The FDA conditionally approved Biogen’s drug aducanumab for Alzheimer’s disease yesterday, the first new treatment for this disease approved in decades. As a physician caring for patients with Alzheimer’s disease, I’ve been looking forward to the day when I can offer a course altering therapy for this unfair and frustrating disease. So why don’t I feel better today?
The FDA’s approval of aducanumab does not change the facts, and the facts in this case are daunting. The potential benefits of this drug, even assuming the most optimistic interpretations promoted by the drug developer are true, are small – so small they are miniscule. This is not a drug that gives people their memory back. More importantly, the risks are high. In some patients, the drug causes an immune reaction on the blood vessels of the brain compromising blood brain barrier function. As a result, more than one-third of patients treated with this drug developed swelling and/or bleeding of the brain. This side-effect has been widely downplayed, but the long-term effects have not been adequately studied. This drug has taken a tragically misguided pathway to become approved. The phase 3 trials were terminated prematurely for futility, then revived on the basis of a tenuous sub-group analysis. The approval of aducanumab comes in opposition to a near-unanimous recommendation against approval from the FDA’s scientific advisory committee and at the behest of intense pressure from advocacy groups.
One of the key arguments advanced in favor of approval was that approval would spur future drug development. I suspect this decision will promote the development of additional anti-amyloid therapies but it is likely to reduce the focus on developing novel drug targets. The amyloid cascade hypothesis has been tested and tested over the last decades to the exclusion of other meaningful ideas. The long series of clinical trial failures related to this hypothesis was building toward a major recalibration. If this is derailed by the actions of the FDA today, it will be a significant harm.
I want to point out three other surprising details in yesterday’s approval. First, aducanumab was approved for all patients with Alzheimer’s disease. Biogen’s trials only enrolled patients with early Alzheimer’s disease, so the approval including patients with advanced disease is hard to explain. Second, patients enrolled in the trials were proven to have β-amyloid in their brain. This is critical, because a diagnosis based only on symptoms is wrong a substantial portion of the time. However, the FDA does not require selection of patients with amyloid-PET scan or cerebrospinal fluid analysis. Finally, the FDA approved continuing treatment even in patients who developed severe brain swelling and hemorrhage once the acute episode has stabilized. This is a disturbing disregard for the significance of even the most severe spectrum of this important side effect. These decisions expose patients to unnecessary risks and introduce variables that will make effective post-market surveillance extremely difficult.
There is so much wrong with this data and this process. This isn’t the turning point in the fight against Alzheimer’s disease, in fact, I am very concerned that it may be a major setback. For the safety of our patients, we should proceed with great caution.