Aduhelm: Great Expectations Fizzle

Before its approval on June 7, 2021, Aduhelm (aducanumab) was seen as possibly being one of the most important drugs launched in decades. It was heralded as the first new agent to treat Alzheimer’s disease in almost two decades. Moreover, data suggested it worked by reducing beta amyloid plaques in the brain, which many experts believe causes the disease.

At the time of its approval, some analysts projected that annual sales of Aduhelm could be between $8.2 billion and $10 billion. But now, a year after the FDA gave the drug an accelerated approval, those heady projections look like so many popped balloons. In 2021, Aduhelm generated just $3 million in sales, and in the first quarter of 2022, just $2.8 million. Biogen’s stock is trading at less than half the price it was in the days after the approval. The company is reducing its “commercial infrastructure” that supported Aduhelm and taking other cost-reduction measures, including inventory write-offs. One analyst told Bloomberg that the Cambridge, Massachusetts, company was “essentially throwing in the towel on Aduhelm.” In early May, Biogen announced that CEO Michel Vounatsos was stepping down.

Aduhelm’s apparent fizzle might have been foretold by all the controversy it kicked up. The late-stage development program for the drug consisted of two phase 3 clinical trials: one met the primary end point, showing a reduction in clinical measures of the effects of Alzheimer’s on cognition, but the other did not. The FDA approved the therapy even after an advisory committee voted against it, saying the data created uncertainties about the drug’s clinical benefit. Several committee members resigned in protest.

Biogen’s pricing strategy added fuel to the fire. The initial price tag for a year’s supply was $56,000. The Alzheimer’s Association, an important advocacy group to which Biogen has donated, called that price “simply unacceptable.” In December 2021, Biogen slashed the price in half. Still, the Institute for Clinical and Economic Review (ICER), an independent cost-effectiveness assessment organization in Boston, said Aduhelm would have to be priced far lower — between $3,000 and $8,000 — to meet typical cost-effectiveness thresholds.

Aduhelm got a cold reception payers. Almost immediately after its approval, several Blue plans and the Department of Veterans Affairs indicated they wouldn’t cover the drug because they considered it experimental and not medically necessary. Health systems such as Cleveland Clinic and Mount Sinai said they would not administer Aduhelm. In early April 2022, CMS issued its final coverage decision for Aduhelm, limiting Medicare coverage to prescriptions for people who are enrolled in clinical trials. UnitedHealthcare, which had been waiting for the CMS decision, said it would not cover the therapy either.

Supriya Munshaw

The CMS decision is likely to have a big impact, notes Supriya Munshaw, Ph.D., a senior lecturer at the Johns Hopkins Carey Business School. “A lot of private payers were waiting to see what CMS was going to say. This will affect other decisions to cover the drug as well.”

“Biogen was expecting a lot more adoption” Munshaw continues. “A $20,000 drug that is not going to be reimbursed will certainly affect how many patients will be able to use it, because not many patients can afford this out of pocket.”

Biomarker controversy

Munshaw says Aduhelm’s woes can be traced to data from the two pivotal studies showing only a marginal effect on a biomarker, which not everyone agrees is a good indicator of the drug having a positive effect on the cognitive difficulties caused by Alzheimer’s.

“Biogen ran two trials for this drug, and only one of them showed marginal differences in the populations between the control and the treatment arm based on a particular marker and not necessarily the disease outcome,” she said. “There is some controversy surrounding the use of that marker to predict Alzheimer’s disease. If the experts in the biology are not even consistent on whether or not this marker is important in Alzheimer’s, the fact that (the drug) got approved based on this marginal improvement of this marker is pretty controversial.” That marker is the accumulation of beta amyloid protein in the brain. Some evidence points to beta amyloid deposits, often called plaques, as having a causative role. Animal studies have shown this connection, but the results from human studies are mixed results.

Aduhelm had excited researchers when early data showed that not only could it block the production of beta amyloid plaques but it also could clear some existing ones. Biogen’s two studies were designed to assess the impact of Aduhelm on cognitive function using the Clinical Dementia Rating Scale Sum of Boxes score, an integrated scale that assesses function and cognition. Other outcomes that assessed behavior and biomarker end points were also used. But both studies were stopped when they were at their halfway point of enrollment. A pooled analysis showed only one study had met its end point.

Biogen has recently begun enrolling patients for a phase 4 confirmatory trial of Aduhelm. Researchers eventually will enroll 1,500 patients with early Alzheimer’s disease in the study, with a primary clinical end point at 18 months after treatment initiation. Biogen expects the study to be completed in about four years. It will use the same end point scale as the previous studies and will also include a trial extension to collect longer-term treatment data for up to 48 months. Biogen also indicated that about 18% of participants enrolled will be Black/African American and Latino.

ICER scrutiny

Aduhlem’s downward arc may make the findings somewhat anticlimactic, but ICER is planning to do a cost-effectiveness evaluation of Aduhelm compared with two as yet unapproved Alzheimer’s therapies, Eli Lilly’s donanemab and Eisai’s lecanemab. Originally, ICER planned to discuss the findings of its report during a meeting scheduled for July 2022, but it has been moved to the first quarter of 2023.

Eisai, a Japanese company and a partner of Biogen, completed a rolling submission in May 2022 for an accelerated approval of lecanemab, a monoclonal antibody that targets beta amyloid, to treat patients with early Alzheimer’s disease. Eisai has requested a priority review. The company’s application is based on data from a phase 2b trial in patients with confirmed presence of beta amyloid plaques in the brain, an open-label extension study, and a confirmatory phase 3 trial.

Results from a simulation model conducted by Eisai, published in April 2022 in Neurology and Therapy, found that lecanemab can potentially slow the rate of disease progression, maintaining treated patients for a longer duration in earlier stages of Alzheimer’s disease. In this projection, the mean time to advancing to mild, moderate and severe Alzheimer’s dementia was longer for patients in the lecanemab group than for patients in the standard of care group by two and half years.

Eisai is continuing with a confirmatory phase 3 study of lecanemab with results expected in the fall of this year. The FDA has agreed that this trial could be used to verify clinical benefit.

Eli Lilly announced separately in fall 2021 that it had begun a rolling submission to the FDA for donanemab, which also acts on beta amyloid, for accelerated approval. The company intends to complete its submission in the second quarter of 2022, which could result in an FDA decision in early 2023. Lilly also plans to conduct a phase 3, head-to-head clinical trial comparing donanemab with Aduhelm. This open-label study will enroll 200 patients and will assess plaque clearance of the two therapies based on positron emission tomography scans