December 2, 2023

It wasn’t the best of news for sufferers of Duchenne muscular dystrophy (DMD). But neither was it dismal. It does appear that the first FDA-approved gene therapy, called Elevidys, can, with a one-time administration, slow the progression of the disease made famous by the Jerry Lewis–hosted Labor Day telethons. Non-Sarepta “researchers largely agreed the data indicated the drug was having an effect,” reported the popular scientific publication STAT. (Unfortunately, the article is paywalled.)

I first wrote about the therapy, produced by Sarepta Therapeutics, last May, saying that the “FDA Should Fast-Track New Muscular Dystrophy Drug.” It’s believed about 10,000 to 12,000 American children currently suffer from DMD. Those afflicted suffer a gradual weakening of the muscles, leading to difficulties with walking, standing, and other movements. Symptoms can range from mild to severe and may include muscle stiffness, frequent falls, difficulty climbing stairs, and trouble breathing. Death is not pleasant. (READ MORE: Being Vaccinated Against Anti-Semitism)

I noted that, currently, there are five FDA-approved drugs that can help slow the progression of the disease and improve muscle strength, but they don’t address the underlying genetic cause of the disease. Last month the FDA approved a sixth such drug. If Elevidys (then called by its clinical name SRP-9001) succeeds, I observed, it will be the first to actually address the cause. And it’s a one-time treatment. 

The Only Game in Town

Without finishing its Phase 3 clinical trial (usually, there are three phases), Sarepta sought a “fast-track” via conditional approval for a limited population and ultimately hoped to be able to treat anyone with DMD with expanded approvals. That would be the largest patient pool for any gene therapy developed to date.

I wrote previously that I normally oppose early approval of drugs or therapies, but that, among other aspects, this was the only game in town and would be indefinitely. I noted that the Cambridge-based biopharmaceutical company, Sarepta, only researches degenerative muscular diseases, primarily DMD. I said the therapy had reported positive results to date. And, finally, I mentioned that there were very few adverse side effects.

The FDA agreed with my position (um, no, I don’t take credit, although maybe somebody there saw my work) and granted accelerated approval for treating DMD kids aged 4–5 years with a confirmed mutation in the DMD gene. This is where evidence for benefit was strongest. (READ MORE: When Binding Is Not Enough)

Well, now Sarepta has reported results from that Phase 3 trial, called EMBARK. And judging from the immediate 37.5 percent drop in the company’s stock price, you might think it not only completely failed but also turned the recipients into flying monkeys. But the market is not rational (poor Mister Spock would lose his blue polyester shirt), and, in any case, the stock significantly recovered when investors were able to digest the actual news.

Indeed, Sarepta and its European distributor, Roche, said the results called for an expansion of the “label,” that is, those eligible for treatment, to all DMD patients. No more age restrictions and no regard for how ambulatory the recipient is. At a glance, that struck me as a pretty ballsy damage-control spin — especially for a treatment with an eye-watering sticker charge of $3.2 million. Until I gave the whole dataset a good look, that is. Including that price.

Do P-Values Even Matter?

The stock plummeted because Elevidys didn’t meet what’s called its primary endpoint. That’s important; it’s not called “primary” for nothing.

Both the company and the FDA agreed upon it. But that hardly justifies losing the essence in pursuit of perfection, better known by the trite expression “throwing the baby out with the bathwater.” (ChatGPT informs me that waging war against clichés does not categorize me as a “grammar Nazi,” which relieves me to no end.)

The EMBARK primary endpoint was functional motor abilities in children 4–7, as measured by scores on something called the North Star Ambulatory Assessment (NSAA) 52 weeks after treatment. Patients treated with the gene therapy saw a 2.6-point improvement on the NSAA, while scores of those on the placebo increased by 1.9 points. However, the difference of 0.65 points was not statistically significant, according to Sarepta.

Statistical significance, usually measured by something called a “p-value,” is somewhat controversial, made so in part by the alarmists I often criticize who want to scare the bleep out of us on any issue they’re advocating. They find an excess rate of cancer or hangnails associated with some chemical and ignore that one, association is not causation; two, there’s often no evidence that there was even exposure; and, three, it wasn’t statistically significant, meaning the results were quite possibly just by chance.

