Biogen’s Aduhelm: Slow to Launch with Controversy Continuing

Biogen_Courtesy of  Biogen

Biogens Aduhelm was approved on June 7, 2021, for Alzheimer’s patients, and the controversy continues to grow. Bickering still continues over the drug’s efficacy, the approval process, its cost, whether the company’s ties with the U.S. Food and Drug Administration (FDA) were inappropriate, and if and how Medicare and insurers will pay for it.

The primary criticism is that the drug hasn’t demonstrated clear clinical benefit. The agency also shifted its approval from a clinical benefit endpoint to a surrogate biomarker endpoint utilizing an accelerated approval process. This resulted in three of the adcom members resigning in protest.

The agency’s acting commissioner, Janet Woodcock, has requested the independent Office of the Inspector General to investigate how the FDA and Biogen representatives interacted before the approval. Also, the House Committee on Oversight and Reform announced plans to investigate the approval and pricing of Aduhelm. There are concerns that with the $56,000 price tag, and most of the millions of potential patients for the drug on Medicare, it could bankrupt the program.

At least six affiliates of Blue Cross and Blue Shield likely won’t cover the drug. The affiliates are in Florida, New York, Michigan, North Carolina, and Pennsylvania. They have indicated in postings online that they will not cover the drug because they consider it “investigational” or “experimental” or because “a clinical benefit has not been established.” The price of the drug is $56,000 per patient per year.

Medicare has indicated it is planning a nine-month process to determine standardized national procedures for Aduhelm coverage. At the moment, though, the Centers for Medicare & Medicaid Services (CMS) indicates it is processing claims on a case-by-case basis. According to Reuters, the first institutions to utilize Aduhelm since the approval report the claims haven’t been paid yet.

“Medicare does this very, very rarely for drugs and issues these coverage restrictions, again, very, rarely,” said Dr. Aaron Kesselheim of Brigham and Women’s Hospital during an online interview presented jointly by The Forum at the Harvard T.H. Chan School of Public Health and Reuters. Kesselheim was one of three members of an FDA advisory panel that resigned over the Aduhelm approval.

The Michigan Institute for Neurological Disorders (MIND) has indicated it has only treated one patient to date using Aduhelm. According to Sonda Rossman, MIND’s head of disease state initiatives, therapeutics, and clinical research, they are “being very cautious” about financial and medical risks.

The Mayo Clinic is still reviewing whether to use the drug on its own patients. And Mayo has partnered with Biogen on providing diagnostic tests for eligibility for the drug.

Florida’s First Choice Neurology and Butler Hospital’s Memory and Aging Program in Providence, Rhode Island, have reportedly each treated three patients with the drug.

Many experts suggest that Medicare will attempt to decrease the drug’s price by limiting access to it and linking coverage to real-world evidence of patient outcomes. Legally, Medicare can’t negotiate prices with Biogen. Another approach may be to set a fixed payment that combines drug reimbursement with other related costs.

“Given the potential budgetary impact, it could be that things are departing from normal,” Dan Ollendorf, of the Center for the Evaluation of Value and Risk in Health at Tufts University Medical Center in Boston, told Reuters.

There is also continuing investigations into Biogen and the FDA’s relationship prior to the approval, particularly revolving around the FDA’s neuroscience chief Billy Dunn. As Endpoints News reports, in 2017, Dunn co-chaired a data-sharing initiative at the C-Path Institute alongside Biogen senior vice president Samantha Budd Haeberlein. In 2018, Dunn and Budd Haeberlein gave a joint presentation on strengthening communication in the Alzheimer’s drug development community.

Neither is inappropriate or even particularly unusual. The FDA and drug companies interact often, and often informally at conferences. There have been a few examples, however, where this appears to have crossed the line into inappropriate communications. At particular issue is a meeting between Dunn and Biogen executives at a conference where they discussed the Aduhelm application. This is viewed by experts as being out of line with appropriate FDA-sponsor communications.

There are similarities between the Aduhelm controversy and another drug approval. Both, at least peripherally, involve Janet Woodcock, who is currently the interim commissioner of the FDA. In 2016, while then director of the FDA’s Center for Drug Evaluation and Research (CDER), she pushed through an approval for Sarepta Therapeutics’ Exondys 51 (eteplirsen) for Duchenne muscular dystrophy (DMD) after a highly controversial process, and against the recommendations of the agency’s acting chief scientist, Luciana Borio, and director of the office of drug evaluation, Ellis Unger. Like Aduhelm, it was approved under an accelerated approval process based on a surrogate endpoint, removal of amyloid plaque, rather than clinical efficacy.

Billy Dunn, the director of the FDA’s Office of Neuroscience, said at the November 2020 advisory committee meeting, “We’re not using the amyloid as a surrogate for efficacy.” As such, the advisory committee did not take that into account when they made their decision.

Then in June, the agency said they did take it into consideration. Dunn sent a letter to the chair of the panel, saying that after the panel hearing, the FDA had held “further discussions” that “raised further consideration of the accelerated approval pathway…. Our discussions leading up to the decision to grant an accelerated approval for aducanumab considered a wide range of views, both external and internal to FDA. We appreciate the comments from the advisory committee members and can assure you that we listened carefully and viewed the meeting proceedings as an important source of input as we discussed the appropriate action.”

DMD is caused by a shortage of dystrophin protein due to a gene mutation. The drug was able to generate slightly higher levels of the protein, which was a surrogate endpoint. The children involved in the trials also conducted a walk test, which can be subjective, and the data on the walk tests were not convincing to the scientists at the FDA.

The parallels also underline a disparity in pricing issues. A key difference between DMD and Alzheimer’s is that DMD is a rare disease while Alzheimer’s effects millions of people worldwide. Exondys 51 runs about $750,000 per year for one patient, depending on the weight of the patient. This is dramatically more expensive than the proposed price of aducanumab, at $56,000 per patient per year. However, DMD is a rare disease, while Alzheimer’s affects about 6 million people in the U.S. alone. In 2019, there were about 362 cases of DMD diagnosed in the U.S.

Despite this controversy, Woodcock has broad support within the agency, particularly after the Trump administration’s difficult relationship with the agency, when President Trump was pressuring it to approve COVID-19 vaccines before the November presidential election, and his push for approval of unproven treatments, such as malaria drug hydroxychloroquine. Some patient groups have also endorsed Woodcock, appreciating her sensitivity to people afflicted with diseases for which there are few effective treatments.

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