Development of effective treatments for amyotrophic lateral sclerosis has been slow, which makes reports of potential therapies always welcome news — even when the news is early, as in the case of the result of a phase II trial of an investigational agent. But slowing of functional decline, which was demonstrated in the CENTAUR trial, made a compelling case for including this report, originally published Sept. 2, in the BreakingMED year-end clinical review series.
Sodium phenylbutyrate-taurursodiol, an investigational drug known as AMX0035, favorably modified monthly functional decline in amyotrophic lateral sclerosis (ALS) patients, the randomized, placebo-controlled, phase II CENTAUR trial found.
Modified intention-to-treat analysis comparing active treatment with placebo showed mean monthly declines in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R, which ranges from 0 to 48, with higher scores indicating better function) of −1.24 points per month versus −1.66 points per month for placebo (difference 0.42 points per month; 95% CI 0.03-0.81; P = 0.03) through 24 weeks, reported Sabrina Paganoni, MD, PhD, of the Massachusetts General Hospital in Boston, and coauthors in New England Journal of Medicine. Secondary outcomes did not differ between groups, and included decline in isometric muscle strength; plasma phosphorylated axonal neurofilament H subunit (a potential biomarker of motor neuron degeneration); rate of slow vital capacity decline; and the individual components and composite of time to death, tracheostomy, permanent ventilation, or hospitalization.
“Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS,” Paganoni and colleagues wrote.
In an accompanying editorial, Michael Benatar, MD, PhD, of the University of Miami in Florida, and Michael McDermott, PhD, of the University of Rochester in New York, wrote that the trial showed “an approximately 25% drug-associated slowing of the rate of functional decline.
“The ALSFRS-R is the most commonly used clinical outcome measure in ALS clinical trials, with patients typically declining by approximately 1 point per month on average,” they noted.
“The trial cohort was effectively enriched for patients with more rapidly progressive disease, as evidenced by the mean ALSFRS-R slope of −1.66 points per month in the placebo group,” Benatar and McDermott added. “The strategy of focusing trial eligibility on a more homogeneous subgroup of the population of patients with ALS with faster progressing disease builds on experience and lessons learned from previous studies, but also raises questions about generalizability to the broader population of patients with ALS.”
Sodium phenylbutyrate is a histone deacetylase inhibitor and ammonia scavenger with potential effects on neuroinflammation. It is approved for treatment of urea cycle disorders and being investigated in cancer, hemoglobinopathies, and cystic fibrosis. In motor neuron disease, it may address transcription dysregulation, and phase II safety data in ALS suggested that the lowest dose tested (range 9-21 grams daily) effectively improved histone acetylation levels and was well tolerated.
Tauroursodeoxycholic acid, a more hydrophilic form of ursodeoxycholic acid, inhibits liver cholesterol secretion and synthesis as well as intestinal cholesterol absorption, and also has potential neuroprotective, anti-apoptotic action. It is being studied as an add-on treatment with riluzole in ALS. A proof-of-principle study in ALS found slower ALSFRS-R progression with tauroursodeoxycholic acid versus placebo.
The combination of the two agents may reduce neuronal death in ALS by reducing endoplasmic reticulum and mitochondrial dysfunction.
In the trial, Paganoni and colleagues enrolled adults with a diagnosis of definite ALS within 18 months of symptom onset between June 2017 and September 2019. If used, riluzole was at a stable dose for 30 days or more prior to screening. Edaravone, which became available in August 2017, was permitted before and during the trial.
The researchers analyzed data for 135 participants randomized to sodium phenylbutyrate–taurursodiol (n=87 participants given 3 g of sodium phenylbutyrate and 1 g of taurursodiol orally or through a feeding tube daily for 3 weeks, then twice daily) or placebo (n=48).
The overall cohort was 69% male, 95% white, and had mean age of 57.5. Followup was done every 3 weeks for 24 weeks with a final phone call at 28 weeks, with optional open-label extension up to 132 weeks.
The full course of the trial was completed by 69% of the participants in the sodium phenylbutyrate–taurursodiol group and 77% in the placebo group.
At trial entry, a majority used either riluzole or edaravone (77%), and 28% used both, with edaravone use more common in the placebo group (50% versus 25% in the active treatment group).
Baseline ALSFRS-R total score was mean 36.0, with mean baseline sub-domain scores of bulbar 9.7, fine motor 8.0, gross motor 7.6, and breathing 10.8.
One or more adverse events were reported by 97% in the active treatment and 96% of those in the placebo groups.
Events with 2% or more frequency in the active treatment group were primarily gastrointestinal — diarrhea, nausea, and abdominal discomfort — known to be associated with taurursodiol. Salivary hypersecretion was also reported. After the first 3 weeks, gastrointestinal adverse events were reported more frequently in the placebo group. Dose reduction and dose interruption due to gastrointestinal events occurred more frequently in the sodium phenylbutyrate–taurursodiol group (3% and 9%, respectively) than in the placebo group (0% and 2%, respectively). Mean weight change from baseline to week 24 was similar in the two groups.
Serious adverse events were more frequent in the placebo group than the active treatment group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the sodium phenylbutyrate–taurursodiol group.
Trial discontinuation occurred in about 25% of the active drug group (19% due to adverse events) and 21% of placebo participants (8% due to adverse events). The most common adverse events leading to discontinuation were diarrhea (6% in the active treatment group and 0% for placebo) and respiratory failure (6% in the placebo group and 0% in the active treatment group).
“There has been understandable frustration with the slow pace of development of therapy for ALS,” the editorialists observed. “Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival — and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope.”
Limitations of the study include uncertainty as to what constitutes a clinically meaningful change in ALSFRS-R total score.
Paul Smyth, MD, Contributing Writer, BreakingMED™
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association.
Paganoni reported grants from Revalesio Corporation, Ra Pharma, Biohaven, Clene, and Prilenia outside the submitted work.
Cat ID: 130
Topic ID: 82,130,730,130,192,925