The 2008 Pipeline Report - Pharmaceutical Executive


The 2008 Pipeline Report

Pharmaceutical Executive

Both apixaban (from BMS and Pfizer) and Xarelto (rivaroxaban, from Bayer and J&J), are in Phase III trials for treatment of deep vein thrombosis (DVT) and pulmonary embolism, which is often a consequence of DVT. BMS is testing apixaban head-to-head against enoxaparin/warfarin, the current standard of care for DVT in the United States. Xarelto has been approved in Canada and Europe for prevention of post-surgical venous thromboembolism in patients undergoing elective hip or knee-replacement surgery, and it is currently in registration in the United States for a similar indication.

But the potentially big payoff for both drugs turns on the results of the Phase III acute coronary syndrome (ACS) and stroke-prevention trials. "The problem with these cardiovascular indications like ACS and stroke is that it all comes down to the outcome studies," Ryan says. "Before that you are just looking at markers and it's hard to say."

Alzheimer's disease

Getting new drugs into the brain

Since June, when Encore/Myriad's Flurizan failed to achieve its efficacy endpoints in Phase III, experts have been divided on the future of Alzheimer's drugs in the pipeline. A key question: Will the beta-amyloid pathway turn out to be the right target?

But Jeffrey Cummings, MD, director of the Alzheimer's Disease Center at UCLA, sees the issue as challenging technical problems rather than a problem with the approach. "What we learned from the Flurizan trials was that the drug did not enter the brain adequately to effect a response," says Cummings.

Cummings said that recent research suggests that lipid-soluble drugs are more likely than water-soluble chemicals to enter the brain, and that the three current Phase III Alzheimer's candidates are more likely to be found in concentrations large enough to actually attack the beta-amyloid plaque that, it is widely believed, causes the dementia suffered by Alzheimer's patients.

"In the development program, they have actually been measured in the spinal fluid to make sure that they are entering the brain," Cummings said.

Indeed, Cummings remains cautiously optimistic about Elan/Wyeth's monoclonal antibody bapineuzumab and Lilly's gamma-secretase inhibitor semagacestat. For him, the real question is about the point of intervention. Amyloid has been detected in the brains of people five to ten years before the onset of symptoms. Some of these have been followed long enough to confirm the hypothesis that they are the ones who will get Alzheimer's.

"We have amyloid scans that show the presence of amyloid in the brain of people who are normal, or at most mildly impaired," Cummings says. "One possibility is that treating patients as we choose them now—by the presence of the dementia syndrome—may already be too late for the optimal intervention with drugs that are aimed at amyloid."

"The drug that is currently in the lead to become the next treatment of Alzheimer's disease is called Dimebon," Cummings says. Dimebon (dimebolin) originated in Russia in the 1980s as an oral antihistamine. Medivation, which began development for neurodegenerative disorders, licensed the drug to Pfizer in September. Dimebon appears to affect the beta-amyloid pathway, although the precise mechanism of action is not known. The drug did well in a US-run Phase II trial with cognitively impaired patients in Russia. "It appears to be a neuro-protective agent that could work much later in the disease when people are symptomatic," Cummings says.

CTS 21166 is a beta-secretase inhibitor that aims to block the beta-amyloid pathway at a new point of attack. In early Phase II, it is one of the most promising drugs further up the pipeline, Cummings says.


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