New Drug Monographs

New Drug

RelyvrioTM

(sodium phenylbutyrate and taurursodiol)

By: Benita Mukenge, PharmD Candidate 2023

Classification: Histone Deacetylase Inhibitor; Hydrophilic Bile Acid

FDA Approval: September 29, 2022

Indication1: Treatment of amyotrophic lateral sclerosis (ALS) in adult patients

Contraindications: None

Pharmacology1,2: The exact mechanism of action is unknown; however, the combination of sodium phenylbutyrate and taurursodiol minimizes physical function decline by slowing down neuronal death.

Pharmacokinetics1,2 Absorption: Sodium phenylbutyrate is rapidly absorbed; however, co-administration with high-fat meals diminishes absorption and exposure (Cmax by 76% and AUC by 54%). The presence of food had no effect on taurursodiol, although overall exposure after a high-fat meal increased AUC by 39%.

Distribution: Both taurursodiol and sodium phenylbutyrate are highly protein bound (98% and 82%, respectively).

Metabolism: Major metabolites: phenylacetate (sodium phenylbutyrate); ursodiol and glycol-ursodiol (taurursodiol).

Elimination: Approximately 80100% of phenylacetylglutamine is excreted through the urine within 24 hours.

Clinical Efficacy3,4,5: The Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis (CENTAUR) evaluated sodium phenylbutyrate and taurursodiol’s effect on prolonging the life of patients with amyotrophic lateral sclerosis (ALS), which also goes by the term Lou Gehrig’s disease, by slowing down functional decline. The multicenter, randomized, double-blind trial enrolled 137 individuals with ALS who had an onset of symptoms within the previous 18 months. Eligible participants were recruited from 25 centers of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS) in the United States from June 2017 through September 2019. The study included adults 18-80 years of age with sporadic or familial ALS diagnoses. A positive ALS diagnosis was defined as clinical evidence of both upper and lower motor neuron signs in at least three body regions within 18 months of symptom onset. Additional inclusion criteria were a slow vital capacity (SVC) exceeding 60% of the predicted value for a person’s age, sex, and height without being treated with riluzole at the start of the trial or treatment with riluzole at a stable dose for at least 4 weeks prior to screening. Inclusion criteria were revised in August 2017 to include the use of edaravone before and during the trial once available. Participants were excluded if there was a presence of tracheostomy, exposure to sodium phenylbutyrate (PB), taurursodiol (TUDCA or UDCA) within 90 days before screening or planning to use those medications during the study, abnormal liver and renal functions, uncontrolled hypertension, pregnant/ breastfeeding. Both males and females agreed to use adequate birth control during the study

Randomization occurred in a 2:1 ratio in which participants received sodium phenylbutyrate-taurursodiol (3 g sodium phenylbutyrate and 1 g taurursodiol per sachet; n=89) or placebo (n=48). The route of administration was either orally or through a feeding tube for 24 weeks. Both sodium phenylbutyrate-taurursodiol and placebo were provided as powders to be dissolved in room-temperature water before administration in a single-use sachet. For the first 3 weeks, patients were instructed to take 1 sachet per day and then 2 sachets (1 in and morning and 1 in the evening) daily for the remainder of the trial.

The primary efficacy endpoint was the rate of decline in the total score of the Amyotrophic Lateral Sclerosis Functional Rating Scare-Revised (ALSFRS-R) from baseline through the end of the trial. The ALSFR-R consists of 12 items with 4 subdomains of bodily functions (bulbar, fine motor, gross motor, and breathing). These subdomains were scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function), meaning total scores range from 0 to 48, with higher scores suggesting better function. The estimated mean rates of change of the ALSFRS-R total score in the intention-to-treat population were -1.24 per month with sodium phenylbutyrate-taurursodiol and -1.66 per month with placebo (difference, 0.42 points per month; 95% confidence interval [CI], 0.03 to 0.81; p=.03). Apart from the fine-motor subscore, there were no statistical differences in the ALSFRS-R subdomain scores between the 2 groups in the exploratory analyses.

