The FDA’s approval of Amylyx’s Relyvrio has ignited the growing momentum in the ALS space. BioSpace spoke with Amylyx co-CEOs Justin Klee and Josh Cohen and leading ALS researcher Dr. Merit Cudkowicz.
From left: Amylyx Co-CEOs Justin Klee and Josh Cohen/courtesy Amylyx
Say what you will about the $158 thousand price tag on Amylyx’s newly minted Relyvrio or the worthiness of the CENTAUR trial, the FDA’s approval of its third-ever ALS drug has ignited the growing momentum in the space.
Coming on the heels of Biogen and Eisai’s seeming breakthrough – and possible redemption of the anti-amyloid theory – in Alzheimer’s disease, hope in neurodegenerative disease research is at a heady high.
Justin Klee, co-founder and co-CEO of Amylyx, quoted Genzyme founder and long-time CEO Henri Termeer, whom he and co-founder/CEO Josh Cohen count as a mentor.
“Henri used to often say that there’s a point where a treatment goes from being an opportunity to a responsibility,” he said. “I think we’re very much in that position now.”
It’s a responsibility the co-founders take seriously. They shared that quality teams have been working around the clock for months in preparation for an approval and that Relyvrio should reach U.S. pharmacies within 4-6 weeks.
Based on conversations with leaders in the ALS community, Amylyx is prepared for “rapid uptake,” Cohen said.
Measuring the Milestone
Post-hoc analyses of the Phase II CENTAUR trial using the rank-preserving structural failure time model (RPSFTM) to account for placebo cross-over estimated an 18.8-month longer median survival duration with Relyvrio.
While Mitsubishi Tanabe’s Radicava (edaravone), which was approved in 2017, showed an impact on survival, Relyvrio demonstrated an impact on both functional progression and median survival.
“In our understanding, there haven’t been other trials that have seen both differences,” Cohen said.
The CENTAUR trial did not formally measure quality of life but, “As people with ALS progress, they lose functional abilities, and as you lose functional abilities, that can have an impact on your quality of life,” Klee added.
Greg Canter, a CENTAUR trial participant from Cincinnati, Ohio was diagnosed with ALS in October 2018.
When Canter began the trial in January 2019, his forced vital capacity was at 60%. At the end of the trial, this number dropped to 44%. He joined the open-label extension part of the study in July 2019, and at his last check-in, his FVC was 39%.
“If it wasn’t for the [AMX0035/ Relyvrio], I would not be alive today,” he told BioSpace in an interview. “My data speaks for itself. Since I’ve been guaranteed the drug, I’ve only dropped around 5% In three years and three months. If I hadn’t had the medicine in me and continued that deep decline, who knows how long I would have lasted.”
Quality of life will be officially measured in the ongoing Phase III PHOENIX trial, as well as potential impact on disease progression over a 38-week period.
Lessons Learned
Relyvrio is not being hailed as a game-changer for ALS, a progressive neurodegenerative disease that steals a person’s ability to control their muscles, speak, and finally, breathe.
“While we’re very excited about the results, [Relyvrio] is not a cure, so we need to keep pushing until we get to that point,” Klee said.
The road to Relyvrio’s approval has offered several lessons for ALS drug developers.
“We’re strong believers that the answer to ALS, and probably all neurodegenerative diseases, is going to be combination therapy,” Klee added. “It may be that different combinations work for different groups of people, but the only way we’re going to know that is if we keep driving and keep studying.”
Klee pointed to the HEALEY ALS Platform Trial, a multi-center clinical trial investigating several investigational drugs simultaneously with a single master protocol. The Amylyx team hopes to investigate the potential of using Relyvrio in combination with some of these treatments.
“It’s how we’ve gotten to major advances in oncology and other disease areas and we hope to do the same with ALS,” he said.
Dr. Merit Cudkowicz, director of The Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, shared that the first results from the original therapies in the study are expected soon.
