Aduhelm Adverse Event Reports Come In, Another Potential Hurdle To Uptake
Executive Summary
One patient treated with Aduhelm died who was diagnosed with cerebral edema thought to be ARIA-E, a known risk, Biogen confirmed.
Biogen, Inc.'s first-in-class beta-amyloid antibody therapy Aduhelm (aducanumab) for Alzheimer's disease has gotten off to a rocky commercial start and initial adverse event reports could add to physician caution about prescribing the medicine.
One death in a patient treated with Aduhelm was reported to the US Food and Drug Administration's Adverse Event Reporting System (FAERS), which is updated quarterly. The report does not mean that the treatment caused the adverse event, however.
Biogen confirmed the death was in a 75-year-old patient whose cause of death remains under investigation and who was diagnosed during hospitalization with cerebral edema thought to be ARIA-E. Amyloid Related Imaging Abnormalities, called ARIA, are a known risk associated with Aduhelm and are included in the warnings in the prescribing information for the drug. Brain MRIs are required before initiating treatment and prior to the 7th and 12th infusions of the drug to monitor for ARIA.
The risk of ARIA has already been a concern of some physicians who have been reluctant to prescribe the drug given that it was approved by the FDA with limited efficacy data. Management warned investors to expect a slow commercial rollout after it was approved in June, but Biogen has since admitted that reluctance from physicians has been even greater than was anticipated. (Also see "With Aduhelm Out Of The Gate, Biogen Focuses On Clearing Commercial Bottlenecks" - Scrip, 8 Jun, 2021.)Several major medical centers have announced decisions not to administer Aduhelm, including hospitals like the Cleveland Clinic and Mount Sinai Health System. (Also see "Biogen Fires Back At Critics In Defense Of Aduhelm" - Scrip, 22 Jul, 2021.)
Biogen reported only $300,000 in revenue from the sale of Aduhelm in the third quarter, lower than even the most bearish analyst estimates. (Also see "Biogen Fires Back At Critics In Defense Of Aduhelm" - Scrip, 22 Jul, 2021.) Adding to the commercial challenges for Aduhelm would be if serious safety issues were linked to the drug beyond what was seen in clinical trials. Very few patients have taken the drug so far as demonstrated by the limited commercial sale. Analysts estimate that around 200 patients were treated with the commercial product in the third quarter.
In the Phase III clinical studies of Aduhelm, 0.3% of patients treated with the FDA-approved dose reported serious symptoms associated with ARIA and none resulted in death. Reported deaths in the aducanumab clinical trials were consistent with those that are common in patients with Alzheimer's disease and with other serious medical conditions for the study age population, according to Biogen.
"No medicine is without risk, and we believe that the potential benefits of Aduhelm continue to outweigh potential risks," Biogen said in a statement.
Biogen said it is continuing to investigate the patient death and monitor other sources of safety information.
"We continue to work with the reporting physician as well as global regulators to further understand the case," Biogen said. "Alzheimer's disease is complex, and patients affected by this devastating disease often suffer from other serious medical conditions."
RBC Capital Markets analyst Brian Abrahams, in an 8 November note, cautioned against overinterpreting causality from the FAERS database. Nonetheless, he said, "this illustrates why physicians may be more conservative about initial prescribing even once there is greater access, until experience with benefit/risk accrue."
If the patient death were attributed to Aduhelm, it would most likely be the first ARIA-related death reported for the drug, as no such deaths were reported in the clinical trials, Abrahams said.
"This would potentially highlight that ARIA is a real adverse event that can lead to negative outcomes, something that may maintain physician cautiousness on [aducanumab] use at least initially and limit the medium-term market opportunity," he added.
Abrahams also pointed to seizures reported in the FAERS data, which has not been a known adverse event associated with Aduhelm. The FAERS database appears to include six patients with reported adverse events who likely received commercial product in the US but also includes experience from ongoing global long-term follow up studies.
"Despite no imbalances in the clinical trial, we see increasing reports of seizures with [aducanumab]," Abrahams said. "We note there are four new seizures reported, two ex-US and two in the US potentially on commercial product; all four events were deemed serious."
"While the clinical trial experience did not show an imbalance on seizure frequency across the arms and seizures can happen in AD patients, we believe it is worth monitoring for this possibly emerging signal in this more heterogeneous real-world population," he added.