“My experience with ALS has not been kind. So, every day is like, hey, we’re winning.”
A new drug is creating hope for some stricken with the devastating disease amyotrophic lateral sclerosis (ALS) where, for so long, there was none.
ALS is a progressive disease that affects nerve cells in the brain and spinal cord that control voluntary muscle movement. Eventually muscles weaken, then atrophy, and the brain loses the ability to control voluntary movements, robbing people of their ability to walk, talk, eat, and breathe. There is no cure.
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 Todd’s lower spine.
Todd 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, Todd’s arms were weakening, his right arm especially. He was having more and more trouble breathing. And his stamina was nonexistent. Todd, who was 48 when he was diagnosed, says that he felt like he went from his late 40s to his late 70s in the span of a year.
But over the last two years, the rate at which his ALS is progressing seems to have slowed dramatically. His arms — shoulders, really; he can’t raise his right arm to his shoulder – have weakened slightly more. However, his legs remain strong, and his breathing ability has 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,” Dr. Quinn says.
Todd says Qalsody™’s effects were strong enough that he could appreciate a “plateau” in his condition before he and Dr. Quinn fully understood what was going on. Since that time, Dr. Quinn has become convinced of Qalsody™’s ability to slow the progression of Todd’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 says. “And I’ve never had that before.”
Dr. Quinn has been involved in more than a dozen clinical trials for ALS drugs. Even with the ones that were eventually approved by the FDA, he says he had difficulty discerning whether they worked.
But Qalsody™’s impact, he says, is undeniable.
“I’ve talked to several other clinicians involved in the trial, and they all say the same thing,” Dr. Quinn says. “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 adds. “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.”
At last, a breakthrough
In April, the FDA granted accelerated approval to the drug, making it available to people beyond trial participants. But only those with Todd’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 that Todd 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.
Dr. 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 Dr. 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 the mutations are causing the disease. (That goes for Todd’s mutation, too.) But it’s more than what they know about the causes of sporadic ALS.
Still, Dr. 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 says. “There are now 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,” Dr. Quinn says. “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.”
Gaining precious time
During the several months that preceded his diagnosis, Todd was in denial about his various symptoms. Appearing before an FDA advisory committee that was reviewing evidence for Qalsody™ in March, he described his diagnosis as a “death sentence.”
“My experience with ALS has not been kind,” Todd says. “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’s caused Todd’s ALS.)
“My experience is you don’t have long,” he says. “So, every day is like, hey, we’re winning.”
Beyond Qalsody™’s impact, Todd 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 says. “I don’t want to give in and ask for help, so I keep finding new ways to do stuff.”
Todd continues to be a handyman around his home in upstate Pennsylvania, load his woodburning stove with logs, teach math at Montrose Junior-Senior High School, and coach his son’s Little League team. He readily admits he’s not as efficient at any of it as he’d like to be, but he’s managed to cultivate some patience for himself and gratitude that he’s able to do any of it at all.
This summer, he’ll be playing golf with his wife in a local couples’ league.
“It’ll be ugly golf, but it’ll still be golf,” he says.
All the while, he’ll continue to receive his injection of Qalsody™ from Dr. Quinn every four weeks.
“I couldn’t ask for better care,” Todd says of his ongoing treatment at Penn. “The interaction with everybody there has been great. And coming from a town with two stoplights, our visits are not only helping us move forward and gain precious time, they’re also giving us experiences we would have never had.”