Updated June 21, 2008.
17 June 2008. Today, Elan and Wyeth announced preliminary results of one of their closely watched Phase 2 clinical trials of bapineuzumab, a humanized monoclonal antibody designed to treat AD by removing amyloid pathology. According to the company press release, the overall study did not reach statistical significance. When analyzed post-hoc by ApoE genotype, patients appeared to fall into two groups. According to the company release, patients not carrying the high-risk E4 allele showed a statistically significant and clinically meaningful (those aren’t always the same thing; see ACT-AD story) benefit in the trial’s outcome measures, whereas E4 carriers as a group had a trend that was not statistically significant. It is not clear how large the treatment groups were to support this distinction.
On safety, too, ApoE4 non-carriers fared better, the company states. While adverse events were very common in both placebo and treatment groups overall, non-E4 carriers in the treatment and placebo groups tended to have similar numbers of them. By contrast, E4 carriers on bapineuzumab suffered a greater number of serious adverse events than those on placebo. The press release mentions vasogenic edema, where a damaged blood-brain barrier lets fluid leak from blood vessels into the brain parenchyma. This was not seen in placebo recipients, the release states, but occurred increasingly often with higher doses of the biologic drug in E4 carriers.
Observers of the field may have guessed as much from the companies’ decision last year to design their phase 3 trial program in a pharmacogenetic way. Separate trials are enrolling ApoE2 and 3 carriers into a study administering higher doses of bapineuzumab, and ApoE4 carriers into a study administering a lower dose intended to reduce the likelihood of this complication. The decision to begin phase 3 was made before the phase 2 trials had ended (see D.C. conference story).
This apparent pharmacogenomic dichotomy based on ApoE genotype follows a similar finding in a large rosiglitazone trial by GlaxoSmithKline. There, overall results had been negative, too, but subsequent post-hoc analysis revealed a clear distinction between ApoE4 non-carriers (who had benefited from the drug) and carriers (who had not), triggering follow-up trials to investigate the drug separately in these populations. Both trials, of bapineuzumab and rosiglitazone, had not set out to test the hypothesis that apoE4 patients may fare worse. That this indication came up in post-hoc analysis leaves open the possibility that it is due to chance. Associations found in subgroup analysis are generally viewed as generating hypothesis and require direct testing in follow-up trials.
ApoE4 is by far the strongest known genetic risk factor for late-onset AD, but some 40 to 70 percent of AD patients have the disease without carrying an ApoE4 allele, according to the press release. This cuts a slice out of the market the companies envision, but leaves plenty enough for their share price to have edged up since the announcement. On another front, the finding raises the thorny question of whether the brains of ApoE4 carriers may be more vulnerable, and by extension more difficult to treat, than those of non-carriers. Already, scientists know that ApoE4 carriers not only have an increased risk of developing AD, but also tend to recover less well from brain trauma and severe concussions. Clearly, therapies targeted to ApoE4 are needed.
If future trials increasingly take ApoE into account to sort patients into separate treatment groups, more people may seek genetic testing for this gene. Testing is usually done within the context of a research or drug study, but is now even offered through the mail by a private company. Professional leadership groups advise against ApoE4 genotyping except in certain research situations. This stance may slowly change in the aftermath of pharmacogenetic trial results such as this and in response to a growing chorus of scientists who argue that immunotherapy might work best if begun as early as possible. The REVEAL study over the past decade has assessed the impact ApoE genotype disclosure can have on people (see Live Discussion; Lay Introduction. Last month, the Genetic Information Nondiscrimination Act, meant to protect against insurance and employment discrimination, became law.
Meanwhile, the bapineuzumab phase 2 trial data will be presented in more detail at ICAD next month in Chicago. The phase 3 studies are currently enrolling at sites in the U.S. and Europe. For details of the phase 2 study—design, cognitive, clinical, and imaging outcome measures, patient numbers, and imbalances in the patient groups —see Elan/Wyeth press release.—Gabrielle Strobel.