FDA Approves AMX0035 (Relyvrio) for ALS

On September 29, 2022, the U.S. Food and Drug Administration (FDA) approved AMX0035 (Relyvrio) for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The drug was developed by Amylyx Pharmaceuticals.

ALS is the most common neurodegenerative disorder of midlife; more than 120,000 people worldwide have ALS, including approximately 29,000 adults in the United States. When a person has ALS, the neurons in the brain and spinal cord degenerate and can no longer communicate with the muscles.

ALS is in the same family of diseases as Alzheimer’s disease or Parkinson’s disease, explains Jim Caress, MD, a neurologist and researcher at Atrium Health Wake Forest Baptist in Winston-Salem, North Carolina. Dr. Caress was one of several researchers involved in the phase 2 trial of the drug. “With Alzheimer’s disease, it affects memory, with Parkinson’s disease, it’s movement, and with ALS, it’s strength,” he says.

Over time, people with ALS are no longer able to move, talk, swallow, and breathe. There is no cure, and 80 percent of people with the disease die within two to five years of diagnosis.

More Data and Patient Advocacy Helped Spur Drug’s Approval

Relyvrio joins two other FDA-approved medications for treating ALS, riluzole (Rilutek) and edaravone (Radicava). “Riluzole can extend survival for several months, and edaravone has been shown to slow the progression of ALS,” says Caress.

Both of these drugs have modest effects on ALS, he says. “They are neuroprotective drugs, and they actually help neurons live longer. Although patients don’t typically feel better, these medications do actually slow the disease down,” he says.

Earlier this year, AMX0035 was approved in Canada, where it’s sold as Albrioza, with the condition that the company provide stronger evidence that the treatment works (the company is currently conducting a larger phase 3 trial for the drug in Europe and the United States.)

Yesterday’s nod from the FDA comes about six months after an advisory committee voted against approving the drug based on the phase 2 data, stating that although the findings with AMX0035 in treating ALS appeared promising, “we have considerable concerns that the data may not be sufficiently robust to meet the approval standard for substantial evidence of effectiveness.”

After that announcement, thousands of ALS patients and patient advocates, including the ALS Association, lobbied fiercely in favor of giving people with the disease an opportunity to take the medication, according to NPR. That, along with some additional analyses of data that were submitted to the FDA, was enough to persuade the advisory committee to support the approval of AMX0035.

How Relyvrio Works

Relyvrio is a combination of two different drugs, sodium phenylbutyrate (Buphenyl), a supplement that can be used to regulate liver enzymes, and tauroursodeoxycholic acid, or TUDCA, a medication for pediatric urea disorder. It comes as a powder that is mixed with water and drunk or delivered via a feeding tube twice a day.

In the lab, both of these medications have shown some success protecting neurons by preventing dysfunction of two structures in the cells, the mitochondria and the endoplasmic reticulum, says Caress.

“The founders of the company looked at the data and thought that putting these two drugs together might have a synergistic effect in helping ‘sick cells’ manage their stress better and survive longer,” says Caress.

Patients Taking Relyvrio Lived an Average of 6 Months Longer

The approval is based on the findings from CENTAUR, a multicenter phase 2 clinical trial published on September 3, 2020, in The New England Journal of Medicine. The six-month, randomized placebo-controlled trial included 137 participants with ALS; an open-label extension, long-term follow-up phase was conducted at the end of that trial.

The data from that study was very robust, says Caress. “In the first paper, there was a slowing of the progression by about 40 percent, and then further analysis showed a survival advantage of about six months, which is longer than other drugs we have. Because the average life expectancy of someone diagnosed with ALS is about two and a half years, a six-month survival advantage is big,” he says.

Additionally, analysis from that same study showed that hospitalization was delayed, and tracheostomy was delayed, says Caress.

Muscle weakness caused by ALS also affects the muscles required to breathe, which eventually makes respiratory support needed. Some people with ALS elect to get a tracheostomy, a surgically created hole in the windpipe that provides an alternative airway for breathing.

“Researchers could see multiple good things happening — not just survival, but progression, and not just progression, but hospitalization. This group of patients clearly did better in multiple measures,” he says.

Although these results are very encouraging, there is a concern due to the small size of the study, says Caress. “In the phase 2 trial, there were 89 patients on the drug and 48 patients on placebo; that’s a small number. Most trials are significantly bigger than that,” he says.

On top of that, ALS is not an easy disease to study, he says. “It’s a diverse disease, and patients are just different. Because it can be so different in different people, it’s hard to measure disease progression uniformly,” says Caress.

In studying a drug’s effect on any condition, but particularly in the case of ALS, when there’s a small number of patients, there’s a concern that the way the groups were randomly divided might lead to results that wouldn’t be found in a larger sample of people, he says.

There’s a larger phase 3 trial underway, per a press release, but the company doesn’t expect results from that study until 2024. “The FDA could approve this now and then reevaluate once the results from that larger trial come in,” says Caress.

Relyvrio Is Well Tolerated With Only Mild Side Effects

The most common side effects were gastrointestinal and included diarrhea, nausea, salivary hypersecretion, and abdominal discomfort, which were reported at a higher rate than in the group taking placebo, according to the findings.

After the first three weeks of the trial, the gastrointestinal side effects were actually reported more frequently in the placebo group than in the group taking the drug.

This drug is very well tolerated, and the GI side effect didn’t cause participants to discontinue the drug, says Caress, noting that the drug is also able to be taken with other ALS drugs.

“There’s a hope that putting all these drugs together may have an even greater synergistic effect, and that we’re going to make real headway in treating ALS, not just a few months, but really start to slow things down,” he says.

How Much Will Relyvrio Cost?

Following the FDA approval of Relyvrio, Amylyx Co-CEOs Josh Cohen and Justin Klee released the following statement regarding pricing of the drug:

“We have met with many stakeholders throughout the ALS community, including leading doctors, people living with ALS, and leaders in advocacy to discuss potential pricing and reimbursement of Relyvrio. We have also talked with every major insurance company in the United States and done extensive modeling to understand impacts to people’s potential out-of-pocket expenses.

“Taking all of that into account, we made the decision to price Relyvrio below the latest FDA-approved product available to people with ALS. The wholesale acquisition cost, or WAC, for a 28-day prescription of Relyvrio will be $12,504.24, or about $158,000 per year for the first year; however, this does not reflect the price people living with ALS can expect to pay. In instances of financial need:

  • "For people with ALS who have commercial insurance, Amylyx is committed to providing financial assistance by bringing copays to $0.
  • While pharmaceutical manufacturers cannot offset copayments for people covered by government insurance, we are working to ensure that people with government-funded insurance, like Medicare or Medicaid, will have access to Relyvrio as quickly as possible. The Amylyx Care Team will be able to provide people with government-funded insurance information on potential options for financial assistance with copays.
  • In addition, for U.S. residents with ALS that are uninsured or underinsured, meet certain financial eligibility criteria, and who have exhausted all other options, we intend to provide Relyvrio at no cost.”

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