New Directions for New Directions for Treatment in ALSTreatment in ALS

Robert G. Miller, M.D.Robert G. Miller, M.D.

Forbes Norris MDA/ALS Research CenterForbes Norris MDA/ALS Research Center

California Pacific Medical CenterCalifornia Pacific Medical Center

San Francisco, CA San Francisco, CA

May 6, 2006May 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 StrategiesTreatment Strategies

Anti-glutamateAnti-glutamate

RiluzoleRiluzole

Gabapentin Gabapentin

TopiramateTopiramate

CeftriaxoneCeftriaxone

RiluzoleRiluzole AAN Practice Advisory - Neurology 1997AAN Practice Advisory - Neurology 1997

Approved in Canada 2000 Approved in Canada 2000 (U.S., Europe 1996)(U.S., Europe 1996)

National Institute for Clinical Effectiveness (National Institute for Clinical Effectiveness (NICENICE)) systematic review 4 trialssystematic review 4 trials approved in U.K. (2001)approved in U.K. (2001)Cochrane Review 2005 - 2-3 mos survival benefitCochrane Review 2005 - 2-3 mos survival benefit

Registry Data (UK, IR, Italy, Holland, UW) -- 4 to Registry Data (UK, IR, Italy, Holland, UW) -- 4 to 16mos increased survival16mos increased survival

Implications for PracticeImplications for Practice

Proven efficacy - modest effect sizeProven efficacy - modest effect size

Generally safe and well toleratedGenerally safe and well tolerated

Expensive ($10,000 US/yr)Expensive ($10,000 US/yr)

Provides hope - none beforeProvides hope - none before

Education - adjustment/perceptionEducation - adjustment/perception

Treatment StrategiesTreatment Strategies

Anti-oxidants Anti-oxidants

– Vitamin E - 2 large trials negativeVitamin E - 2 large trials negative

– Creatine - 3 negative trialsCreatine - 3 negative trials

– Edaravone (small phase 2)Edaravone (small phase 2)

– Manganese-porphyrin (phase I)Manganese-porphyrin (phase I)

– CoQ10CoQ10

Treatment StrategiesTreatment Strategies

Neurotrophic factorNeurotrophic factors (subcutaneous)s (subcutaneous)– CNTFCNTF– BDNFBDNF– GDNFGDNF– IGF-1IGF-1 (Repeat study is on-going)(Repeat study is on-going)

Novel delivery techniquesNovel delivery techniques

Anti-inflammatoryAnti-inflammatory

Immunosuppressive agents - negative trials Immunosuppressive agents - negative trials (cytoxan, XRT, Plasma Exchange)(cytoxan, XRT, Plasma Exchange)

COX-2 inhibitorsCOX-2 inhibitors– Celecoxib - large trial negative in 2004Celecoxib - large trial negative in 2004

Anti-microglial agentsAnti-microglial agents– Minocycline - enrollment completeMinocycline - enrollment complete

Treatment StrategiesTreatment Strategies Anti-apoptotic agentsAnti-apoptotic agents

– Indinavir (small phase II)Indinavir (small phase II) - negative - negative– TCH 346 (Novartis)TCH 346 (Novartis)– MinocyclineMinocycline– Methyl-cobalaminMethyl-cobalamin

Preserve cAMP and cGMPPreserve cAMP and cGMP– Pentoxyfilline (ExonHit)Pentoxyfilline (ExonHit)

Astrocyte modulatorAstrocyte modulator– Ono-2506 (Ono)Ono-2506 (Ono)

Protein kinase C inhibitorProtein kinase C inhibitor – TamoxifenTamoxifen

Hyperbaric oxygen therapy (small phase I)Hyperbaric oxygen therapy (small phase I)

CURRENT and UPCOMING CURRENT and UPCOMING MAJOR TRIALSMAJOR TRIALS

IGF-I (NIH– GLALS, USA) IGF-I (NIH– GLALS, USA) -- enrolled-- enrolled Minocycline (NIH– WALS/Columbia, USA)Minocycline (NIH– WALS/Columbia, USA) -- enrolled -- enrolled CoQ10 (NIH– Columbia, USA)CoQ10 (NIH– Columbia, USA) – enrolled Stage I (120 pts) – enrolled Stage I (120 pts) Manganese-porphyrin (Aeolus, USA) Manganese-porphyrin (Aeolus, USA) – – phase I, in progressphase I, in progress Arimoclomol (NEALS) --enrollingArimoclomol (NEALS) --enrolling Ceftriaxone (NIH funded) – Ceftriaxone (NIH funded) – phase II study (high throughput phase II study (high throughput

screening)--launch mid 2006screening)--launch mid 2006 Respiratory and nutritional treatment in ALS (NIH– Univ of Respiratory and nutritional treatment in ALS (NIH– Univ of

Kentucky, USA)Kentucky, USA) --- --- phase II study (in progress)phase II study (in progress) Multi Drug Combination Trial - summer 2006 (ALSA, CUMC)Multi Drug Combination Trial - summer 2006 (ALSA, CUMC)

Ceftriaxone clinical trial in patients with ALS

NINDS fundedPhase I- III

– 60 subjects – PK and safety study– 600 subjects – efficacy study

FDA Requirement for additional animal toxicologyEnrollment planned for summer 2006Northeast ALS Consortium (NEALS)

– 46 centers US and Canada

Coenzyme Q10

Encouraging results in ParkinsonismStage 1 – compare 1800 & 2700mg/dayStage 2 – compare best dose to placeboPhase II, 20 sites, 10 monthsNIH funding, PI-Petra Kaufman, Columbia Univ.

