By: Yu Jeng Lee, PharmD Candidate c/o 2023
Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that affects both the upper motor neurons (UMN) and lower motor neurons (LMN). This disease causes muscle weakness, which progresses to disability, and subsequently death, primarily due to respiratory failure.1,2 There are approximately 1.6 new cases of ALS per 100,000 persons annually worldwide, with higher occurrences seen in patients that are Caucasian, male, and ≥ 55 years of age.1,2 Despite these risk factors, there is currently no single cause identified for ALS.1,2 However, multiple mechanisms have been proposed, predominantly via genetic mutations (i.e., superoxide dismutase type 1 mutations).1 Patients with ALS often present with a combination of UMN and LMN signs and symptoms. Symptoms associated with UMN involvement include hyperreflexia, spasticity, muscle weakness, and slowness, while LMN involvement symptoms include fasciculations, amyotrophy, muscle weakness, and atrophy.1
Current ALS Therapeutic Landscape
The clinical practice guideline for the management of ALS was published by the American Academy of Neurology (AAN) in 1999, with the most updated version revised in 2009.3 AAN’s practice parameter aims to provide evidence-based recommendations for optimal care in ALS patients. Currently, there is no cure for ALS, hence treatment is focused on symptom management and quality of life prolongation.1 Depending on a patient’s symptoms, various nonpharmacological and pharmacological options can be utilized. Some therapies include noninvasive positive pressure ventilation for respiratory insufficiency, percutaneous endoscopic gastrostomy tube placement for dysphagia, mexiletine for muscle spasms, nonopioid analgesics for pain, and amitriptyline for sialorrhea, depression, insomnia, and pseudobulbar affect.1,3 Currently, there are three medications approved by the Food and Drug Administration (FDA) to slow the progression of ALS: Relyvrio (sodium phenylbutyrate-taururs-odiol), Rilutek (riluzole), and Radicava (edaravone).2,3
Relyvrio was FDA-approved in September 2022 for the treatment of ALS in adults.4,5 There are two active ingredients in Relyvrio: sodium phenylbutyrate and taurursodiol.4 The exact mechanism of action is unknown, however, it is proposed that both components work in conjunction to reduce neuronal cell death, as sodium phenylbutyrate reduces ameliorating toxicity from endoplasmic reticulum stress while taurursodiol increases the cellular apoptosis threshold.4,6 Sodium phenylbutyrate-taurursodiol is available as a suspension and can be administered either orally or through a feeding tube. Abdominal pain, diarrhea, nausea, and upper respiratory tract infection were the most common (≥ 5%) adverse effects (AE) observed with the use of this medication.4 The approval of sodium phenylbutyrate-taurursodiol for the treatment of ALS was based on the results of the CENTAUR trial.5
Overview of the CENTAUR Trial
The CENTAUR trial was a 24-week, randomized, multicenter, placebo-controlled, double-blinded, phase 2 clinical trial conducted at 25 centers of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS) in the United States.6 Eligible patients included adults ≥ 18 years of age with a definite ALS diagnosis, as defined by the revised El Escorial criteria, who were within 18 months of ALS symptom onset, and had a slow vital capacity (SVC) greater than 60% of the predicted value for that patient’s specific demographic. Any patients on riluzole had to be at a stable dose for at least 30 days prior to screening to be included.6 Exclusion criteria included abnormal liver function tests greater than 3x the upper limit of normal, renal insufficiency, and uncontrolled hypertension.6
A total of 137 patients were randomized in a 2:1 ratio to receive either sodium phenylbutyrate-taurursodiol (n=89) or placebo (n=48) for 24 weeks.6 The typical patient in this study was a 58 year old white male with a body-mass index of 27, history of riluzole use, SVC score of 84%, Revised ALS Functional Rating Scale (ALSFRS-R) total score of 36, and Accurate Test of Limb Isometric Strength upper-limb score of 54 and lower-limb score of 57. On average, included patients were within 14 months of ALS symptom onset and 6 months of ALS diagnosis.6
