Biogen's Aduhelm Faces Another Setback as EU Votes No

Exterior view of the headquarters of the European Medicines Agency

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Biogen's controversial Alzheimer’s drug, Aduhelm (aducanumab), faced another hurdle this week. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a negative trend vote on the company’s Marketing Authorization Application (MAA) for the drug. CHMP will have a meeting on December 13-16, 2021, and is expected to give a formal opinion.

“While we are disappointed with the trend vote, we strongly believe in the strength of our data and that aducanumab has the potential to make a positive and meaningful difference for people and families affected by Alzheimer’s disease,” said Priya Singhal, head of Global Safety & Regulatory Sciences and interim head of Research & Development at Biogen.

The drug, which was approved by the U.S. Food and Drug Administration (FDA) on June 7, 2021, has faced criticism and controversy while being slow to gain traction. Biogen reported the drug only brought in $300,000 in third-quarter sales, which is dramatically lower than original analyst average estimates of $10.79 million. There are questions about the drug’s efficacy, potential side effects, price, and the overall approval process. 

The Office of the Inspector General for Health and Human Services (HHS) is investigating the approval process at the request of the FDA’s acting director Janet Woodcock. Congress has questioned the price of $56,000 per patient per year, and Medicare is still conducting its review, with a final decision on reimbursement not expected until March 2022. It’s not that the price is that high, but instead, there are potentially three million patients for the drug in the U.S., most on Medicare. If the drug was broadly adopted at that price, it would likely bankrupt Medicare.

Still, Biogen continues to produce data in support of the drug. The recent Clinical Trials on Alzheimer’s Disease conference presented data from two Phase III trials that demonstrated Aduhelm reduced amyloid plaque and significantly lowered plasma p-tau181, a biomarker of tau tangles in Alzheimer’s disease. 

Alzheimer’s pathology is associated with the accumulation of two types of abnormal proteins in the brain, beta-amyloid and tau. Typically, beta-amyloid is seen earlier in the disease and tau is seen later. The original approval of the drug was primarily based on the drug’s ability to clear beta-amyloid. The clinical benefit seen in the earlier Phase III studies was not as clear, which was part of the controversy. 

When the FDA’s advisory committee met to discuss the drug in late 2020, they asked the FDA if the agency was considering an accelerated approval pathway, which would base approval on a biomarker instead of clinical benefit. The FDA said they did not. So the advisory committee largely voted against recommending the drug. 

The FDA went ahead and approved it but did so under an accelerated approval pathway based on biomarkers indicating clearance of beta-amyloid and required a post-marketing study to verify clinical effectiveness. But the post-marketing research did not have to report for nine years. Tau was not part of the approval.

In the most recent studies, Biogen reported that the change in plasma p-tau181 was significantly tied with changes in beta-amyloid and that the shift decreased the decline of cognition and memory on all primary and secondary outcomes measures in Alzheimer’s patients. In short, Biogen argued, the latest data offered additional evidence of the drug’s efficacy.

High doses of Aduhelm significantly lowered plasma p-tau181 in a dose- and time-dependent fashion compared to placebo, according to its studies. In the Phase III EMERGE study, p-tau was reduced 13% from baseline compared to an 8% increase in placebo patients. In the Phase III ENGAGE trial, there was a 16% reduction of p-tau and a 9% increase in the placebo cohort.

Alfred Sandrock Jr., head of Research and Development at Biogen, who announced his retirement today, said of the studies, “We now have robust and concordant data that Aduhelm has effect on two core defining pathologies of Alzheimer’s disease, and substantial evidence of treatment correlation between changes in plasma p-tau181 and the slowing of disease progression.”

Biogen shares dropped 4% at the news. It is unclear if the newly announced data was part of the submission package to the EMA or if the company will submit more data ahead of the December 13-16 meeting.

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