Dimebon is by far the best news of this summer. Positive reports from Medivation Inc. and the Huntington Study Group (HSG) from their Phase 2 trial in Huntington's are encouraging. Indeed if degree of benefit seen in this Huntington's trial approaches that seen in Alzheimer's, this could be a very big advance.
In this article, we discuss results for both reported trials, and speculate on how soon this drug might reach people if further Phase 3 trials in the U.S. confirm effectiveness. We further suggest that a successful Dimebon trial could also lead to advances in biomarker discovery and validation.
Results in Alzheimer's: Striking results were recently reported from a twelve-month Phase 3 Alzheimer's trial performed in Russia [Doody RS 2008]. The group receiving Dimebon showed clinically important improvement in standard cognitive and psychometric testing, while those who received placebo showed the expected decline. The degree of benefit reported is far greater than any drug presently used in Alzheimer's. Drug benefit was seen early, in the first three months with continued improvement over the year of testing. In more good news, improvement occurred across all study measures. This gives greater support that these results will be validated in the next trial that includes U.S. participants.
Following this published report, results from the six-month extension of this trial when all participants received Dimebon was announced at a scientific conference and reported in a Medivation press release. For those who had received the drug during the prior twelve months, benefit continued up to 18 months. This effect is longer than that seen in any drug used in Alzheimer's. Those who had worsened while receiving placebo during the first 12 months of the trial stabilized after Dimebon was started --but at a lower level than the earlier treated group. These results lend support to two separate conclusions: Dimebon is an effective treatment and that this effect is due at least partly to neuroprotection, not limited to symptom treatment.
Results in Huntington's: Positive results were recently announced from a three-month Phase 2 Huntington's trial. Though the full published analysis is still pending, Medivation reported positive results in cognitive testing for those who received drug compared to those who received placebo. Though degree of benefit is important for drawing better conclusions, the announced positive results so far reported from this short trial are encouraging.
What is the Drug Mechanism? New evidence presented at the recent International Alzheimer's Disease Conference (IADC) in Chicago suggests that Dimebon enhances mitochondrial function and preserves nerve dendrite function and structure similar to that seen with BDNF. How the drug does this is not known.
How Soon Might this Drug get to People?
For Alzheimer's: The six-month Phase 3 trial for Alzheimer's began in May, 2008. Medivation anticipates completion of this trial in approximately one year. Add another several months to analyze the results and (if results are positive) to present a New Drug Application (NDA) to the FDA. If results are similar to earlier trials, Dimebon would be a "break-through" drug, and FDA fast track approval processes are likely to be prompt. For example, initial FDA approval for L-Dopa, a "break-through" drug for Parkinson's disease took only four months [Kaitin KI 1991]. This time sequence as outlined fits Medivation's goal of bringing this drug to market for Alzheimer's in 2010.
For Huntington's: The six-month trial for Huntington's is still being planned. After the plan is approved by the FDA, it takes HSG -- on average-- six to nine months to actually start recruiting for a clinical trial. Add at least another six (maybe more) months to recruit for and complete the six-month trial. Add more time for analysis and FDA submission. So optimistically it is 2011 before the FDA approves the Huntington's indication. Compassionate Use programs would not be useful for Huntington's -- if Dimebon is approved for Alzheimer's, it will likely be available by prescription during or shortly after completion of the trial for Huntington's.
Dimebon: More Hope than Hype? I believe there are several good reasons to have hope for this drug. Multiple positive signals in human clinical trials in both Alzheimer's and Huntington trials lend support that we may finally have a drug that makes a real difference and -- it may be pretty close. More potential good news: if this trial is successful for Huntington's we could also have a unique opportunity to identify, and possibly validate useful biomarkers from study of sequential blood samples obtained and saved during the trial.
This would be a dream come true: A clinical trial that delivers a useful drug and identifies useful biomarkers that shorten clinical trials for other drugs. We can hope.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19;372(9634):207-15. doi: 10.1016/S0140-6736(08)61074-0. PubMed abstract
Kaitin KI. Case studies of expedited review: AZT and L-dopa. Law Med Health Care. 1991 Fall-Winter;19(3-4):242-6. PubMed abstract