Real‐World Clinical Experience With Sodium Phenylbutyrate and Taurursodiol at a Single Amyotrophic Lateral Sclerosis Center in the United States

ABSTRACT

Introduction/Aims

Sodium phenylbutyrate (PB) and taurursodiol (TURSO)—PB and TURSO—was approved as a treatment for amyotrophic lateral sclerosis (ALS) in the United States in 2022 based on the results of a phase 2 trial, but was voluntarily withdrawn from the market in 2024 after negative results from its phase 3 trial. The objective of our study was to describe the real‐world clinical experience with PB and TURSO at one ALS clinic.

Methods

This was a retrospective chart review of all ALS patients receiving a PB and TURSO prescription at the Massachusetts General Hospital ALS Clinic between October 1, 2022, and September 30, 2023. Data were extracted from patients' electronical medical records up to December 31, 2023.

Results

A total of 441 ALS patients received a PB and TURSO prescription, with 329 (75%) initiating the medication. The average length of treatment was 285 days, and the rate of drug discontinuation during the study period was 41% (N=135). The most common reason for drug discontinuation was side effects (N=93, 69%), with the most common being gastrointestinal issues (N=69). No hospitalizations, deaths, or serious adverse events were considered related to treatment with PB and TURSO.

Discussion

Experience in real‐world clinical settings can help supplement trial data with information on the drug performance at various stages of disease progression. Adverse events impacted treatment persistence in routine clinical practice, underscoring the need for vigilant monitoring and tailored supportive interventions to optimize treatment adherence.

Abbreviations

ALS

amyotrophic lateral sclerosis

FDA

Food and Drug Administration

GI

gastrointestinal

ICD

International Classification of Disease

MGH

Massachusetts General Hospital

PB

phenylbutyrate

PSP

progressive supranuclear palsy

RCT

randomized‐controlled trial

TURSO

taurursodiol

US

United States

1. Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure [1]. Despite intensive research efforts [2], ALS remains a fatal disease with limited treatment options to slow its progression [3, 4].

AMX0035 is an oral agent combining sodium phenylbutyrate (PB) and taurursodiol (TURSO), hereafter referred to as PB and TURSO, designed to reduce neuronal death by targeting the endoplasmic reticulum and mitochondria, respectively [5, 6, 7]. In September 2022, PB and TURSO received approval from the Food and Drug Administration (FDA) and were marketed as Relyvrio for ALS treatment in the United States. The drug was also approved with conditions by Health Canada. Both approvals were based on the results of CENTAUR, a phase 2 randomized‐controlled trial (RCT) conducted in 137 participants with definite ALS by revised El Escorial Criteria (EEC) within 18 months from onset [8]. The main adverse events were gastrointestinal (GI) (diarrhea 21%, nausea 19%, salivary hypersecretion 10%, and abdominal discomfort 6%) [8].

While people living with ALS in the United States and Canada began having access to the drug in 2022, a phase 3 trial, PHOENIX, was launched primarily in Europe to confirm the effects of the drug in a broader ALS population. The trial enrolled 664 participants from 12 countries with definite or probable ALS by EEC criteria within 24 months since onset. The primary results of PHOENIX, announced in March 2024 [9], showed no statistically significant differences in disease progression between the active and placebo arms, prompting the voluntary withdrawal of the drug from the United States and Canadian markets. In PHOENIX, the rate of diarrhea in the active group was 31%, compared to 10% in the placebo group [9].

RCTs are the gold standard for evaluating safety and tolerability of investigational products, but typically enroll selected cohorts based on specific inclusion and exclusion criteria, which can limit the generalizability of trial results. Both CENTAUR and PHOENIX enrolled participants relatively early in their disease course [8, 9]. Once drugs are approved and marketed, use often extends beyond trial‐eligible populations; therefore, experience in clinical practice complements trial data by evaluating drug performance in a real‐world setting. Here, we present the cumulative clinical experience with PB and TURSO at our ALS clinic, focusing on treatment duration, dose adjustments, and side effects.

2. Methods

2.1. Study Design

This was a retrospective chart review aimed at exploring the real‐world use, safety, and tolerability of PB and TURSO in a broad ALS population seen at the Massachusetts General Hospital (MGH) ALS multidisciplinary clinic (Figure 1). The protocol was approved by the Massachusetts General Brigham Institutional Review Board. Data were gathered through electronic medical records. Patients included those diagnosed with ALS (International Classification of Disease [ICD]‐9: 335.20, ICD‐10: G12.21) or Motor Neuron Disease (ICD‐9: 335.2, ICD‐10: G12.20), aged 18 years or older, and prescribed PB and TURSO by an MGH provider between October 1, 2022, and September 30, 2023, and received at least one dose. Data collection extended through December 31, 2023, ensuring at least 3 months of follow‐up per patient. Patients using compounded formulations of PB and/or TURSO (i.e., non‐brand‐name) were excluded. Any prior exposure to research‐grade PB and TURSO before its commercialization, including participation in the CENTAUR or PHOENIX trials, their open‐label extensions, or expanded access protocol, was included.

