That Alzheimer’s drug that flunked a PhII? On second look, Biogen/Eisai say it’s a winner

Seven months ago, Biogen and Eisai were forced to abandon their plans for a quick pivot into Phase III as their Alzheimer’s drug BAN2401 failed a decisive Phase II. Now, with the full 18-month analysis in hand, the partners are saying they were right to persist.

Biogen’s stock $BIIB surged 17.48% in pre-market trading on an updated snapshot, a considerable boost given the size of the company. So far, the company has added roughly $10 billion to its market cap since yesterday. Meanwhile BioArctic, the small Swedish biotech whose research alliance with Eisai first gave birth to the product, saw their shares (CPH: $BIOA-B) skyrocket 209% as of press time.

Here’s what changed: When evaluated by the Alzheimer’s Disease Composite Score (ADCOMS), the highest dose of BAN2401 showed to cause “statistically significant slowing of disease progression” after 18 months of treatment. The trial recruited 856 patients with early Alzheimer’s disease (and confirmed amyloid pathology in the brain), a cohort comprising those with mild cognitive impairment due to Alzheimer’s and others with mild Alzheimer’s dementia.

Lynn Kramer, Eisai

What does this mean for a field fraught with failures, a field that absorbed the millions of dollars thrown at it by big pharmas and biotechs alike and churned out nothing in return? While past failures have repeated called the amyloid hypothesis — the idea that targeting the plaques observed in the brains of most Alzheimer’s patients could change the trajectory of the disease — into question, for Eisai CMO Lynn Kramer, their data are “further validating the amyloid hypothesis.” Some might also see it as a validation of aducanumab, the much-touted late-stage drug that’s also hitting the amyloid beta pathway.

“We will discuss these very encouraging results with regulatory authorities to determine the best path forward,” Kramer said in a statement.

It would be a huge feat to demonstrate improvement in cognition linked with a decline in amyloid beta clusters. But until the full data is out at a future medical conference, experts are carefully managing their expectations.

“Given the state of the field we have to be cautiously optimistic about a finding like this,” Mayo Clinic Alzheimer’s Disease Research Center director Ron Petersen told Forbes.

Leerink’s Geoffrey Porges is more skeptical, pointing out how little information was given in the press release.

We do not feel that Biogen, Eisai or the whole amyloid field deserves much credit for this disclosure, particularly given the lack of external validation of the ADCOMS endpoint. There is very little detail about other more validated cognitive measures in the joint press release and we find no reason to believe this either proves or disproves the amyloid hypothesis or has any impact on the likelihood that aducanumab will succeed in its ongoing phase III trial.

A few details in the trial design may also prove problematic.

For one, the turnaround comes down to statistics. When Biogen and Eisai reported in December that the study failed its primary endpoint, it was referring to a Bayesian analysis, in which the drug would have to hit a certain probability for causing a certain outcome to be deemed effective. Because of that, and an adaptive trial design, researchers could make changes during the trial and patients could be switched to different doses. That didn’t work, so they waited until the standard 18-month mark to evaluate the results again with “conventional statistical methods.” Looking back with this new framework, the partners now say their drug showed statistically significant clinical benefit as early as six months.

The positive outcome being highlighted today also concerns only the 10mg/kg biweekly dose, which was one of five doses tested in the trial. It’s unclear how many patients ended up on that dosing scheme.

And finally there’s ADCOMS, the chosen measure of cognition, which was a novel endpoint that combines a few standard scales in Alzheimer’s.

But if there’s one thing we’re sure about, it’s that Biogen and Eisai are all in. The Japanese company recently wagered more than $100 million on a bespoke Alzheimer’s research center in its partner’s home of Cambridge, MA. And Biogen just tossed in an extra $50 million for a bigger slice of the royalties for aducanumab.

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Sr. Manager, Regulatory Affairs, CMC
CytomX Therapeutics San Francisco, CA
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Catalytic Data Science Charleston, SC
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Flatiron Health New York City or San Francisco

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