The Saga of Biogen’s Alzheimer Drug Aducanumab

Aducanumab is an investigational compound being studied for the treatment of early Alzheimer’s disease co-developed by Biogen and Eisai. Aducanumab is a human immunoglobulin gamma 1 (IgG1) anti‐amyloid beta monoclonal antibody (mAb) targeting aggregated forms of amyloid beta - a fundamental pathological hallmark of the disease.

After the ‘successful’ phase I study (PRIME trial) to demonstrated that Aducanumab had an acceptable safety and tolerability profile and reduced brain amyloid-beta accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE) scores, Biogen designed two pivotal studies (ENGAGE and EMERGE) to evaluate the efficacy and safety of aducanumab in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease dementia.

Then the saga began,… a roller-coaster year in 2019.

In March 2019, Biogen and Eisai announced to discontinue Phase 3 ENGAGE and EMERGE trials of aducanumab in Alzheimer’s disease after the interim analyses found that the futility boundaries were crossed. The independent data monitoring committee advised that aducanumab would be unlikely to meet primary endpoints even the studies would be continued to the completion.

While everybody thought that aducanumab was dead in the water, Biogen unexpectedly announced that they would plan regulatory filing for aducanumab in Alzheimer’s disease based on a new analysis of larger data set from Phase 3 studies.

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• Questions EMERGE as Biogen claims aducanumab turnaround
• Biogen’s good news on aducanumab could ‘open the floodgates’ for Alzheimer’s drugs

On July 08, 2020, Biogen announced that they had completed the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for the approval of aducanumab, an investigational treatment for Alzheimer's disease.

Given that their BLA submission was based on the re-analyses from studies that had been discontinued due to futility, the common understanding would be that the FDA would reject their BLA and require them to do another Phase 3 study.

Then came the last week,…a roller-coaster week last week

For a drug application with controversies, FDA will usually organize an advisory committee meeting to seek the opinions from outside experts including representatives from patients’ organization, patient advocate group, and consumer citizen groups. There is no exception to BLA for aducanumab. Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting was scheduled for November 6, 2020 and the meeting materials were posted online two days before the meeting on November 4, 2020.

The documents released by FDA came as shocking to outsides. With one negative trial and one very positive trial in one of the dose groups, one would expect that the FDA would give a negative tone and demand a third trial to confirm the efficacy. Usually, the sponsor would try everything to convince FDA that the drug was efficacious and safe while FDA would be conservative and poke and probe the data to identify the issues to discredit the sponsor’s claim about the efficacy and safety.

However, this time for aducanumab, FDA is on the sponsor’s side. The briefing book from the FDA (actually combined FDA and Biogen Briefing Information) depicted a very rosy picture for aducanumab’s efficacy and safety.

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With FDA’s backing, one would think that aducanumab is on its way to get a positive opinion from advisory committee members and eventually to be the first FDA approved novel medication for the treatment of Alzheimer’s disease since 2004.

Then the shocking news continued,…

At Friday’s advisory committee meeting, committee members resoundingly concluded Friday that clinical data did not support the approval of Biogen’s much-watched Alzheimer’s drug, aducanumab, while providing a rebuke to the Food and Drug Administration, whose reviewers had given the medicine a glowing appraisal.

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Here are the voting results:

FDA’s Questions to the Advisory Committee	Voting Results
Does Study 302, Viewed independently and without regard for Study 301, provide strong evidence that supports the effectiveness of aducanumab for the treatment of AD?	1	8	2
Does Study 103 provide supportive evidence of the effective of aducanumab for the treatment of AD?	0	7	4
Has the applicant presented strong evidence of a pharmacodynamic effect on AD pathophysiology?	5	0	6
In light of the understanding provided by the exploratory analyses of Study 301 and Study 302, along with the results of Study 103 and evidence of a pharmacodynamic effect on AD pathophysiology, is it reasonable to consider Study 302 as primary evidence of effectiveness of aducanumab for the treatment of AD?	0	10	1

Note: Study 301 was the pivotal study (ENGAGE trial) with the negative outcome; Study 302 was the pivotal study (EMERGE trial) with a positive outcome in high dose group; Study 103 was the phase I proof-of-concept study (PRIME trial).

 

Not sure where aducanumab will go from here. It will be another shocking if FDA approves aducanumab for the treatment of Alzheimer’s disease given the extremely negative view/voting outcome from the advisory committee panel even though everybody understands there is a huge, urgent, unmet need for a new AD drug. As one of the experts said, "with FDA's reputation already in a precarious position, it could be difficult -- maybe impossible -- to go against an expert panel at this time no matter how badly they want this". The best path forward would be to conduct a third pivotal study if Biogen has confidence in aducanumab. In Chinese idiom, true gold fears no fire.

The briefing book from the combined FDA and Biogen Briefing Information revealed the discordance in viewers about the aducanumab efficacy and the study issues among FDA reviewers. The conclusions from the clinical reviewer and the statistical reviewers were dramatically different. As one of the panel members commented on this, “It feels like the audio and video on TV are out of sync”. Unfortunately, in the overall conclusion and the FDA’s presentation, the clinical reviewer’s opinion trumped the statistical reviewer’s opinion. The statistical reviewer wasn’t even given an opportunity to present at the steering committee meeting.

Here is the conclusion from the clinical reviewer:

“……the applicant has provided substantial evidence of effectiveness to support approval. Study 302 provided the primary evidence of effectiveness as robust and exceptionally persuasive study demonstrating a treatment effect on a clinically meaningful endpoint and reinforced by effects on secondary endpoints, biomarkers, and in relevant sugroups. Study 103 was an adequate and well-controlled study that included design components consistent with Study 302 and demonstrated a persuative treatment effect on both clinical endpoints. The dose-response relationship for Aβ reduction provides support for the positive finding in the 10 mgkg treatment arm to the apparently dose-related effects observed on clinical outcomes in Studies 103 and 302. Study 301 does not contribute to the evidence of effectiveness. The results of exploratory analyses, however, contribute to the overall understanding of Study 301 and together do not meaningfully detract from the persuasiveness of Study 302."

 Here is the conclusion from the statistical reviewers:

“In summary, the totality of the data does not seem to support the efficacy of the high dose. There is only one positive study at best and a second study which directly conflicts with the positive study. Both studies were not fully completed as they were terminated early for futility and had sporadic unblinding for dose management of ARIA cases which was much higher in the drug group(s). The Amyloid PET sub-study data suggested a larger effect in APOE- (non-carriers) which is the opposite of what was observed for the clinical outcome data. Within the high dose group at the patient level, there is no correlation between the Week 78 change in the primary biomarker Ab in the cerebellum and the Week 78 Change from baseline in CDR-SB. In study 302, the on-face positive study, the raw correlation had the wrong +/- sign to support a realistic link between biomarker and long-term clinical change in cognition/function as measured by CDR-SB. For these reasons, the reviewer believes there is no compelling substantial evidence of treatment effect or disease slowing and that another study is needed to confirm or deny the positive study and the negative study. "