The Alzheimer’s Divide: Wyeth Phase II Underscores Key Choice For Sponsors
Executive Summary
Wyeth/Elan's Phase II bapineuzumab trial for Alzheimer's disease did not impress investors, but the sponsors are convinced they made the right bet in how they designed the study
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Wyeth/Elan's Phase II bapineuzumab trial for Alzheimer's disease did not impress investors, but the sponsors are convinced they made the right bet in how they designed the study. "The basic trial design we chose a year ago, based on what we looked at when we finally unblinded the full study, looks like the right decision," says Wyeth Assistant VP-Neuroscience Ron Black. The results were presented during the International Conference on Alzheimer's Disease in July, and the bottom line is that bapineuzumab did not meet the primary endpoint. But Black is convinced the choice to conduct a more robust study will pay off. "When you try to accelerate a program because of its importance to the company and to the medical community, you take those kinds of risks. You don't always get things right. Yet at least for me personally, when we unblinded it, it looks like we made the right decisions." That assessment of bapineuzumab - high marks for the trial design, question marks for the drug itself - seems perfectly in line with the state of Alzheimer's disease research, at least as represented at ICAD. [Editor's note: This article is an excerpt from "The Alzheimer's Divide," which appears in the September issue of FDC-Windhover's IN VIVO. For a 1 three-month trial , please visit www.windhover.com/trial/invivo.asp?utm_source=Pink] Few Biomarkers, Tough Choices Like other AD drug sponsors, Wyeth and Elan had a choice to make. Given the immense uncertainty surrounding biomarkers for AD, one option is to conduct a relatively simple Phase II trial to define the pharmacodynamics of the compound and elucidate any unique toxicity concerns - and then make an all-or-nothing bet on efficacy in Phase III. That is essentially the route Lilly is taking with its most advanced Alzheimer's projects, a gamma secretase inhibitor and a passive immunotherapy antibody. Lilly opted to do shorter-term Phase II trials - its antibody trial was only 12 weeks in duration - that would give some indication of drug activity, but not necessarily efficacy, before advancing into Phase III. For both compounds, biomarker results encouraged Lilly sufficiently to begin pivotal studies (2 (Also see "Anti-Amyloid Still All The RAGE At Alzheimer’s Disease Conference" - Pink Sheet, 4 Aug, 2008.), p. 15). Lilly is cutting its financial risk by offloading pivotal trial expenses for both programs to the investment firm TPG-Axon and Nova-Quest, the partnering arm of Quintiles Transnational Corp. (See "Alzheimer's Development Financing: Risky Therapies Call for Innovative Deals," IN VIVO, September 2008.) With bapineuzumab, Elan and Wyeth took the other path, conducting a lengthy (18-month) Phase II trial. The main focus was dosing and safety, since the sponsors were already aware that the drug might cause vasogenic edema. But it was also set to look at efficacy. Wall Street passed judgment on the ICAD presentation immediately, sending Elan shares into a tailspin (3 (Also see "Wyeth’s Pipeline Star Bapineuzumab Looks More Long Shot Than Sure Bet" - Pink Sheet, 30 Jul, 2008.)). The sell-off only got worse when Elan reported new cases of a potential fatal side effect associated with its multiple sclerosis therapy Tysabri (4 (Also see "Tysabri Risk Redux: Additional PML Cases Create REMS Challenge For FDA" - Pink Sheet, 4 Aug, 2008.), p. 9). APOE4's Big Impact "Given the limitations of the study - it was a small study with very limited power - we are very encouraged by what we saw," Black says. In effect, the investigators were assessing four different doses in parallel for descriptive signals of safety and efficacy, with the intention of averaging them together. But what they found was that carriers of the APOE4 gene did not show much of a benefit from therapy as measured on cognitive or behavioral scales, except for the small number out of the total enrollment who completed the full course. The APOE4 completers were "more positive" and the efficacy signal "may be of interest," noted Sid Gilman, MD, director of the Michigan Alzheimer's Disease Research Center at the University of Michigan, the chairman of the independent safety monitoring committee for bapineuzumab who presented the Phase II data at ICAD. Moreover, there was "quite substantial" improvement in the APOE4 non-carriers and "absolutely dynamite" data in the APOE4 non-carrier-completers, Gilman said. - Mark Ratner ([email protected]) |