Relyvrio (Sodium Phenylbutyrate and Taurursodiol) for ALS

Last updated Oct. 3, 2022, by Marisa Wexler, MS

✅ Fact-checked by Inês Martins, PhD


What is Relyvrio for ALS?

Relyvrio (sodium phenylbutyrate and taurursodiol) is an oral treatment now approved in the U.S. and Canada to help slow disease progression in people with amyotrophic lateral sclerosis (ALS).

Developed by Amylyx Pharmaceuticals, the therapy is under regulatory review for possible ALS approval in Europe. It also is being explored as a potential treatment for other neurodegenerative disorders, including Alzheimer’s disease and Wolfram syndrome.

How does Relyvrio work?

Relyvrio, formerly known as AMX0035, is a fixed-dose combination of two compounds — tauroursodeoxycholic acid and sodium phenylbutyrate — that had been used in the clinic and were proven to be safe and well-tolerated.

The medication’s exact mechanism of action is incompletely understood, but it’s broadly thought the two compounds work together to prevent nerve cell death by blocking stress signals within two cellular compartments, specifically mitochondria and the endoplasmic reticulum.

Mitochondria, the so-called powerhouses of a cell, are organelles responsible for generating energy, among many other crucial roles. Dysfunction of mitochondria in motor neurons, the nerve cells that are progressively lost in ALS, is one of the earliest disease-related events to occur.

The endoplasmic reticulum is involved in protein production, modification, and transport. In most ALS cases, certain proteins fail to fold properly and accumulate in abnormal clumps; this induces stress signals in the endoplasmic reticulum that can ultimately result in cell death.

Relyvrio was designed to target these damaging mechanisms simultaneously. While tauroursodeoxycholic acid improves mitochondria energy production, phenylbutyrate helps proteins acquire their normal shape, thereby preventing the formation of protein clumps that cause nerve cell death.

Notably, the compounds act synergistically, meaning that the effects of the two drugs combined are greater than those seen with either of the medications alone. Some metabolic effects are unique to the combination.

Who can take Relyvrio?

The U.S. Food and Drug Administration (FDA) approved Relyvrio in September 2022 for the treatment of adults with ALS.

A few months earlier, in June 2022, the medication had received conditional approval to treat ALS in Canada, where it is marketed under the brand name Albrioza. This was the treatment’s first approval by a regulatory authority in any country.

Who should not take Relyvrio?

Relyvrio has no contraindications, though patients with certain underlying conditions affecting bile acid circulation or causing a sensitivity to salt may require additional monitoring and clinical considerations.

How is Relyvrio administered in ALS?

Relyvrio is available in single-dose packets containing 3 g sodium phenylbutyrate and 1 g taurursodiol, which can be taken by mouth or administered into a feeding tube.

The recommended initial dose of the medication is one packet a day for the first three weeks. Then, after three weeks, patients should take two daily packets — one in the morning and one at night — for the remainder of their treatment.

The contents of each package should be poured into a cup containing eight ounces (about 240 ml, or one full cup) of room temperature water and stirred vigorously. The mixture should be administered within one one hour of mixing.

It’s recommended that Relyvrio be taken before a snack or meal, and patients should avoid taking aluminum-based antacids, which could interfere with the absorption of taurursodiol.

Relyvrio in clinical trials

CENTAUR

Relyvrio’s regulatory approvals were supported by data from a Phase 2 clinical trial called CENTAUR (NCT03127514), which tested the experimental therapy in 137 adults with recently diagnosed ALS. All had rapidly progressing disease — a stringent enrollment criteria meant to provide the most statistically powerful results possible.

Participants were randomly assigned to either Relyvrio (89 participants) or a placebo (48 participants), taken by mouth once daily for the first three weeks, and then twice daily, for a total of 24 weeks (about six months).

Full results from CENTAUR showed that the trial met its primary goal of slowing functional decline, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R). On average, patients on Relyvrio experienced a decline of 1.24 points per month on their ALSFRS-R scores, which was clinically meaningful and significantly slower than the 1.66 points lost monthly by those on a placebo.

Most participants (77%) were receiving or had previously been given other approved ALS treatments, but Relyvrio’s ability to slow disease progression was deemed independent of the use or duration of such medications.

Relyvrio was generally safe and well-tolerated in the CENTAUR trial. The rates of serious safety problems were higher for patients given the placebo than for Relyvrio (19% vs. 12%), though more patients on Relyvrio discontinued treatment due to side effects (19% vs. 8%).

After completing the six-month trial, 90 of 98 eligible participants (92%) chose to enter an open-label extension study (NCT03488524), in which all received Relyvrio for up to 30 months (about 2.5 years).

Findings from CENTAUR and its extension study showed that patients consistently on Relyvrio lived a mean of 6.9 months longer compared with those initially assigned to a placebo — 25.8 months vs. 18.9 months, reflecting a 43% lower risk of death.

The risk of any event, which included tracheostomy (a tube inserted into the windpipe to make breathing easier), permanent assisted ventilation, or hospitalization also was reduced by 47% among patients initially assigned to Relyvrio.

An additional analysis estimated that, if the placebo group had never switched to the active medication on the extension trial, Relyvrio would extend median survival time by more than 10 months, representing a 61% lower risk of death.

Ongoing PNOENIX trial

Amylyx is running a Phase 3 trial called PHOENIX (NCT05021536), which is expected to confirm Relyvrio’s efficacy in about 600 people with early ALS, or those who have been experiencing symptoms for less than two years. Participants are being randomly assigned to receive Relyvrio or a placebo for about one year (48 weeks), followed by open-label treatment for up to two years.

The main goals of the study are to assess safety and the rate of decline in function as measured by ALSFRS-R. Other outcomes include measures of lung function, quality of life, and survival. The study is being conducted at sites in the U.S. and Europe; many sites in Europe are still recruiting participants.

Common side effects of Relyvrio

The most common side effects associated with Relyvrio include:

  • diarrhea
  • nausea
  • abdominal pain
  • upper respiratory tract infection

Changes in bile acid levels

Relivrio can increase levels of bile acids, which can lead to worsening diarrhea in patients with some disorders of the pancreas, intestines, and/or liver. These conditions also may reduce how much of Relyvrio’s active ingredients are absorbed by the body. It’s advised that patients with these conditions consult with a specialist before starting on Relyvrio. Those treated with the medication should be monitored for new or worsening diarrhea.

Salt (sodium) retention

Relyvrio has a high salt content. Appropriate considerations and monitoring should be taken into account when using the medication to treat patients who are sensitive to salt intake. This includes those with some kidney disorders, high blood pressure, or heart failure.

Pregnancy and breastfeeding

No studies have evaluated Relyvrio in pregnant or breastfeeding patients with ALS, but studies done in animals suggest that using the medication during pregnancy or lactation leads to an increased risk of death for the offspring.


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