By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a third drug (after riluzole and edaravone) to treat amyotrophic lateral sclerosis (ALS). The drug is a fixed-dose co-formulation of sodium phenylbutyrate and taurursodiol (PB-TURSO). This blends an inhibitor of histone deacetylases (PB) with a hydrophilic bile acid (TURSO), a combination that has been shown to reduce neural death rates in ALS models.1 The FDA granted PB-TURSO a priority review, a fast-track breakthrough therapy designation, and an orphan drug designation.2 It is distributed as Relyvrio.
INDICATIONS
PB-TURSO can be prescribed to treat ALS in adults.3
DOSAGE
The recommended dose is one packet daily for three weeks, then one packet twice daily thereafter.3 The packet is suspended in 8 ounces of water at room temperature and taken before a snack or meal. Each packet contains 3 g of PB and 1 g of TURSO.
POTENTIAL ADVANTAGES
PB-TURSO can slow the rate of decline associated with ALS as assessed by the ALS functional rating scale (ALSFRS-R) and may provide survival benefit compared to placebo.1-4
POTENTIAL DISADVANTAGES
In vitro data suggest PB-TURSO could produce numerous drug-drug interactions.3 This combination induces CYP1A2, CYP2B6, and CYP3A4 isoenzymes and inhibits CYP2C8 and CYP2B6 isoenzymes. They also inhibit organic anion transporter 1 (OAT1), P-glycoprotein, and breast cancer resistance protein (BCRP) transporter. The combination also is a substrate of various transporters (OATP1B3, MTE2-K, and BSEP). For these reasons, clinicians should avoid co-prescribing numerous drugs, as numerated in the prescribing information.3 A total of 20.2% of subjects randomized to PB-TURSO discontinued treatment vs. 10.4% of the placebo group.4 The combination has a bitter taste, leading to transient gastrointestinal symptoms.4 The most frequent adverse reactions are diarrhea, abdominal pain, nausea, and upper respiratory tract infection.3
COMMENTS
The efficacy of PB-TURSO was demonstrated in a 24-week, randomized, double-blind, placebo-controlled trial that included subjects with sporadic or familial ALS. Symptom onset had started within the past 18 months, and participants exhibited a slow vital capacity exceeding 60% of the predicted value for gender, height, and age.1,3,4 Subjects were allowed to be on stable doses of riluzole or edaravone or initiate edaravone during the study. Subjects were randomized to PB-TURSO (n = 89) or placebo (n = 48). The primary prespecified endpoint was the rate of decline from baseline to week 24 of the total ALSFRS-R score. This score rates functional activity across four domains (bulbar, fine motor, gross motor, and breathing).
The mean (SD) baseline ALSFRS-R scores were 35.7 (5.8) for the PB-TURSO group and 36.7 (5.1) for the placebo group. The mean scores at week 24 were 29.1 (0.78) and 26.9 (0.97), respectively. This translated to an estimated treatment difference of 2.32 (1.09) points (95% confidence interval, 0.18-4.47; P = 0.034. Secondary endpoints included strength measurement, plasma biomarker (phosphorylated neurofilament heavy subunit, a potential biomarker for disease progression of ALS), slowed vital capacity, and a composite endpoint of death, tracheostomy, or hospitalization. Investigators assessed these, but none achieved statistical significance.1,4 A long-term post-hoc analysis and a supplemental post-hoc exploratory analysis conducted by the sponsor suggest survival benefit (median of 4.8 to 9.9 months).4 While the FDA noted limitations with these analyses, the agency acknowledged a nominally significant benefit on survival.4
CLINICAL IMPLICATIONS
ALS is a rapidly progressive neurodegenerative disease with an incidence of two per 100,000 per year. Fifty percent of individuals die within three years from onset of symptoms and 90% within five years.4 Current FDA-approved treatment options are riluzole and edaravone. Riluzole may provide improved early survival but no benefit on muscle or neurological function. Edaravone slows decline in ALSFS-R, but is not known to improve survival.4,5 However, there remains an unmet need; the FDA believes the benefits of PB-TURSO outweigh the risk.4 The price of the drug is expected to be $158,000 per year, which is considerably more than the Institute for Clinical and Economic Review believes is cost-effective.6 The cost-effective annual cost is $13,700 at the $150,000 per quality adjusted life year threshold. A randomized, double-blind, placebo-controlled, Phase III trial (NCT05021536) to evaluate the safety and efficacy of PB-TURSO for treatment of ALS is in progress and should be completed in November 2023.
REFERENCES
1. Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med 2020;383:919-930.
2. U.S. Food & Drug Administration. FDA approves new treatment option for patients with ALS. Sept. 29, 2022.
3. Amylyx Pharmaceuticals, Inc. Relyvrio prescribing information. September 2022.
4. U.S. Food & Drug Administration. Summary memorandum. Relyvrio. Sept. 29, 2022.
5. Johnson SA, Fang T, De Marchi F, et al. Pharmacotherapy for amyotrophic lateral sclerosis: A review of approved and upcoming agents. Drugs 2022;82:1367-1388.
6. Institute for Clinical and Economic Review. Amyotrophic lateral sclerosis (ALS). An assessment of AMX0035 and oral edaravone. August 2022.
Relyvrio can be prescribed to treat amyotrophic lateral sclerosis in adults.
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