leisure time

Last week, Biogen announced it will cease both the study and sale of Aduhelm, its FDA-approved monoclonal antibody for the treatment of Alzheimer’s disease. Its decision, the company explained, is not a response to new data about the drug’s safety or efficacy, but instead “a reprioritization of resources.” Simply put, it wasn’t about science or medicine. It was about money.

In the eight years between the drug’s spectacular 2016 debut on the cover of Nature and its ignominious end, Biogen made multiple, really bad decisions. I don’t condone the company’s behavior, but I do understand it. In America, corporations develop drugs, and corporations are made up of ambitious, competitive people. Their measure of success is a simple language: profit.

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What I cannot understand is the Food and Drug Administration. It twisted the practice of regulatory science so as to allow Biogen to walk itself into a mess. Two of the agency’s decisions in particular cause me to worry another Aduhelm-like decision could happen again, and, when it does, this mess will be huge.

The first is the FDA’s use of evidence of amyloid lowering with no evidence of clinical benefit as sufficient to approve aducanumab. This surrogate endpoint standard remains controversial. A surrogate ought to be supported by broad and unequivocal consensus, such as how internists accept that a measure of blood pressure stands for cardiovascular disease. Amyloid lowering as measured by PET has not yet met that mark.

Further reading

Aduhelm: A look back

• Inside "Project Onyx," Biogen's use of an FDA back channel to win approval for Aduhelm.
• A look at a key FDA player in the Aduhelm approval process, Billy Dunn.
• Early Aduhelm sales were well below expectations, leading stock analysts to question the strategy of charging a premium price for a treatment with unproven benefits.
• A STAT series, The Aduhelm Files, based on a congressional investigation into the drug. Among the findings: FDA approval was "rife with irregularities."

And yet, the FDA seems oblivious. It continues to use this weak surrogate to review anti-amyloid drugs, first Eisai’s lecanemab (approval) and then Lilly’s donanemab (no accelerated approval). Unlike with Aduhelm, my colleagues and I shrugged off these decisions. We’d seen the results of the positive Phase 3 studies. We tolerated how Eisai now had permission to christen its drug — called Leqembi — and so could market and talk it up. That’s strictly business. Our attitude was “wait for the FDA to review those Phase 3 data. If full approval follows, then we’ll prescribe.”

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The second FDA decision was the initial label for Aduhelm, which reads: “Aduhelm is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease.” Like many of my colleagues, I thought these 14 words were a stunner. The drug had been studied in persons with mild cognitive impairment or mild-stage dementia. Yet this label was an invitation for wide-open prescribing to a person at any stage of the disease.

Within a month, Biogen and the FDA would revise the label to read: “Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.” The initial label wasn’t an editing error. Instead, it was a premature rollout of a redefinition of Alzheimer’s disease.

Related: The lessons of Aduhelm, Biogen’s Alzheimer’s drug that was not to be

Some background is in order.

For much of the 20th century, Alzheimer’s disease has been defined by clinical features. The disease label follows from a clinician’s interview and examination of a person for the diagnostic signs and symptoms, such as memory loss and problems performing day-to-day activities. The breathtaking discoveries of biomarkers of Alzheimer’s disease — in particular, measures of beta-amyloid and hyperphosphorylated tau protein — has initiated a sensible, science-driven process to redefine the disease using biomarkers and only biomarkers.

Once validated, these new diagnostic criteria will have enormous public health implications. They’ll guide the diagnosis of disease beforea person has cognitive impairment, so-called preclinical Alzheimer’s disease. Validating this stage is a critical scientific step to achieve goal No. 1 of our country’s Alzheimer’s plan, “Prevent and Effectively Treat Alzheimer’s Disease and Related Dementias by 2025.”

I’m one among many clinicians who look forward to diagnosing and treating a patient long before she has disabling cognitive impairments, but science, not corporate zeal to maximize profits, will lead me to that golden day. Hence the outcry over that first Aduhelm label.

My colleagues and I are patiently waiting for the completion of trials testing lecanemab and donanemab in people who have elevated amyloid and are cognitively unimpaired (AHEAD and Trailblazer-3, respectively).

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But I worry the FDA will lead Eisai to commit “Aduhelm Redux.”

Over the winter holidays, Nikkei Asia reported Eisai may seek FDA approval for the use of lecanemab in people who are cognitively unimpaired. The critical bit in this announcement is a date. Eisai may apply for FDA approval in April 2026. This is nearly one and a half years beforeOctober 2027, the estimated date for completion of the AHEAD study.

Suppose this interim look at the data shows lecanemab reduces amyloid. This is quite possible. With treatment, amyloid lowering precedes changes observed in cognitive data. Couple this with the FDA’s willingness to approve using amyloid lowering alone and its willingness to write that wide-open label for Aduhelm.

Related: Listen: Is the medical system ready for Alzheimer’s drugs that work?

Suddenly millions of cognitively unimpaired Americans worried about their risk of developing mild cognitive impairment or dementia will see ads urging them to “talk to your doctor about Leqembi.” Their doctors will have thin — really no — evidence to write a prescription. Insurers such as Medicare and private plans (many of these people are under 65) will undoubtedly refuse to pay. Enter the patient advocates, the amyloid skeptics, the amyloid proponents, the anti-pharma crowd, the advocates for innovation. Behold the mess.

The collateral damage to science will be enormous. As many of the people in the AHEAD trial drop out, the trial will grind to a sad, premature ending. Without this trial, science won’t be able to validate a redefinition of Alzheimer’s disease, and doctors and patients won’t have evidence to know beyond a reasonable doubt whether a drug given to cognitively unimpaired persons with elevated amyloid is safe and effective.

Eisai, like Biogen, is a company driven by a zeal for profits. (Remember Aduhelm’s initial price: $56,000 a year!) People are desperate to avoid dementia. Assembled together, these all-too-human sentiments could collectively precipitate a mess.

The FDA must step in and serve the public interest. For a start, it should drop using amyloid lowering as a surrogate worthy of drug approval. It must demand rock-solid clinical data.

Jason Karlawish is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine and co-director of the Penn Memory Center. In the past three years, he has been a site co-investigator on clinical trials sponsored by Biogen, Eisai, and Lilly.

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