ALS drug is debated, but one guy has no doubt
Recently approved by FDA, medicine is effective for at least this patient
Todd Legg started to have trouble breathing in December 2019. He noticed that his hands and arms would cramp when washing dishes at home in Brackney, Pennsylvania, north of Scranton.
His wife feared the worst, remembering that Legg’s mother had died of ALS, or amyotrophic lateral sclerosis, which causes loss of muscle control and eventually robs people of their ability to walk, talk, eat and breathe.
No way, Legg said. He was only 47. It was wintertime, so he was probably just out of shape or dehydrated, he reasoned.
Yet within months, after his breathing grew weaker, Legg’s doctors determined that his wife’s hunch was correct. He had ALS, and he likely would become paralyzed and die in a few years. The doctors said there was little they could do — unless he was willing to try an experimental new drug.
Two years after Legg started getting injections of the drug at the University of Pennsylvania, his breathing has remained fairly stable, good enough for him to hunt, fish and coach his son’s Little League team. Recently, the Food and Drug Administration granted accelerated approval to the drug, tofersen, meaning others with Legg’s type of mutation will be able to get the treatment, too — if insurers agree to pay.
The news was cheered by people with the deadly disease, though most of them have forms of ALS for which the drug won’t work. Most cases have no known
genetic cause. About 10% of cases are caused by a genetic mutation, and tofersen treats a fraction of those. And even for those who do qualify for the treatment, there is debate over its effectiveness.
In the first six months of a clinical trial, patients getting the drug fared no better than those who received a placebo, as measured on a combined scale of everyday functions such as breathing, swallowing and walking. Still, those who received the drug had significantly lower levels of a key biomarker — a telltale substance in the blood that indicates when the person’s nerves are degenerating.
That was enough for the FDA to grant accelerated approval, which is reserved for serious diseases without good treatments. Further research is underway to confirm that the drug, to be sold as Qalsody, is effective, including a study of people with the mutation who have yet to
show symptoms.
In Legg’s case, Penn Medicine neurologist Colin Quinn has no doubt that the drug worked.
Yet he almost didn’t get to try it. When the research team first evaluated Legg, his breathing ability had declined too much for him to qualify for the trial. So the team sent a nurse to Legg’s home to measure his breathing strength a second time, and he just made it. In October 2020, he was in Philadelphia to get the first injection.
“That’s the difference between him being alive today and not,” Quinn said, “which is so scary to think about.”
In patients with Legg’s form of ALS, the genetic mutation causes them to make an abnormal, toxic version of a protein called SOD1. As the protein accumulates in the central nervous system, it causes deterioration in the nerves that control muscles, which start to wither away as a
result. Patients — currently numbering several hundred in the U.S. — typically die within a few years.
Tofersen tamps down the body’s ability to make the toxic protein. It consists of short strands of genetic material called antisense oligonucleotides, or ASO, delivered via periodic injections into the spine.
It is made by Cambridge, Mass.-based Biogen. Among the scientists overseeing the drug’s development at the company is Toby Ferguson, formerly a researcher at Temple University and Penn.
After a few months on the drug, levels of the protein decline by about one-third — enough to slow the rate of nerve damage, Quinn says.
Legg, a high school math teacher, likes to repeat an analogy that an acquaintance came up with: “Let’s say you have a pond and it’s full of some kind of fish or critter than you want out, so you put in there a bigger fish that’s going to eat them,” he said. “It’s not going to happen overnight.”
The FDA’s process for approving certain drugs without conclusive evidence has sparked controversy.
The agency followed the same pathway in its recent approval of a drug for Alzheimer’s called Leqembi. As with the drug for ALS, the strongest evidence in favor of Leqembi consisted of biomarkers — indirect measurements suggesting that the drug is effective.
Underwhelmed by the results, the Centers for Medicare and Medicaid Services has declined to pay for the drug until additional evidence emerges. Yet in March, the VA agreed to cover the drug for veterans.
Quinn is optimistic there will be no such uncertainty with the ALS drug — that all insurers will cover it.
He cited the fact that after the first six months of the trial, participants who had been taking the placebo switched to the real drug. In the two years since, their condition has stabilized somewhat.
David Weisman, a neurologist who served on the FDA advisory panel that reviewed the evidence for the ALS drug, agreed that signs are promising.
“I think it works over a longer timeframe,” he said.
On March 22, Weisman and his fellow advisers voted unanimously that the drug was “reasonably likely” to prove beneficial, paving the way for the agency to approve it.
That happened to be the same day as Legg’s 36th injection.
Sitting on an examination table at Penn’s Perelman Center for Advanced Medicine, Legg leaned forward so Quinn could insert a slender needle into his lower spine.
First, the physician drew a few drops of Legg’s spinal fluid for analysis. Then he injected the drug, slowly depressing a syringe over the course of two minutes.
The first three injections in 2021 were two weeks apart. Since then, they’ve been every four weeks.
By now, Legg is so comfortable with the process that even with a needle in his back, he is able to use his smartphone.
At home, he has learned to live with his condition. Though the drug appears to have slowed nerve damage and stabilized his breathing ability, the muscles in his right arm have grown substantially weaker.
Naturally right-handed, Legg taught himself to write with his left hand on the board in his classroom. He has even managed to throw left-handed for his son’s Little League team for batting practice.
“I keep trying to everything that I can do,” he said. “It’s not nearly as fast. Maybe not as good. But we try to do what we can.”