“Water? Never touch the stuff – fishes swim in it .”
Attributed to actor and comic W.C. Fields.
(This is the cleaned-up version, we run a “PG” blog.)
Yes, even water can have side effects, as W. C. Fields points out. All medications have side effects and risks. It is the job of the US Federal Drug Administration (FDA) to balance the risks with the benefits before they grant approval for a drug to go public.
This week, the FDA’s credibility is in disarray after the agency approved the Alzheimer’s drug aducanumab on Monday, June 7. Three experts resigned this week from the 11-member independent advisory committee, which had nearly unanimously recommended denial last November.
So what is aducanumab? (This awkward generic name looks like something spelled backwards. The marketing name is the slightly more memorable “Aduhelm”.) Unlike other Alzheimer drugs which only manage symptoms,, aducanumab purports to actually slow the progression of the disease and delay cognitive decline. The drug is being developed by Biogen.
The controversy about approval centers on the testing. Alzheimer’s (like Parkinson’s) is notoriously difficult to test. Your test subjects are…well, in dementia…but you are primarily dependent on their responses since there is no objective biomarker to measure improvement. Alzheimer’s progresses over years so it can take years to test. One patient’s testing was described as 1 year on a placebo, 1 year on lower dose aducanumab, 2 years on a higher dose aducanumab. Whew – four years of testing.
Phase 1 of drug testing was a small trial to evaluate safety. The trial had promising results: they showed amyloid reduction. The drug is designed to clean up the amyloid plaques that many experts contend is the cause of Alzheimer’s . The hypothesis is that destroying plaques if done early enough can delay cognitive decline.
Under its “accelerated approval” program, the FDA allowed Biogen to skip Phase 2, the “efficacy” stage which answers the question “Does this drug work?” and start Phase 3, the “efficiency” stage, “Does this drug deliver therapy efficiently?”
Two Phase 3 trials were stopped early in March 2019 when an independent data monitoring committee said adcanumab didn’t appear to be working. Consequently, over a third of the 3,285 participants i were never able to complete the 78-week trials. However, by October 2019, Biogen announced it found benefit in one of the two trials for 318 participants who finished before the trials were stopped but after the cutoff point for results the monitoring committee assessed. Biogen said the highest dose slowed cognitive decline by 22 percent. There was no statistically significant improvement in the lower dose for this trial and in the other identically designed trial.
And on this tiny sample from an incomplete trial, the drug was approved. Oh yes, there are significant potential side effects. About 40 percent of Phase 3 trial participants receiving the high dose experienced brain swelling or brain bleeding. Yikes.
There’s also the painful side effect on your wallet (and the Medicare budget). Aducanumab is not a pill, it is an infusion that has to be delivered in a hospital setting. The monthly infusions will cost a mind-boggling $56,000 a year (wholesale!) – and that doesn’t include the MRI scans, the neurologists’ time, etc, Biogen has magnanimously said it won’t raise prices for the next four years.
The Alzheimer’s community (some six million in the US) is desperate for new drugs, and has lobbied hard for aducanumab approval. There are only five drugs approved for Alzheimer’s and none have been approved since 2003, 18 years ago. At least three major drug testing programs have heartbreakingly failed since then. Currently, some other drugs in clinical trials are more promising, but they are most likely three or four years away from potential approval.
To me, the worst aspect of this puzzling approval is the impact on future testing. Why volunteer for a test of these other drugs when you could get a therapy approved by the FDA? And why do further testing of aducanumab after market when you might run the risk of getting a placebo?