Admittedly, I knew little about amyotrophic lateral sclerosis (ALS, or, more commonly, Lou Gehrig’s disease) until quite recently when a friend’s friend received the horrible diagnosis. On average, survival is 2-5 years and it’s a terrible way to go. What’s more, that survival time is hardly better than when Lou Gehrig was diagnosed. But the Food and Drug Administration has fixed that by approving a “new” drug that appears to probably be useless — except as an incredible cash cow for its maker.
The approval of the drug, Relyvrio from Amylyx Pharmaceuticals, is based on results from one small, mid-stage study in which patients with the debilitating disease appeared to progress more slowly and survive a few months longer. Typically, the FDA requires two large studies or one study with “very persuasive” survival results for approval.
ALS destroys nerve cells needed for basic functions like walking, talking, and swallowing. About 30,000 people in the U.S. currently have the disease.
The approval, based on a single study of 137 patients, followed a very turbulent path, including two negative reviews by the FDA’s internal scientists, who called the company’s results “borderline” and “not persuasive.” A panel of outside advisers backed that negative opinion in March, narrowly voting against the drug.
In an editorial published by the New England Journal of Medicine, two neuroscience experts, Michael Benatar and Michael McDermott, argued that the “lack of convincing supporting evidence” in the study the agency relied upon raised questions about the effectiveness of the drug.
The FDA’s own scientists voiced similar concerns in published documents. They viewed the data related to functional decline as weak and potentially compromised by how it was measured. There was also considerable missing data, which FDA staff noted could change the study’s conclusions if included.
As for the proposed survival benefit, the FDA’s staff didn’t find the supporting evidence to be compelling. “The overall lack of statistical persuasiveness of the survival benefit, as well as the lack of replication of the results raises concern that the modest survival benefit seen may potentially be due to underlying disease heterogeneity rather than an effect of the drug,” they wrote.
Almost without exception, the FDA only approves drugs after three phases of human testing: phase 1 is essentially safety; phase 2 is safety and efficacy; phase 3 includes a large number of people to evaluate efficacy. But FDA approved Relyvrio with just phase 2 data, the one the New England Journal of Medicine editorial criticized. Amylyx indicated that if the ongoing phase 3 study didn’t show positive results, it would pull its drug voluntarily. But that pledge came with caveats: if Amylyx determines the drug is still effective for a subgroup of patients, the company may not pull the drug, it said. As for the FDA, as a rule, it will pull a drug that proves to be dangerous. But not if it proves to be a sham.
Oh, and ready for this? This alleged semi-miracle is just a combination of two drugs that many patients have already been taking for ALS. In that sense, it’s not new at all. It’s rather like combining aspirin with a readily available prescription drug and charging a fortune when people can and have been doing their own combining, thank you very much. This also means it was cheap to develop, since all that testing on animals and even safety testing on humans could be skipped.
Could the FDA have rejected it on those grounds alone? Of course! “Um, why not, um, just let the patients take the medicines, you know, well, um, separately as many have been?”
This comes not too long after its controversial approval of Aduhelm, which I wrote about twice. Aduhelm received agency approval for treating Alzheimer’s despite unanimous rejection by its own committee that saw no evidence it slowed the progression of the disease by so much as a day. Initially, the maker, Biogen, was ecstatic and slapped a monstrous price tag of $56,000 on the drug. It expected to roll in cash like Scrooge McDuck.
It didn’t quite work out that way. The FDA can approve drugs, but it can’t make insurers shell out for something they think is worthless. Largely, insurers refused, as did Medicare. Now, Aduhelm has proved to cost the maker a fortune and Biogen’s CEO has resigned in the wake.
My guess as to why Aduhelm got FDA approval has two aspects. One is the “something, anything” mentality. There had been no new approvals of drugs to treat Alzheimer’s in decades. The other is “regulatory capture.” That’s a form of crony capitalism based on an understanding that when regulators leave their positions, they will get cushy jobs or consulting agreements with those they favored.
As Maxim Jacobs has noted in the American Conservative, “The FDA has been captured for quite a while. In a 2016 study published in the British Medical Journal, the majority of the FDA’s hematology-oncology reviewers who left the agency ended up working or consulting for the biopharmaceutical industry.”
Presumably, both of those apply with Relyvrio, as there are only three unique ALS drugs, the last approved five years ago. And none of them do much. Fact is, the drug discovery paradigm has largely shifted. When you hear of “cures” or “breakthroughs” these days, it’s almost always in rodents and rarely plays out in humans. We cure cancer in rats and mice pretty much every week, and sometimes twice. There’s a whole clickbait website, The Brighter Side of News, devoted to this strain of clickbait.
Relyvrio fits what’s become an all-too-familiar pattern for new drugs. Even if it does what its maker claims, it barely does what it claims. And it costs a bloody fortune. Aduhelm’s price was comparatively a bargain, with its price originally set at $56,000 annually. Relyvrio, on the other hand, is $158,000 per year. So if ALS victims make it three years, Amylyx reaps close to half a million.
