Kevin W. Chamberlin, PharmD, FASCP

On September 29, 2022, the FDA approved sodium phenylbutyrate and taurursodiol (Relyvrio) for the treatment of amyotrophic lateral sclerosis (ALS) in adults

 based on promising data from a small phase 2 clinical trial (NCT03127514).

 Sodium phenylbutyrate and taurursodiol is designed to slow disease progression and can be given as monotherapy or in combination with other agents. The mechanism by which this medication exerts its therapeutic effects on patients with ALS is unknown. A large phase 3 study (NCT05021536) is ongoing to confirm the safety and efficacy of sodium phenylbutyrate and taurursodiol in this patient population.

The efficacy of sodium phenylbutyrate and taurursodiol for the treatment of ALS was demonstrated in a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adult patients with ALS. A total of 137 patients were randomly assigned 2:1 to receive either sodium phenylbutyrate and taurursodiol (n = 89) or placebo (n = 48) for 24 weeks. The prespecified primary efficacy end point was a comparison of the rate of reduction in the revised ALS Functional Rating Scale (ALSFRS-R) total scores from baseline to week 24. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS. Each item is scored from 0 to 4, with higher scores indicating higher 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 patients who received sodium phenylbutyrate and taurursodiol compared with patients who received placebo (

Data demonstrated that patients with ALS treated with sodium phenylbutyrate and taurursodiol vs placebo had a slower rate of decline on a clinical assessment of daily functioning and longer median overall survival. Secondary outcomes were not significantly different between the 2 groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate and taurursodiol in patients living with ALS.

The medication contains taurursodiol, a bile acid, so in patients with disorders that interfere with bile acid circulation or alter concentrations, there may be an increased risk of worsening diarrhea. Bile acid–sequestering agents may interfere with the absorption of sodium phenylbutyrate and taurursodiol, and it is recommended to avoid concomitant use.

Each packet of sodium phenylbutyrate and taurursodiol contains 464 mg of sodium, so in patients sensitive to salt intake (eg, those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose and monitor for hypernatremia.

The most common adverse reactions (at least 15% and at least 5% greater than placebo) with sodium phenylbutyrate and taurursodiol were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal-related adverse reactions occurred throughout the study but were more frequent during the first 3 weeks of treatment.

The recommended initial dosage of sodium phenylbutyrate and taurursodiol for oral suspension is 1 packet (3-g sodium phenylbutyrate and 1-g taurursodiol) daily for the first 3 weeks. After 3 weeks, increase the dose to 1 packet twice daily.

To prepare a dose, empty the contents of 1 packet into 8 oz of room temperature water and stir vigorously to combine the mixture. Instruct to take orally or administer via feeding tube. Sodium phenylbutyrate and taurursodiol should be given before a snack or meal and within 1 hour of preparation. Any unused, reconstituted suspension should be discarded after 1 hour.

1. Relyvrio. Prescribing information.Amylyx Pharmaceuticals Inc; 2022.Accessed November 10, 2022. 

https://www.amylyx.com/document/RELYVRIO-US-Prescribing-Information.pdf

2. FDA approves first ALS treatment funded by Ice Bucket Challenge. News release. ALS Association. September 29, 2022. Accessed November 9, 2022. 

https://www.als.org/stories-news/fda-approves-first-als-treatment-funded-ice-bucket-challenge

3. Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. 

.2020;383(10):919-930. doi:10.1056/NEJMoa1916945

Articles

Relyvrio is intended to slow the disease progression of amyotrophic lateral sclerosis.

Relyvrio: A New FDA-Approved Treatment for Patients With ALS

On August 31, 2022, the FDA approved olipudase alfa-rpcp (Xenpozyme) for intravenous (IV) infusion in pediatric and adult patients with acid sphingomyelinase deficiency (ASMD),

 a rare genetic disease that causes premature death due to the accumulation of a complex lipid called sphingomyelin. Olipudase alfa-rpcp is an enzyme replacement therapy and provides an exogenous source of ASM. It is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. Olipudase alfa-rpcp received fast track, breakthrough therapy, priority review, and orphan drug designations from the FDA.

Investigators evaluated the efficacy of olipudase alfa-rpcp across 3 clinical trials. The first, ASCEND (NCT02004691), a multicenter, randomized, double-blinded, placebo-controlled, repeat-dose phase 2/3 study, evaluated adults with ASMD in 2 groups: a treatment group, receiving olipudase alfa-rpcp for 104 weeks (n = 13), and the placebo group (n = 18). At week 52, patients in the placebo group crossed over to receive olipudase alfa-rpcp treatment to reach the targeted maintenance dose of 3 mg/kg.

By week 104, patients who were initially in the placebo group had received olipudase alfa-rpcp for 52 weeks and demonstrated the following mean changes from baseline: predicted diffusion capacity of the lungs for carbon monoxide (DLco) increased by 26.8%; spleen volume reduced by 36.5%; liver volume reduced by 29.5%; and platelet count increased by 19.5%.

Patients in the previous olipudase alfa-rpcp group demonstrated improvement from baseline in the following parameters: predicted DLco increased by 34.1%; spleen volume reduced by 48.3%; liver volume reduced by 31.7%; and platelet count increased by 24%.

Trial 2, ASCEND-Peds (NCT02292654), enrolled 8 pediatric patients who received an IV infusion of olipudase alfa every 2 weeks over a 64-week period. During a 6-month extension study (Trial 3; NCT02004704), efficacy analyses showed continued improvements in the 3 patients evaluated for percent predicted DLco, the 6 patients evaluated for platelet counts, and all 8 patients evaluated for spleen and liver volumes, compared with baseline.

Two pediatric patients reported a serious adverse event (anaphylactic reaction). The most frequently reported adverse drug reactions in adults were headache, cough, diarrhea, hypotension, and ocular hyperemia. In pediatric patients, these reactions included pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis.

Treatment-related serious adverse events, hypersensitivity reactions including anaphylaxis, and infusion-associated reactions occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than adult patients.

Olipudase alfa-rpcp is administered via IV infusion every 2 weeks for adult and pediatric patients. In adults, the recommended starting dose is 0.1 mg/kg on day 1/week 0. The recommended maintenance dose is 3 mg/kg every 2 weeks. The dose escalation regimen is as follows: 0.3 mg/kg at week 2 and week 4; 0.6 mg/kg at week 6 and week 8; 1 mg/kg at week 10; 2 mg/kg at week 12; and 3 mg/kg at week 14 and thereafter.

In pediatric patients, the recommended starting dose is 0.03 mg/kg on day 1/week 0. The recommended maintenance dose is 3 mg/kg every 2 weeks. The dose escalation regimen is as follows: 0.1 mg/kg at week 2; 0.3 mg/kg at week 4 and week 6; 0.6 mg/kg at week 8 and week 10; 1 mg/kg at week 12; 2 mg/kg at week 14; and 3 mg/kg at week 16 and thereafter.

Reconstituted olipudase alfa-rpcp vials not used immediately and diluted solutions not to be administered immediately should be refrigerated at 2 to 8 °C (36-46 °F) for up to 24 hours, or at room temperature at 20 to 25 °C (68-77 °F) for up to 12 hours.

FDA approves first treatment for acid sphingomyelinase deficiency, a rare genetic disease. News release. FDA. August 31, 2022. Accessed October 2, 2022. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-acid-sphingomyelinase-deficiency-rare-genetic-disease

Xenpozyme. Prescribing information. Genzyme; 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761261s000lbl.pdf

Acid sphingomyelinase deficiency is a rare, progressive genetic disease associated with significant morbidity and mortality.