>>Medivation: some experts skeptical of Dimebon's chances of attaining FDA approval
Medivation's Dimebon is still under scrutiny, and the drug's chances of attaining FDA approval are questionable, according to a number of industry specialists interviewed by Pharmawire.
An FDA consultant, who has been following Dimebon's development for years, said Medivation has made the claim on mitochondrial pore inhibition. "I’ve been following that drug for years," he said. "But I’m still skeptical on the Russian trial. The data is too good to be true."
From his review of the Russian literature on the drug's mechanism of action, the papers claim that Dimebon has five different mechanisms of action, including memantine-like effects. It works on the NMDA receptor, and also has mitochondrial pore protective properties, the consultant said.
The consultant added that although the company has stated the drug's mechanism of action is due to mitochondrial pore inhibition, he has not seen anything yet in terms of reported literature.
He also said that he was 'amazed' of news that Pfizer had partnered with Medivation on Dimebon in September, and was 'doubtful that the drug works.' The company is also conducting trials in South America, in addition to the US, he added.
"I hope when the [final] results come out, they will reveal the mechanism of action. My worry is they will throw all the data together," he added.
He was also skeptical of the data from treatment-naïve patients in the Russian Phase II study.
The consultant said he also predicted the previous failures, Neurochem’s Alzhemed and Myriad’s Flurizan. On Myriad, he said the company ran an open-label trial, and did not conduct an adequate Phase II trial. “I was skeptical on Flurizan because their Phase II trial was a subgroup analysis,” he added.
Medivation is currently enrolling patients for a six-month confirmatory Phase III study to determine the safety and efficacy of Dimebon in the treatment of mild-to-moderate Alzheimer's disease. It is a six-month study enrolling 525 patients in the United States, Europe, and South America. The study started in May 2008, with an estimated enrolment of 525 patients. The trial has an estimated primary completion data of July 2010, according to clinicaltrials.gov.
One physician affiliated with Pfizer, who has seen Dimebon’s data said, “there are all these sorts of problems with the Russian study,” and difficulty knowing whether the trial endpoint was really done to standard protocol. He agreed that the patients on in the Russian Phase II trial were of younger age, and were treatment naïve.
The same physician said almost every patient in the US who has Alzheimer’s will be on a cholinesterase inhibitor. He said "it just seems like a losing proposition" to try to test this drug on treatment-naïve patients, or patients who are not on medication, as anyone in the US who has Alzheimer’s who is not taking a cholinesterase inhibitor is probably someone who tried it and they dropped it because they had side–effects, or have become so demented that there is no effect anymore.
Exclusion criteria for the Phase III US trial include: anti-dementia drugs including cholinesterase-inhibitors or NMDA receptor antagonists within 90 days, according to clinicaltrials.gov.
“You’d have to wonder, you’ll have an odd population. To pick out people with a diagnosis of AD in the US and say I’m going to run a drug trial in people who don’t take cholinesterase inhibitors, it’s unethical,” the physician said.
He went on to say that the only population the drug company would get would be people who do not want to take cholinesterase inhibitors and that will be non-representative of the overall population. “I don’t know why any company would want to do that in the US.” He said. “Maybe for people who can’t tolerate, or have GI side effects from cholinesterase inhibitors.”
The physician also added that he has seen the data, and "there are some funny things about the data." He explained that some of the trajectories on the cognitive endpoints look positive, but on some other time trajectories on other endpoints, there does not appear "too much on anything." He questioned why, if Dimebon worked, there would be an effect on one cognitive instrument and not on another endpoint.
A researcher who used to work for the Department of Mental Health, said "thank God" Dimebon does not hit the histamine receptors. He added that Pfizer's leading anticholinesterase candidate, Aricept, increases blood pressure, and increases circulation to the brain, and anti-histamines should do the opposite.
When asked whether Dimebon and Pfizer’s Aricept could be combined in one pill, the researcher said that could create a psychedelic. He hypothesized that Dimebon’s proposed mechanism of action may be due to a blocking of the pathways and the cause of dendritic branching may be due to an asphyxiation effect, or a reduction of oxygen flow to the brain. It appears that Dimebon causes dendritic branching, but the neurogenesisis is just on the dendritic level and not the axonal or cell body type level, he added.
“So the branching is just dendrites,” the researcher said. “And you have dendrites branching out, obviously you will get psychoactive activation.”
Dr William Potter, who serves on the FDA's Psychopharmacologic Drugs Advisory Committee, and vice president for translational neuroscience at Merck, said from a scientific view, the industry should find a drug that could potentially block amyloid formation.
“The ideal thing to test from a scientific target is BACE,” said Potter. “But it’s been very difficult for the industry or anyone to generate the ideal compound. Just a very hard target.”
The company did not comment to this story as of press time.
However, CEO David Hung told investors at a conference in New York in September that the company is seeking approval for Dimebon as a symptomatic treatment of Alzheimer’s, and not a disease modifying therapy. Medivation will not be conducting autopsies on the Russian Phase II trial patients, Hung also added at the same conference.
The company has stated publically that "Dimebon is an orally-available, small molecule that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer’s disease and Huntington’s disease…based on clinical and preclinical data generated to date, Medivation believes that Dimebon works through a novel mechanism of action improving mitochondria function."
Medivation has a current market cap of USD 561m.
by Kimberly Ha in New York
Source Pharmawire<<
Thanks to Ihub's pharmaclown35 for the dig.
Cheers, Tuck |
