Relyvrio (sodium phenylbutyrate and taurursodiol) for amyotrophic lateral sclerosis
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What is Relyvrio for ALS?
Relyvrio (sodium phenylbutyrate and taurursodiol) was an oral treatment approved in the U.S. and Canada to slow disease progression in adults with amyotrophic lateral sclerosis (ALS) that has now been discontinued.
The therapy had shown in early clinical trials the ability to slow functional declines and to significantly extend patient survival. However, it failed to demonstrate benefits in a confirmatory Phase 3 trial, per study results released in March 2024.
That led its developer Amylyx Pharmaceuticals to voluntarily remove Relyvrio from the market in the U.S. and in Canada, where it was sold under the brand name Albrioza. In Europe, an advisory committee of the European Medicines Agency had recommended against Relyvrio’s approval for ALS based on the earlier data; the therapy was never approved for use in the European Union.
Amylyx now is developing Relyvrio as a potential treatment for other neurodegenerative conditions, including Wolfram syndrome and progressive supranuclear palsy.
Therapy Snapshot
| Brand Name: | Relyvrio |
| Chemical Name: | Sodium phenylbutyrate and taurursodiol |
| Usage: | Used to treat ALS; but discontinued after negative Phase 3 data |
| Administration: | Powder that was dissolved in water and taken by mouth or via a feeding tube |
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 was expected to improve mitochondria energy production, phenylbutyrate was thought to help proteins acquire their normal shape, thereby preventing the formation of protein clumps that cause nerve cell death.
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?
Relyvrio was approved by the U.S. Food and Drug Administration (FDA) in September 2022 to treat adults with ALS.
A few months earlier, in June 2022, the medication had received conditional approval in Canada for treating ALS. That was the treatment’s first approval by a regulatory authority in any country. In Canada, it was marketed under the brand name Albrioza.
However, Amylyx decided in April 2024 to voluntarily discontinue the marketing authorizations for Relyvrio in both countries, after the therapy failed to slow disease progression in a confirmatory Phase 3 clinical trial.
Who should not take Relyvrio?
Relyvrio’s prescribing information listed no contraindications, but patients with certain underlying conditions affecting bile acid circulation or causing a sensitivity to salt could require additional monitoring and clinical considerations.
How is Relyvrio administered in ALS?
Relyvrio was available in single-dose packets containing 3 g sodium phenylbutyrate and 1 g taurursodiol, which could be taken by mouth or administered via a feeding tube.
The recommended initial dose of the medication was one packet a day for the first three weeks, followed by two daily packets — one in the morning and one at night — for the remainder of the treatment.
The contents of each package were poured into a cup containing eight ounces (about 240 ml, or one full cup) of water at room temperature and stirred vigorously. The mixture had to be administered within one hour of mixing.
It was recommended that Relyvrio be taken before a snack or meal, and patients were to avoid taking aluminum-based antacids, which could interfere with the absorption of taurursodiol.
Relyvrio in clinical trials
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.
CENTAUR
Participants in CENTAUR all had rapidly progressing disease — a stringent enrollment criteria meant to provide the most statistically powerful results possible. Each was 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, or just shy of 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. However, 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%).
Open-label extension
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, or about 2.5 years.
Findings from CENTAUR and its extension study showed 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 to include 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. A 10.4-month survival benefit was similarly observed when patients who were always on Relyvrio were compared with a matched group of control patients from previous ALS trials.
PHOENIX Phase 3 trial
The PHOENIX Phase 3 trial (NCT05021536) was designed to confirm Relyvrio’s efficacy in people with early ALS — those whose symptoms had emerged less than two years prior.
A total of 664 participants were enrolled at more than 70 sites in the U.S. and Europe. All were randomly assigned to receive Relyvrio or a placebo in addition to their standard ALS medications for about one year (48 weeks).
As its main endpoints, or goals, the study was assessing safety and changes in the rate of functional decline, as measured by ALSFRS-R. Other outcomes include measures of lung function, quality of life, and survival.
Top-line data, however, showed the trial failed to meet its primary goal of slowing disease progression, with patients given Relyvrio in addition to standard ALS medications experiencing a similar rate of progression as those given standard treatments alone.
The company now will continue to analyze PHOENIX’s findings, as well as data from the ongoing PHOENIX open-label extension study (NCT05619783) in Europe, where participants will continue to receive the therapy for up to two years.
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 could increase levels of bile acids, which had the potential to lead to worsening diarrhea in patients with some disorders of the pancreas, intestines, and/or liver. Such conditions also could reduce how much of Relyvrio’s active ingredients were absorbed by the body, so patients were advised to consult with a specialist before starting on Relyvrio.
Salt retention
Relyvrio has a high salt or sodium content. Appropriate considerations and monitoring had to be taken into account when using the medication to treat patients who were sensitive to salt intake. This included those with some kidney disorders, as well as individuals with high blood pressure or heart failure.
Pregnancy and breastfeeding
No studies had evaluated Relyvrio in pregnant or breastfeeding patients with ALS, but studies done in animals suggested that using the medication during pregnancy or lactation could increase the risk of death for any offspring.
ALS News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Relyvrio
The U.S. Food and Drug Administration (FDA) approved Relyvrio for the treatment of adults with amyotrophic lateral sclerosis in 2022. The decision came just a few months after the medication gained its first approval in Canada, where it is sold under the brand name Albrioza.
Relyvrio was approved for the treatment of amyotrophic lateral sclerosis (ALS) after clinical trials showed it could slow declines in the ability to function and extend survival by several months. However, like other available ALS therapies, Relyvrio generally cannot reverse or reduce symptoms that already existed at the time of the treatment’s start.
According to data from CENTAUR, the Phase 2 clinical trial that supported Relyvrio’s approval, the medication significantly slowed disease progression compared with a placebo after six months of treatment. Still, each patient has a different experience with amyotrophic lateral sclerosis and responses to treatment also will differ, so there’s no way of knowing exactly when someone will start to benefit from Relyvrio.
While no interaction between alcohol and Relyvrio has been reported, it is recommended that patients discuss with their care team if and how much alcohol is safe to drink while on the medication.
Relyvrio is not a cure for amyotrophic lateral sclerosis (ALS). The medication can slow, but will not stop disease progression, and patients will continue to experience worsening symptoms and be less able to perform their daily activities as time goes on.
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