LISBON, Portugal — Adding rasagiline, a monoamine oxidase B (MAO-B) inhibitor, to riluzole, a standard drug used to treat amyotrophic lateral sclerosis (ALS), does not provide additional benefit in terms of survival, a new randomized trial shows.
However, post hoc analysis of the results suggests that adding rasagiline may have potential benefit for patients whose disease progresses at a more rapid rate.
"The bad news is that the intention-to-treat analysis did not show an effect with 1 mg of rasagiline on the primary endpoint, but the good news is that the post hoc analysis showed a positive effect on function and survival on fast progressors," said Albert Ludolph, MD, professor of neurology, Ulm University, Germany.
Ludolph presented the results here at the Congress of the European Academy of Neurology (EAN) 2018 to coincide with the findings being published online June 19 in Lancet Neurology.
"This observation should be confirmed in a second, specifically designed clinical trial before its use can be considered in clinical practice," the authors conclude in their publication. "This study also strongly calls for a stratification of future trials according to fast and slow progressors to identify subgroups most likely to benefit from a treatment."
Previous studies using an ALS mouse model have shown rasagiline had a significant dose-dependent therapeutic effect on motor function and survival. The longest extension of life — about 20% — was in mice receiving a combination of riluzole and rasagiline.
As well as being an MAO-B inhibitor, rasagiline is an antiapoptotic compound. It has also been shown to have neuroprotective effects in Parkinson's disease.
The primary endpoint of this new phase 2 study was survival time (time from randomization to death or end of trial) in the experimental group compared to a control group. "For the trial objective, we were very conservative," Ludolph told meeting delegates.
A secondary outcome measure was change in total score on the ALS Functional Rating Scale–Revised (ALS-RFS-R), which Ludolph said is an established score to measure ALS function.
The inclusion criteria were "broad," said Ludolph. "We were anxious to include early patients, therefore we included possible ALS patients" as well as probable or definite ALS cases.
Eligible patients had to have the disease for at least 6 months but less than 3 years. They had been treated with riluzole (100 mg/day) for more than 4 weeks and had a slow vital capacity of greater than 50% of predicted normal.
"We wanted to have heavily affected patients, which also included fast progressors," explained Ludolph.
The analysis included 126 patients in the treatment group (30 with bulbar and 96 with spinal site of onset) and 125 in the placebo group (28 with bulbar and 97 with spinal site of onset).
The study design as well was "very conservative," Ludolph said. Each of the bulbar and spinal groups were randomly assigned to rasagiline or placebo and were seen 8 times over 18 months.
Rasagiline did not cause major adverse events. The most common side effects in the intention-to-treat population included dysphagia, respiratory failure, dyspnea, and falls, but all of these effects "are mostly complications of ALS," said Ludolph.
"The important message is that they are not different between the rasagiline patients and controls."
Comparison of survival curves for the two groups showed that at 6 months, they differed (P = .02), but at 18 months, the P value was 0.31, "which clearly indicated that the result was not significant," said Ludolph.
The researchers looked more closely at the statistically significant result at 6 months. "We thought perhaps the results were biased" in terms of inclusion of fast progressors, defined by a slope of ALS-FRS-R of 1.1 points per month or greater.
Indeed, 20.4% of patients taking placebo were deemed to be fast progressors compared with 11.5% in the treatment group at baseline (P = .07).
Post hoc Analysis
The researchers carried out a post hoc analysis using the median of the ALS-FRS-R slope before randomization to define a cutoff for the two groups. As Ludolph explained, this median divided the slopes into two halves at a cutoff of a loss of 0.5 points on the ALS-FRS-R per month at baseline.
For patients with a progression rate of less than 0.5 point per month, decline during the study was about 0.6, but in patients who had a slope of more than 0.5 per month, the progression rate was more than 1 point per month.
Although survival in the fast progressors was not statistically significant at the end of study, "the results at 6 and 12 months clearly indicate in this post hoc analysis that survival was improved," said Ludolph.
Examining disease progression in the fast progression group, the investigators found that the effect of rasagiline was significant at 6, 12, and 18 months (P = .0103, P = .0099, and P = .0051, respectively, vs placebo per month).
The results led researchers to conclude that "we have to consider different treatment effects in fast and slow progressors in ALS, and perhaps in other neurodegenerative diseases," said Ludolph.
Negative Trial, Positive Effect
In an accompanying Comment, Nazem Atassi, MD, associate director, Neurological Clinical Research Institute, Massachusetts General Hospital, and associate professor, neurology, Harvard Medical School, Boston, muses on how a "negative trial in ALS can have a positive effect on research."
In the past 5 years, he writes, "amazing" progress that has been made in developing ALS therapies. Atassi noted that last year, for example, the US Food and Drug Administration approved edaravone as an ALS therapy, and the pipeline of therapies in development "continues to grow." New genetic causes of the disease have been identified, providing "key insights" into underlying mechanisms.
The current study showed no differences between the rasagiline and placebo groups but post hoc analysis showed a difference in slow and faster progressors in ALS, a disease population that can have high heterogeneity in disease progression, he notes.
The researchers' proposed cohort enrichment strategy "aims to exclude outliers with slow-progressing disease to decrease the clinical heterogeneity in the future trial population and increase the statistical power to test the benefit of rasagiline treatment on survival. A similar cohort enrichment strategy has proven to be successful in the trial of edaravone," he points out.
"Ludolph and colleagues report a well conducted placebo-controlled clinical trial of rasagiline that was negative for all of the prespecified primary and secondary outcomes," Atassi concludes. "However, the post-hoc analyses provide valuable data that can be used for planning cohort enrichment strategies in future clinical trials of patients with amyotrophic lateral sclerosis."
Asked to comment on the study for Medscape Medical News, Marianne de Visser, MD, PhD, a neurologist and professor of neuromuscular disorders, Amsterdam Medical Center, the Netherlands, said she is "thrilled" that an add-on treatment without major side effects may be "on the horizon" for patients with fast-progressing ALS.
However, she said she wanted "to sound a word of caution" regarding the new results.
"There are methodological limitations regarding post hoc analyses, and therefore a confirmatory study stratifying for rate of progression is still needed" as was indicated by Ludolph, she said.
The study was partially supported by Teva Pharmaceutical Industries. Ludolph and de Visser have disclosed no relevant financial relationships.
Congress of the European Academy of Neurology (EAN) 2018. Presented during Plenary Symposium: Highlights and Breaking News, June 19, 2018.
Lancet. Published online June 19, 2018. Abstract, Comment
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Cite this: Rasagiline Added to Riluzole in ALS May Help 'Fast Progressors' - Medscape - Jun 21, 2018.