Encouraging results from the Phase II Dimebon trial

HD Lighthouse Contributing Editor's Comment: 

I am very encouraged by these results. The study results show that Dimebon was safe and well tolerated by HD patients over the 90 day study and in addition, there are some indications of effectiveness.

Lighthouse readers have been following Dimebon since the successful Phase I trial first started recruiting. Dimebon was developed in Russia as an antihistamine and it has been used safely for that purpose for more than two decades in that country. Russian scientists discovered that the drug has neurologic properties and identified it as a potential treatment for Alzheimer's Disease.

Medivation licensed the drug and also began researching it as a potential treatment for Alzheimer's disease; a Phase III trial for AD patients is ongoing. Medivation also decided to look at its potential for Huntington's Disease since both diseases involve progressive neurodegeneration and abnormal protein accumulation, and both have abnormal mitochondrial function. The results of a Phase I study in 2007 encouraged Medivation to conduct the Phase II study.

The mechanism by which Dimebon is thought to work is through its effect on the mitochondria. The brain has a high need for energy. The mitochondria are like 'tiny gas stations' to provide fuel to cells so that they can carry out their normal function. The brain has about 100 billion brain cells and each of these has 1000 mitochondria. Dimebon appears to have a potent effect on mitochondria function. Medivation will present data later in July at a scientific conference on Dimebon's effect on the mitochondria. However, work with animals continues and it is possible that there may be other helpful methods of action that are also operating.

Clearly, as the results indicate below, Dimebon was safe with minimal side effects. Although the results didn't reach statistical significance, the Dimebon group was nearly half as likely to fall as the placebo group. In addition, those who were randomized to the Dimebon group were more likely to complete the study than those who were randomized to the placebo. The Dimebon completion rate was 87 percent compared with 82 percent for the placebo group, again suggesting that the drug was well-tolerated.

If the news stopped there, it would be very good news indeed since a Phase II trial is conducted for just that purpose -- to find out whether the drug is safe and well-tolerated for patients with the disease.  However, there is more good news. We do not often see indications of effectiveness in a Phase II trial because these trials are short and involve a small group and you wouldn't expect to be able to see much difference in a slowly progressive disease like Huntington's Disease. So the cognitive results are very exciting. There was a statistically significant difference between those taking the Dimebon and those in the placebo group, as measured by the Mini Mental States Exam.

These are just the top line results. There is more data mining to be done and more information will be presented later about trends in the study. I would especially like to know about the behavioral improvement that didn't reach statistically significance.

It's exciting to see this drug take another step forward on the research pipeline. There are three Phase III clinical trials underway or planned for 2008 already, for CoQ10, creatine, and ACR-16, the dopamine stabilizer. Hopefully Medivation can make Dimebon the fourth. We won't know for sure whether Dimebon is a treatment for HD until a Phase III trial is completed, but the Phase II results suggest that such a trial is warranted and it sounds like Medivation is excited about moving forward as soon as possible.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 07-07-2008

Dr. Karl Kieburtz, M.D., Professor of Neurology at the University of Rochester and clinical director of the Dimebon trial

SAN FRANCISCO, July 7, 2008 /PRNewswire-FirstCall via COMTEX News Network/ -- Medivation, Inc. (Nasdaq: MDVN) today announced top-line results of a Phase 2 study showing that its investigational drug Dimebon(TM) significantly improved cognitive function in patients with mild-to-moderate Huntington's disease (HD). Cognitive function was significantly improved over placebo (p=0.03) as measured by the Mini-Mental State Examination (MMSE), the cognition scale most widely used by clinicians to assess patients with neurodegenerative diseases. Dimebon-treated patients also demonstrated favorable results on the behavioral component of the United Huntington's Disease Rating Scale (UHDRS), a composite scale measuring several components of HD, but these results did not reach statistical significance.

Dimebon was very well tolerated in this trial. The overall incidence of adverse events was lower in the Dimebon group than in the placebo group, an unusual finding in a clinical study of any drug. This result is consistent with a similar finding from the first pivotal Alzheimer's disease trial in which Dimebon-treated patients had significantly fewer serious adverse events after one year of treatment. Of particular note, Huntington's disease patients treated with Dimebon had fewer falls (9%), a common problem in this patient population that often results in injury and associated health care costs, than did patients on placebo (16%). The most common adverse event in the Dimebon group was headache, which occurred in 19% of treated patients compared to 7% of placebo patients. Headaches were generally mild in severity. Dry mouth and depressed mood were similar in both treated and placebo groups (4% and 7%, respectively).

"To my knowledge, no other drug has resulted in statistically significant benefit in cognition in Huntington's disease patients in a randomized, well-controlled trial," said Karl Kieburtz, M.D., M.P.H., professor of neurology at the University of Rochester, director of the HSG Clinical Trials Coordination Center, and principal investigator in this trial. "Cognitive impairment is the most important therapeutic unmet need in Huntington's disease. I am pleased by this result and Dimebon's favorable safety profile, and believe that further development of this compound is warranted."

The randomized, double-blinded, placebo-controlled Phase 2 trial was conducted at 16 centers in the United States and the United Kingdom in collaboration with the Huntington Study Group (HSG), a network of more than 250 experienced clinical trial investigators, coordinators and consultants from more than 60 academic and research institutions throughout the United States, Canada, Europe and Australia dedicated to clinical research of Huntington's disease. The trial enrolled 90 HD patients, with half randomized to Dimebon and the other half to placebo for a three-month dosing period. The primary endpoint of the trial was safety and tolerability. The secondary endpoint was efficacy, as measured by the MMSE, the UHDRS and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), a cognition scale generally used in Alzheimer's disease clinical trials.

"We are very encouraged that Dimebon improved cognition and was well tolerated in both trials assessing efficacy that we have conducted to date -- this trial and our first pivotal trial in Alzheimer's disease. The consistency seen in the data between these two trials underscores the potential for this drug," said Lynn Seely, M.D., chief medical officer of Medivation. "These data are also important because they provide further support for our belief that Dimebon is exerting its benefits through a novel mechanism of action targeting mitochondrial dysfunction, a contributor to the loss of neuronal function in Huntington's disease. Medivation is committed to aggressively advancing development of Dimebon for patients and families devastated by Huntington's disease."

Full results from the Phase 2 study will be submitted for presentation at an upcoming scientific meeting.