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Advances in ALS Therapy: A Brave New World

Advances in ALS Therapy: A Brave New World. ASENT 2008. The hallmark of ALS is muscle denervation and wasting. Survival 2-5 years Loss of neurons in the brain and spinal cord in the motor pathways 10-18% ALS familial SOD1 mutations -20% of familial ALS Dynactin, VAPB, Sentaxin, TDP43.

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Advances in ALS Therapy: A Brave New World

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  1. Advances in ALS Therapy: A Brave New World ASENT 2008

  2. The hallmark of ALS ismuscle denervation and wasting • Survival 2-5 years • Loss of neurons in the brain and spinal cord in the motor pathways • 10-18% ALS familial • SOD1 mutations -20% of familial ALS • Dynactin, VAPB, Sentaxin, TDP43

  3. There are multiple targets for ALS treatment. Familial ALS Sporadic ALS Cures/ Medicines Neuroprotection Anti-excitoxicity mito function Ca buffering Augment Transport Protein inactivation Apoptosis Gene Inactivation ?

  4. Successes for ALS • Improved understanding of disease • One approved drug, riluzole • Many tried, several in development • Improved symptomatic care • Longer survival • Trial experience • Hope • Change in mind set (incremental gains) Lacomblez et al., 1996

  5. Exercise – improved function Drory et al, J Neurol Sci, 2002 Dal Bello-Haas V, et al. Neurology 2007 Early G-tube – improved survival Early non-invasive ventilation improved survival, FVC, cognition, QOL Success: Improvements in symptomatic care Desport et al, Neurology, 1999 Heiman-Pattersen et al

  6. Survival has improved in placebo arms of clinical trials

  7. 25 unique therapeutic approaches have been tried • Antioxidants/bioenergetics • Creatine (5 and 10 g) • Vitamin E • Selegiline • Acetylcysteine • Anti-inflammatory • Celecoxib • Minocycline • Anti-apoptotic • TCH386 • Pentoxyfilline • Tamoxifen • Lithium • Calcium channel blockade • Nimodipine • Verapamil • Anti-glutamate • Riluzole • Talampanel • Gabapentin • Topiramate • Dextromethorphan • ONO-2506 • Valproic acid • Growth factors • BDNF-IT and SC • CNTF • IGF-1 • Xaliproden • G-CSF

  8. ONO-2506 Topiramate CNTF Minocycline Pentoxyfilline TCH386 Several agents worse than placebo Importance of trial participation and placebo cohorts

  9. Riluzole TCH386 Only a few really convincing… TCH 346 failed in ALS – but was a well designed and conducted study placebo 2.5 mg 7.5 mg 1.0 mg 15 mg Neurology 2007; 69:776-784.

  10. Predictive ability of pre-clinical models not yet known (Not a go – no –go assay) Study Design Sample Size Dosage Selection Drug Delivery and Pharmacodynamics Study Conduct G93A mouse (Day Lab) Lessons learned from failed trials

  11. Dextromethorphan Creatine (5 g) Selegiline Acetylcysteine Nimodipine Verapamil Trials with too few participants

  12. ALS Trial Challenges: Sample size • Heterogenity of features is high • ALSFRS_R - Drops on average one unit per month Sample Size for ALSFRS-R(90% power, 5% p 1 year, 2 arms) • 30% (1.0 0.7) 356 patients • 40% (1.0 0.6) 200 patients • http://hedwig.mgh.harvard.edu/biostatistics/software

  13. Sample Size for Survival; One Year Placebo Rate=75% (90% power , 5% p) http://hedwig.mgh.harvard.edu/sample_size/size.html

  14. Trials with inadequate dosing informationPicking the right dosage is one of biggest challenges • ? Too high • Topiramate • Minocycline • ? Too low • Creatine • Celebrex • Unknown (only one dosage tested) • Pentoxyfilline • ONO-2506

  15. Several clinical challenges impact study conduct. • Delay in diagnosis – starting late already • Restrictive inclusion criteria • Drug interactions/off label use • Study retention • Low enrollment

  16. 120 100 ## 80 60 * 40 0 M 6 M 15 M 45 # # 40 # # # # # 35 * * 30 * 25 * * 20 0 M 3 M 6 M 9 M 12 M 15 M 100 100 # # 96 71 82 71 0 M 3 M 6 M 9 M 12 M 15 M FVC Survival ALSFRS_R

  17. Participation in ALS clinical trials is low. • Enrollment slow • Average 2 people/site/month • SD=1.9, range 0.1-7.5 • Duke University and MGH • 9.9% enrolled in a clinical trial @ Duke • 7.4% enrolled in a clinical trial @ MGH • Possible reasons • lack of information @ multiple levels • Travel, burden

  18. Early Drug Discontinuation in ALS Clinical Trials: 1996 - 2007 Courtesy of Kevin Boylan and Swati Aggarwal

  19. IGF-1 (#3) Ceftriaxone Arimoclomol Thalidomide Copaxone ONO-2506 (#2) Memantine Diaphragm pacing MCI-186 Antisense oligonucleotide SOD1 Talampanal Trophos R+ Pramipexole (KNS‑760704 ) Lithium New Approaches to ALS Treatment Current Upcoming

  20. Summary of Prospects • New concepts are emerging in the understanding of ALS and its possible treatment • (novel drugs, gene and protein therapy, RNAi stem cells). • At present, a record number of ALS therapeutic modalities are in trial or ready for trial. • New approaches needed to facilitate translation • Dosage/PK/PK studies • Biomarkers of efficacy • Proof of Concept phase 2 trials

  21. Preclinical Studies Robert Brown Jeffrey Rothstein Tim Miller Don Cleveland Bob Ferrante Terry Heiman Patterson Clinical Studies Jeremy Shefner David Schoenfeld Tim Miller Northeast ALS Consortium Collaborators

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