Results

Biogen, Eisai fight back against accusations their big BAN2401 study was skewed — but this fight isn’t over yet

After getting slapped hard by critics for the way it handled their recent trial summary for their Alzheimer’s drug BAN2401, Eisai and their partners at Biogen $BIIB turned up at an Alzheimer’s conference in Barcelona to present their defense of the data after crunching the numbers again. But it’s not playing their way, with Biogen’s stock sliding as key analysts refused to forgive or forget.

The two companies managed to lose a lot of credibility when analysts found out that at the request of regulators — deeply concerned about the threat of ARIA-E — investigators pulled high-risk APOE4 carriers out of the highest treatment arm in their study, creating an imbalance between the drug group and placebo that may have skewed the results in the drug’s favor.

Today, the researchers are back after extracting the specific APOE4 results in a closely-watched subgroup analysis, concluding:

At the highest treatment dose, APOE4 carriers treated with BAN2401 saw 63% less decline in disease progression, while non-carriers saw 7% less decline, as measured by ADCOMS versus placebo at 18 months. These results suggest that the treatment effect for the 10 mg/kg bi-weekly dose is related to treatment with BAN2401 and not due to an imbalance in subject allocation by APOE4 status. (Emphasis added.) In addition, the pooled 10 mg/kg bi-weekly and 10 mg/kg monthly doses result in less decline on ADCOMS versus placebo at 18 months (overall; 21%, APOE4 carriers; 25%, APOE4 non-carriers; 6%).

Clinical Effects in APOE4 Carriers and Non-carriers at 18 Months (Page 20, Eisai slides)


Biogen’s shares dropped 2.6% on the latest data. Why?

Both companies clearly came out of the APOE4 controversy with lost credibility. Getting it back won’t be easy. And that was evident in some remarks from prominent analysts.

Baird’s Brian Skorney:

While the presenters claim that this analysis resolves outstanding questions around the mismatched allocation of APOE4+ patients between placebo and treatment groups, we continue to think that issues with trial design and the fact of the imbalance make the data impossible to interpret, hence we find it difficult to draw any conclusions, much less the positive ones Biogen and Eisai are inferring.

Count Geoffrey Porges, a skeptic, as deeply disappointed by what was on display today.

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.

We are surprised by the lack of consistent effect by ApoE4 subtype, particularly following aducanumab data earlier this morning showing relatively consistent effect in both carrier and non-carrier populations. Additionally we are disappointed that the effect of lower BAN2401 dose cohorts was not included in this analysis.

And…

Eisai showed that the lower proportion of ApoE4+ subjects in the active drug arm compared to placebo actually diluted BAN2401’s effect since nearly all of the efficacy was driven by the benefit in the ApoE4+ subpopulation. However, the number of subjects remaining in the analysis at 18 months was small (n=77 total) and there were just 10 ApoE4+ subjects included in this analysis.

Expect plenty of additional feedback on this one. All subgroup analysis is subject to question. Some observers have already noted that you can’t pull out these comparisons on enough patients to offer a clear picture on outcomes relative to APOE4. The companies also came up with a new endpoint to assess, which isn’t always endorsed. And the high dose was clearly linked to a much higher rate of ARIA-E, with 10% and 14% of the patients in the two highest doses suffering from brain swelling, which won’t help its chances.

Biogen has a tremendous amount at stake here. There’s been a growing chorus of critics who say the data are increasingly clear that symptomatic patients can’t significantly benefit from any drug targeting amyloid beta. And that makes their big play on aducanumab increasingly risky.


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