Biogen and Eisai try to defend Alzheimer’s drug BAN2401 against skeptics

Amyloid plaques in Alzheimer's disease
The drug eliminated amyloid plaques in 80% of patients at the highest dose tested. (Jensflorian/Wikimedia Commons)

Biogen and Eisai have revealed much-anticipated new data on Alzheimer’s drug BAN2401 that was supposed to answer some concerns about the study earlier this year—but investors don’t seem too impressed.

Shares in Biogen dipped almost 4% while Eisai declined nearly 6% after the presentation at the CTAD meeting in Barcelona, which tried to use subgroup analyses and biomarker data to build the argument that the anti-amyloid drug was showing a significant effect on the progression of Alzheimer’s disease. Biogen, however, clawed back some ground as the news sunk in.

There was a lot of excitement when the two companies reported 18-month data from the phase 2 trial at AAIC earlier this year that found a significant effect on cognitive decline in mild AD patients that hadn’t been shown at 12 months, the study’s primary endpoint. The study also revealed a startling effect on amyloid plaque build-up in the brain, eliminating signs of this on PET scans in more than 80% of patients.

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There was one problem with the dataset, however, and that was a big imbalance in the proportion of patients who were carriers of APOE4, a mutation that increases the risk of developing AD, in the high dose group (10mg/kg biweekly) that seemed to be getting the most benefit from the drug.

The imbalance was caused by regulatory demands to stop recruiting APOE4 carriers into the study because of a fear of side effects, and that led to suggestions that the benefit of the drug may have been overestimated.

At CTAD, Biogen and Eisai tried to answer those suggestions with a series of analyses that they claimed show the APO4 carrier imbalance didn’t amplify BAN2401’s effects, and according to Eisai scientist Chad Swanson, Ph.D., senior director of clinical research for neurology, may in fact have underestimated its benefit as patients with the mutation actually did better on the drug than those without.

He said there was a “statistically meaningful effect of 30% less decline in disease progression seen for 10 mg/kg bi-weekly dose versus placebo at 18 months on ADCOMS [that] was driven by BAN2401 treatment effect and not an imbalance in subject allocation by APOE4 status.”

To back up that position, Swanson provided data on three biomarkers taken from cerebrospinal fluid (CSF) that correlated with the clinical benefits and seemed to be consistent with treatment of the underlying disease process in AD.

The continuing skepticism about BAN2401 seems to stem from the small number of APOE4 carriers in the high-dose group relative to placebo, and a pooled analysis of 10mg/kg bi-weekly and monthly groups. The latter showed 21% less decline overall versus placebo on the ADCOMS score at 18 months, but that was skewed to the carrier group who had a 25% benefit compared to 6% for noncarriers.

Analysts at Jefferies said the data has some good elements but "seems a bit all over the place." In particular, it is encouraging that disease progression of carriers and noncarriers is generally consistent "and suggests that the placebo arm and carrier imbalance did not help drive the drug."

They don't quite buy the companies' position that the efficacy of BAN2401 may have been under-represented, as there was a big benefit in carriers but these were only a small proportion of the high-dose group.

As they wrote in a research note: “Thus if it was more balanced—the high dose arm would be even better than the average +30%, but the non carriers was only 7% benefit ... so the drug seems really good in carriers only but good and bad in non-carriers? This doesn't necessarily make scientific sense to us and flies in the theme that these drugs work in BOTH patient groups."

Ahead of today’s presentation, they said they felt Biogen management was being a not more conservative in its Alzheimer’s commentary than before, but that—assuming the company found no difference between the APOE4 carriers and non-carriers—it would be reasonable to progress to a phase 3 program.

There’s no word on that yet, but Eisai says it is currently discussing the next steps for BAN2401 with regulatory authorities. Meanwhile, an open-label extension for patients previously enrolled in the phase 2b clinical study is planned, with enrollment expected to begin this year.

“We see today's results as somewhat confirming a view the drug is active and promising—and should go to phase 3,” said Jefferies. 

But we also see why there will be more questions, because even if it's possible the drug is under-reporting the possible effect, this is only in the carrier group and it's small number of pts; and the non carriers efficacy is more mixed.”

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