New safety data published last week in JAMA Neurology showed that 41% of Aduhelm patients experienced either bleeding or swelling in the brain. And while these symptoms have been known side effects, the recent death of an Aduhelm patient is adding to the drug's continued controversy.

3 questions providers must ask themselves about Aduhelm’s approval

Background

Biogen originally sought FDA approval for Aduhelm in 2019, after a company analysis of clinical trial data found a high dose of the medication provided a small benefit in slowing cognitive decline, and that the drug was effective at removing the beta-amyloid proteins associated with Alzheimer's disease.

However, Biogen's analysis also revealed significant side effects. Around 40% of participants receiving the higher dosage of Aduhelm developed brain swelling or bleeding, and around 6% of high-dose participants stopped taking the drug due to side effects. Further, one person died in an earlier safety trial after an adverse reaction.

In 2020, a panel of independent experts convened by FDA reviewed the clinical trial data, determined there was not enough evidence to suggest the treatment had significant benefit for patients, and recommended against approval. However, some patient groups advocated strongly for approval, particularly because Alzheimer's patients have few other medical options to slow their cognitive decline.

Ultimately, FDA on June 7 announced its decision to approve Aduhelm on a conditional basis—saying Biogen must conduct a large clinical trial in order to confirm that removing beta-amyloid proteins actually leads to cognitive benefits for patients.

Since Aduhelm's approval, concerns over the drug's safety have grown with mounting reports of serious side effects, FDA and CMS have both initiated processes that could limit access to the drug, and it is currently being investigated by HHS' Office of Inspector General.

According to the Times, because brain swelling and bleeding have been known possible side effects of the drug, FDA on Aduhelm's label issued a warning about these brain side effects, known as amyloid related imaging abnormalities (ARIA)—cases can range from asymptomatic to very serious. However, according to the American Academy of Neurology, "[T]he FDA label calls for less frequent monitoring than was performed in clinical trials" of the drug, and that "additional MRIs will often be needed in response to changes in patients' clinical condition."

Currently, FDA advises physicians to monitor Aduhelm patients and obtain two MRI brain scans throughout a patient's first year of treatment. However, the label does not suggest that people with ARIA need to be taken off Aduhelm.

A disputed patient death

Concern has grown recently following the death of a 75-year-old woman who had been participating in an Aduhelm clinical trial. The woman died in September after she was diagnosed with brain swelling, and her death was reported by a doctor to FDA's adverse event reporting system.

Though Biogen said the cause of death is unknown, it said in a statement, "We know the 75-year-old clinical trial patient was admitted to the hospital with a seizure," and was subsequently diagnosed with brain swelling.

"Following a prolonged hospitalization, the patient was being prepared for discharge when she deteriorated and was transferred to another facility," the company continued. "We have requested missing information, including brain imaging, from the critical last nine days of hospitalization."

In light of this news, Brian Abrahams, a biotech analyst with RBC Capital Markets who has a medical degree, accessed the woman's case report through a public records report, and told his clients that the brain swelling was the most probable cause of the woman's death.

However, Biogen argued the RBC report only provided a partial view of the case, and said, "We take this event very seriously and continue to work with the reporting investigator."

Biogen is also investigating three other cases reported to FDA's adverse event database between July and September.

Newly analyzed patient outcomes

Most available safety data about Aduhelm comes from two Phase 3 clinical trials conducted before Biogen applied for FDA approval. And although both trials were prematurely shut down because a monitoring committee found little drug benefit, a study published last week in JAMA Neurology, which included eight authors from Biogen, analyzed safety data from these trials.

In the study, 425 out of 1,029 patients—or 41% of patients—who received the FDA-approved high dose of the drug reported either brain swelling or bleeding. In addition, 64 patients stopped participating in the trials due to swelling or bleeding.

Notably, 362 of the affected patients experienced swelling—with 94 symptomatic participants—although the study noted that most cases of swelling resolved within 16 weeks. According to Biogen, swelling typically emerged during the early stages of treatment, either when patients were first introduced to the high dose or during increases in dosage.

In addition to brain swelling, 103 participants taking the high dose of the drug reported symptoms including headaches, confusion, dizziness, or nausea. According the New York Times, some of the less frequent symptoms included fatigue, visual impairment, blurred vision, and gait disturbance. Among patients who had microbleeds, the study found that roughly 12% showed severe effects.

Patients who experienced moderate to severe swelling were taken off Aduhelm until their symptoms resolved. However, patients who were asymptomatic and only experienced mild swelling could stay on the drug—and, according to the study, their swelling did not worsen.

The study states that brain swelling or bleeding did not result in any deaths in either of the trials. According to Biogen, the 75-year-old woman who died in September had been participating in an extension trial of the drug. (Belluck, New York Times, 11/22; George, MedPage Today, 11/22)