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Two Drug Combination Slows ALS Decline in Phase 2 Trial

Article In Brief

A two-drug combination—sodium phenylbutrate-taurursodiol—targets two different pathways implicated in amyotrophic lateral sclerosis and showed a modest benefit over a 24-week period in a phase 2 trial.

It may not be a homerun, or even a triple, but doubling up two promising drugs to treat amyotrophic lateral sclerosis (ALS) has some researchers calling the latest phase 2 trial results “a solid single” for its demonstration that treatment of the fastest progressing patients can slow loss of function in a clinically meaningful way over 24 weeks. In a disease in which many potential therapies have struck out, that may be enough for the developers of the drug to seek marketing approval even without a phase 3 trial.

“In a phase 2 trial we are looking for some evidence that the drug engaged the target we are trying to hit,” commented Robert G. Miller, MD, FAAN, chair of neurology at California Pacific Medical Center in San Francisco, who was not involved in the trial. “With the positive response on the primary endpoint”—change in the Revised ALS Functional Rating Scale (ALSFRS-R)—“there is a strong suggestion that this happened.”

The trial, reported September 3 in the New England Journal of Medicine, compared a combination of sodium phenylbutyrate and taurursodiol to placebo. Sodium phenylbutyrate is available by prescription for urea cycle disorders. Taurursodiol (also known as TUDCA) is an over-the-counter supplement.

The two drugs each have shown some evidence of impact on models of the disease and have individually been shown to be safe in small clinical trials of ALS patients. Sodium phenylbutyrate is a histone deacetylase inhibitor that stimulates production of heat shock proteins, reducing stress in the endoplasmic reticulum, which is believed to be a late pathogenic event in many if not all forms of ALS. Taurursodiol stabilizes mitochondrial membranes and reduces apoptosis, another late pathogenic event in the disease.

“We thought a combination of these two might provide additive benefits in ALS by blocking different pathways,” said lead investigator Sabrina Pagonini, MD, PhD, a researcher at the Healey & AMG Center for ALS at Mass General, assistant pofessor of physical medicine and rehabilitation at Harvard Medical School/Spaulding Rehabilitation Hospital, and co-director of the Massachusetts General Hospital Neurological Clinical Research Institute.

Study Details

The trial was conducted at 25 sites across the country by the NEALS clinical trial network, an international consortium of ALS clinical researchers.

A common problem in clinical trials in ALS has been the variable rate of progression among patients, which has raised the number needed to enroll to show a benefit from treatment. To get around that problem, Dr. Paganoni and colleagues drew on data from the PROACT database, which includes clinical data from over 10,000 ALS patients from previous clinical trials. Previous analysis of that data revealed that patients who developed motor neuron signs in at least three body regions within 18 months of symptom onset went on to progress more rapidly, and more uniformly, than the average patient.

Restricting entry into the trial to such rapidly and homogenously progressing patients “increased our statistical power to see an effect if there was one,” Dr. Paganoni said. Entry was not restricted to a specific type of ALS, based on genes or site of first symptoms, for instance, “so we don't have reasons to believe that our patients differ mechanistically from other ALS patients.”

Of 177 individuals screened, 137 were enrolled and randomly assigned 2:1 to either active treatment or placebo. Most patients were also receiving riluzole, or more recently edaravone, which became available during the trial and prompted a protocol modification to allow its use. Compared to the active-treatment group, more patients in the placebo group were taking edaravone and fewer had bulbar onset, both of which had the potential to favor the placebo group, Dr. Paganoni noted.

The two drugs in the trial are water-soluble and were taken orally or through a feeding tube. The primary outcome measure was the rate of decline in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R) between baseline and week 24. The ALSFRS-R scale measures bulbar, gross motor, fine motor and breathing function, where scores range from 0 to 48, and 48 indicates no impairment. Across all ALS patients, the average rate of decline is approximately one point per month.

Sixty-nine percent of the 89 patients who received active treatment completed the 24-week trial regimen, compared with 77 percent in the placebo group. Gastrointestinal discomfort and diarrhea were the principal adverse events and led to discontinuation for 19 percent of the active-treatment group, versus 8 percent for those taking a placebo.

At the end of the trial, the mean rate of change in the ALSFRS-R was -1.24 points per month for those in the active treatment group, and -1.66 points per month for those in the placebo group, for a difference of 0.42 points per month (95% confidence interval, 0.03 to 0.81; p=0.03). A graph of the total ALSFRS-R score for the two groups showed the scores separated early and increased their separation over time, with no overlap of confidence intervals at any point.

A slowing of the loss of fine motor skills was the main contributor to the benefit seen from active treatment, which Dr. Paganoni pointed out was to be expected from natural history studies, which have shown that the fine motor domain is the most sensitive to change.

None of a variety of secondary and exploratory endpoints indicated a significant difference between the two groups, including subdomain scores, for strength and slow vital capacity, but the study was not powered to reveal subtle differences in these measures, Dr. Paganoni said. However, she pointed out, all of the numerical differences between the two groups favored active treatment.

“I think these are important results,” Dr. Paganoni said. “Treatment did not stop or reverse the disease—it is not a cure—but it could potentially be a helpful treatment.”

Results from an open-label extension are likely to be available soon, and will add more information about the long-tern effects of the drugs, she said.

A spokesperson for Amylyx Pharmaceuticals said the company is currently in discussions with the FDA and other health authorities in Europe and Canada to find the fastest path for patients to gain access to the drug. The company plans to share an update as soon as details are finalized based on those ongoing conversations.

Expert Commentary

“While I don't think this trial is a home run, it is a strong single,” commented Dr. Miller, a neuromuscular specialist at California Pacific Medical Center. “A home run would have shown more than a modest benefit on the primary outcome measure,” along with secondary outcomes that were also statistically significant, “and would have had a biomarker that went along with the clinical response. For all those reasons, there is more work to do. To approve a drug at phase 2 would be very unusual,” given the degree of benefit demonstrated here, he added.

Nonetheless, Dr. Miller said, “with the secondary outcomes all headed in the right direction, I am encouraged, more so than I have been for some other phase 2 trials. The results are suggestive of a real benefit, albeit of a modest effect.”

If the treatment proves itself in a larger and longer trial, “I'd take this modest benefit, especially if it is additive with the other two approved treatments,” riluzole and edaravone.

Angela L. Genge, MD, director of the ALS Clinic and the Clinical Research Unit at the Montreal Neurological Institute-Hospital, commented, “It is very exciting to have another trial come out with positive results. The trial design was excellent, with the choice to focus on the rapidly progressing patients, and then to show a benefit—that is encouraging.”

Dr. Genge added that the researchers' designated targets—endoplasmic reticulum stress and mitochondrial dysfunction—are important, since it is likely that most ALS patients would benefit from alleviating these pathologies. “This program is important for the general population of ALS patients,” she said.

Despite the positive outcome, the total number of patients who received active treatment seemed small for the goal of going straight for approval, she added, especially since the strict inclusion criteria might lead insurers to pay for the drug only for patients who also meet those criteria. “I hope when they do the next trial, the patient inclusion criteria are expanded, so we can see the benefits across a larger patient population.”


Dr. Paganoni has received research grants from Amylyx Pharmaceuticals. Dr. Miller has no relevant disclosures.

Link Up for More Information

• Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutrate-taurursodiol for amyotrophic lateral sclerosis N Engl J Med 2020; 383:919–930.
• Benatar M, McDermott MP. Incremental gains in the battle against ALS N Engl J Med 2020; 383:979–980.