FIGURE 1.

Study design. ALS, amyotrophic lateral sclerosis; MGH, Massachusetts General Hospital; PB, sodium phenylbutyrate; TURSO, taurursodiol.

2.2. Data Collection

All study data were managed using REDCap. Data included demographics, site and date of symptom onset, ALS diagnosis date, family history, genetic testing results, functional scores, and use of other ALS‐related medications. For patients who initiated PB and TURSO, detailed treatment data, including dosage, dose modification, duration of therapy, and reasons for discontinuation, were recorded. Side effects were closely tracked.

2.3. Aims and Analysis

The primary objective was to describe the overall clinical experience with PB and TURSO at the MGH ALS multidisciplinary clinic. Safety and tolerability assessment included the total number of patients experiencing side effects. If a side effect led to hospitalization, prolongation of an existing hospitalization, or death, it was categorized as serious.

Data were analyzed using R (version 4.2.2). Descriptive statistics were reported for all categorical and continuous variables. For categorical variables, frequencies and percentages were provided, while for continuous variables, the mean, standard deviation, median, minimum, and maximum were reported. This analysis is exploratory, and no power analysis was conducted.

3. Results

3.1. Participant Characteristics

Between October 1, 2022, and September 30, 2023, 441 patients with ALS received a PB and TURSO prescription by their providers at the MGH ALS multidisciplinary clinic. Of these, 329 (75%) initiated the treatment. Baseline demographic and disease‐related characteristics are shown in Table 1. The most common reasons for not starting treatment are reported in Table 2.

TABLE 1.

Demographic and clinical characteristics of the study cohort.

	Started PB and TURSO N = 329 (75%) a	Never started PB and TURSO N = 112 (25%) a
Sex, no (%)
Male	184 (56%)	60 (54%)
Female	145 (44%)	52 (46%)
Age of onset (years, range)	61 (26–87)	65 (22–86)
Age at PB and TURSO initiation (years, range)	64 (29–88)	NA
Site of symptom onset, no (%)
Limb	233 (71%)	74 (66%)
Bulbar	82 (25%)	33 (29.5%)
Other b	14 (4%)	5 (4.5%)
Disease duration
(from onset to PB and TURSO initiation), months a	24 (4–266) c	NA
(from diagnosis to PB and TURSO initiation), months a	10 (0–266) d	NA
Positive family history of neurodegenerative diseases, no (%)
ALS	24 (7.3%)	Not collected
FTD	6 (1.8%)	Not collected
ALS‐specific treatments, no (%)
Riluzole	321 (98%)	Not collected
Edaravone	276 (84%)	Not collected

Abbreviations: ALS, amyotrophic lateral sclerosis; BID, twice a day; FTD, frontotemporal dementia; NA, not available; PB, sodium phenylbutyrate; TURSO, taurursodiol.

^a n (%); median (minimum–maximum).

^b Includes respiratory, other, and unknown.

^c The majority of patients had disease duration less than 115 months. Only six patients had longer disease duration.

^d The majority of patients had disease duration less than 96 months. Only five patients had longer disease duration.

TABLE 2.

Reason for not starting PB and TURSO.

	N = 112
Clinical/medical reasons
Death or transition to Hospice Care before treatment initiation	24 (21.4%) a
Diagnosis revised to a non‐ALS condition	3 (2.7%)
Intolerance to off‐label medication	1 (0.9%)
Ongoing chemotherapy treatment	1 (0.9%)
Patient preference
Opted not to start	5 (4.5%)
Preference to continue off‐label TUDCA only	17 (15.1%)
Concerns about potential gastrointestinal side effects or preexisting GI issues	9 (8%)
Enrollment in a clinical trial	1 (0.9%)
Financial
High cost or insurance denial	15 (13.4%)
Missing data
Insufficient data available in EMRs or due to transfer outside MGH	36 (32.1%)

Abbreviations: EMRs, electronic medical records; FTD, frontotemporal dementia; GI, gastrointestinal; MGH, Massachusetts General Hospital; PB, sodium phenylbutyrate; TUDCA, tauroursodeoxycholic acid; TURSO, taurursodiol.

^a n (%).

3.2. Treatment Duration

The average duration on drug during the study period was 285 days (range 18–452 days). The overall rate of discontinuation was 41% (N = 135), most commonly due to side effects (N = 93, 69%), predominantly GI (N = 69) and taste‐related (N = 12). Among those who terminated, the average treatment duration was 57 days.

3.3. Safety and Tolerability

Most patients (90%) adhered to standard dosage (twice daily), while 10% modified the dosage, including dose reduction or unspecified dosing changes.

The most common side effects were GI issues, affecting 128 (39%) patients. Among these, diarrhea was the most frequent (N = 73, 57%), followed by abdominal pain/discomfort (N = 54, 42%), and nausea (N = 46, 36%). Vomiting was uncommon (< 10%). None of the GI side effects were categorized as serious.

