New drug offers hope after an ALS diagnosis: Todd's story

In October 2020, two months after he was diagnosed with ALS and about a year after he started experiencing symptoms, Todd Legg received his first injection in a clinical trial studying the effects of a new ALS drug called Qalsody™ (tofersen). Colin Quinn, MD, co-director of the Penn Neuromuscular Center for Advanced Therapeutics, administered the shot to Legg's lower spine.

Legg doesn’t know whether he got the drug or a placebo for the first six months. But he and the other trial participants have received the drug since that point, and the results are unlike anything ALS researchers have seen before.

At the start of the trial, Legg's arms were weakening, his right arm especially. He was having more and more trouble breathing. And his stamina was nonexistent. Legg, who was 48 when he was diagnosed, said he felt like he went from his late 40s to his late 70s in the span of a year.

Promising results

But two years after his treatment began, the rate at which his ALS was progressing seemed to have slowed dramatically. While his arms and shoulders weakened slightly more, his legs remained strong, and his breathing ability basically stabilized, which is unheard of.

“Usually, once your breathing is affected and going down at a certain rate, it tends to keep going down at a similar rate until a bottom point,” Quinn said.

Legg said Qalsody™’s effects were strong enough that he could appreciate a “plateau” in his condition before he and Quinn fully understood what was going on. Since that time, Quinn has become convinced of Qalsody™’s ability to slow the progression of Legg's ALS.

“With the trajectory he was on, there’s just no way—the statistical probability of this just being his disease stopping or completely changing the slope is so unlikely,” he said. “And I’ve never had that before.”

Quinn has been involved in more than a dozen clinical trials for ALS drugs. Even with those eventually approved by the FDA, he had difficulty discerning whether they worked.

But Qalsody™’s impact, he said, is undeniable.

“I’ve talked to several other clinicians involved in the trial, and they all say the same thing,” Quinn said. “I wouldn’t say that about every patient, but we all have patients where the disease has been largely frozen in place.

“To be clear: Todd’s ALS is progressing, but at a much slower rate than it was,” he added. “He came into the trial as a ‘rapid progressor.’ He changed an enormous amount before we met. But now he’s been changed to an entirely different track.”

FDA accelerated approval

In April 2023, the FDA granted accelerated approval to the drug, making it available to people beyond trial participants. But only those with Legg's particular type of genetic mutation could potentially benefit from the treatment.

About 90 percent of ALS cases are considered sporadic, meaning they have no known cause. The other 10 percent are caused by various genetic mutations. The one Legg has causes him to make an abnormal, toxic version of a protein called SOD1. As it accumulates in the central nervous system, it causes the nerves that control muscles to deteriorate.

Quinn estimates that those with this SOD1 mutation represent two percent of ALS cases, or several hundred people in the United States. Most die within a few years.

Qalsody™ is designed to limit the body’s ability to make this toxic protein. After a few months on the drug, levels of SOD1 decrease by about a third, which is enough to significantly slow the rate of nerve damage, according to Quinn.

ALS drugs, to this point, have focused on the genetic mutations that are believed to cause the disease because the mutations are targets, even though researchers aren’t entirely clear how they cause the disease. (That goes for Legg's mutation, too.) But it’s more than what they know about the causes of sporadic ALS.

Still, Quinn believes this could be a watershed moment. For the first time, researchers have proven an ability to engage one of these targets and affect the disease in a meaningful way.

“Now, the great leap forward is finding targets for sporadic disease because they exist,” he said. “There are multiple trials looking at trying to affect abnormal pathways in sporadic ALS, which could have huge ramifications for a much larger population.”

The Qalsody™ trial has also afforded a unique opportunity to observe its impact over years, not just months. The other three ALS drugs approved by the FDA–RELYVRIO, Radicava, and riluzole—have been shown to add two to five months to a patient’s life. Even then, it’s hard to say whether their lives were improved by having taken the drug.

“That’s the frustrating thing about the medicines that we’ve had approved: it’s very hard for anyone to know,” Quinn said. “The patients don’t notice. And I have a hard time noticing. Whereas the effect size feels larger for Qalsody™ because I’m following someone over a longer period of time.”

During the several months that preceded his diagnosis, Legg was in denial about his various symptoms. Appearing before an FDA advisory committee that was reviewing evidence for Qalsody™, he described his diagnosis as a “death sentence.”

“My experience with ALS has not been kind,” Legg said. “When my mother was diagnosed, she was in the hospital probably two weeks later. And we had to decide what to do. We were able to keep her at home for about a year, which was an immense amount of work for our whole community, really.”

She died 15 months after she was diagnosed with ALS. She was 58. (She was never tested for the genetic mutation that caused Legg's ALS.)

“My experience is you don’t have long,” he said. “So, every day is like, hey, we’re winning.”

Beyond Qalsody™’s impact, Legg is resilient, a quality he attributes it to his “pig-headed and stubborn nature.”

“It got me into a lot of trouble over the years, but I feel it’s the one thing that keeps me going pretty steadily now,” he said. “I don’t want to give in and ask for help, so I keep finding new ways to do stuff.”

Legg continued to be a handyman around his home in upstate Pennsylvania, loading his woodburning stove with logs, teaching math at Montrose Junior-Senior High School, and coaching his son’s little league team. He readily admitted he’s not as efficient at any of it as he’d like to be but has managed to cultivate some patience for himself and gratitude that he’s able to do any of it at all.

He also continued to play golf with his wife in a local couples’ league.

“It’s ugly golf, but it’s still golf,” he said.

All the while, he received his injection of Qalsody™ from Quinn every four weeks.

“I couldn’t ask for better care,” Legg said of his ongoing treatment at Penn Medicine. “The interaction with everybody there has been great. And coming from a town with two stoplights, our visits not only help us move forward and gain precious time, they also give us experiences we would have never had.”