Why the FDA Was Correct in Approving Biogen’s Aducanumab

The Food and Drug Administration on June 7 approved the first drug in 18 years intended to treat Alzheimer’s disease, aducanumab, despite its advisory committee and Alzheimer’s experts citing a lack of evidence that the drug works. In response, three scientists who served on the advisory committee resigned.

To get a handle on the approval of the drug, branded as Aduhelm and manufactured by Biogen, Eric Dimise of GLG’s Healthcare Events team spoke with Dr. Anton Porsteinsson, Director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester. There, he has spent more than a decade as the principal investigator of Biogen’s clinical trial for aducanumab. Below are a few select excerpts from our broader discussion.

What was your gut response to aducanumab’s approval?

First excitement, followed by caution. I would have wanted to see a more traditional approval based on therapeutic benefit in one study. But it feels to me like the FDA was trying to thread a needle here, not really ignoring the input from the advisory board, but trying to stick with the overall positive impression that the clinical team at the FDA appeared to have toward the EMERGE data in particular.

There is a provisional path to approval available to the FDA. This is a drug that treats a serious condition with a meaningful advantage over available therapies. It demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. In this situation, the approval was based on aducanumab’s well-established reduction of amyloid plaque burden.

The label — “for the treatment of Alzheimer’s disease” — was a surprise, and the approval as an amyloid-lowering agent was a surprise to me. You’d expect that people with elevated amyloid have Alzheimer’s disease. There was no clarity on the severity in the label. There was no clarity on required biomarker verification. This drug isn’t for everyone with elevated amyloid. Much is now left for payers and clinicians to decide. We need to define who are the appropriate patients and what the clinical and safety monitoring should be.

What’s the patient demand for a drug like this? Do you see a situation where you’re going to have to have difficult conversations with patients, saying, “I know this drug is approved, but we’re not ready to give it to you yet”?

There’s been a lot of media coverage, and people are certainly desperate for hope when it comes to Alzheimer’s disease. First, we need the media firestorm to settle down. People jump on the mention of just about anything that might help patients with Alzheimer’s. Obviously, aducanumab is not available right now. It will take some time to get into distribution, and there is still a limited bandwidth in terms of the appropriate infusion centers, biomarker verification, etc. This will ramp up slowly.

With some of my patients who are in a more advanced stage, I’ve already had the difficult conversation where I say, “I do not believe that this medication will be of any help or benefit to your loved one.” We have no data to suggest that this is a reasonable therapeutic option for people in the severe stage of Alzheimer’s disease. We also don’t have evidence for using this drug in patients that have no cognitive impairment but have biomarker evidence of the Alzheimer’s disease pathological process. Participants in the phase III studies of aducanumab had early symptomatic Alzheimer’s — that is mild cognitive impairment due to Alzheimer’s. These are the appropriate patients for aducanumab at this point.

I’ve been clear with colleagues and others that we need to be thoughtful, careful, and measured in terms of making the right decisions regarding patient selection and safety/tolerability monitoring. People that disagree with the FDA decision will watch aducanumab closely. If things don’t go well, we’ll hear “We told you so,” and that will hurt the field.

I understand why some of my colleagues see this approval differently. You have two studies, one convincingly positive, the other convincingly negative. The fact is that this medication, for the right patients, may provide a modest but meaningful delay in the progression of disease in the form of 20% to 40% delay in progression compared with placebo. But there is a meaningful risk of tolerability problems, adverse events such as vasogenic edema, and micro-hemorrhages that are manageable but require careful monitoring. We need to take a very sober approach to this and be careful about what we know and what we do not.

Could physicians follow through on not prescribing the drug even though it’s approved?

Every doctor will make their own decision. My hope is that we can meet in the middle. I was supportive of the approval, but I’m cautious and measured. But some of my colleagues who are concerned have said publicly they’ll never prescribe it. Still others say they will reluctantly prescribe it after expressing their concerns to their patients. I hope my reluctant colleagues opt for the latter as their patients need their expertise and ongoing care. The Alzheimer’s disease field is small. We get along quite well. Even if we disagree, we’re on a similar mission. We want to see better treatments and better options. We’ll find a way to work through this controversy. While aducanumab may be first in class, we do not want it to remain best in class for long.

Biogen announced the list price of Aduhelm would be $56,000 a year. How big of a barrier will the cost of the drug be for patients?

The cost was higher than I anticipated. I hear Biogen when it says that compared with some other treatments, this is not outsized. But it’s twice as expensive as I expected. That’s just the direct price — you also have to pay for the biomarker verification, at least three MRIs in the first year, and some people have to do a few more if they develop amyloid-related imaging abnormalities. Then there’s the infusions and clinical monitoring as well. Put together, it could be up to $30,000 in the first year, then less in subsequent years. It’s very expensive, and it will be important to see what payers do. They’re probably scrambling right now to try to calculate what they might have to expect in terms of numbers of patients and overall cost if this is something that they feel obligated to approve.

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About Anton Porsteinsson
Anton Porsteinsson, MD, is the Director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester, New York. He also serves as the William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine. Dr. Porsteinsson is board certified in psychiatry with added qualifications in geriatric psychiatry. He has clinical and research interests in both the cognitive deficits and behavioral changes associated with dementia. Dr. Porsteinsson is active in clinical research with an interest in novel pharmacologic agents in the treatment of Alzheimer’s disease and other dementias.

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