Despite Manipulation, Phase 2 Bapineuzumab Study Still Disappoints

Authors of the peer-reviewed phase 2 study of bapineuzumab in patients with Alzheimer disease conclude that the "trial provides insufficient evidence to support or refute a benefit" of the anti-amyloid mAb. The results of the Elan/Wyeth-funded trial, which are now available in an online issue of Neurology, were originally made public in a less-than-candid June 2008 company press release and at the International Conference on Alzheimer's Disease 1 month later.

The major drawback of the multidose study now appears to be related to a change in its primary outcome. The trial was originally designed and powered to assess the safety of bapineuzumab in AD, but the protocol was amended on the basis of phase 1 data. The authors write, "It was recognized that the small cohorts in this study would provide sufficient power to detect only very large treatment differences; however, if successful, the urgency of delivering an effective treatment to patients with AD argued for making the efficacy the primary outcome."

In other words, the investigators changed the primary endpoint of the phase 2 study on the chance that differences in efficacy outcomes might be substantial. In addition, the authors report the results of a modified intent-to-treat (mITT) population (n = 227), which consisted of patients who received at least 1 dose of study drug and underwent 1 or more efficacy evaluations during the study.

Despite these modifications, there were no statistically significant primary-efficacy* differences between placebo- and bapineuzumab-treated patients at 18 months. However, "exploratory analyses" showed "potential treatment differences" in the completer population (ie, patients who completed bapineuzumab treatment and underwent week-78 assessment) and in the subpopulation that did not have an ApoE4 allele.

Reversible vasogenic edema was observed in nearly 10% of bapineuzumab-treated patients and was dose dependent. Vasogenic edema was also more likely in ApoE4 carriers. In August, Elan and Wyeth announced that the highest bapineuzumab dosage, 2.0 mg/kg, would be discontinued in 2 ongoing phase 3 studies of ApoE4 noncarriers (40%-70% of AD patients), because of the risk of vasogenic edema. (Protocols for phase 3 trials of the mAb in ApoE4 carriers remain unchanged; these trials are assessing only 1 bapineuzumab dosage, 0.5 mg/kg.)

During the 18-month phase 2 study, bapineuzumab was given IV every 13 weeks at 1 of 4 doses (0.15, 0.5, 1.0, or 2.0 mg/kg). The smallest dose was added to the study after investigators identified vasogenic edema on some brain MR images of patients receiving 0.5 mg/kg.

An aside: The disclosures of the authors, several of whom are industry employees, consume about 3 columns of small type.

N.B. Bapineuzumab now belongs to JNJ, instead of Elan. Wyeth now belongs to Pfizer.

ADAS-Cog/12 = 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale; DAD = Disability Assessment for Dementia; mAb = monoclonal antibody.

* Measured by using changes in ADAS-Cog/12 and DAD scores. 

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