Phase II data on Wyeth/Elan's bapineuzumab - an Alzheimer's disease drug that recently looked to be a potential pipeline standout - failed to excite investors after detailed results were released during the International Conference on Alzheimer's Disease in Chicago July 29.

Weaker than expected efficacy data puts more pressure on Wyeth, which already has faced several challenges this year, including regulatory setbacks, the launch of generic Protonix (pantoprazole), its blockbuster heartburn medication, and head count reductions.

After the release of the data, Wyeth's stock fell 13.5 percent from its July 29 closing price to close July 30 at $39.74, and Elan's plunged 41 percent to close at $19.63; talk of Wyeth as a takeover target also resurfaced.

"There are other aspects of Wyeth to like," Sanford Bernstein & Co. analyst Tim Anderson reminded investors. "These include Wyeth's low exposure to the generic 'cliff' of 2011/2012 (because Wyeth is in its cliff today already), and certain franchises (like Prevnar ) and capabilities (like biologic manufacturing) that could ultimately position the company as a take-out candidate."

Disease-modifying drugs for Alzheimer's have evaded the industry, and the research area commonly is recognized as one of medicine's most challenging. Nonetheless, despite the known development hurdles, investors had held out hope that Wyeth would deliver stronger efficacy results on bapineuzumab.

Optimism for bapineuzumab - a monoclonal antibody thought to induce an immune response to clear beta amyloid plaque buildup in the brain - was reenergized in June, when Elan/Wyeth released top-line Phase II data.

Although the companies acknowledged at the time that the study failed to meet its primary efficacy endpoints, the firms maintained that the monoclonal antibody showed "statistically significant" and "clinically meaningful" benefits in non-carriers of apolipoprotein E4, a subgroup estimated to include 40 percent to 70 percent of Alzheimer's patients, in a post-hoc analysis (¹ Also see "Elan, Wyeth’s Bapineuzumab Data Mixed In Phase II For AD" - Pink Sheet, 17 June, 2008.).

Investor curiosity also was ignited last year after Wyeth/Elan initiated a comprehensive Phase III clinical program, enrolling 4,100 patients, before the Phase II program wrapped up.

Subgroup data fails to live up to expectations

The prespecified primary efficacy endpoints the Phase II study failed to meet were: change from baseline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Disability Assessment Scale for Dementia (DAD). Other efficacy measures included change in concentrations of tau in cerebral spinal fluid, the Neuropsychological Test Battery, the Clinical Dementia Rating Sum of Boxes, the Mini Mental State Examination and brain volume as measured by MRI. Efficacy was assessed from baseline at 78 weeks.

The trial enrolled 234 patients randomized to one of four doses of bapineuzumab (0.15 mg/kg, 0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg) or placebo by intravenous infusion every 13 weeks. Findings were reported for 229 patients in a modified intent-to-treat analysis.

In the post-hoc efficacy analysis, ApoE4 non-carrier patients treated with bapineuzumab showed statistically significant differences from baseline to week 78 on both cognitive and functional efficacy endpoints (ADAS-Cog difference of 5.0 and NTB treatment difference of 0.35). In addition, MRI results of non-carrier patients showed significantly less brain volume reduction versus placebo as measured by the Brain Boundary Shift Integral at 71 weeks. However, ApoE4 non-carriers did not show efficacy for the other primary endpoint, DAD.

In the ApoE4 carrier patients, no statistically significant changes were observed in cognitive or functional efficacy endpoints.

Wall Street took issue with the post-hoc analysis' use of a modified intent-to-treat patient population, which included any patient who had at least one dose and one post baseline efficacy assessment. The analysis also assumed a non-linearity of the data over time, while the original analysis assumed a linear decline in the measured outcomes of the study.

"A key driver for our view that this data was not compelling was the multiple layers of post hoc analysis that were conducted to arrive at the conclusions of efficacy," Canaccord Adams analyst Karl Keegan said in a July 30 research note.

Additionally, some safety signals also emerged, including 12 cases of vasogenic edema in the treatment group versus none in the placebo arm. Ten of the 12 were in ApoE4 carrier patients, however. Three deaths occurred in the treatment group compared with no reported deaths in the placebo group, although the deaths were not considered by investigators to be treatment related.

Credit Suisse analyst Catherine Arnold called the market reaction on Wyeth "overdone" and noted "the non-carrier data does support the notion that bapineuzumab can be a big drug even with benefit isolated to this cohort." She maintained sales forecasts of $2.24 billion for the drug by 2015 and a 50 percent probability of success.

Wyeth and Elan said they are using the data results to inform the Phase III program.

"Our overall assessment of this Phase II study, which has given us an awful lot of learning, is that it supports the design and the further evaluation of bapineuzumab in the ongoing Phase III trial," Elan Head of Global Development Allison Hulme said during the companies' presentation.

The firms have not outlined a timeline for filing bapineuzumab.

-Jessica Merrill (j.merrill@elsevier.com)

Wyeth’s Pipeline Star Bapineuzumab Looks More Long Shot Than Sure Bet

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