Experimental treatment shows promise for ALS
Experts caution a cure is not imminent but drugs making impact
Seven years ago, Joshua Cohen, then a junior at Brown University majoring in biomedical engineering, wondered why people develop brain disorders. “How does a neuron die?” he thought.
After poring over scientific studies, he sketched out his ideas for a way to treat them. “I was sitting in my dorm room and I had kind of written out the research on these crazy-looking diagrams,” he recalled.
A study published last week in the New England Journal of Medicine reported that the experimental treatment he and another Brown student, Justin Klee, conceived may hold promise for slowing progression of amyotrophic lateral sclerosis, which robs people of their ability to move, speak, eat and breathe.
More than 50 clinical trials over 25 years have failed to find effective treatments for ALS, also called Lou Gehrig’s disease, which often causes death within two to five years. But now, scientific advances and an influx of funding are driving clinical trials for many potential therapies.
The new study reported that a two-drug combination slowed progression of ALS paralysis by about six weeks over about six months, approximately 25 percent more than a placebo. On average, patients on a placebo declined in 18 weeks to a level that patients receiving the treatment didn’t reach until 24 weeks, said the principal investigator, Dr. Sabrina Paganoni, a neuromuscular medicine specialist at Massachusetts General Hospital’s Healey & AMG Center for ALS.
“It’s such a terrible disease and as you can imagine, for the folks who have it or the family members, it’s just desperation that something’s going to work,” said Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, who wasn’t involved in the new study. “Any kind of slowing of progression for a patient with ALS might be valuable even though it’s not a big effect.”
He and other experts were careful not to overstate the results and noted that the drug wasn’t shown to improve patients’ condition or halt decline. The study evaluated safety and efficacy in a Phase 2 trial with 137 participants, not as large and long as many Phase 3 trials often required for regulatory approval. Experts and the authors themselves said further trials were necessary.
Still, doctors and advocates said the relentlessness of the illness and the availability of only two approved ALS medications gives urgency to finding additional treatments. The ALS Association, an advocacy group, said that since the study found the drug to be safe and patients can die waiting for other trials, it should be made available to people with the disease as soon as possible.ALS, the most common motor neuron disorder, diagnosed in about 6,000 people worldwide each year, has drawn greater attention of late, bolstered by prominent people with the disease, like Stephen Hawking, the astrophysicist who died in 2018; Steve Gleason, a former professional football player; and Ady Barkan, a health care activist who used a computer-generated voice at this year’s Democratic National Convention because he can no longer speak.
There is now legislation in Congress to accelerate ALS therapy access and a $25 million federal research program. The Ice Bucket
Challenge, a 2014 fundraising campaign featuring celebrities and others dumping icy water on their heads, generated about $220 million. More than 20 treatments are being tested, including stem cells, immunotherapy and genetic therapies for the 10 percent of cases caused by known mutations. Results from other trials are expected soon.The study is the first clinical trial supported by Ice Bucket Challenge money to publish results, said the ALS Association. Amylyx financed the bulk of the study and agreed to use a percentage of income from sales of the drug to repay 150 percent of the association’s grant to fund more research.
Cohen’s idea in 2013 was that a combination of taurursodiol, a supplement, and sodium phenylbutyrate, a medication for a pediatric urea disorder, could safeguard neurons by preventing dysfunction of two structures in cells, mitochondria and the endoplasmic reticulum.
He quickly involved Klee, a senior neuroscience major who was a fraternity brother and fellow player on the university’s club tennis team. Over cheap sparkling wine, “we both said ‘let’s start a company,’” Klee said. “We had no idea what we were doing.”In most secondary measures, including muscle strength, respiratory ability and whether patients were hospitalized, AMX0035 appeared better than the placebo, although it wasn’t statistically significant. Another measure, a biomarker of neurodegeneration, didn’t seem significantly affected. A few patients died in both groups, but experts said identifying the effect on mortality would require evaluation over a longer period.
“This is very encouraging,” said Dr. Neil Shneider, director of the Eleanor and Lou Gehrig ALS Center at Columbia University, who was not involved. “The question is, is the effect on function sustained beyond the sixmonth trial period and does it have an effect on survival?”
Experts said that making the drug available soon might make it difficult to recruit patients for subsequent trials. And insurers may not cover drugs approved based on Phase 2 results, Koroshetz said. Some patients have had difficulty getting insurance coverage for edaravone, which costs about $148,000 a year and was approved after a Phase 3 trial of the same size and duration as Centaur. Amylyx officials declined to provide a price estimate for their treatment.
In interviews, two trial participants said they believed AMX0035 was beneficial. Given the unpredictable trajectory of the disease, they said any specific effects were hard to describe. Neither knows if they received the drug or placebo during the trial, but they’ve received the treatment since.
Mike Teal, 52, of Tallahassee, Fla., began having symptoms in 2016 and has taken the drug since at least the spring of 2018, when his trial ended. Soon after, he also started edaravone.
He currently has limited speech, needs a feeding tube, often uses a wheelchair and requires a breathing machine every few hours. Last year, he had to stop working at the gift and accessories store he owns with his wife, Lauren.
He said he has had no negative side effects and believes the drug may have eased cramps in his neck, abdomen and legs. “I’m confident it has slowed my progression,” he wrote in an email. “But it’s difficult to measure.”