Briefly, here’s what led to its approval. Biogen’s drug clears amyloid from the brain, a buildup of plaques that are hypothesized to be part of how Alzheimer’s progresses and disrupts cognition. Yet many other agents that clear amyloid have ultimately been found ineffective in clinical trials, and for a while, it looked like aducanumab would have a similar fate. Then Biogen reported that the drug had worked in the high-dose arm of one of its late-stage trials. “Worked,” here, was stretching it: The average degree of improvement on a 0-18 point cognitive scale was just 0.39 points relative to placebo, far smaller than the 1 or 2 point threshold typically used to define a clinically important difference.
The FDA ultimately did not see enough evidence that aducanumab improved quality of life to approve it using standard criteria. But it greenlit the drug anyway, using the “accelerated approval” pathway based on improvements in “surrogate markers” of disease progression. And so an expensive, difficult treatment protocol was approved based only on its impact on test results — not meaningful patient outcomes.
This would all be one thing if prescribing aducanumab was only a matter of wasted money. But that won’t be the case here. We believe the drug’s approval will worsen care for Alzheimer’s patients and their families.
First, the drug may impose significant burdens on patients and caregivers. Adacunamab was only tested in people who have “mild cognitive impairment” — the very earliest stages of Alzheimer’s. But the FDA, surprisingly, approved its use for patients at any stage of the disease. While individuals with mild cognitive impairment usually retain the capacity to make complex decisions about their own care, those with more advanced disease lose this ability. Caregivers take over the work of making a patient’s choices and getting them through their days, in increasingly difficult circumstances. As dementia progresses, the risk-to-benefit calculation changes around even small things, like the effort required to safely take a shower.
And adacunamab will be an onerous treatment to deliver. To qualify for the drug, some insurers could require that patients first undergo a PET scan or even an invasive lumbar puncture (or “spinal tap”). Patients on adacunamab will subsequently require MRI scans at regular intervals to assess for complications, which requires patients to lie totally still in a confined space. In addition, they will require blood draws and monthly visits to an infusion suite where they’ll have an IV placed in their arm. Such scans, evaluations and procedures are often poorly tolerated by anxious individuals with dementia, and indeed may cause significant distress. Yet caregivers who want to do everything they can for a loved one may feel guilty about saying no to adacunamab, however slim the evidence for benefit.
Second, the drug will also impose heavy costs on patients and families. While much of the $56,000 a year will be covered by insurers, some patients with Medicare Part B — the expected insurer for the majority of those with Alzheimer’s — will pay a deductible and 20 percent of the price of the drug out-of-pocket. There will also be out-of-pocket costs for related care, including MRIs and other testing. We strongly believe that insurance should fully cover all uniquely effective therapies, even those that are very costly. But that is not the case in the U.S. health-care system today — and adacunamab may be totally ineffective.
This is particularly galling because Alzheimer’s is already an inordinately expensive disease — and one in which the best interventions we have, including skilled home care and support for familial caregivers, are inadequately covered and frequently out of reach. With universal long-term care coverage, we could fund seniors’ programs, home health aides, equipment to make apartments safer to navigate and more. None of these interventions can turn back the clock on a difficult diagnosis. But they do make it possible to live with the disease at home longer, and they address some of the things we know accelerate a person’s decline, including loneliness, institutionalization, depression and neglect. Our current system prefers to pay for feeding tubes than for the labor required to carefully hand-feed a patient with swallowing issues. The adacunamab approval exemplifies these misplaced values.
But perhaps our biggest concern about adacunamab is how its availability will reshape patient expectations and influence decision-making. Alzheimer’s disease is a devastating diagnosis. It takes years to progress to its final stages; along the way patients lose their ability to communicate, to swallow, even to smile. Advocates for adacunamab argue that families and patients are desperate, and that a new treatment, even if the benefits are slim or uncertain, offers hope.
Yet in the context of a terminal disease diagnosis, “hope” can mean a lot of things. It can mean hoping for the avoidance of suffering. It can mean hoping for a few good years in which to enjoy life, to make amends and to spend time with loved ones. And it can mean hoping for a miracle, a discovery of cure before it’s too late. As doctors we can share this hope, but we can also help families plan for the possibility that a miracle won’t arrive — and to see that there is still much that can be done to make life comfortable and meaningful, even joyful.
These conversations are made much harder when patients have been encouraged to seek medications that promise more than they deliver. Once a drug is approved, physicians may feel compelled to offer it, and desperate families will have difficulty saying no to a new therapy advertised as the first (and only) to slow Alzheimer’s progression. But the FDA’s (and Biogen’s) satisfaction with improvement in surrogate markers means patients and families will end up focusing on surrogate markers, too. And if they experience a disconnect between what the drug is said to accomplish and what they’re experiencing at home — a loved one who continues to deteriorate, even as amyloid levels presumably fall — it will be difficult to give up the “hope” that is attached to the drug, even when it doesn’t offer anything meaningful in the life of the patient. This is already a frequent challenge when treating patients with advanced cancers; another clinical trial or dubiously helpful therapy is always available, and as a result, patients often miss opportunities to prioritize what they most care about with the time they have left.
This adacunamab saga is a stunning example of how things have gone awry in the way our country tests, approves and prices drugs. It exemplifies a worrisome trend toward weaker standards for drug approval. It shows that we are more willing to fund expensive yet ineffective drugs but not lower-tech, more beneficial, long-term care services. And at the end of the day, the consequences of offering false hope — at great personal expense, with all the confusion, discomfort, risk and disappointment that implies — are going to fall most squarely on patients and their families. We join our patients in hoping for a miracle cure for this disease. Adacunamab, unfortunately, could be worse than no new drug at all.