The primary endpoint of this study evaluated the efficacy of sodium phenylbutyrate-taurursodiol based on the rate of decline in ALSFRS-R score from baseline through week 24.6 ALSFRS-R is a validated questionnaire-based scale that is used for the assessment of the physical function of ALS patients. The score is comprised of 12 items across 4 subdomains (bulbar, fine motor, gross motor, and respiratory function). Each item is scored on a scale from 0 (total loss of function) to 4 (normal function) points, with a possible total score ranging from 0 to 48 points.7
Regarding primary efficacy data, results were statistically significant and demonstrated a slower decline of patients’ ALSFRS-R scores in the treatment group compared to placebo.6 In the modified intention-to-treat population, the mean rates of change of the total ALSFRS-R scores in the sodium phenylbutyrate-taurursodiol and placebo groups were –1.24 and –1.66 points per month, respectively (Mean Difference [MD] 0.42; 95% confidence interval [CI] 0.03 to 0.81; p=0.03). The mean ALSFRS-R total score was 29.06 points in the sodium phenylbutyrate-taurursodiol group and 26.73 points in the placebo group (MD 2.32; 95% CI 0.18 to 4.47).6 Additionally, analyses of ALSFRS-R subdomain scores were also conducted. The ALSFRS-R fine motor score was the only subdomain that favored sodium phenylbutyrate-taurursodiol over placebo with a MD of 1.04 points (CI 0.20 to 1.87). There was no statistical significance between sodium phenylbutyrate-taurursodiol and placebo for the remaining three subdomains, although the data for each subdomain leaned towards sodium phenylbutyrate-taurursodiol in being clinically superior to placebo.6
Regarding safety data, gastrointestinal-related events were the most common type of AE for both the sodium phenylbutyrate-taurursodiol and placebo groups, with an incidence of 67% and 60%, respectively. Approximately 20% of patients in the sodium phenylbutyrate-taurursodiol group discontinued the trial regimen due to either an AE (19%) or serious AE (1%) compared to 14% of patients in the placebo group (AE 8%; serious AE 6%). Diarrhea and respiratory failure were the two most common AE that resulted in trial regimen discontinuation.6 An open-label extension trial was conducted to analyze and evaluate the long-term safety of sodium phenylbutyrate-taurursodiol for up to 132 weeks. Participants who have completed the study were eligible for enrollment in the open-label extension.6,8
Overall, ALS is a rare, progressive, and incurable neurodegenerative disease with a median survival from onset of approximately three to five years.1 Therefore, managing symptoms and slowing disease progression are the mainstay therapies for ALS patients. In the CENTAUR trial, use of sodium phenylbutyrate-taurursodiol led to a slower decline in the function of daily activities.6 This can be clinically significant as there are only two other FDA-approved medications for the treatment of ALS in addition to sodium phenylbutyrate-taurursodiol. Sodium phenylbutyrate-taurursod-iol can act as an alternative option for patients with ALS who are unable to tolerate riluzole or edaravone or have demonstrated limited efficacy on these medications. Despite the results from the CENTAUR trial, larger and longer studies are required to provide more data on the efficacy and safety of sodium phenylbutyrate-taurursodiol in ALS patients. There are many factors to take into consideration prior to initiating sodium phenylbutyrate-taurursodiol. Thus, interprofessional collaboration along with shared decision making with both the patient and their families is crucial to providing optimal care to patients with ALS.
- Brotman R, Moreno-Escobar M, Joseph J, et al. Amyotrophic lateral sclerosis. National Institutes of Health National Library of Medicine. https://www-ncbi-nlm-nih-gov.jerome.stjohns.edu/books/NBK556151/. Last Updated 08/22/2022.
- Amyotrophic Lateral Sclerosis (ALS). National Institutes of Health National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als. Last Updated 03/08/2023.
- Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-26. doi: 10.1212/WNL.0b013e3181bc0141.
- Relyvrio (sodium phenylbutyrate and taurursodiol) [package insert]. Cambridge, MA; Amylyx Pharmaceuticals, Inc.; Revised 09/29/22.
- FDA approves new treatment option for patients with ALS. U.S. Food & Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-als. Published 09/29/22.
- Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919-930. doi: 10.1056/NEJMoa1916945.
- Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1-2):13-21. doi: 10.1016/s0022-510x(99)00210-5.
- Paganoni S, Hendrix S, Dickson SP, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve. 2021;63(1):31-39. doi: 10.1002/mus.27091