Combination therapy shows promising efficacy against ALS decline

Neurodegenerative disorders

By Michael Woodhead

3 Sep 2020

A combination of sodium phenylbutyrate and taurursodiol has shown tantalising preliminary results against functional decline in patients with amyotrophic lateral sclerosis (ALS).

In a 24-week phase 2 randomised controlled trial, US researchers showed that the combination – also known as tauroursodeoxycholic acid – was associated with a 25% drug-associated slowing of the rate of functional decline in patients with more rapidly progressive forms of ALS.

Results from the multicentre study, published in NEJM, showed a difference of 0.42 points per month in rate of change in the total score on the ALS Functional Rating Scale–Revised (ALSFRS-R) between the active-drug group (89 participants) and placebo (48 participants).

The mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (P=0.03). The study authors noted that most prominent changes were seen with the fine-motor subscale of ALSFRS-R scores and less apparent for the other subscales.

However there were no significant differences between the groups in secondary outcomes such as rate of decline in isometric muscle strength or breathing function, change in levels of  pNF-H levels (a biomarker of motor neuron degeneration), and the time to events including death, tracheostomy, permanent ventilation, and hospitalization.

Adverse events were more frequent with the active drug and were mainly gastrointestinal, (diarrhoea, nausea, salivary hypersecretion, and abdominal discomfort), and about 19% of patient discontinued treatment due to side effects.

The study investigators, led by Dr Sabrina Paganoni of the AMG Center for ALS, Massachusetts General Hospital, explained that the combination had been postulated to reduce progression of ALS by reducing neuronal death. The mechanism of action was proposed to be simultaneous mitigation of endoplasmic reticulum stress and mitochondrial dysfunction.

The concluded that the findings were promising but “longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”

An accompanying commentary by Professor Michael Benatar of the University of Miami said the benefits seen with the short trial of tauroursodeoxycholic acid were tantalising but modest and would need to be confirmed in a phase 3 trial with broader enrolment criteria to include patients with less rapidly progressive forms of ALS.

It was not clear whether the benefit was attributable to one or both the components of the combination, the commentary said, but an ongoing phase 3 trial of tauroursodeoxycholic acid alone may provide more answers when it is completed in 2021.

“There has been understandable frustration with the slow pace of development of therapy for ALS. 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,” it concluded.

Already a member?

Login to keep reading.

Email me a login link