There have been two important developments in Alzheimer’s Disease treatment in recent months: The release of a congressional investigation of Aduhelm’s approval and the approval of new drug Lecanemab. What can we learn from these events?
Aduhelm under fire
In the summer of 2021, the US Food and Drug Administration (FDA) caused a stir when they approved the drug Aduhelm for early Alzheimer’s Disease, over the objections of their advisory group. Experts worried that Aduhelm’s lack of proven effectiveness and ridiculously high price set a dangerous precedent for future drug approvals. The approval was so controversial that the Centers for Medicare and Medicaid Services (CMS) declined to cover the cost of the drug for Medicare patients outside of clinical trials.
Now, a recent congressional investigation found that the FDA and Aduhelm’s manufacturer Biogen collaborated in atypical and often inappropriate ways during the development process to assure the drug’s approval. For example, FDA staff had 66 calls with Biogen that were not documented (which is against agency protocol); FDA staff worked closely with Biogen on a briefing document for an agency committee and gave Biogen material to add to their presentation; and the FDA approved the drug for anyone with Alzheimer’s Disease despite the drug only being tested on those with mild cognitive impairment, and Biogen being aware of the lack of evidence for effectiveness and safety in this population.
In addition, the Congressional report revealed that Biogen priced Aduhelm far above what they knew would be affordable for patients and for Medicare, basing the original $56,000 annual price on what they thought the market would bear.
The Aduhelm case is an egregious one, but reveals larger trends about the FDA that experts have pointed out: Lowering the bar for evidence in favor of getting drugs to market faster, regulators catering to drug manufacturer’s needs rather than the public’s, the lack of transparency in conflicts of interest between drugmakers and the FDA, and use of surrogate outcomes (instead of clinically meaningful outcomes) to justify drug approvals.
Does Leqembi work?
In the wake of the Aduhelm investigation, the same drugmaker Biogen had another drug for early Alzheimer’s lecanemab (brand name Leqembi) approved under the accelerated approval process. Because of the controversy around Aduhelm, the Leqembi approval has been under greater scrutiny. Let’s take a look at the evidence.
First, the good news. According to the clinical trial of Leqembi published in the New England Journal of Medicine, the drug actually shows a statistically significant impact on measures of cognitive decline (not just a reduction of beta amyloid like Aduhelm). However, experts are still unsure of whether the result is clinically significant (a big enough difference to improve patients’ quality of life), given that the differences in cognitive decline between the two groups was small.
The trial measured patients’ performance on the Clinical Dementia Rating before and after taking Leqembi. The CDR measures cognition and daily function in the domains of memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care on a scale of 0-18. One study of the rating’s clinical significance estimated that a 1-2 point increase on the scale indicates a “meaningful decline.” Another study created a scale for the rating showing that zero means no cognitive impairment, 4.5 or higher is classified as mild dementia, 9.5 or higher as moderate dementia, and 16 or higher as severe dementia.
Both patient groups started the trial with an average of 3.2 on the CDR. The group taking Leqembi ended the trial 18 months later with a score of 4.41 and the control group had a score of 4.86. This technically puts the control group into the “mild dementia” category (as opposed to “very mild dementia” in the intervention group). But the 0.45 point difference between the two groups doesn’t indicate a “meaningful” clinical change. In all, it’s hard to know whether patients and families will see a positive difference from this drug in the real world. It’s also important to restate that both groups had cognitive decline, just that the Leqembi group declined slightly less.
The small effect of the drug may not be an issue if there weren’t also serious safety concerns. In the NEJM trial, about one quarter of patients taking Leqembi experienced brain bleeding or swelling, although most cases were asymptomatic. Leqembi resulted in symptomatic brain swelling in 2.8% of participants, with symptoms such as headache, visual disturbance, and confusion. Serious adverse events were experienced by 14.0% of participants in the lecanemab group and 11.3% of participants in the placebo group.
Even more concerning are three patient deaths linked to Leqembi that have prompted warnings from experts to limit access to the drug for certain patients. Patients taking blood thinners and those with amyloid deposits in blood vessels, a condition known as cerebral amyloid angiopathy, are particularly at risk of serious brain swelling and bleeding.
What have we learned?
In the wake of Aduhelm’s controversial approval and investigation, one would hope that Biogen’s next attempt would include airtight evidence and a reasonable price, and that the FDA would hold them to a higher standard.
Looking at Leqembi, Biogen and the FDA still haven’t quite hit the mark. While the trial evidence for Leqembi is certainly more rigorous than the Aduhelm trials and actually do show a reduction in cognitive decline, the FDA has not done enough to put the small benefit of Leqembi into perspective for doctors and patients given the risks of harm.
The independent advocacy group Doctors For America pointed out that there has not yet been an advisory committee meeting to evaluate the evidence. They recently called for an independent committee to discuss “whether the statistically significant changes seen among patients receiving the drug correspond with meaningful clinical benefit” and to evaluate whether “evidence of harm outweigh its benefits in light of the deaths reported,” among other issues.
Biogen is also pushing it on the price. Their suggested price for Leqembi is $26,500, not as egregious as Aduhelm’s $50K, but still higher than the $8,500-$20,600 cost-effective range recommended by the Institute for Clinical and Economic Review. Currently, Medicare will only pay for these types of monoclonal antibody drugs when used in clinical trials–but if Leqembi receives full approval from the FDA beyond the accelerated pathway, there could be at least a million Americans eligible for this drug, and Medicare’s funds would be strained. The cost of the drug also doesn’t count the brain scans that patients need to undertake before and during treatment.
On the policy front, the Aduhelm controversy has led to some small but good changes. As part of an end-of-the-year spending bill signed into law in late December, Congress made some changes to the FDA’s accelerated approval process to hold drugmakers accountable for doing timely postmarketing studies and created a new council specifically to “support the consistent and appropriate use of accelerated approval.”
However, the Leqembi approval shows the FDA still has a long way to go to reach the standards of evidence, transparency, and value that America needs for new drugs and devices.