Secondary efficacy endpoints consisted of the rate of decline in isometric muscle strength measured by the Accurate Test of Limb Isometric Strength (ATLIS) device; the rate of decline in plasma levels of the phosphorylated axonal neurofilament H subunit (pNF-H), which constitutes as a potential biomarker for motor neuron degeneration; the rate of decline in the SCV; time to death, tracheostomy, or permanent assisted ventilation (>22 hours daily for > 7 days); time to death, tracheostomy, or permanent assisted, or any hospitalization; the pharmacokinetics of sodium phenylbutyrate and taurursodiol; and 18-kD translocator protein (TSPO) uptake on magnetic resonance-position emission tomography. The average rate of change per month in the sodium phenylbutyrate-taurursodiol treatment group and the placebo group in the ATLIS total score was -3.03% and -3.54% of the predicted normal value per month (difference, 0.51 percentage points per month; 95% CI, -0.12 to 1.14) respectively. The plasma pNF-H concentration mean rate of change was 3.58 pg/mL per month with sodium phenylbutyrate-taurursodiol and -2.34 pg/ mL per month with placebo (differences, 5.92 pg/mL per month; 95% CI, -4.41 to 16.26) and the average rate of change in the SVC was -3.10% and -4.03% (difference, 0.93 percentage points per month; 95% CI, -0.10 to 1.95). In participants being treated with sodium phenylbutyrate-taurursodiol, death occurred in five participants (6%) and 2 participants (4%) in the placebo group. The study reported the most common cause of death as respiratory failure, which accounted for 4 of the 7 deaths.

Adverse events were recorded as ALS progression symptoms and assessed during each trial visit throughout the study. The most common adverse event reported with sodium phenylbutyrate-taurursodiol was gastrointestinal disturbance (nausea, diarrhea, abdominal pain) in the first 3 weeks compared to placebo. These events were transient, and incidents decreased for the entirety of the study. Patients were more likely to reduce the dose or discontinue treatment in the sodium phenylbutyrate-taurursodiol due to GI events. Treatment discontinuation in the active-ingredient group accounted for 19% compared to 8% in the placebo group.

Additional research was conducted for eligible patients who completed the CENTAUR trial to evaluate the long-term efficacy and safety of sodium phenylbutyrate-taurursodiol in an open-label extension (OLE) trial. Patients who consented to the OLE received sodium phenylbutyrate-taurursodiol for up to 30 months (132 weeks). Modifications for riluzole or edaravone from the CENTAUR trial, as well as dose and frequency of the active ingredient (2 sachets daily or 1 sachet daily), remained the same in the follow-up OLE to maintain the integrity of the trial.

ed the CENTAUR trial, 90 (92%) were eligible and enrolled in the follow-up OLE trial in which 56 of them were treated with the active drug and 34 with a placebo. Upon randomization from CENTAUR, the longest follow-up period was 35 months, with 18 patients in the active drug cohort and 9 in the placebo. Baseline characteristics were comparable between the 2 groups. In the follow-up OLE trial, the placebo cohort generally had a high probability (77%) of patients receiving edaravone and both edaravone and riluzole compared to CENTAUR.

According to the overall survival analyses from the CENTAUR trial, the risk of death in patients receiving sodium phenylbutyrate-taurursodiol was 44% lower (HR, 0.56; 95% CI, 0.34-0.92; p=.023) with a mean survival duration of 25 months (95% CI, 19.0-33.6 months) in comparison to 18.5 months in the placebo cohort (95% CI, 13.5-23.2 months). When comparing the probability of survival in 12 months with the active ingredient group and the placebo group, it was approximately 80.9% (95% CI, 71.1%-87.7%) and 72.9% (95% CI, 58.0%-83.3%), respectively. At 24 months, the estimated probability of survival was 51.6% (95% CI, 38.9%-62.9%) and 33.9% (95% CI, 19.4%-49.1%), respectively.

Drug Interactions1

Potential for Other Drugs to Affect sodium phenylbutyrate or taurursodiol Bile Acid Sequestering Agents Avoid co-administration of bile acid agents (e.g., cholestyramine, colestipol, colesevelam) with sodium phenylbutyrate or taurursodiol. It may interfere with the absorption of bile acids such as taurursodiol. Consider alternative cholesterol-lowering agents.

Inhibitor of Bile Acid Transporters Avoid co-administration of strong bile salt export pump (BSEP) with sodium phenylbutyrate and taurursodiol. Concomitant medications that inhibit canalicular membrane bile acid transporters may exacerbate the accumulation of conjugated bile salts in the liver. If co-administration is warranted, administer with caution, and monitor serum transaminases and bilirubin.

Aluminum-based Antacids Avoid the use of aluminum-based antacids with sodium phenylbutyrate and taurursodiol due to the adsorption of bile acids that may interfere with the absorption of taurursodiol. Consider alternative acid-lowering agents.

Probenecid Avoid co-administration of probenecid with sodium phenylbutyrate or taurursodiol. May affect the renal excretion of sodium phenylbutyrate metabolites.

