Pharmaceuticals are tightly regulated in the USA, and we expect regulators like the FDA to maintain consistent standards for approving a drug. In exchange for the costs and risks of toxicity or side effects, we should anticipate that if a drug has been approved, that is actually effective. It could be reducing the likelihood of death, eliminating an infection, or improving quality of life in some way. But the expected benefits should be understood, and they should be meaningful.
Regulators sometimes approve drugs based on “surrogate” measures. The surrogate doesn’t mean anything in and of itself, but it believed to be proxy for something that is meaningful. Ideally there is a well-established or proven relationship between the surrogate and an outcome we care about. A number of factors go into an assessment. It may be reasonable to approve a drug based on a weak surrogate, if the condition it treats has no other good alternatives, and the preliminary evidence is promising.
When the FDA approved adacanumab for the treatment of Alzheimer’s disease in 2021, it did based on on an unconvincing surrogate, creating a major controversy within and outside the agency. Private insurers largely refused to cover it. America’s biggest insurer, Centers for Medicare & Medicaid Services (CMS), said it would only fund the drug when part of a clinical trial. There was little use of the drug. About two weeks ago, the manufacturer announced that is discontinuing the drug. With this discontinuation, the confirmatory trial that was mandated by the FDA (to see if the drug actually works) is also abandoned. The only positive out of this whole debacle is it ends further funding and research into a drug that lacked any strong signals that it worked.
The Therapeutic Challenge of Alzheimer’s Disease
Alzheimer’s disease (AD) is a neurological disease that is the most common cause of dementia. AD tends to be a disease of the elderly that commonly presents initially as memory impairment (particularly of recent events) and progresses to include greater deficits including inability to problem solve, and impaired judgement. Overtime, AD can include psychiatric and other behavioral symptoms. Progressive disease is inevitable, but the rate of decline can range from a few years to decades. AD is common, and affects an estimated 6 million Americans, with that prevalence expected to increase as the population ages.
How AD develops is not known, but it produces changes in the brain that are destructive, progressive, and irreversible. A common feature of AD is the accumulation of protein called “beta amyloid” in the form of plaques that are thought to interfere with signalling and eventually cause cell death. Another feature is called “tau tangles,” where tau protein fibers twist and collapse, which are also thought to cause cell death.
Despite decades of research there has been little progress in developing medications or therapies that can improve symptoms or slow the progression of the disease. A class of drugs called cholinesterase inhibitors provide modest benefit for some of the symptoms of the disease, but do not affect its progressive nature. Memantine, another drug, works differently from the cholinesterase inhibitors and may provide some benefit in moderate AD. In the past few years, new drugs from Eli Lilly (donanemab) are moving closer to approval and Eisai’s drug Leqembi (lecanemab) was approved in 2023.
Unimpressive Evidence
I will refer the curious reader to my 2021 post on the Aduhelm approval for more details, but will include the highlights here. For over twenty years, researchers have pursued treatments against beta amyloid after trials in mice showed promising results. Biogen has been studying aducanumab, an antibody which targets beta amyloid, for years. Two large Phase 3 clinical trials called ENGAGE and EMERGE were established to evaluate the efficacy of the drug in patients with mild AD. These were 18 month trials that measured the effect of aducanumab in early AD. Patients were randomized 1:1:1 to low-dose aducanumab, high-dose aducanumab, or placebo, and the drug was given as an intravenous infusion every 4 weeks. The primary endpoint measured was the Clinical Dementia Rating Scale Sum of Boxes test (CDR-SB), which can assess the severity of Alzheimer’s dementia. In March 2019 both ENGAGE and EMERGE were discontinued after an independent data safety monitoring board concluded that the trials were unlikely to meet their primary endpoint. That is, in the language of clinical trials, they were discontinued “for futility”. However, in analyses done after the trials were stopped (i.e., a “post-hoc” analysis), the manufacturer claimed that the drug was actually effective, and it intended to pursue regulatory approval. (Post-trial or “post-hoc” analysis like this can be important to generate hypotheses, but are the statistical equivalent of shooting at a wall and painting the bullseye around what you hit.) In short, the manufacturer claimed that after the futility analysis, additional data was made available that provided sufficient evidence of efficacy to merit moving forward with seeking approval.
It’s worth noting that despite the lack of efficacy, the drug had harms. It can cause swelling of the brain called amyloid-related imaging abnormalities (ARIA), common to this category of drugs, which can cause symptoms like headache.
Aducanumab was reviewed in November 2020 at an FDA advisory committee meeting. Among those documents included endorsements from FDA staff members supporting the manufacturer’s contention that the drug is effective. The report also contained comments from other FDA staff members criticizing these efficacy statements, and the manufacturer’s reliance on post-hoc analyses, which were (justifiably) described as biased. Ultimately the panel votes on the evidence were strongly negative. Despite the negative recommendation, the FDA granted accelerated approval for aducanumab, now branded Aduhelm, while requiring Biogen to do a confirmatory clinical trial over the next nine years. Really incredibly, it did not even limit approval to patients similar to those in the clinical trial, who had mild disease and confirmed amyloid plaques. Instead, it put no restrictions on its use. There was zero evidence that aducanumab was effective in patients with advanced Alzheimer’s disease, but the drug cleared the drug for these patients, too.
Little Uptake, and a Quick Exit
In June 2021 the House Committee on Oversight and Reform announced it would investigate Aduhelm’s FDA approval and its pricing. They pointed to the broad approval labeling and the decision to approve based on a surrogate endpoint in an array of criticisms it levied at the regulator.
Uptake of Aduhelm, given the controversy and persistent questions about efficacy was slow after approval. Clincians were skeptical. More importantly, many private insurers simply refused to cover the drug. As I noted above, the Centers Medicare & Medicaid Services announced it would only fund the drug when patients take part in a clinical trial.The European Medicines Agency rejected the drug outright. In December 2021, the manufacturer lowered the annual cost of the drug from $56,000 to $28,200. It had no effect. While Biogen did launch the clinical trial that the FDA mandated as part of its approval, sales were dismal. In February 2022, Biogen’s financial statements revealed only $3 million in revenue for all of 2021.
In January 2024 Biogen announced it was discontinuing Aduhelm. Only 2,500 people are currently taking the drug worldwide, and they can continue to receive the drug until November. This was expected (by Biogen at least) to be a multi-billion dollar drug, considering the list price and how prevalent Alzheimer’s disease is. Biogen says they’re turning their focus to Leqembi, which it has partnered with Eisai to market. They have relinquished the marketing rights back to Neurimmune, the company that discovered the drug, and terminated the clinical trial the FDA had mandated.
So where does this leave patients with AD and their families? Given there was no evidence aducanumab actually worked, the approval was premature and may ultimately have doomed the drug. How this drug’s approval influenced the FDA’s perspective on the newer Alzheimer’s drugs is not clear, but the data for those looks more promising. Whether those benefits are meaningful is perhaps an open question, and one which will be debated and hopefully studied carefully.