Normally, I’d be excited to explore and write about a breakthrough medical development that could vastly improve and extend the quality of life for more than 6 million people. But I am worried about that newly approved drug for Alzheimer’s disease—and not just about the drug itself.
Before the FDA’s approval of Biogen’s new monoclonal antibody (aducanumab—brand name Aduhelm), two compelling/competing narratives were emerging.
The first was that families and adherents were pushing hard for approval because there have been so many failed clinical trials, the suffering is great and growing, and We have to do something!
Statnews quoted a 57-year-old man named Jeff Borghoff, who’s had Alzheimer’s symptoms for six years and has been receiving the new drug on and off during clinical trials since 2018. He said the drug has helped his cognition and ability to focus and has been great for his family. He’s building memories with them now, he stated. “Ultimately, I’ll lose those memories, but they won’t.”
The other narrative is from many in the scientific community. They warned that the evidence for approval was shaky at best, and that giving this drug the green light would set a bad precedent by approving a new drug for widespread use based on such weak evidence.
The FDA ignored an independent panel of experts who found Biogen’s clinical trial data unconvincing and strongly advised the FDA not to approve it.
What’s more, the clinical trial was conducted with people who have early stage Alzheimer’s and evidence of amyloid plaques: clumps of a protein that is believed to destroy neurons; their presence in these patients’ brains was confirmed by PET scan.
But the FDA approval doesn’t specify which patients are best suited to receive the therapy.
“Many experts were left stunned by that decision,” reports another statnews article. “On a press call, FDA officials argued that because Aduhelm helped clear amyloid plaques, it could provide benefits for people in any stage of the disease — at the same time as they acknowledged that any benefit from Aduhelm, even for patients in the early stages of the disease, was still unclear.
“(Many experts also strongly push back against the claim that erasing amyloid plaques could help people in the late stages of the disease. Clinical trials of other amyloid-targeting therapies in moderate and severe Alzheimer’s have repeatedly failed to show a clinical benefit.)”
The drug didn’t show any improvements in cognition, but it did show destruction of beta-amyloid, the protein in question. An FDA spokesman stated that amyloid pathology is a marker of the disease across the severity spectrum. Apparently, that was the thinking behind leaving its use up to the clinician caring for the patient.
In attempting to thread the needle between the two communities, the FDA seems to have been reaching for a compromise. Let Biogen market the drug while doing a more extensive clinical trial intended to show that removing the plaques resulted in cognitive benefits. If the trial results are negative, the FDA can withdraw its approval.
Huh? This new med is no simple home pop-a-pill remedy. It requires monthly infusions (for which clinicians get paid more). The list price for a year’s treatment, according to Biogen, is $56,000. It had been expected to cost between $10,000 and $25,000 a year—already a high figure for a medication that will be marketed to primary care physicians.
The cost to patients will depend on their insurance. Medicare will cover it, but patients on traditional Medicare will have a 20% copayment. And Medicare hasn’t routinely covered the PET scans to detect the amyloid plaques, a necessary step prior to treatment. (The impact on Medicare could be substantial.)
It’s not surprising that we’re already hearing warnings about impending healthcare disparities, as wealthy people rush to pay for the treatment themselves, while it’s simply out of reach for many others.
There are also expectations that insurance companies generally will make access to the drug extremely difficult.
As for the side effects/safety, about 40% of the patients in the clinical trials developed brain swelling, which reportedly goes away in time and doesn’t cause symptoms, but the FDA website cites the prescribing information:
“…some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. Another warning for Aduhelm is for a risk of hypersensitivity reactions, including angioedema [swelling under the skin] and urticaria [itchy rashes].
“The most common side effects of Aduhelm were ARIA [amyloid-related imaging abnormalities], headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.”
About 17%-18% had small bleeds in their brains.
Patients will be monitored for swelling prior to the infusions in weeks 7 and 12. If it’s severe, they’ll be able to continue treatment only after imaging and evaluation show their condition has stabilized.
Here’s what’s really strange: Biogen had tested this drug in two Phase 3 randomized placebo-controlled trials with the same designs. An interim analysis of the data in March, 2019, by independent monitors resulted in both trials being halted because they didn’t seem likely to be beneficial. Some called the results a “stunning failure.”
Biogen then stated in October, 2019, that it had evaluated data showing that one of the studies slowed cognitive decline to a statistically significant degree. The benefit: on an 18-point scale, the drug outperformed placebo by less than one point (!). And when Biogen did that analysis on the data from the other trial, it didn’t even show those small positive results.
One thing’s for sure: Biogen will do well—possibly $5 billion well.
It would be wonderful if the subsequent clinical trial results show that this drug is truly effective in enhancing cognition and delaying the dementia that makes Alzheimer’s such a dreadful disease.
But there seem to be so many questions about whether that’s a realistic expectation based on the trials to date.
Is the FDA decision simply giving in to pressure from the understandably desperate Alzheimer’s community, and allowing an expensive, unproven drug with side effects that could be serious in an already vulnerable population?
Is it wise—even fair—to give people what they want when the preponderance of evidence suggests it’s not worth it? Is this simply a very expensive placebo?
And what does the FDA decision suggest about the agency’s decision-making for future drugs to alleviate terrible diseases and conditions that we all wish could be effectively slowed or, better still, eradicated?
I’d rather not be questioning the FDA at this point, when we’ve just emerged from such a sustained attack against the government institutions that we depend upon for good scientific judgment. It looks like they’re still organizing: there’s an Acting FDA Commissioner, Janet Woodcock, and the position of Principal Deputy Commissioner remains vacant.
However, plenty of highly trained career people work there, and I think we have a right and obligation to pursue what seems to many with far more knowledge than I possess to be a questionable decision with large ramifications.
It’s noteworthy that nearly all the clinical trials targeting amyloid-beta plaques until now have failed. In fact, researchers at the Salk Institute have offered another hypothesis. According to Science Daily, they published an article in April, 2021, suggesting that “dense core plaques play a protective role, so treatments to destroy them may do more harm than good.”
“IT’S A NEW DAY IN THE FIGHT AGAINST ALZHEIMER’S,” trumpeted a full-page ad placed by the Alzheimer’s Association in today’s New York Times. It called the FDA approval “a milestone in the treatment of Alzheimer’s” and urged readers to “Join us at alz.org/newday.”
I sure hope they’re right, and the folks at the Salk Institute and on the expert panel that opposed approval are wrong. UPDATE: See clarification below.
Photo by Steven HWG @rebelvisual. Found via unsplash.com.
Additional information derived from a statnews FAQ.
AN IMPORTANT CLARIFICATION:
I’m adding information from the Science Digest article to clarify the position stated by Greg Lemke, a professor in the Salk Institute’s Molecular Neurobiology Lab, which shows a more complex view of amyloid-beta than I believe I presented above.
“Lemke, who holds the Françoise Gilot-Salk Chair, believes that the current failure rate of most Alzheimer’s drug trials is about to end. ‘Some people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain,’ says Lemke. ‘But we argue that amyloid-beta is still clearly a bad thing; it’s just that you’ve got to ask whether dense-core plaques are a bad thing.’
“Lemke suggests that scientists looking for a cure for Alzheimer’s should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.”