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

2. 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

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

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. Success: Improvements in symptomatic care 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 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 Anti-glutamate –Riluzole –Talampanel –Gabapentin –Topiramate –Dextromethorphan –ONO-2506 –Valproic acid Growth factors –BDNF-IT and SC –CNTF –IGF-1 –Xaliproden –G-CSF 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

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

9. Only a few really convincing… RiluzoleTCH386 TCH 346 failed in ALS – but was a well designed and conducted study Neurology 2007; 69:776-784. placebo 2.5 mg 1.0 mg 7.5 mg 15 mg

10. Lessons learned from failed trials 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)

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

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

13. Sample Size for Survival; One Year Placebo Rate=75% (90% power, 5% p) ChangeChange in median Change in one year survival rate Sample size 100%2.5 yrs11%400/(years of follow up) 50%1.3 yrs7.5%1200/(years) 33%10 months5.5%2300/(years) http://hedwig.mgh.harvard.edu/sample_size/size.html

14. Trials with inadequate dosing information Picking 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. 100 96 82 71 0 M3 M6 M9 M12 M15 M # # 20 25 30 35 40 45 0 M3 M6 M9 M12 M15 M # # # # # * * * * * 0 M6 M15 M 40 60 80 100 120# * SurvivalALSFRS_R FVC

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. New Approaches to ALS Treatment 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 CurrentUpcoming

20. 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 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 Summary of Prospects

21. Collaborators 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