Manganoporphyrin

Novel antioxidant (AEOLUS)Novel antioxidant (AEOLUS)38% increase survival in SOD1 mouse38% increase survival in SOD1 mousePhase I, subcutaneous injectionsPhase I, subcutaneous injectionsSingle doses well toleratedSingle doses well toleratedMulti-dose study underwayMulti-dose study underway

IGF-1IGF-1

Growth factor nourishing muscle, nerveGrowth factor nourishing muscle, nerve

Positive study in US, 1997Positive study in US, 1997

Negative study in Europe (Mayo, Eric Negative study in Europe (Mayo, Eric Sorensen, M.D.)Sorensen, M.D.)

NIH fundingNIH funding

24 months, muscle strength24 months, muscle strength

Combination Drug TrialCombination Drug Trial

2 arms (60 patients each), 6 months, selection trial2 arms (60 patients each), 6 months, selection trial Minocycline 200/d, creatine 20/d vs. celecoxib 800/d, Minocycline 200/d, creatine 20/d vs. celecoxib 800/d,

creatine 20/dcreatine 20/d Safety with riluzoleSafety with riluzole Design Phase III trialDesign Phase III trial PI Paul Gordon, ColumbiaPI Paul Gordon, Columbia

New Treatment StrategiesNew Treatment Strategies

Stem Cell TherapyStem Cell Therapy Appel S, et al. A small clinical trial with allogeneic Appel S, et al. A small clinical trial with allogeneic

hematopoietic stem cell (from HLA-matched siblings) hematopoietic stem cell (from HLA-matched siblings) transplantation in 6 patients. (transplantation in 6 patients. (Reported at the 15Reported at the 15thth International ALS/MND Symposium, Philadelphia, Nov 2004)International ALS/MND Symposium, Philadelphia, Nov 2004)

– 2 died, 1 progressed, 1 experienced a slowing of 2 died, 1 progressed, 1 experienced a slowing of progression, and 1 had an unexpectedly stable course. progression, and 1 had an unexpectedly stable course.

– 17% to 25% of total DNA in CNS was donor-derived, 17% to 25% of total DNA in CNS was donor-derived, although only 1% was donor-derived DNA in the motor although only 1% was donor-derived DNA in the motor cortex. cortex.

– Unusually high numbers of CD68+ cells were found in the Unusually high numbers of CD68+ cells were found in the CNS, suggesting a neuroinflammation induced by CNS, suggesting a neuroinflammation induced by chemokine signaling.chemokine signaling.

Mazzini L, et al. Stem cell therapy in amyotrophic Mazzini L, et al. Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in lateral sclerosis: a methodological approach in humans. (humans. (Amyotroph Lateral Scler Other Motor Neuron Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:158-61Disord. 2003;4:158-61) ) – No preliminary studies in rodents or primates.No preliminary studies in rodents or primates.

– 9 patients direct injections of their own BM mesenchymal 9 patients direct injections of their own BM mesenchymal cells into the spinal cord. Claimed to note“stabilization” cells into the spinal cord. Claimed to note“stabilization” but eventually a few patients died without autopsy.but eventually a few patients died without autopsy.

Stem Cell TherapyStem Cell Therapy (cont'd)(cont'd)

Gene TherapyGene Therapy

Retrograde Viral Delivery of IGF-1 Prolongs Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS ModelSurvival in a Mouse ALS Model

((Brian K. et al.Brian K. et al. Science 2003;Science 2003; 301: 839-842.) 301: 839-842.)

Exercise in ALSExercise in ALS

Little evidence, conflicting adviceLittle evidence, conflicting advice

RCT (n=25) - slower decline ALSFRS, RCT (n=25) - slower decline ALSFRS, Ashworth at 3 mos, trend at 6 mos Ashworth at 3 mos, trend at 6 mos

Transgenic SOD1 mice treadmill 10 wks vs Transgenic SOD1 mice treadmill 10 wks vs no exercise - prolonged survivalno exercise - prolonged survival

Worse high intensity exerciseWorse high intensity exercise

Drory 2001, Kirkinezos 2003, Mahoney, 2004Drory 2001, Kirkinezos 2003, Mahoney, 2004

Exercise and Insulin-like Growth Exercise and Insulin-like Growth Factor-1Factor-1

Comparison of exercise (0,2,6,12hr/day) and gene Comparison of exercise (0,2,6,12hr/day) and gene therapy (AAV-IGF-1) in ALS mousetherapy (AAV-IGF-1) in ALS mouse

Prolonged survival (30-40d) and functionality with Prolonged survival (30-40d) and functionality with exercise (6,12h) and also with IGF-1 exercise (6,12h) and also with IGF-1

Remarkable synergistic effect with both exercise and Remarkable synergistic effect with both exercise and IGF-1 on survival (83 days!) and functionalityIGF-1 on survival (83 days!) and functionality

Emerging evidence about exercise in ALSEmerging evidence about exercise in ALS

Kaspar, May 2005Kaspar, May 2005

Summary and ConclusionsSummary and Conclusions Unprecedented number of clinical trials in ALS at one Unprecedented number of clinical trials in ALS at one

timetime Marked diversity in technology and targeting different Marked diversity in technology and targeting different

disease mechanisms. disease mechanisms. We will have more clinical trials in ALS in the next We will have more clinical trials in ALS in the next

few years.few years. Partnerships between NIH, ALSA, MDA and Partnerships between NIH, ALSA, MDA and

corporate sector are formingcorporate sector are forming New national ALS research group formedNew national ALS research group formed We need to improve patient access issues and the We need to improve patient access issues and the

efficiency of clinical trials.efficiency of clinical trials.