I’m not ready to accept that statistical significance should be ignored. But neither is it one of the Ten Commandments, even in any New Age translation of the Bible. Indeed, in 2019, over 800 scientists signed a letter calling for an end to p-value in scientific research, arguing it shouldn’t be concluded that there’s “no difference” or “no association” just because a p-value is larger than a given threshold. They said the errors waste research and misinform public policy.

I disagree. The better alternative is to say p-values still count but aren’t everything. We need to look at the bigger picture. 

We can ask: Was there any difference at all, even if not significant? As noted, with EMBARK there was. 

We should also consider biological plausibility. Can we think of why something might cause benefit or harm?

I fought a losing battle against those trying to associate so-called passive smoking with a million trillion conditions, probably including bunions and excess nasal hair. I’m not particularly sad about losing that battle, since I personally loathe even the smell of cigarette smoke and because it achieved its goal of shaming smokers into quitting. It was a matter of scientific honesty. And one aspect I pointed out was that there might be biological plausibility linking it to, say, asthma. But a lot of health problems attributed to those exposed to passive smoke haven’t been found in active smokers! (READ MORE from Michael Fumento: Is the World Finally Realizing ‘Long COVID’ Is a Harmful Fraud?)

Regarding positive biological plausibility, DMD results from genetic mutations that interfere with making the protein dystrophin, essential for muscle health. Elevidys was designed to deliver a gene encoding micro-dystrophin — a shortened, albeit functional, version of the protein — to muscle cells. Designs, especially interacting with biology, oft go aglay. If Sarepta also claimed it cured cancer and reduced excess nasal hair growth, we would rightly be suspicious. But it makes sense that Elevidys would be helpful. It is biologically plausible. 

EMBARK also indicated a greater impact on younger recipients — those with the least amount of damage. Biologically, that makes sense.

And this is very important. Throughout the trial, there was increasing measurable improvement in therapy recipients not seen in the matched controls. But the trial was set for 52 weeks and that’s that. “I’m fairly optimistic that, actually, if we would look in two years time,” Volker Straub, head of the British Muscular Dystrophy Research Center at Newcastle University, told STAT, “the difference between the treatment group and the placebo group will become bigger.”

Miracle Drug?

Now let’s consider the secondary endpoints of the trial. Sarepta noted the secondary efficacy findings all significantly outperformed the placebo, both overall and in all the predetermined age subgroups. Tina Duong, who studies neuromuscular outcome measures at Stanford and worked on the study, told STAT that the secondary measures may well be the best ones for children aged 4 to 7.

These included both time to rise (from the floor) and a 10-meter walk test. The gene therapy also showed treatment benefits in other timed functional endpoints, including stride velocity and time to ascend four steps.

“Passing five seconds on time to rise is the strongest predictor of early loss of ambulation,” and, in EMBARK, “Elevidys reduced those odds over 52 weeks by greater than 90%,” Sarepta CEO Doug Ingram said in a public statement, adding that EMBARK supported “the conclusion that Elevidys modifies the trajectory of Duchenne and benefits patients across age groups.” Here are the data.

Effective, yes. Safe? EMBARK didn’t reveal any new problems. About one-tenth of patients experienced a serious side effect related to treatment, but all were within the known range of safety issues, according to Sarepta. The most common treatment-related side effects were fever and digestive issues like vomiting, nausea, and decreased appetite. Typically you find a lot of that in groups that receive placebos as well. The most worrisome side effect found was liver damage, so the FDA requires a baseline liver test with a follow-up at three months.

The final argument for the continued use of Sarepta is that, sadly, there’s nothing else remotely similar available. No gene therapies.

That will eventually change. Pfizer has gotten a lot of attention for its DMD gene therapy, but, unfortunately, it’s mostly been negative. Testing has already been paused twice, once after three non-lethal “severe adverse events” and once after a death. It has since resumed testing. Likewise, Solid Biosciences has had a DMD gene therapy placed on hold twice but is again proceeding with early-stage clinical testing. I wish both companies well and hope more enter the field. No matter how well Elevidys works, every genome is unique, so we want various tools. Further, theoretically, the Pfizer and Solid Biosciences treatments could be superior overall.

