Back in March, Pharma Manufacturing ran a cover story attempting to untangle the web of issues surrounding the FDA’s then forthcoming decision about Biogen’s Alzheimer’s treatment, Aduhelm (aducanumab). “The Alzheimer’s approval maze,” featured insights from a range of experts on all sides of the debate, including market analysts, patient advocates, a clinical site investigator for one of the Aduhelm trials who supported its approval, and a member of the FDA’s advisory committee who staunchly opposed the drug.
Then in June, the FDA rendered its fateful decision. How accurately did our article predict the fallout? Now several months after the approval, here’s what we got right — and what we didn’t see coming.
Where we nailed it
The FDA would give it a conditional approval
Part of the debate surrounding Aduhelm was focused on the mismatched results from the drug’s two phase 3 trials — one showed a benefit, while the other did not. Although Biogen presented data suggesting that a discrepancy in dose exposure between patients in the two studies explained the diverging results, not everyone was convinced. But rather than denying the drug, the Alzheimer’s Association, a patient advocacy group, argued that the FDA should grant it a conditional approval. On June 7, the agency did just that, saying that Biogen would have to “conduct a new randomized, controlled clinical trial to verify the drug’s clinical benefit,” or it could be yanked from the market.
Clearing the way for other amyloid drugs
As predicted by an analyst in the article, the approval of Aduhelm serves as a vindication of sorts for the “amyloid hypothesis” — the idea that clearing sticky beta-amyloid plaques from the brain could lead to clinical improvements on the dementia rating scale. Although many drugmakers have long abandoned amyloid-targeting drugs like Aduhelm due to a lack of success, the FDA’s approval was a signal to others in the space that it is open to green-lighting this class of medications, even if the benefits appear modest.
Hot off the heels of the Aduhelm approval, Eli Lilly and Co. submitted an application for its amyloid-targeting medication, donanemab. Although the company had not previously planned on submitting the drug until 2023, the agency’s decision on Aduhelm changed all that, and Eli Lilly asked for an accelerated approval in October.
The pricing issue
When our article was published, the price estimate for what Aduhelm would cost was about $50,000 a year. Ultimately, Biogen slapped a $56,000 price tag on Aduhelm and, as expected, concerns over how patients and insurers would cover the cost have dogged the drug ever since.
Where we missed the mark
The impact of ARIA
Amyloid related imaging abnormalities (ARIA), a potentially dangerous side effect of Aduhelm that could cause strokes or brain hemorrhage, was well documented in Biogen’s late-stage trials. In fact, a safety analysis published recently in JAMA Neurology showed that ARIA impacted about 41% of patients in the studies.
But what wasn’t discussed in our article — and what some physicians are now raising alarm bells about — is that the patients in the studies were likely healthy aside from having Alzheimer’s. Now that the drug is being used in a real-world setting, it’s unclear how it could impact patients with a number of comorbidities. In mid-November, news broke that a 75-year-old patient taking Aduhelm — who had been diagnosed with ARIA — died. Biogen has launched an investigation to determine what role ARIA might have played in her death. The fatality, so early in Aduhelm’s rollout, is likely to cast another dark cloud over the drug.
Blockbuster blues
With no other approved Alzheimer’s treatments on the market and a massive patient population, the common refrain was that Aduhelm would quickly skyrocket to blockbuster heights — some analysts even speculated that it could become the best-selling drug of all time. So far, reality has failed to live up to the hype.
The key issue that was perhaps not accounted for by many analysts was that despite the FDA approval, ongoing controversy surrounding the drug has led to low prescriber confidence. Two hospital systems — Mount Sinai and Cleveland Clinic — have even refused to prescribe Aduhelm due to safety and efficacy concerns.
In October, Biogen revealed in an earnings report that Aduhelm pulled in just $30,000 in sales during Q3 — well below the $10 million forecasted by analysts.
The backlash
In our March article, we called the Aduhelm question “one of the FDA’s biggest decisions of the decade.” However, the enormity of the backlash from the approval was unforeseen in our coverage. For many, the decision is already being used as a case-in-point that the FDA — which was blasted for its cozy relationship with Biogen during the review process — can’t be trusted. From doctors to former FDA officials to industry commentators, the approval has been harshly criticized and called one of the worst in recent history. Given the potential impact the approval could have on public trust in the FDA, the decision on Aduhelm is actually going down as “one of the biggest of all time.”
