#VisualAbstract: Sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis patients

1. Sodium phenylbutyrate-taurursodiol slowed the functional decline in patients with amyotrophic lateral sclerosis.

2. The mean rate of change for slow vital capacity and plasma phosphorylated axonal neurofilament H subunit were not significantly different between the treatment and control groups.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration in the motor cortex of the spinal cord which leads to progressive muscle weakness. Current approved treatments manage symptoms, however, they do not slow neuronal degeneration. The coformulation of sodium phenylbutyrate and taurursodiol reduce neuronal death, ease endoplasmic reticulum stress, and mitigate mitochondrial function. As such, this study evaluated the safety and efficacy of sodium phenylbutyrate-taurursodiol in patients with ALS. The results of this study demonstrated that coformulation slowed the functional decline in patients though causing more adverse events. This randomized trial had several limitations including the quantification strategy. Further, the study used the Revised Amyotrophic Lateral Sclerosis Functional Ration Scale (ALSFRS-R), which has been suggested to not be a valid representation of disease severity. Nonetheless, the results of this study are significant as it evaluated a new therapy for a disorder with very few treatment possibilities.

Click to read the study in NEJM

Relevant Reading: Assessment of the factorial validity and reliability of the ALSFRS-R: a revision of its measurement model

In-Depth [randomized controlled trial]: This randomized control trial enrolled 137 participants in a multicenter study at 25 centers in the United States. Participants included in the study had a definite ALS diagnosis and had a slow vital capacity (SVC) of at least 60%. Participants with symptom onset longer than 18 months were excluded from this study. Study participants were randomized in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol or placebo, respectively. The primary outcome was the rate slope of decline in the total score on the ALSFRS-R from baseline. The ALSFRS-R contains 12 items across four subdomains of bodily function such as bulbar, fine motor, gross motor, and breathing. The total scale ranges from 0 to 48 with a higher score indicating better function. At week 24, the estimated mean rate of change in the ALSFRS-R total score was -1.24 points per month with the active-drug group compared to -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval [CI], 0.03 to 0.81; P=0.03). Additionally, secondary outcomes were also analyzed during the study. The mean rate of change in the plasma phosphorylated axonal neurofilament H subunit (pNF-H) concentration was 3.58 picogram (pg) per milliliter per month with the active-drug treatment compared to -2.34 pg per milliliter per month with placebo treatment (difference, 5.92 pg per milliliter per month, 95% CI, -4.41 to 16.26). The mean rate of change in SVC was -3.10% of the predicted normal value per month in the sodium phenylbutyrate-taurursodial group compared to -4.03% of the predicted normal value per month in the placebo group (difference, 0.93 percentage points per month; 95% CI, -0.10 to 1.95). Also, the cumulative hazard ratio for death, tracheostomy, or hospitalization in the active-drug group compared to placebo was 0.53 (95% CI, 0.27 to 1.05). Taken together, the sodium phenylbutyrate-taurursodiol coformulation slowed the functional decline of patients with ALS.

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