If the FDA approves Biogen’s Alzheimer’s treatment, I won’t prescribe it

 Most visits to the memory center where I care for individuals living with Alzheimer’s disease end in disappointment.

“Are there any new treatments, Dr. Karlawish?” patients or family members hopefully ask.

I shake my head and say, “No.”

I’ve been saying that for the past 18 years.

The few drug treatments I do prescribe are only modestly effective in easing the disease’s cognitive problems. None of them slow its relentless chipping away at individuals’ ability to control their lives or their caregivers’ steady accumulation of commitments of time and task.

So you might think that I’m among those hoping the FDA will approve aducanumab, an experimental Alzheimer’s drug developed by Biogen, a decision the agency is supposed to make by June 7.

But I’m not. And if it gets the green light, I can’t see myself recommending it to my patients. Colleagues of mine in the Alzheimer’s sphere are also reluctant about approving aducanumab. Why? Biogen hasn’t made a convincing case for it.

The consequences of FDA approval are as disturbing as they are vast. Around 2 million Americans could be prescribed aducanumab, at an estimated cost that ranges from $20,000 to $50,000 per person per year. Biogen claims the benefits of slowing declines in cognition and day-to-day function are worth this price. I think the company is wrong, and I agree with the analyses by the Institute for Clinical and Economic Review; the data to make this case are murky and, even if they were clear, the drug’s benefits are ambiguous at best and not worth this cost. Putting it on the market will stress Medicare’s resources.

These marginal benefits mean that if aducanumab is approved, patients and families will struggle over whether it’s right for them. One of its risks is small bleeds in the brain, a risk that is heightened in those with the APOE4 gene, a gene associated with late-onset Alzheimer’s disease. Families will be drawn into these risk-benefit discussions, because treating a parent’s Alzheimer’s with aducanumab may well mean their children will learn their genetic risk of developing the disease. I have little doubt that these at-risk individuals will push the margins of when to begin prescribing aducanumab.

Aducanumab is not the drug to launch a new era of Alzheimer’s treatment. It hasn’t been properly studied, and so the FDA has incomplete data to form a judgment. The cause of this is a series of decisions that were good for business but bad for science and patient care.

Aducanumab started with a bang. On September 1, 2016, the cover of Nature, the prestigious “international journal of science,” ran an all-caps headline: “TARGETING AMYLOID.” Inside were the results of a study that showed aducanumab cleared amyloid, a protein thought to cause the destruction of brain cells in people with Alzheimer’s disease. Even more exciting, the study suggested — but did not prove — that reducing amyloid might slow declines in memory and other cognitive abilities. An accompanying editorial proclaimed that confirming this result would be a “game changer in the fight against Alzheimer’s disease.”

Following these results, Biogen launched two identically designed late-phase clinical trials, one called ENGAGE, the other EMERGE. Those studies, however, have created an imbroglio. There are two root causes for it.

One cause is that the FDA allowed Biogen to skip a crucial step in drug development: the Phase 2 trial, a “learn and confirm” study to assure that the final phase of testing (Phase 3) will make a convincing case that the drug should be marketed to providers and patients. Phase 2 results are an opportunity to learn how to dose a drug to achieve the right balance of safety and benefit, a fact of great importance for aducanumab.

Skipping Phase 2 meant that the two Phase 3 trials weren’t informed by good information about effective doses of the drug. In fact, as ENGAGE and EMERGE enrolled participants, Biogen learned more about dosing and so had to amend the instructions on the dosage given to those who were APOE4 carriers.

The other cause of confusion is that a planned interim look at the trials’ results only made things worse. This analysis of interim data was done to decide whether the studies were “futile.”

In clinical care, futility describes care that no longer has a chance of benefitting a patient. It’s a controversial concept because it relies on the often seriously ill patient, their family, and their clinicians aligning around a common perception of both the benefit of care and the chances of success.

Futility analyses are also controversial in pharmaceutical research. Companies defend them as part of the business of research. Each day of conducting a clinical trial costs money, often lots of it. Time and money spent on a study that won’t succeed is time and money wasted. Cut your losses and move on to the next drug.

I disagree with that approach and am bothered that futility analyses are becoming a more routine part of late-phase Alzheimer’s disease clinical trials. I’m not convinced that they save money, because by the time a futility analysis is executed much of the money has already been spent on recruitment and other study procedures.

A negative trial is a disappointment, and the Alzheimer’s field has lots of them. But even these trials make discoveries that inform the design of other studies. Stopping early to save some money leaves the field with an incomplete data set, and this is precisely what vexes the analyses of aducanumab.

Skipping the learn-and-confirm phase, and then performing a futility analysis, unleashed a frustrating series of events, none of which have benefitted the discovery of better treatments for Alzheimer’s disease. On March 21, 2019, Biogen announced that the futility analysis supported shutting down ENGAGE and EMERGE. The price of a share of Biogen stock dropped from $320 to $226.

Aducanumab was finished.

But then it wasn’t.

In the three months between when the data set was locked for the futility analyses and the announcement of their results, more data came in from 318 participants who completed the trials. The company took another look at this larger data set.

Seven months after its March reveal, Biogen announced it had changed its mind. Aducanumab looked to be effective and the company was going to submit its data to the FDA for approval. The stock price returned to its pre-March 21 value.

And just what was this new good news? New results from EMERGE showed that participants who received the high dose of aducanumab outperformed those getting placebo on a measure that blends assessments of cognition and function. No such differences were seen in ENGAGE.

Biogen’s application for approval divided the FDA. At a November 6 meeting of the advisory committee reviewing the application, Dr. Billy Dunn, director of the FDA’s Office of Neuroscience, spoke in favor of approving aducanumab. Tristan Massie, a statistician in Dunn’s office, concluded the opposite. The advisory committee sided with the statistician and voted overwhelmingly against approval.

In January, Biogen issued a cryptic announcement. In response to an information request from the FDA, the company had submitted still more data and analyses — the details aren’t publicly known — and said the FDA was pushing its decision from March to June 7.

The crux of the confusion over aducanumab? The data. They’re incomplete and contradictory.

Advocates of aducanumab have tried to explain away the contradictory findings from EMERGE and ENGAGE — clinical trials that tested the same drug on similar populations — with sophisticated statistical analyses. But these kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.

None of this had to happen. Skipping a key phase of research and performing a futility analysis weren’t scientific decisions; they were business decisions about the pace of research to discover an effective Alzheimer’s treatment and how much a company will spend to sustain that pace.

Ironically, approval of aducanumab will likely slow the pace of discovery. A person who’s willing to take on risks and uncertainties will likely choose the guarantee of taking aducanumab instead of enrolling in a clinical trial.

People with Alzheimer’s and their families are desperate for effective treatments for the disease. Aducanumab might be that treatment, but we won’t know until Biogen invests the time and money needed to run well-designed trials and complete them. The day such a trial brings home positive results will be a turning point for my practice.

Visits to my memory center will no longer end with bad news, but begin with good news: “There’s now a safe and effective Alzheimer’s treatment for you.”

Jason Karlawish is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine; co-director of the Penn Memory Center; and author of “The Problem of Alzheimer’s: How Science, Culture and Politics Turned a Rare Disease Into a Crisis and What We Can Do About It” (MacMillan, 2021). He is also a site investigator on clinical trials sponsored by Biogen, Esai, and Eli Lilly.

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