23 July 2012. Today, Pfizer conceded that results of the first of four Phase 3 trials of intravenous bapineuzumab, a monoclonal antibody against Aβ, failed to meet its co-primary endpoints in some 1,100 patients with mild to moderate Alzheimer’s disease who carry at least one ApoE4 allele. The endpoints were the ADAS-cog and the DAD.
The announcement of topline clinical results took researchers by surprise, mostly with regard to its timing. They had expected two of the four widely anticipated Phase 3 trials—the two run in the U.S. that had started earlier—to be announced together. At the recent Alzheimer’s Association International Conference held 14-19 July 2012 in Vancouver, Canada, word began spreading that topline results for those two trials would come in early August, and clinical and biomarker data would be presented this September at the European Federation of Neurological Societies Conference in Stockholm, Sweden. The latter is still true, but apparently, efficacy in the carrier study was so clearly absent that the Janssen AI and Pfizer Joint Steering Committee for the Alzheimer Immunotherapy Program decided to stop dosing patients in the ongoing open-label extension trial. They informed regulators and site investigators, and made the topline results public earlier.
Beyond timing, the finding was a setback, but not altogether a surprise, to clinician-researchers. After all, the Phase 2 study that formed the basis for the Phase 3 program missed primary endpoints and showed a potential benefit only for ApoE4 non-carriers, not for carriers, in a post-hoc exploratory subgroup analysis (Salloway et al., 2009). “This is a replication of that finding. It is no different from what we saw previously in a much smaller group. We are hoping that we will also replicate the benefit for carriers that we saw in Phase 2,” Steven Salloway told Alzforum. Salloway is at Brown University and Butler Hospital, Providence, Rhode Island, a bapineuzumab trial site. He also chairs the steering committee for the 301 (mild to moderate non-carriers) and the present 302 trials of bapineuzumab run by Janssen’s Alzheimer Immunotherapy Program.
“These results are disappointing. But we need to evaluate the full dataset from this trial and the three other trials still under way. Then we can draw conclusions regarding efficacy, safety and target engagement, and see the implications for AD therapeutic research,” said Paul Aisen of the University of California, San Diego.
Pfizer is conducting a second Phase 3 trial in ApoE4 carriers in Europe. That trial is ongoing, but Janssen AI's media spokeswoman Ellen Rose said that its site investigators would inform patients there and in the U.S. of the negative result of the U.S. trial in the coming days. Janssen AI is the J&J company that works with Pfizer on bapineuzumab. Moreover, the companies will expedite interim analysis of that trial, implying that they may be considering whether to discontinue dosing if there is no hint of efficacy. The decision to stop dosing in the U.S. study's open-label extension implies that there was no efficacy signal at all in the carriers who received treatment in the double-blind phase.
Efficacy was the primary problem, not so much safety, according to Salloway. Apparently, the data safety monitoring board that evaluated the unblinded data found no new safety concerns. “As we know, there is a rate of Aria-E, but they tended to be on the mild side and were usually asymptomatic,” Salloway said.
At this point, the dataset is incomplete. Still, it is probably a real finding that bapineuzumab treatment is not effective for mild to moderate AD in E4 carriers, Salloway said. "Beyond that, we do not know yet what effect it will have in non-carriers. It is too early to make a real evaluation of who might benefit, and at what stage, from bapineuzumab.”
What is clear, however, is that this trial has little bearing on Alzheimer’s immunotherapy in general, Salloway said, “We cannot interpret broadly. We have to deal with one compound at a time.” Other companies that have AD immunotherapies in Phase 3 and 2 include Lilly, Eisai, Novartis, Roche, and others.
To cynics who might suspect corporate communications to have timed release of the bad news for after AAIC to evade the collective glare of the news media, Rose insisted, “That is not possible.” Indeed, stories sprouted online within minutes of Pfizer’s release. Instead, Rose said, what drove the timing was communication of the results and discussion of the extension trial halt with regulators and investigators.
Reisa Sperling of Brigham and Women’s Hospital in Boston, another site trialing bapineuzumab, issued this statement: “We are very disappointed about the lack of clinical efficacy in the ApoE ε4 carriers at the stage of mild to moderate dementia. However, we are hopeful that we might see a more positive clinical result in the ApoE non-carriers. … We eagerly await the biomarker evidence, including PET amyloid imaging and spinal fluid markers, to determine whether there are any signals of disease-modifying activity that would support earlier intervention.”
Two papers reported a lowering of CSF tau (Blennow et al., 2012) and brain amyloid by PIB PET (Rinne et al., 2010) with bapineuzumab. For details, see press release.—Gabrielle Strobel.