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From the Neurology Clinical Trials Unit (B.J.T., M.E.C.), Department of Neurology, Massachusetts General Hospital, Boston; The ALS Association (L.B.), Palm Harbor, FL; National Institute of Neurological Diseases and Stroke (NINDS) (R.C.), Bethesda, MD; Department of Neurology (F.B.), Weill Medical College of Cornell University, New York, NY; Biogen Idec Inc. (G.O.), Cambridge, MA; and University of Georgia College of Pharmacy and Medical College of Georgia (S.C.F.), Augusta.
Address correspondence and reprint requests to Dr. Bryan J. Traynor, SDGE, NIMH, Building 35, Room 1A110, 35 Convent Drive, Bethesda, MD 20892-3720; e-mail: traynorb{at}mail.nih.gov
Background: Riluzole is currently the only Food and Drug Administration–approved treatment for ALS, but its effect on survival is modest.
Objective: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug.
Methods: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation.
Results: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1–viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered.
Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 11 issue to find the title link for this article.
Disclosure: The authors report no conflicts of interest.
Received August 23, 2005. Accepted in final form March 10, 2006.
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