- Biogen stock was down by as much as 3% Thursday morning as more comprehensive data on one of the biotech's investigational Alzheimer's disease drugs left investors with more questions than answers.
- The data came from a mid-stage trial testing Biogen and partner Eisai's BAN2401 as a treatment for early Alzheimer's. The companies highlighted earlier this year how cognitive decline was slower for patients receiving the highest tested dose of their amyloid-targeting antibody. But the highest-dose arm also had fewer patients who carry a genetic risk factor for developing late-onset Alzheimer's. As such, there were worries the slowed cognitive decline was due to an imbalance between trial arms rather than BAN2401.
- On Thursday, researchers from Eisai said additional analyses showed there was not a statistically significant difference in cognitive decline between carriers and non-carriers of the risk factor, suggesting BAN2401 could be responsible for the benefits seen in the highest dose arm. However, the methods used to conduct those analyses caused much confusion and, in some cases, criticism that Biogen and Eisai were painting an unrealistic picture of the treatment given the available data.
Study 201 was already complicated.
Initial results after one year turned up negative in December 2017, but testing continued to assess BAN2401's effect over 18 months. This summer, Biogen and Eisai unveiled data that showed what appeared to be a significant benefit for patients who received the highest dose of the anti-amyloid antibody.
But that positive picture was muddied by an imbalance between dose groups of patients who tested positive for an allele called APOE4 that's known to be a risk factor for Alzheimer's.
Back in 2014, an unnamed non-U.S. regulator had required Eisai to amend its study protocol and prevent those higher-risk patients from being randomized to the highest-dose arm, which administered 10 mg/kg of BAN2401 bi-weekly.
The question of whether BAN2401 actually worked, then, appeared tied to how that imbalance affected patient outcomes.
Updated results presented Oct. 25 at the Clinical Trials on Alzheimer's Disease annual conference didn't do much to clear things up. In fact, they may have painted an even murkier picture.
In the trial, investigators evaluated BAN2401's efficacy by looking at how patients performed over time on ADCOMS, a composite of several different Alzheimer's disease severity measurements. According to results, after 18 months patients on the 10 mg/kg of BAN2401 bi-weekly regimen declined 30% less as measured by ADCOMS than those on placebo
But digging deeper into that 30% figure, there are some noteworthy caveats. APOE4-positive patients on the highest dose did experience markedly less cognitive decline from baseline than APOE4-negative patients. But only 10 carriers actually had 18-month results, leaving investigators with a very small amount of data to pull from in evaluating clinical effects among APOE4-positive patients.
APOE4-negative patients, meanwhile, saw very little benefit at all, raising questions about whether the drug works as intended.
"In our view this data is confusing, suggesting only limited value for BAN2401 in the carrier population, while the small number of patients remaining on drug at the 18-month time point and lack of clear dose responses diminish the reliability of this dataset," wrote Leerink analyst Geoffrey Porges.
Other analysts took a slightly more optimistic view of the data and a small survey conducted by Mizuho's Salim Syed found investors almost equally split on how to interpret the results.
It's worth noting that Biogen and Eisai's trial is Phase 2, leaving room for further study to clear up the many questions left unanswered.
The divergent reactions, however, make the study a Rorschach test of sorts. Those who remain convinced that targeting amyloid is the right approach to treating Alzheimer's can find reasons for hope in BAN2401's future. More skeptical observers, however, are unlikely to see Thursday's presentation as cause to change their assessment.