The Food and Drug Administration (FDA) has approved the combination drug sodium phenylbutyrate-taurursodiol (Relyvrio) to treat amyotrophic lateral sclerosis (ALS). ALS is a rare, progressive, and fatal neurodegenerative disease in which motor neurons gradually deteriorate and die. After significant motor neuron death, the brain loses its ability to initiate and control voluntary movements. Most patients with ALS die from respiratory failure within three to five years of symptom onset. The incidence of new U.S. cases of ALS is estimated to be between 5.5 and 7.7 per 100,000 persons per year.1

Relyvrio's exact mechanism of action is not fully known. Sodium phenylbutyrate is known to increase nitrogen excretion in the kidneys and affects protein folding and appears to prevent misfolded proteins and reduce protein aggregation.2 Taurursodiol is a bile acid and has been used for biliary cirrhosis. It also appears to have effects on apoptosis pathways.2

Relyvrio was evaluated in a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study followed by an open-label extension study for 132 weeks. A total of 137 adult patients with ALS were enrolled in the trial and randomized 2:1 to Relyvrio or placebo. The primary efficacy end point was the rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline to 24 weeks. The ALSFRS-R is a 12-item tool used to evaluate functional ability by assessing the patient's fine motor, gross motor, bulbar, and respiratory function. The higher the score, the greater the patient's functional ability. Patients receiving Relyvrio had scores indicating a slower loss of functioning compared with patients taking placebo. After an initial review by the FDA's Peripheral and Central Nervous System Drugs (PCNS) advisory committee in March, the manufacturer completed a post hoc, long-term analysis to determine if the survival rate improved with Relyvrio. Longer median overall survival was found in those who were randomized to Relyvrio compared with those given placebo, but it was a nominally significant survival benefit.

In an unusual step for the FDA, there were two meetings to discuss Relyvrio's approval, one in March and one in September. Although the product was ultimately approved at the September meeting, some members of the FDA's PCNS advisory committee did not vote to approve it, citing that the trial's sample size was small, that there was no substantial evidence of effectiveness, and that they believed approval should wait until results from an ongoing phase 3 study could be evaluated. Some members were also concerned that the results of the post hoc analysis of the drug's effect on survival could limit the credence of the phase 2 study findings. However, the majority of members agreed that the current data appeared to indicate an extended life span with Relyvrio, which, owing to the severity of the disease, was sufficient to approve the drug, with the understanding that it might need to be removed from the market if the phase 3 trial did not confirm clinical effectiveness. These data are expected in 2024. To listen to the full September 7 webcast of the FDA advisory committee meeting on Relyvrio, go to https://collaboration.fda.gov/pf061o7o9lhs.

The issue of questionable effectiveness is important, as the drug will have a list price of $158,000 per year.3 According to an article in the New York Times, the list price of Relyvrio "is much higher than that recommended by the Institute for Clinical and Economic Review, a nonprofit organization that evaluates the value of medicines."3 That organization suggests an annual list price of between $9,100 and $30,700 if the drug is effective. The cost of combination therapy also needs to be considered. Two other drugs are approved for ALS-riluzole (Rilutek) and edaravone (Radicava). Patients would be expected to take one, or both, in addition to Relyvrio. Relyvrio's manufacturer has predicted that few patients will need to pay the full amount for the drug, as both private and public insurance are expected to cover its cost.3

Relyvrio's labeling warns that the drug is high in sodium (464 mg per packet) and may pose complications for patients who are highly salt sensitive, such as those with heart failure, hypertension, and renal impairment. Patients taking Relyvrio should be monitored for adverse effects from hypernatremia and fluid overload. Relyvrio can also pose a risk to patients with pancreatic, intestinal, and enterohepatic circulation disorders, because its component taurursodiol is a bile acid. Patients with these disorders should be monitored for new or worsening diarrhea. Patients with a condition that interferes with bile acid circulation may need to be evaluated by a specialist prior to starting drug therapy.

The most common adverse effects of treatment are diarrhea, abdominal pain, nausea, and upper respiratory tract infection.

No clinical drug interaction studies involving Relyvrio have been performed; however, in vitro studies showed that several drug interactions are possible. Nurses should use a drug database to look for potential interactions with other drugs that could alter the clinically relevant concentration of Relyvrio. Nurses should consult with the prescriber if the patient has moderate to severe renal impairment or hepatic impairment, as Relyvrio should not be used in these patients. Relyvrio is taken orally and can also be given through a feeding tube. Nurses should teach patients and families to dissolve the drug in eight ounces of room temperature water.

For complete prescribing information for Relyvrio, go to http://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216660s000lbledt.pdf.

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