4. Discussion

We report the clinical experience with PB and TURSO at a single ALS clinic in the first year following its approval. Most patients who received a prescription initiated the treatment, though some were unable to for various reasons. Notably, 13.4% of patients who never initiated therapy cited high cost or insurance denial, underscoring the significant impact of financial and administrative hurdles on access to newly approved therapies. Among patients who initiated treatment, the discontinuation rate was 41%, with side effects being the leading cause, higher than the trials. The most common side effects were GI‐related, especially diarrhea. Differences in adverse event ascertainment between the prospective RCTs and our study limit direct comparison; however, the pattern observed in our cohort was consistent with trial reports. Although no serious GI events occurred, these symptoms had a substantial impact on treatment persistence in clinical practice, accounting for 51% of discontinuations (69/135). This suggests that the RCTs underestimated the impact of GI events on treatment discontinuation in clinical practice. This highlights the need for proactive identification and targeted management of side effects to support long‐term therapy and maximize the real‐world adherence to newly approved drugs.

A strength of this study is the inclusion of a large, real‐world clinic population in the period immediately following the approval of a new drug for ALS. Practice‐based experience during this window offers important insights into drug utilization in routine care. To our knowledge, this represents the largest reported cohort of patients treated with PB and TURSO in clinical practice. Lessons learned from clinical experience can supplement the body of knowledge about newly approved drugs beyond the setting of tightly controlled trials [10]. Two prior studies describing the clinical use of PB and TURSO at single ALS centers in the US identified insurance approval and out‐of‐pocket expenses as the main reasons for not starting the medication, and GI side effects as the main reason for discontinuation [11, 12]. Our report aligns with these studies, highlighting the importance of practical aspects of clinical care, such as cost, reimbursement processes, and side effects, as major drivers of drug adoption and adherence in ALS.

This study has several limitations. First, as a retrospective chart review, it relied solely on data collected as part of routine clinical care. While structured collection processes were used to support consistent data extraction, the level of detail available in individual medical records varied, and some clinic notes had missing data, limiting the scope of the study objectives. A prospective study design would have allowed for the systematic capture of additional variables and more granular insight into treatment effects. Furthermore, larger multi‐center studies would have improved the generalizability of findings and provided a more comprehensive understanding of real‐world use. Lastly, the manufacturer's voluntary withdrawal of the drug for the ALS indication curtailed the observation period, which limits the evaluation of long‐term clinical outcomes. Nonetheless, this study provides valuable insights into the safety, tolerability, and implementation of PB and TURSO in a heterogeneous ALS population during its initial period of availability. As the drug continues to be evaluated in other neurodegenerative conditions such as Wolfram syndrome and progressive supranuclear palsy (PSP), these findings may help inform expectations around tolerability and real‐world use in broader patient populations. For instance, our data underscore the importance of closely monitoring for GI adverse events and tailoring supportive strategies to optimize patient adherence.

In conclusion, insurance barriers, drug costs, and side effects are key factors influencing ALS patients' decision to start and remain on newly approved medications. These topics should be areas of focus in the ALS drug development process.

Author Contributions

Narghes Calcagno: conceptualization, methodology, investigation, data curation, project administration, writing – original draft, writing – review and editing. Erica Scirocco: methodology, data curation, investigation, project administration, writing – original draft, writing – review and editing. Erin Clampffer: investigation, project administration, writing – review and editing. Grace Addy: investigation, project administration, writing – review and editing. Sean Morgan: investigation, project administration, writing – review and editing. Neel Parikh: project administration, investigation, writing – review and editing. Dylan V. Neel: project administration, writing – review and editing. Jennifer Scalia: data curation, project administration, writing – review and editing. Rebekah Young: formal analysis, data curation, software, writing – review and editing. Matteo Locatelli: formal analysis, data curation, software, writing – review and editing. deMauri S. Mackie: conceptualization, methodology, data curation, project administration, resources, supervision, writing – review and editing. James D. Berry: conceptualization, formal analysis, methodology, project administration, supervision, writing – original draft, writing – review and editing. Sabrina Paganoni: conceptualization, data curation, formal analysis, methodology, project administration, supervision, writing – original draft, writing – review and editing.

Ethics Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

Rebekah Young and deMauri Mackie were full‐time employees at Amylyx Pharmaceuticals while conducting the project. Dr. Berry reports research grants from Biogen, MT Pharma of America, Alexion, Rapa Therapeutics, the ALS Association, the Muscular Dystrophy Association, ALS One, Tambourine, ALS Finding a Cure, and reports personal consulting fees from Biogen, Clene Nanomedicine, MT Pharma of America, Janssen. Dr. Paganoni reports research grants from Amylyx Therapeutics, Revalesio, Eledon, Alector, UCB Pharma, Biohaven, Clene Nanomedicine, Prilenia Therapeutics, Seelos, Calico, Denali, NIH, DoD, the Muscular Dystrophy Association and reports consulting fees from Amylyx, Arrowhead, Biogen, BMS, Clene, Cytokinetics, Eikonizo, J&J, Merck, PharmAust, Prilenia, and Sola. She has been a paid educational speaker for Medscape, PeerView, and i3Health. The remaining authors declare no potential conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.