Hopes for a new drug to treat the symptoms of Alzheimer disease (AD) diminished again on March 3 when Pfizer and Medivation reported Phase III results showing that Dimebon failed to meet its co-primary and secondary efficacy endpoints. Pfizer had shelled out $225 million up front and agreed to pay Medivation $500 million in milestones for rights to Dimebon.
The AD drug development arena is viewed with great skepticism, fraught with expectation, and littered with failure. Yet the lure of the AD market is significant enough to keep firms that are financially capable interested. Their biggest enemy, however, may be the impact of overhyping the potential of their candidates.
Clinical Data on Dimebon
Reincarnated from its life as an antihistamine in Russia, the drug has several potential activities: It may act by blocking NMDA receptors or voltage-gated Ca2+ channels and by preventing mitochondrial permeability pore transition.
Currently marketed drugs are either cholinesterase inhibitors (Eisai’s Aricept, Ortho-McNeil-Janssen Pharmaceuticals’ Razadyne, and Novartis’ Exelon) or MMDA glutamate receptor inhibitors (Forest Laboratories’ Namenda).
Pfizer’s failed trial, called Connection, was part of a seven-study Phase III program to assess Dimebon across all stages of AD and in Huntington disease. The results are in sharp contrast to a Phase II study published in The Lancet in 2008 by researchers from the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine and Georgetown University. They found that Dimebon was safe and well tolerated and that it significantly improved the clinical course of patients studied.
The Baylor trial enrolled roughly 183 AD patients at 11 sites in Russia. Patients received either Dimebon 20 mg three times a day (TID), 60 mg TID, or placebo TID. Other antidementia drugs were not allowed during the study course. The primary endpoint was improvement in cognition.
The Connection trial involved 598 patients with mild-to-moderate AD at 63 sites in North America, Europe, and South America. More than 40% of the patients enrolled were in the U.S. Patients were randomized to one of three treatment groups receiving Dimebon 20 mg TID, 5 mg TID, or placebo TID for six months. No statistically significant improvements for the 20 mg TID group relative to placebo were achieved on the co-primary endpoints of cognition and independently rated global function.
The Phase III failure was not a complete surprise. The Phase II study had its skeptics, among them the director of geriatric psychiatry at New York’s Montefiore Medical Center, Gary J. Kennedy, M.D. Dr. Kennedy, who had said that placebo-treated Alzheimer’s patients in Russia get different care than U.S. patients and must be allowed access to existing treatments. This means that any effect of Dimebon as seen in the Phase II Baylor trial would be an improvement compared to a placebo.
While Datamonitor called AD “the ultimate high-risk, high-reward therapy market” that firm also predicted multibillion dollar sales for Pfizer and Medivation’s Dimebon. The huge and, unfortunately, growing AD market makes the potential reward worth the risk to companies that can afford the requisite high stakes.
The lure of developing AD drugs can also be attributed to upcoming patent expirations for available drugs and the fact that there are no drug approvals on the horizon. On March 4, Eisai said that it expected annual U.S. sales of Aricept to fall 60% in three years, hit by the drug’s patent expiration later this year.
Razadyne’s patent expired in 2008, Exelon’s protection ends in 2014, and Namenda goes off patent in 2015. Namenda was the last therapeutic to be sanctioned for this disease. It was cleared in 2003 to treat moderate-to-severe AD but disapproved a year later for mild Alzheimer. Myriad Genetics’ Flurizan, thought to work by inhibiting enzymes that produce one form of amyloid, failed in Phase III in June 2008.
Success Continues to Be Evasive
While Flurizan was expected to treat the underlying causes of the disease, the four currently marketed treatments simply alleviate symptoms. Several drugs that aim to prevent plaque production are in Phase III trials.
No one believes that developing new AD drugs is easy; over 20 have failed Phase III since 2002. AD patients and their physicians, however, are ill-served by the uber-hype engendered by results from poorly controlled clinical trials and pharma company tap dancing.
Patricia F. Dimond, PhD, ([email protected]), is a principal at BioInsight Consulting.