The company is investigating the death of a 75-year-old woman who died of ARIA while receiving Aduhelm.
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Brain swelling is one of the possible severe side effects of Biogen’s controversial Alzheimer’s drug Aduhelm (aducanumab). Specifically, ARIA, or amyloid-related imaging abnormalities, were seen in clinical trials of the drug. Now the company is investigating the death of a 75-year-old woman who died of ARIA while receiving Aduhelm. The company indicates it does not yet know if her death was related to the therapeutic.
“We continue to work with the reporting physician as well as global regulators to further understand the case,” Biogen told Reuters.
The U.S. Food and Drug Administration (FDA) warned physicians in the drug’s label to monitor ARIA-E, but not necessarily take the individuals off the drug. In the clinical trials of the recommended dose, only 0.3% of patients reported severe symptoms associated with ARIA, and there were no deaths as a result. The label recommends explicitly physicians track ARIA events with MRI before starting the treatment and after the seventh and twelfth infusions.
An August analysis of Aduhelm and ARIA by Clinical Trials Arena noted that ARIA is a “known class side effect of antibodies like Aduhelm that target amyloid plaque in the brain.” ARIA-E is the most common form of ARIA, which includes cerebral edema. It is associated with headache, confusion, nausea, and gait disturbances.
Clinical Trials Arena’s analysis suggests that some of the public data on Aduhelm and ARIA were “seemingly incomplete,” which led to some experts being wary of the drug’s long-term safety.
In the EMERGE and ENGAGE Phase III trials that were part of the approval submission for the drug, 35% of patients on the approved dose showed signs of ARIA-E. However, Biogen indicated that 98% of ARIA-E cases resolved on MRI during the studies and a full 76% were asymptomatic.
Christopher Van Dyck, M.D., director of the Yale University Alzheimer’s Disease Research Center, told Clinical Trials Arena that there was currently no evidence that resolved ARIA has long-term harmful effects, it warranted further analysis on individual patients. Van Dyck has personally treated 300 patients with anti-amyloid drugs as a clinical trial investigator and has observed more than 50 cases of ARIA.
There also appears to be a correlation between ARIA and a common gene associated with Alzheimer’s risk, APoE4. The Biogen studies found that patients receiving Aduhelm at the approved dose and who were carriers of the APoE4 gene variant had an incidence of 42% of ARIA compared to only 20% in noncarriers.
The patient’s death was reported to the FDA’s Adverse Event Reporting System (FAERS). The 75-year-old woman lived in Canada. In addition to her death, FAERS has recorded three other new ARIA cases from July to September, all requiring hospitalization, all outside the U.S. According to a note to investors by Brian Abrahams, an analyst with RBC Capital Markets, the ARIA cases in the FAERS system probably originated from a Phase IIIb open-label EMBARK safety trial of the drug. Abrahams also pointed out that it was too early to say if Aduhelm was the cause of death..
Abraham did write, however, that if a link is determined, “This would potentially highlight that ARIA is a real adverse event that can lead to negative outcomes, something that may maintain physician cautiousness on adu use at least initially and limit the medium-term” market opportunity.
The drug is falling well short of sales projections. Biogen reported only $300,000 in third-quarter sales of the drug compared to original analyst average estimates of $10.79 million. It’s not surprising, given report after report of the company’s inability to gain traction among payers and physicians for the drug.
The drug was approved by the U.S. Food and Drug Administration (FDA) on June 7, the first new Alzheimer’s drug approved in 20 years. It was approved by the agency against the recommendation of its own Peripheral and Central Nervous System Drugs Advisory Committee, who voted against recommending it in November 2020. Three members of the panel have since resigned in protest.
The FDA also leveraged an Accelerated Approval pathway, which requires follow-up studies for continued approval. The approval was ultimately based on a surrogate endpoint, clearance of beta-amyloid, instead of relief of symptoms. The advisory committee had asked if the agency planned on using surrogate endpoints and was told the agency did not expect to do so.
In addition, the drug has a price tag of approximately $56,000 per patient per year. Although nowhere near being the most expensive drug on the market, the number of Alzheimer’s patients in the U.S. exceeds 3 million. Although Biogen and the FDA have since modified the drug’s label to early-stage disease, that’s a very high expense for a large population of patients, most of which would be on Medicare. Many insurers have declined to reimburse for the drug until the Centers for Medicare and Medicaid Services (CMS) makes a final recommendation, which isn’t expected until at least January 2022, and probably not a final decision until March.
