RELYVRIO Powder for oral suspension Ref.[50247] Active ingredients: Sodium phenylbutyrate Ursodoxicoltaurine

Cardiac Electrophysiology

At the maximum recommended dose, RELYVRIO does not cause large mean increases (>20 ms) in the QT interval.

Absorption

Following oral administration of a single dose of RELYVRIO in healthy subjects under fasting conditions, sodium phenylbutyrate reaches a median T_max of 0.5 hour. Taurursodiol reaches a median T_max of 4.5 hours.

Effect of Food

Administration of RELYVRIO in the presence of a high-fat meal resulted in both significantly slower absorption (C_max reduced by 76%) and lower overall exposure (AUC reduced by 54%) of sodium phenylbutyrate. A high-fat meal did not significantly affect the C_max for taurursodiol, but AUC was increased by 39% [see Dosage and Administration (2.2)].

Distribution

Human plasma protein binding for sodium phenylbutyrate and taurursodiol is 82% and 98%, respectively.

Elimination

Metabolism

No mass balance studies of sodium phenylbutyrate and taurursodiol have been conducted in humans to confirm the metabolic pathways and elimination routes. Phenylacetate was found to be a major metabolite of phenylbutyrate. Ursodiol and glyco-ursodiol were found as major metabolites of taurursodiol.

Excretion

The majority of administered sodium phenylbutyrate (~80-100%) is excreted in the urine within 24 hours as the conjugated product, phenylacetylglutamine.

Specific Populations

The effect of age, gender, racial, or ethnic groups on the pharmacokinetics of RELYVRIO is unknown.

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of RELYVRIO has not been studied. There were no reports of safety issues with patients with mild renal impairment who were enrolled in Study 1. However, there is no clinical experience for subjects with moderate and severe renal impairment [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of RELYVRIO has not been studied. There were no reports of safety issues with patients with mild hepatic impairment (using National Cancer Institute Classification system) who were enrolled in Study 1. However, there is no clinical experience for subjects with moderate and severe hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interaction Studies [see Drug Interactions (7.1, 7.2)]

No clinical interaction studies between RELYVRIO and other medicinal products have been performed.

In vitro studies showed that the combination of sodium phenylbutyrate and taurursodiol:

• induces CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations
• inhibits CYP2C8 and CYP2B6 at clinically relevant concentrations.
• inhibits OAT1, P-gP, and BCRP at clinically relevant concentrations
• is a substrate of OATP1B3, MATE2-K, OAT3, and BSEP

Carcinogenesis

Studies to assess the carcinogenic potential of RELYVRIO have not been conducted.

Mutagenesis

The combination of sodium phenylbutyrate and taurursodiol (3:1 ratio of sodium phenylbutyrate and taurursodiol) was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

Oral administration of the combination of sodium phenylbutyrate and taurursodiol (0, 375, 750, or 1500 mg/kg/day) prior to and throughout mating in male and female rats and continuing to gestation day 7 in females resulted in no adverse effects on fertility. At the highest dose of the combination of sodium phenylbutyrate and taurursodiol tested, doses of sodium phenylbutyrate and taurursodiol were approximately 2 times the maximum recommended doses (6 g sodium phenylbutyrate and 2 g taurursodiol) in humans, based on body surface area (mg/m²).

14.1 Clinical Efficacy

The efficacy of RELYVRIO for the treatment of ALS was demonstrated in a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study that evaluated RELYVRIO in adult patients with amyotrophic lateral sclerosis (ALS) (Study 1; NCT03127514). For inclusion in the study, patients had to have a definite diagnosis of sporadic or familial ALS as defined by the revised El Escorial criteria, with symptom onset within the past 18 months, and a slow vital capacity (SVC) greater than 60% of predicted at screening.

A total of 137 patients were randomized 2:1 to receive either RELYVRIO (n=89) or placebo (n=48) for 24 weeks (Intent-to-Treat [ITT] population).

Baseline disease characteristics were generally comparable between the two treatment groups; 95% were Caucasian, the median age was 57.7 years, and 68% were males. Thirty percent of patients in the RELYVRIO treatment group had bulbar disease onset vs. 21% in the placebo group. On average, patients had been diagnosed with ALS six months prior to baseline with a time since onset of first symptom of approximately 13.5 months. At or prior to study entry, 71% of patients were taking riluzole and 34% were taking edaravone. The average (standard deviation) baseline ALS Functional Rating Scale-Revised (ALSFRS-R) total score was 35.7 (5.8) in the RELYVRIO treatment group and 36.7 (5.1) in the placebo group.

Patients were administered the contents of one packet of RELYVRIO or placebo, once daily for the first 3 weeks. After 3 weeks of treatment, the dose was increased to one packet twice daily if tolerated.

The prespecified primary efficacy endpoint was a comparison of the rate of reduction in the ALSFRS-R total scores from baseline to Week 24 in the mITT population. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0-4, with higher scores representing greater functional ability.

There was a statistically significant difference in the rate of reduction in the ALSFRS-R total score from baseline to Week 24 in RELYVRIO-treated patients compared to placebo-treated patients (p=0.034) (see Table 2).

Table 2. ALSFRS-R Total Score in Patients with ALS at Week 24—Shared Baseline Mixed Effects Statistical Analysis (Primary, Prespecified Analysis) in Study 1:

In a post hoc, long-term survival analysis, vital status was ascertained in 136 of 137 patients who were enrolled in Study 1. Longer median overall survival was observed in the patients originally randomized to RELYVRIO compared to those originally randomized to placebo. This exploratory analysis should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.