Earlier this year, Biogen discontinued the Phase III trial of aducanumab in March 2019 following a futility analysis. Biogen’s stock tanked more than 29 percent from $320.59/shr, closing at $226.88/shr on March 21.
Expectations had been high for aducanumab as Goldman Sachs analysts had projected at one time that sales of the drug could reach $12 billion.
When Biogen said on October 22 that it is going to file its amyloid-beta MAb aducanumab for US approval based on discussions with the FDA, its share price reached $318.00 during the day and closed at $281.87/shr (up more than 26%).
What has changed
Biogen said that, far from throwing in the towel on aducanumab, it has been busy. A “type C” meeting with the US FDA took place in June to discuss a possible path forward; then, just yesterday, there was a second such meeting, at which a new analysis was discussed [EvaluatePharma]
While the issues are complex the group’s new analysis points to a single, simple fact, which has been aired before: if an amyloid-beta MAb can be dosed high enough, for long enough, without insurmountable toxicities, then it should show some effect in a sufficiently early Alzheimer’s population.
An amendment in March 2017 allowed ApoE4 carriers who had earlier been on either 6mg/kg or 10mg/kg to be titrated up to 10mg/kg. This saw more patients overall exposed to 10mg/kg, but crucially the December 2018 cutoff was too early for this effect to manifest itself.
| Surprise! Biogen’s longer-term analysis of aducanumab | ||||
|---|---|---|---|---|
| Low dose | High dose | |||
| Emerge | Engage | Emerge | Engage | |
| n=543 | n=547 | n=547 | n=555 | |
| CDR-SB (original primary endpoint) | ||||
| Reduction vs placebo | -14% | -12% | -23% | +2% |
| Nominal p value | 0.117 | 0.236 | 0.010 | 0.825 |
| Adas-Cog (one of 3 secondary endpoints) | ||||
| Reduction vs placebo | -14% | -11% | -27% | -12% |
| Nominal p value | 0.167 | 0.248 | 0.010 | 0.245 |
| Source: Biogen presentation, EvaluatePharma | ||||
Read more on Biogen’s Aducanumab Update
Question Remained
From FierceBiotech:
Biogen saw a divergence between the data generated in the two studies at the time of the futility analysis but was unable to explain the finding. Now, Biogen thinks the greater exposure to the high dose in EMERGE is the primary driver of the divergence. Biogen pointed to the better results seen in a subset of ENGAGE patients it said were exposed to sufficient high-dose aducanumab to make its case.
As the trials were identically designed, Biogen needs a way to explain why patients in EMERGE had greater exposure to high-dose aducanumab. Biogen’s explanation centers on amendments it made to the protocol. The hypothesis is that the timing of enrollment in the trials meant the amendments had different effects in each study. Biogen knew that was possible but not that it could warp the data to the extent it now claims.
And the big question is what the FDA will make of Biogen’s case.
Umer Raffat, an analyst at the investment bank Evercore/ISI, first asked if the departure of Michael Ehlers, Biogen’s previous research and development chief, had anything to do with disagreements over the Alzheimer’s dataset. Vounatsos, the Biogen CEO, said that Ehlers’ departure was personal, implying that disagreement over data did not play a role. [STAT]
Additional, Raffat noted that the patients who did not complete seemed to show benefit as well. He called this “confusing” in a note to investors following the conversation.