Top 10 for '09: No. 6

No. 6: Big Trouble in the AD Pipeline

First suggested by last year's news, targeting amyloid buildup in the brains of people with Alzheimer disease doesn't seem to be the way to go.

In April, Elan and codeveloper Wyeth (now a part of Pfizer) announced that the highest dosage of bapineuzumab, an anti-amyloid mAb that Elan sold to JNJ in September,* would be discontinued in ongoing phase 3 trials. The reason: vasogenic brain edema in phase 2 assessment.

The peer-reviewed, phase 2 dose-ranging trial,* which was finally published in Neurology in September, revealed vasogenic edema in nearly 10% of bapineuzumab-treated enrollees with mild-to-moderate AD (n = 12/124). Vasogenic edema, possibly due to the effect of bapineuzumab on perivascular amyoid, was dose-dependent and more common in subjects who were ApoE4 carriers. Moreover, data supporting the efficacy of the drug were underwhelming, despite manipulation of the primary outcome and the use of a modified population for analysis. The authors concluded that the "trial provides insufficient evidence to support or refute a benefit" of bapineuzumab. Nevertheless, phase 3 study of the drug continues.

Then, 2 short weeks ago, Elan announced the deaths of 9 subjects in a company-sponsored phase 2 trial of another AD drug candidate, scyllo-inositol. The cause or causes of the deaths were not provided, but Elan (along with codeveloper Transition Therapeutics) discontinued the highest-dosage arms (1000 and 2000 mg bid) in development. All that's left now is the hope of blocking the accumulation of soluble amyloid plaques with a measly 250 mg of scyllo-inositol twice daily.

mAb = monoclonal antibody.

* JNJ bought Elan's AD immunotherapy program for $1.4 billion.

** The phase 2 results were originally made public in Elan's less-than-candid July 2008 press release, which the SEC is investigating.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.