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March 2, 2010 10:33 pm

Medivation’s Dimebon fails in Phase III trial despite high hopes for efficacy

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This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
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Medivation’s Alzheimer’s drug Dimebon was expected to produce only modest results in a much-anticipated trial, but the drug’s failure seemed to surprise investigators recently interviewed by Pharmawire.

The company and partner Pfizer today said that the drug did not meet its primary and secondary efficacy endpoints in the Phase III CONNECTION trial, a six-month pivotal study that was evaluating Dimebon in patients with mild-to-moderate Alzheimer’s disease.

The experimental drug - Medivation’s lead product - was being watched for its blockbuster potential in a field with a dearth of treatment options.

When asked whether Pfizer has any plans to drop the compound, a spokesperson for the drug giant said the company will have to continue to further analyze the data and understand the results. “We’re going to continue to do our analysis and continue with the best path forward,” he said.

In interviews prior to the release of the data, investigators had been cautiously optimistic, even though they did not expect the drug to be a game-changer. Some even expressed hopes for FDA approval.

Dr Samuel Gandy, a researcher at Mount Sinai School of Medicine in New York who has studied Dimebon, had recently said he was optimistic about the drug’s chances at approval. “I had the same ’too good to be true’ reaction when I first heard about the drug in 2007, but the combined reputations of the American trialists eventually led me to suspend disbelief,” he said.

Gandy added that his lab is working locally and has an international collaboration on studies looking at Dimebon’s mechanism of action and is seeing some unexpected phenomena. “I think that there is a good chance that Dimebon promotes amyloid clearance and will turn out to be disease-modifying,” Gandy said.

Dr Greg Jicha, a neurologist at the University of Kentucky and an investigator on one of the Dimebon Phase III US studies, said although there is currently a lot of skepticism regarding the drug’s chances at approval, Dimebon’s safety profile will likely lower the bar for approval from an FDA perspective. There is long-term safety data with Dimebon from years of use as an allergy drug in Russia, he added. Cost-effectiveness is also not a major issue, which will play in the company’s favor, he added.

In addition to CONNECTION, the company also conducted a six-month Phase II Russian trial that enrolled 183 patients. That study reported mean drug-placebo differences at week 26 on the ADAS-cog test of 2.4 and 5.8 points in the mild and moderate populations, respectively. Dry mouth, which occurred in 13.5 percent of Dimebon-treated patients, was the only gastrointestinal side effect that occurred with an incidence higher than three percent.

An investigator on one of Dimebon’s Phase III US trials said although the CONNECTION trial enrolled older patients compared to the Russian study, the results should be “plenty positive” based on the increase in statistical power with approximately 600 patients. He agreed that the main concern is that the study may not show that robust of an effect compared to the Russian trial.

Most physicians interviewed by this news service stated that their main concern was over the difference in age of patients between the two trials. Another difference between trials with cognitive outcomes and those with laboratory or imaging outcomes is that the cognitive testing is language-specific and culturally-specific and there may be different results in different populations, another neurologist added.

Jicha noted that the medical community regularly sees smaller trials that originally show stellar results and fail in larger definitive trials. However, he said Pfizer and Medivation are doing a good job trying to create patient samples that are as comparable as possible to the American population, based on all the Phase III trials. “They’re running so many trials right now, to capture all of the different permutations of how Americans might respond differently,” he said.

Additional medications are strongly needed, and although the drug may not be a disease modifying therapy, other drugs in development are high cost infusion therapies, which are not economically feasible, Jicha said.

Dr Mark Smith, a consultant to Medivation and professor of pathology at Case Western Reserve University, said he is not expecting a “feeble result” from the CONNECTION trial. However, if the results only show a “modest improvement” such as a three-point improvement, there will need to be a serious discussion on cost-benefit, he said.

If the data is even half as great as the data reported in Russia, all patients will want this drug, Smith said. In the initial phases, physicians will likely prescribe Dimebon to patients who respond to Pfizer’s Aricept, he said. Although unproven, the drugs may be synergistic in combination, he noted.

Smith said he expects that the CONNECTION trial results will not be as good as the Russian trial, but even replicating 50% of the original results would be meaningful to patients, he said.

Dr Gary Kennedy, director of the division of geriatric psychology at Montefiore Medical Center in New York, who will be presenting some of the Russian data at an upcoming scientific conference on behalf of Pfizer, said he did not expect to see more than a modest benefit from the CONNECTION study, and agreed that a three-point increase in ADAS-cog would be considered modest. From his observations, 10 to 20 percent of patients reported a dramatic benefit, he noted.

Although the Russian study was a treatment-naïve group, these results were especially appealing because after nearly a year of treatment, patients were still above baseline – with the difference between drug and placebo increasing, Kennedy said.

Looking at the curve and separation, Dimebon is about the same as currently marketed agents, said Kennedy, who said he had doubts that it would be a major breakthrough in Alzheimer’s treatment, but more likely be an add-on therapy.

Although the Russian study recruited patients in their mid-60s, in light of the differences in life expectancy, that could be similar to 70-year-old patients in the US, Kennedy said.

Dimebon is tolerable, but the data suggests that it is a ”me-too drug,” and not a real standout, Kennedy said. “We’re not close enough to the cause of this illness to get the silver bullet. People have to be really cautious about this,” Kennedy said.

There is considerable skepticism within the prescribing community about Alzheimer’s drugs in general, he noted, adding that many patients fail to see a benefit and go off therapy in 60-90 days. Maybe one or two patients out of 10 will notice a clear difference, he estimated.

If the CONNECTION trial only shows a one to two point difference, that would be really disappointing, Kennedy said. Yet other physicians such as Jicha said if the drug is approved, neurologists would use it off-label to treat advanced patients, and not just the mild-to-moderate population that the companies are targeting. It could also be used in Parkinson’s, if the drug actually has a potent effect on mitochondria, Jicha added.

“It’s a crap-shoot right now, but I don’t think there’s any data out there right now suggesting that the Dimebon study is not going to prove successful,” Jicha said.

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