The Canadian Institute for Clinical and Economic Review, an influential watchdog group focused on drug costs, released a draft report claiming that Relyvrio would “far exceed” common measures of cost-effectiveness if sold at the price Amylyx has now set. In a final report, it said an appropriate price for Relyvrio would be between $9,100 and $30,600 a year. And no, that’s not based on the cost of actually making and distributing the drug. It takes into account research and development. The institute slammed the cost of Aduhelm.
And since you were wondering, one of the drugs that Relyvrio combines is a generic costing a few thousand per year and the other isn’t actually a drug at all, but just a supplement you can order from Amazon for practically nothing. Yet this stunning breakthrough was part of a Forbes article headlined “Renaissance in Precision Neuroscience Predicted.” Picture the “eyes rolling” emoji.
But this is game that the American medical system allows. Like the hospital that charges you $10 for an aspirin if you’re an inpatient. It slaps your insurer with that and negotiates something in-between. Of course, if you don’t have insurance, it can get a bit tricky.
Medicare also doesn’t pay full price, but a 2021 Congressional Budget Analysis found that of all major federal programs paying for outpatient prescription drugs, Medicare Part D paid the highest average net prices.
Merck charges a $175,000 annual list price for its immunotherapy cancer drug Keytruda. And we don’t know if actually cures anyone. In a model that would make any good conspiracy theorist drool, we have seen a shift from trying to cure cancer to simply lengthening life slightly at an incredible cost. Far from me to put a price to the patient on a few extra months, but at some point, those of us footing the bills have to consider what we’re willing and able to pay. But be sure of this: If we insisted on paying less, Big Pharma would charge less, and patients would still get the drugs.
Just as Relyvrio actually being a combination of two previously used drugs is a twist, there’s another one to how Relyvrio got approved: advocacy groups.
Just before the FDA hearings, hundreds of documents primarily from patients and caregivers were submitted. And the source of what they “knew” about the drug? Why, Amylyx of course! Assuredly, some patients had benefited from the placebo effect. Nobody knows how fast they will degenerate with ALS; as Stephen Hawking’s experience shows, in rare cases, it can progress quite slowly. But if you’re on a specific drug, it’s common to believe a slower-than-expected decline to be from the drug. If 2-5 years is the average, about half of patients will live longer than that by chance. Not from outside intervention. It’s a combination of the fallacies of post hoc ergo propter hoc and confirmation bias.
None of this is science, but it works.
“I think it demonstrates the FDA’s ability to be facile and I think it demonstrates a lot of tenacity on the part of ALS patients and advocates,” Dr. Catherine Lomen-Hoerth, an ALS specialist at the University of California San Francisco, told the Associated Press, putting it delicately.
Another problem with advocacy groups is that “nonprofits” and “not-for-profits” need to turn a profit.
The leading ALS advocacy group has openly pushed for “swift” FDA approval of the drug for all ALS patients. It submitted a petition with 50,000 signatures and held an emotional “We Can’t Wait” action meeting, with more than 10 people who have ALS speaking directly to FDA leaders. It’s the ALS Association, known for the “Ice Bucket Challenge.” Remember that stunt? The association says it raised $115 million from it. And, well, there’s pressure to show results from something like that. That pressure has been reflected in its advocacy for Relyvrio.
Further, does the ALS Association receive direct funding from pharmaceutical companies, including specifically Amylyx? Roll of the eyes. Of course it does. Is this a conflict of interest for ALS sufferers? Roll those eyes, again.
But wait! There’s more! Amylyx was a sponsor of the study, which isn’t that unusual. Taxpayers can’t possibly foot the bill for all the drugs we’d like to see tested. But does industry funding affect clinical trial outcomes? Believe it or not, most definitely. The impact was first recognized over a century ago. The influence can be consciously or subliminal. And when the drug maker actually designs the protocol?
This is known simply as “the funding effect.”
Further, the director of the study works directly for Amylyx while several co-authors admitted to receiving money from the drug maker, including from one: “I am a director of Amylyx and a shareholder.”
To sum it up: we have approval based on a smallish phase 2 trial, two cheap drugs merely combined for a huge price tag, and serious industry and advocacy group involvement. It stinks like a surfeit of skunks. (Yes, that’s the terminology.)
As with Aduhelm, insurance companies can and should reject coverage for Relyvrio, or at least the incredible set price. It would be nice to see a bucket of ice dumped on Amylyx. It would send a powerful message to both the FDA and drug companies. But you can see it now: “They refused to pay for that Alzheimer’s drug and now they’re doing it again! It’s death panels!”
Meanwhile, Amylyx is doing the Scrooge McDuck thing and the FDA and advocacy groups have their “something, anything” drug. As for those dying from ALS? Well, damn; you can’t please everyone!
Michael Fumento (www.fumento.com) has been an attorney, author, and science journalist for over 35 years. His work has appeared in the New York Times, the Washington Post, the Sunday Times, the Atlantic, and many other fora. He has written repeated exposes of controversial (or should-be-controversial) drug industry shenanigans, most recently the alleged “cancer cure” dostarlimab.