Top 10 Medical Stories of 2008: No. 5
When considering drug development for Alzheimer’s disease, 2008 was a colossal disappointment.
In June, Elan and Wyeth pumped up their post-hoc data from a phase 2 trial of the anti-amyloid drug bapineuzumab in patients with mild-moderate AD, despite the fact that the mAb was no better than placebo for the primary endpoints of cognition and disability. Initial reaction on Wall Street was inexplicably optimistic; however, reality sunk in a month later when the very same trial results were presented at the International Conference on Alzheimer’s Disease (ICAD) in Chicago. But Elan and Wyeth aren’t giving up yet on the drug; the companies are recruiting patients for at least 4 phase 3 studies in AD,* according to the NIH database.
However, Elan did abandon work on its synthetic amyloid beta compound (AN1792), when a small, placebo-controlled UK study showed that immunization with the compound cleared plaques in the brains of AD patients but did not improve cognition or survival in the long term. A company-sponsored phase 2 study of the agent in AD patients at multiple US sites (NCT00021723) was terminated.
In June, Myriad Genetics announced that its experimental agent tarenflurbil (Flurizan) failed to affect cognition or activities of daily living in early AD in a large phase 3 trial. The company’s CEO reported that further development of the compound, an NSAID enantiomer of flurbiprofen, would be discontinued.
In September, Targacept and AstraZeneca revealed that their novel molecule, AZD3480, did not significantly change cognition in a short-term, randomized, placebo-controlled, dose-finding study of patients with mild-moderate AD. The agent is a selective agonist of a neuronal nicotinic receptor subtype. According the Targacept web site, a decision regarding the future development of AZD3480 in AD is expected in the first half of 2009, pending completion of an adult ADHD study.
Perhaps going after tangle-related tau protein is more promising. Also at this summer’s ICAD, results of a placebo-controlled phase 2 study revealed that a formulation of methylene blue (yes, the Wright’s stain agent) significantly improved cognition in patients with moderate AD at 24 weeks. The developer, TauRx Therapeutics, plans a large phase 3 trial of the drug.
Given these mostly disappointing trial results, maybe Pfizer wasn’t so crazy to give Medivation $725 million for the worldwide marketing rights to Dimebon, a nonselective histamine blocker in phase 3 development for AD. Pfizer is evidently betting on the chance that the 3-times-per-day Dimebon, a defunct antihistamine, will sail through clinical development, given recent results of a Russian, donepezil-controlled phase 2 study. According to Medivation, the Russian study can be used as 1 of 2 pivotal trials to support the FDA approval of Dimebon, as long as a “significant portion” of the current phase 3 trial occurs within the United States.
ADHD = attention deficit hyperactivity disorder; mAb = monoclonal antibody.
* Enrollees will be distinguished by their apolipoprotein E4 carrier status.
For more details on these AD trials, visit these Pathophilia posts of 2008:
- Elan, Wyeth Bury Missed Primary Endpoints in Phase 2 Trial of AD Drug
- More Missed Primary Endpoints in AD Trials
- Elan’s AN1792: No Clinical Benefit With Clearance of Amyloid Plaques in AD
- Bapineuzumab and Share Prices of Elan/Wyeth: What a Difference Some Undefined Thing Makes
- Anti-Tau Agent Warrants Phase 3 Study in AD
- Pfizer Gambles on Three-Times-per-Day Antihistamine for Alzheimer’s Disease
- Another AD Drug Disappoints (Although Placebo Looks Promising)
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.