The HEALEY trial is “an approach to learn about the biology of ALS through digital and fluid biomarkers,” said Cudkowicz, who was also co-principal investigator of the CENTAUR trial. “We have shared our knowledge with other disease groups interested in platform trials in neurology – like many cancer groups shared their knowledge with us,” she added.
Cudkowicz anticipates “many more platform trials in the neurosciences” as researchers gain a better understanding of disease pathologies and better experimental treatments enter the pipeline.
Since the approval of Biogen’s Aduhelm (aducanumab-avwa) for Alzheimer’s in June 2021, the ALS community has been demanding similar regulatory flexibility.
The approval of Relyvrio can be seen as answering that call, issued this summer by the FDA’s Action Plan for Rare Neurodegenerative Diseases, Including ALS.
“We learned that it is possible to get good data in a 6-month study,” Cudkowicz said. “Like oncology, there is a pathway for approval on a single study if [the] data supports; and especially if a company, like Amylyx, is committed to completing a second phase III trial. This is a great model of how to develop a drug and get it to the people who need it.”
Five Years of Advances
With Relyvrio now approved in both the United States and Canada, Klee and Cohen are looking ahead, both to the PHOENIX trial and further therapeutic possibilities.
“The mechanism has great rationale in other diseases too, so we want to look at trying Relyvrio in other neurodegenerative diseases,” Klee said.
Amylyx has so far only studied Relyvrio at one dose. The company hopes to further optimize it.
“We’ve seen a benefit in this trial,” Cohen said. “Are there ways to modify [and] improve the drug to get even more out of it?”
Advances in the ALS space have piled up over the past five years. Radicava was approved in May 2017 as the first new drug for the disease in 22 years. BrainStorm Cell Therapeutics’ NurOwn demonstrated a “meaningful response” in a subgroup of patients with early-stage disease, and later analyses showed a much broader impact. Most recently, pivotal one-year data showed Biogen’s tofersen slowed decline in superoxide dismutase 1 (SOD1) ALS patients. Researchers have also gained a greater understanding of the link between UNC13A, a gene encoding protein, and the disease process.
“We have a much better understanding of the biology – though a lot still to learn,” Cudkowicz said. “We have more models of the illness - in vitro and in vivo. We know many of the genetic underpinnings. The field is exploding, with new insights literally weekly or monthly. It gives great hope.”
Cohen shared that Relyvrio was designed based on a detailed reading into the pathways of cell death – in 2013.
“In the last decade, the field of cell death has grown tremendously and there are tons of new pathways, new biology, that could be pursued to develop new therapies targeting cell death,” he said.
Canter said he believes this is stage one in the fight against ALS.
“What we’re experiencing right now is something we have never seen in ALS,” he said. “Yes, we’ve had Riluzole and the Radacava, but I feel Amylyx is a little stronger and a little better treatment than that. It provides a little bit more.”
The Next Stage
As for the future, “We need to continue to invest in [the] basic neuroscience of ALS. This is critical particularly for the sporadic form of the illness,” Cudkowicz said.
She also pointed to the need for an earlier diagnosis. Currently, individuals are being diagnosed approximately 12 months after symptom onset.
“We need to move that needle…and even study what happens before symptom onset,” Cudkowicz said. “We have seen the impact of those types of studies in Parkinson’s disease and Alzheimer’s.”
Cohen and Klee offered the following advice to drug developers in the space.
“There are some amazing clinicians, doctors, patients and advocates out there,” Cohen said. “Get out there; talk to them, learn from them, because there are a lot of great ideas and great experience in how to be really thoughtful in designing and executing trials and developing drugs.”
Klee stressed the importance of getting experimental treatments into people.
“For so long, there was great science in ALS [but] there wasn’t the translation into clinical trials, and I think that’s started to change,” Klee added. “We have great preclinical models, but the real test of if this is going to be a treatment that can benefit people is to get it into clinical trials. That’s why we think things like the HEALEY platform trial are revolutionary.”
