A new Alzheimer’s medication has been approved by the US Food and Drug Administration. But such a major milestone, given the present paucity of effective treatments, has been complicated by fresh revelations about the FDA’s prior controversial approval of an Alzheimer’s drug — and lingering concerns among some experts that the hype could once again get out ahead of the science.
The federal agency decided Friday to grant accelerated approval to lecanemab, an intravenous injection developed by the Japanese biopharma company Eisai and the American manufacturer Biogen. Accelerated approval can be granted to new drugs with promising preliminary clinical trial results that meet an unmet medical need.
There is reason for optimism, with the signs that patients who received the drug in clinical trials experienced less cognitive decline than those who did not. An effective drug would be a godsend for the more than 6 million people with Alzheimer’s and their families, a breakthrough after many decades of false starts and disappointments in finding a real treatment to slow the disease’s uniquely devastating deterioration of a person’s sense of self.
But lecanemab’s quest for approval has been shadowed by the previous approval of another Alzheimer’s drug to get accelerated approval: aducanemab, sold as Aduhelm. During aducanemab’s development, clinical trials were halted at one point because analysts had concluded any further investigation was futile: The drug did not work. Nevertheless, in 2021, the FDA approved the drug over the objections of its own scientific advisers and to the bafflement of doctors and patients alike.
A recent House report on the drug’s approval, released in late December, revealed the extent of the FDA and Biogen’s cooperation in pushing the drug to market. Two months after the clinical trials were halted in 2019, a Biogen executive and a senior FDA official met at a pharma conference and decided Biogen would push ahead with seeking approval. What followed was highly unusual coordination between a private company and its regulators, who met dozens of times to review Biogen’s data and even cooperated on briefing documents for the FDA scientific advisers who would give a final recommendation on approval.
Usually, in those documents, the opinions of the applying company and the FDA regulators are kept separate. But this time, any distinction was muddled, according to the House report, with the FDA even asking Biogen to insert FDA-drafted language into the company’s section of the report.
“The findings in this report raise serious concerns about FDA’s lapses in protocol and Biogen’s disregard of efficacy and access in the approval process for Aduhelm,” the House committee wrote. “The criticism surrounding Aduhelm’s approval may have been avoided had FDA adhered to its own guidance and internal practices.”
After the FDA’s scientific advisers pointed to the lack of clear evidence that aducanemab slowed the development of dementia, as well as signs of serious side effects, Biogen and its FDA partners switched gears and sought accelerated approval instead — which has a lower threshold for approval. Biogen just needed to show that the drug did reduce the amount of amyloid plaque in a patient’s brain, not that the reduction then in fact stalled the decline in cognition. Company and FDA staff worked together to produce a statistical analysis that demonstrated the desired result, despite federal officials saying previously that they would not use such a secondary metric to authorize an Alzheimer drug’s approval.
Accelerated approval was granted for aducanemab — for which Biogen initially planned to charge $56,000 — in July 2021. But the drug’s momentum post-approval quickly slowed. Major health care institutions said they would not administer the drug, given the lack of empirical support for its effectiveness. Eventually, Medicare, which had been expected to be the largest purchaser of the drug, said it would generally not cover aducanemab except in a clinical trial setting. That has led to minimal patient uptake over the last 18 months.
The approval of this breakthrough treatment purported to meaningfully improve the prognosis for Alzheimer’s patients instead became a major embarrassment for the pharmaceutical company that had developed it and the federal regulators who approved it.
But there were more treatments in the pipeline, and the next one to come before the FDA was lecanemab.
The leading theory of Alzheimer’s disease has been, in brief, that the accumulation of amyloid plaques in the brain disrupts normal brain functions and leads to its telltale dementia. But some experts have challenged that hypothesis and accused drug companies and academia of overlooking other avenues for trying to treat the disease. Lecanemab, the newly approved drug, and aducanemab are both premised on the so-called amyloid hypothesis and target those plaques in the hope of alleviating dementia symptoms.
The evidence for lecanemab’s effectiveness is stronger than aducanemab’s. The results of its clinical trials published this week in the New England Journal of Medicine show that the patients who were given the drug over 18 months saw less cognitive decline using a broad measure of dementia compared to patients given a placebo.
That has made Eisai, Biogen, and the Alzheimer’s advocacy community optimistic that the FDA will ultimately sign off on its accelerated approval.
“We believe, based on the totality of positive data from clinical trials of this treatment, that the FDA should approve. Peer-reviewed, published results show lecanemab will provide patients in the earliest stages of Alzheimer’s more time to participate in daily life and live independently. It could mean many months more of recognizing their spouse, children and grandchildren,” Maria Carrillo, the Alzheimer’s Association’s chief science officer, said in a statement to CNN.
Some experts have urged caution given the relatively small size of the measured effect, however, with the editors of the Lancet writing in December that “whether lecanemab is the game changer that some have suggested remains to be seen.”
Like aducanemab, this new drug is probably best targeted to people in the early stages of the disease. And like aducanemab, there have been reports of serious side effects, including a number of deaths, as Science reported last month, though the exact interaction in those fatalities remains unclear.
I asked doctors and social workers who work with Alzheimer’s patients about their perception of the new drug’s approval, so soon after the disastrous aducanemab saga. Alison Lynn, director of social work at the Penn Memory Center, told me that she’d heard from excited caregivers and patients.
But the clinical staff has concerns. “Our docs seem very optimistic about the more promising data on lecanemab, but cautiously so,” she said. “Some of the concerns from the debacle with Aduhelm remain the same, even with better data.”
Concerns about equitable access are paramount. Will Medicare cover this drug, unlike aducanemab? If not, access could be limited to the very wealthy, given an estimated price between $9,200 and $35,600 for an annual course of treatment. Ideally, patients would receive a brain scan for amyloid plaque before receiving lecanemab, but that procedure is typically not covered by Medicare and can cost upward of $20,000 out of pocket. Patients will still need to go to a hospital to receive the injection every two weeks, which presents another barrier to access for people who struggle with dementia.
“What will we do when someone with more advanced dementia comes in and asks for this drug even though the data really only supports early-stage use?” Lynn said. “Basically, there are concerns about the logistics and ethics of access.”
The approval of a new Alzheimer’s treatment should be cause for celebration. And there is good reason to believe that lecanemab will prove to be more successful than aducanemab.
But recent events also give good reason to be cautious. That is the unfortunate legacy of aducanemab for future Alzheimer’s drugs: It is a shadow from which they must escape.
Update, January 6, 2:25 pm ET: This story has been updated with the news of lecanemab’s approval.