is a HDAC inhibitor that may be promising for ALS and other neurodegenerative disorders • Currently used for management of urea cycle disorders • In testing phase for Huntington’s Disease and spinal muscular atrophy • Efficacy in ALS mouse model (Ferrante et al) • VA – Northeast ALS Collaboration • Phase 1 safety and dose finding study started 04/05

  33. Currently used for management of urea cycle disorders In testing phase for Huntington’s Disease and spinal muscular atrophy Funded by VA (primary) and MDA Phase 1 safety and dose finding study at 8 sites in April 05 A safety and dose finding study of sodium phenylbutrate, a HDAC inhibitor began in April 2005. Ryu H, Camelo SI, Carreras I, Lee I, Iglesias AH, Kubilus JK, Smith K, Cudkowicz ME, Brown Jr. RH Jr, Dangond F, Ferrante RJ

  34. ArimoclomolTreatment with a co-inducer of heat shock proteins delays disease progression in a murine model of ALS • At 120 days Arimoclomol treatment increases motor unit survival increases motoneuron survival rescues large motoneurons Increases heat shock protein expression • Phase IIA Clinical trial in ALS start October 2005 (NEALS) Dairin Kieran, Bernadett Kalmar, James Dick, Joanna Riddoch-Contreras, Geoffrey Burnstock & Linda Greensmith

  35. Coenzyme Q10 • Encouraging results in Parkinsonism • Stage 1 – compare 1000 & 2000mg/day • Stage 2 – compare best dose to placebo • Phase II, 20 sites, 10 months • NIH funding, PI-Petra Kaufman, Columbia Univ.

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

  37. 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

  38. Arimoclomol • 80 patients, 10 sites • 12 weeks treatment • 4 weeks wash out • Tolerability, toxicity • Pharmacodynamics

  39. New Treatment Strategies

  40. 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.

  41. 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.

  42. Gene Therapy

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

  44. 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

  45. 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

  46. Potential treatments for ALS Drug Trials: Indinavir Celebrex Pentoxyfilline ONO 2506 TCH346 (Novartis) Ritonavir/hydroxyurea IGF-1 Minocycline Coenzyme Q10 Neotrofin AIT-082 NAADALase Talampanel Tamoxifen IV Ceftriaxone Phenyl butyrate AVP-923-Neurodex Aeolus/Incara 10150 Arimoclomol? Thalidomide? Myogane? Cell Therapy Bone Marrow Human Cord Blood Embryonic derived and fetal stem cells Gene Therapy AAV-IGF1 Equine IA Virus – VEGF Gene Shut-down RNAi for mutant SOD1 Anti-sense for mutant SOD1

  47. AlleleInactivation siRNA Anti-sense Multiple therapeutic studies are underway or planned in ALS Drug Trials (14) Celebrex Pentoxyfilline ONO 2506 TCH (Novartis) Topiramate IGF-1 Minocycline Coenzyme Q10 Talampanel Tamoxifen IV ceftriaxone Phenyl butyrate Negative Gene Therapy AAV1-IGF1 EIAV-VEGF Cell Therapy Bone marrow Embryonic stem cells 10/04 1/05 1/06 1/07

  48. Clinical Trials – The Future • Dose finding (Gaba 2400/3600) • Patient selection (early pts) 75% VC, 2yr, poss vs. lab support prob • Markers (MUNE, NI, PGE2, NFL etc) • Innovation (stem cells, gene therapy, new trial designs)

  49. 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.

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