Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

The latest Phase III failure perpetuates skepticism about developing drugs for AD.

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.

Pfizer shares lost $0.19 on the news; the firm already has a major stake in the AD segment with approved drug Aricept, marketed with Eisai. Medivation, however, fared much worse, its stock dropping 68% to $13.04 from its all time high of $40.49 one day prior to the announcement. Medivation now must confront several class-action lawsuits as stock buyers allege SEC rule violations.

The AD drug development arena is viewed with great skepticism, fraught with expectation, and littered with failure. As Corante’s Derek Lowe, Ph.D., put it, “I am most definitely not giving investment advice, though, Alzheimer’s drug development is a total crap shoot and should only be approached with money you can afford to see incinerated.” 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 (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.

The Dangling Carrot for the AD Market

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 disease currently afflicts more than 37 million people worldwide, 5 million of whom are in the U.S. Estimated direct and indirect annual costs are at least $100 billion. The number of people with AD is projected to more than triple by 2050, to 120 million affected individuals. 

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, developer of Aricept, 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. Pfizer reported that Aricept pulled in $121 million in worldwide revenues during 2009.

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, was the last AD candidate to fail in Phase III in June 2008.

Success Continues to Elude Drug Developers

While Flurizan was expected to treat the underlying causes of the disease, the four currently marketed treatments simply alleviate symptoms. Some drugs in development that aim to prevent plaque production include bapineuzumab (Pfizer, Johnson & Johnson, Elan), LY450139 (Eli Lilly), and solanezumab (Lilly); all 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. Samuel Gandy, M.D., Ph.D., a researcher at Mount Sinai School of Medicine who has studied Dimebon, 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.”

Dr. Gandy previously had a hard time reconciling the Dimebon clinical results with his own findings from a mouse study performed in his laboratory. He presented data at a July 2009 AD meeting in Vienna showing that the drug caused amyloid levels to rise. “It was startling to observe that a compound with an apparently beneficial clinical effect on cognition caused acute elevation of amyloid beta levels in three out of three systems, in two labs,” Dr. Gandy noted.

AD remains completely incurable. It leads to death within an average of eight years post diagnosis. The disease is reportedly the leading cause of institutionalization in the U.S. AD patients and their families are the real losers in this drug development crap shoot, as existing approved drugs do little to counter the underlying causes of this devastating disease and no new therapeutics are emerging from the pipeline. “We’re not close enough to the cause of this illness to get the silver bullet,” Dr. Kennedy noted.

Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].

Previous articlePfizer to Assess Tekmira Technology to Deliver siRNAs in Preclinical Models
Next articleAmbry to Offer Sequence-Enrichment Capabilities with RainDance’s RDT1000 Platform