But how about that call for an expansion of the current label to essentially anyone with DMD? In a conference call, Ingram said the FDA seemed “open to” some form of expansion, whatever that means. 

I think the FDA will increase the recipient group. “I would just say that I feel confident that the label should expand compared to where it is right now,” John Brandsema, a pediatric neurologist at Children’s Hospital in Philadelphia who was on the EMBARK, said. “But how broadly, I’m not willing to say.” Ditto.

Sarepta is also running another Phase 3 trial, testing Elevidys in older ambulatory boys (very few girls have DMD because they have two X chromosomes, and only one needs the functioning gene), as well as people with DMD of all ages unable to walk. It started earlier this year and is still recruiting patients. That could provide very helpful information.

Elevidys Is Worth It

Now here’s where we add the Fumento boilerplate that, within 10 years, I expect the rapid advances in binary and quantum computing power, plus AI, to render current drug discovery obsolete; all testing will be done within a computer. No more fruit flies, rodents, or human phase trials. And we will see some of that fruit long before then. Meanwhile, a lot of these poor DMD kids suffer and many will die without treatments approved or developed in the short term.

Regarding Sarepta’s asking price, $3.2 billion is what industry analysts call ALODM. That stands for “a lot of damned money” and is actually my joke. Sarepta says it’s a real deal because cost-effectiveness analyses show the current standard of care in treating DMD ranges from $5 million to $13 million. DMD patients are living longer than previously, especially when treatment begins early. But, unfortunately, that raises treatment costs.

I looked into Sarepta’s claim, and it cites mostly old research. Newer research published in the Journal of Market Access & Health Policy found that “[t]he maximum treatment cost was approximately $5 M,” so, theoretically, Sarepta could be saving $1.5 million. Mind, one problem is that those researchers worked for Sarepta. Ahem! 

Still, this is not Mylan acquiring EpiPen and raising the price from $100 to over $600 despite the cost of an EpiPen dose of epinephrine remaining at around one buck — for which Mylan and its subsidiaries paid a settlement of $264 million.

Americans generally pay vastly more for drugs and therapies than do other countries because of the triumvirate of the AMA, Big Pharma, and the insurance industry. When people ask me how I can live in such corrupt countries as Colombia, Mexico, and the Philippines, I point to this.

I recently wrote in these pixels about GLP-1 agonist drugs that are truly miraculous in causing weight loss, and, since then, studies have shown what we’d expect: that they confer the health benefits associated with being less fat. (Er, plus-sized.) 

With about three-fourths of Americans overweight and most of those outright obese, hell, we should be putting them in the water supply. Instead, an analysis of prices for one of the cheaper ones here found it was $936 in the U.S. (one of its competitors charges $1,349) but only $83 in France, with Japan coming in second at $169. A lot of us would be willing and able to pay $169 out-of-pocket to quickly lose a remarkable amount of weight, but a thousand bucks or more means we’re insurance-dependent.

The system is broken and needs fixing, but Sarepta is a tiny cog in a very big wheel — it doesn’t make the rules; it plays by them. By that standard, the price isn’t so ALODM.

In that first article, I noted there’s a Vimeo video of DMD kids who seem to have recovered lost abilities to walk and even jump around. You can almost never rule out the power of placebos; they seem to help practically everything but cancer. But damn, that video gets to you.

Combined with the EMBARK data, it is reasonable to assume that Elevidys did help some of those children. At the rat tail of the bell curve, some Elevidys recipients may live long normal lives or, at least, be carried into that time when new drugs and treatments are all developed in computers. I suffered from a war injury that made me lame for eight years until I got surgery, along with two prematurely arthritic hips that have now been replaced. To that slight extent, I identify with those kids and their parents and support the expansion of those eligible to receive this novel therapy.

Michael Fumento ([email protected]) is an attorney and author and has been a science journalist for over 35 years. His work has appeared in the New York Times, the Washington Post, the Wall Street Journal, the Sunday Times, the Atlantic, and many other fora. He owns no Sarepta stock and, because he wrote these articles, will not buy any.