ALS can be as quick as it is devastating. The neurodegenerative illness, also known as Lou Gehrig's disease, typically is fatal two to five years after patients first show symptoms.
To understand the disease's progression, clinical researchers use a scorecard that assigns points based on how well patients perform essential functions like speaking, walking, breathing and writing. The maximum number of possible points is 48, with higher scores reflecting less severe disease and longer life expectancy.
Each point matters, according to Sabrina Paganoni, co-director of the Neurological Clinical Research Institute at Massachusetts General Hospital. It could mean the difference between legible or illegible writing, between needing help to walk and not being able to walk at all. That sensitivity, Paganoni said, is a big reason why new data published Wednesday in The New England Journal of Medicine are exciting.
The data show patients with rapidly progressing ALS who took an experimental drug called AMX0035 had better scores than those who didn't. More specifically, drug-treated patients scored an average 2.3 points higher and had slower rates of functional decline than patients given a placebo.
Paganoni, who served as the trial's principal investigator, called the results a milestone in the fight against ALS. Like most nervous system diseases, the complex biology behind ALS has meant many potential treatments have failed in clinical testing. Just three drugs, riluzole, edaravone, and now AMX0035 have been able to demonstrate statistically significant benefits on functional decline.
"A 2- to 3-point change ... might sound small," Paganoni said. "But really, on this scale, even a small change can mean a large impact on daily life."
AMX0035 is far from a cure, nor is it clear how much the drug could change the disease's course. Patients given the drug still declined. Paganoni and her fellow investigators acknowledge too that larger and longer studies of the drug are necessary, both to verify the data seen so far and to address remaining questions.
For Michael Benatar and Michael McDermott, two neuroscience researchers who co-authored an editorial published alongside the trial results, there's a key issue that needs resolving. While patients given AMX0035 did better on the functional scorecard, they did not significantly outperform placebo-treated patients on other "secondary" tests that measured breathing, hospitalization rates and overall muscle strength.
Benatar and McDermott wrote that this "lack of convincing supporting evidence" creates uncertainty around the drug's effect, which they judged to be "incremental."
What's more, the trial sampled patients' blood plasma to look for proteins that scientists think may be indicative of nerve degeneration from ALS. Again, there was an "absence of effect" — which, according to Benatar and McDermott, makes the results more difficult to interpret.
Amylyx Pharmaceuticals, the company developing AMX0035, doesn't necessarily agree with that assessment. Co-founders Josh Cohen and Justin Klee note how the trial wasn't designed to prove whether their drug could beat placebo on the secondary endpoints.
And though AMX0035 wasn't significantly better, it was numerically better than placebo on several of those endpoints. That data, combined with the study meeting its main goal, gives Amylyx confidence its drug will resonate with doctors and patients.
"Just in talking to many physicians, I don't think most people view this as 'incremental,'" Cohen said.
"This is not a cure. I think we all hope that we have cures," Klee added. In the meantime, "we need therapies that help the nervous system not degenerate. That's what we're trying to do with our therapy. And while it's just a start, we also think that the results we're presenting here are some of the best results anyone has produced in ALS."
Amylyx had said in December that its drug met the study's main goal, but didn't disclose any details until Wednesday's publication in NEJM.
In addition to efficacy data, researchers reported nearly all patients experienced an adverse event while in the study, regardless of whether they received the drug or placebo. Most weren't serious, although 19% of patients given the drug had to stop treatment due to adverse events, versus only 8% on placebo.
Amylyx is currently running an extension study to evaluate the long-term use of its drug in patients who completed the earlier trial. According to the company, 92% of eligible participants have chosen to enroll. Interim data are already being submitted to a peer-reviewed journal, and should be published in the coming months.
Cohen and Klee said they're in ongoing discussions with regulatory agencies in the U.S., Europe and Canada about the next steps for their drug. They couldn't say, though, whether another large clinical trial will be required to file for approval.
"In a disease are like ALS — unlike, for example, in oncology — there's just much less precedent," Klee said. "There's not the same: 'Here's how we run the trial, and if it hits this it goes forward.' I think that's why the conversations are still ongoing."
Endaravone, which is sold as Radicava by Mitsubishi Tanabe, was approved in May 2017 for data similar to what Amylyx has collected.
Regardless of the regulatory path, the executives said they do anticipate having to study their drug in a broader pool of ALS patients. The completed trial had enrolled only patients with "definite" ALS who started experiencing symptoms within the previous 18 months, and whose disease was rapidly progressing. Benatar and McDermott wrote that drugs can appear to work more noticeably in these kinds of patients, so it would be valuable for future trials to be open to a wider variety.
Including slower-progressing patients may also help with drop-out rates. About a quarter of drug-treated patients discontinued Amylyx's study early, which is higher than the 20% rate typical for ALS studies. Cohen said the higher rate was due in part to patients wanting to spend more time with family and less time traveling to treatment facilities.
"Studying the drug in a broader population is going to be really important," Cohen said. "Doctors are going to want to know that information. Payers are going to want to know that information."
Amylyx's work comes during a pivotal time for ALS drug research. Armed with a better understanding of disease, companies are trying to develop targeted therapies meant to silence the mutated genes believed to cause it. In July, NEJM published positive clinical data on one such drug being developed by the world's largest neuroscience biotech, Biogen.
The Sean M. Healey and AMG Center for ALS at Mass General, which helped run Amylyx's study, is also studying five other experimental therapies for ALS in a first-of-its-kind trial.