Is Biogen's Alzheimer's drug a historic achievement or red herring? There are plenty of opinions on both sides. Nonetheless, it received FDA approval despite an unanimous downvote from its own expert panel. What is going on here? No one knows, but to me, it just doesn't smell right.
The subject of an email from Rick Berke, the executive editor of STAT, reads: "A landmark day in Alzheimer's disease." Berke then linked to an article by Adam Feuerstein and Damian Garde, which, if it's less enthusiastic, it's not by much: "FDA grants historic approval to Alzheimer’s drug designed to slow cognitive decline."
If you read only the headlines it would be perfectly reasonable to conclude that the demise of this awful disease is right around the corner. Not even the most enthusiastic supporters of Biogen's Alzheimer's drug, Aduhelm (generic name aducanumab) would agree with this, and it is entirely possible that the corner isn't even on a map. Here's why.
Aduhelm, an antibody drug, did accomplish what many experimental AD drugs could not – a measurable decrease in beta-amyloid plaque – a hallmark of the disease. It is indisputable that these plaques go hand-in-hand with AD, but it is far from clear whether the plaques are a cause of the disease or a result of it. If it's the latter, the potential utility of aducanumab will be limited; the damage will have been done.
If I sound a bit pessimistic...
The FDA Overrides Its Expert Panel: A Possible Red Flag
During the drug approval process, the FDA selects a panel of experts to evaluate safety and efficacy data and recommends to the agency whether the drug should be approved, rejected, or requires more data or studies. This is done by majority vote. Although the FDA does not have to follow the panel's recommendation it does so 78% of the time. When the safety and efficacy of the drug are apparent the panel's recommendation is usually followed. If the vote is 6-5 or 9-7 (1) the FDA may be more likely to reject the recommendation. What was the vote for aducanumab? Zero in favor, one abstention, and 10 "no" votes (!). The experts unanimously rejected the approval of the drug. Yet, the FDA gave it the nod anyhow.
One possible explanation for this apparent disconnect is provided by ACSH advisor, Dr. David Shlaes, who has interacted with (and nagged) the FDA for years on his specialty – the development of new antibiotics.
Apparently FDA felt the data were at least somewhat controversial in terms of the risk/benefit ratio. The population involved has a high level of unmet need - there is really nothing else out there that works and is without risk. Furthermore, they have required additional studies as a post-approval commitment and can always withdraw approval at a later date . . .
David Shlaes, M.D., Private communication, June 8, 2021
But another possibility is that "follow the science" morphed into "follow the politics." There is enormous pressure on the FDA to approve new drugs (these numbers are counted every year), and the commissioner of the FDA is a political appointee (2) so it is entirely possible that there was a "nudge" from above to approve aducanumab.
Perhaps most disturbing is the full set of American Tourister baggage that aducanumab carries. Max Nisen, who writes opinion pieces on biotech, pharma, and healthcare for Bloomberg, explains:
Nisen's, whose in-depth article excoriates the FDA for its decision, argues that "Biogen started two identical studies in 2015 to test whether the drug slowed early Alzheimer's. However, the company halted them in March 2019 after an early analysis suggested a low chance of success." He also notes that the drug will cost $56,000 per year (which will be funded by Medicare), and determining its efficacy will be almost impossible
(For an explanation of what happened in 2019, see my colleague Dr. Chuck Dinerstein's article titled Biogen's Bad Day.)
Furthermore, Rebecca Robbins and Pam Belluck writing for the New York Times also provided a blistering critique of the FDA decision, not the least of which is that while the drug (maybe) showed some efficacy in patients with mild cognitive decline (only at the highest dose) the FDA approved aducanumab for all patients, even those with severe decline. There is absolutely no evidence that aducanumab works for advanced AD, although it's a fairly safe bet that families who have a relative with advanced disease are going to want it anyhow.
Mullard makes the following points:
- The beta-amyloid hypothesis is just that. It has not been validated by clinical data.
- Patients in other clinical trials may drop out and start aducanumab instead. This could actually short circuit AD research. He quotes George Perry, a neurobiologist at the University of Texas at San Antonio “This is going to set the research community back 10–20 years."
- Full approval will depend on post-marketing trials to determine if the drug really improves cognition. Biogen has nine years to complete the trials. So, it is possible that millions of people will be taking a very expensive drug for many years only to find out that it didn't work.
- Aducanumab has side effects, for example, swelling of the brain, which can be serious. In Phase 3 trials 40% of patients experienced brain swelling. This may or may not be symptomatic but it needs to be monitored with brain scans. More money. Plenty.
Bottom line: This just doesn't smell right. Are the Phase 3 results signal or noise? The sparse evidence doesn't provide an answer. Right now Biogen's drug is, at best, modestly effective and could well end up being of little or no use. It will cost us a lot of time and money to find out.
(1) There is no fixed size for FDA expert panels. The typical number is 10-15, but sometimes more experts are needed.
(2) The position of FDA Commissioner is currently vacant. Former commissioner Janet Woodcock is serving until President Biden chooses someone.