Potential for sodium phenylbutyrate and taurursodiol to Affect Other Drugs OAT1 Avoid the use of OAT1 substrates. Plasma concentrations of OAT1 substrates may increase if co-administered with sodium phenylbutyrate and taurursodiol which may lead to serious toxicities or loss of efficacy. P-glycoprotein (p-gP) and Breast Cancer Resistance Protein (BCRP) Substrates Avoid co-administration of P-gP and BCRP substrates. Sodium phenylbutyrate and taurursodiol has been shown to inhibit P-gP and BCRP in vitro, which may cause an increase in plasma concentrations of P-gP and BCRP. A small change in substrate concentration may lead to serious toxicities or less efficacy with sodium phenylbutyrate and taurursodiol.

Drugs that are substrates of CYP2C8, CYP1A2, CYP2B6, and CYP3A4 isoenzymes Concentrations of sodium phenylbutyrate and taurursodiol may be increased by CYP2C8 and CYP2B6 isoenzymes. Concentrations of sodium phenylbutyrate or taurursodiol may be reduced by CYP1A2, CYP2B6, and CYP3A4. Avoid the use of CYP450 isoenzymes to avoid serious toxicities or loss of efficacy.

Adverse Events1: The most common adverse events (at least 15% and at least 5% greater than placebo) of sodium phenylbutyrate and taurursodiol are diarrhea, abdominal pain, nausea, and upper respiratory tract infection. The incidence of fatigue, salivary hypersecretion, and dizziness were > 10%.

Dosing1 : The recommended oral suspension or via feeding tube dosing is 1 packet (3 g sodium phenylbutyrate and 1 g taurursodiol) daily for the initial 3 weeks and then increase to a maintenance dose of 1 packet twice daily. Dissolve the packet in 8 ounces of water at room tem-

perature and take within 1 hour of preparation. Administer prior to a meal or snack.

Cost1,2 :There is currently no available cost information.

Renal and Hepatic Impairment1 : No dose adjustment is required. Avoid use in patients with moderate or severe renal and/or liver impairment.

Summary/Use in Clinical Practice1-7: Although there is currently no cure for ALS, a multidisciplinary approach is essential for a favorable prognosis and longer survival. Prior to the approval of sodium phenylbutyrate and taurursodiol, there was two available conventional therapy for the treatment of ALS; riluzole and edaravone. The American Academy of Neurology (AAN) recommended that riluzole 50 mg twice daily be offered to slow disease progression. Riluzole has been shown to increase life expectancy by 2 to 6 months. Edaravone, administered IV or orally to minimize the decline of daily functioning, may be considered an add-on therapy or monotherapy if riluzole is intolerable. Based on results from the CENTAUR trial, the novel drug sodium phenylbutyrate and taurursodiol show promising results of further increasing survival rate and decreasing death rate as a monotherapy or combination with riluzole and/or edaravone.

Due to sodium phenylbutyrate or taurursodiol status, further studies are warranted to evaluate its role in treating ALS. The PHOENIX trial is a Phase III randomized, double-blind, placebo-controlled, multicenter trial that aims to evaluate the safety and efficacy of sodium phenylbutyrate or taurursodiol in adult patients. Thus far, over 600 participants in both the United States and Europe in this trial will be observed for 48 weeks (1 year), and those that complete the entirety of the trial are eligible to enroll in the OLE phase for up to 2 years.

The PHOENIX trial will randomize participants to receive sodium phenylbutyrate and taurursodiol (60% chance) or a placebo (40% chance). Eligible participants include those that are 18 years and older, definite, or clinically probable diagnosis of ALS, time of ALS symptom onset <24 months, and that are on stable doses of riluzole and/or edaravone for at least 2 weeks for riluzole and a full treatment cycle for edaravone. Initiating riluzole or edaravone during the PHOENIX trial is prohibited. Participants are excluded if there is a tracheostomy in place or need permanent assisted ventilation (>22 hours of assisted ventilation daily for > 7 days). Although recruitment in the United States has ended, it is still ongoing in Europe. The study launched on October 28, 2021, and is estimated to end on March 1, 2024. The approval of sodium phenylbutyrate and taurursodiol may be a milestone in the treatment of ALS. Results from the PHOENIX trial will shed additional light on the safety and efficacy of sodium phenylbutyrate and taurursodiol as well as its place in the management of ALS. Although there is currently no cure for ALS, the development of novel medicine Author: Benita Mukenge is a 2023 PharmD Candidate at Campbell University College of Pharmacy and Health Sciences. btmukenge0923@email.campbell.edu

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