#AANAM – Better REFALS Trial Response Seen in ALS Patient Group

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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levosimendan trial subgroup analysis

Editor’s note: The ALS News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

Amyotrophic lateral sclerosis (ALS) patients with a short disease duration and fast progression showed better responses to Orion’s investigational oral therapy levosimendan (ODM-109), an analysis of Phase 3 REFALS study data found.

While the trial failed to meet its goals of showing levosimendan superior to placebo at maintaining patients’ lung function and overall functionality, these findings in a patient subgroup may help to inform future trials, the researchers noted.

This analysis, along with REFALS data on potential ALS biomarkers, were presented at the 2021 virtual American Academy of Neurology annual meeting, running through April 22.

Levosimendan, when administered directly into the bloodstream, is sold as Simdax for the treatment of acute heart failure in nearly 60 countries — although not in the U.S. It works by increasing calcium sensitivity in both heart and skeletal muscle fibers, potentially improving their function.

Since skeletal muscle cells include those responsible for controlling breathing, Orion thought of evaluating whether oral levosimendan could help preserve lung health, delay the need for ventilation support, and maintain overall functionality in people with ALS.

After promising Phase 2 results released in 2017, Orion launched the global REFALS Phase 3 study (NCT03505021) to evaluate the safety and effectiveness of oral levosimendan in 496 adults with ALS and some degree of lung function impairment.

Participants were randomly assigned to receive either 1 mg of levosimendan (329 patients) or a placebo (167 patients), taken once to twice a day for up to 48 weeks (11 months).

Last year, Orion announced that levosimendan failed to meet both the trial’s main goal of maintaining patients’ lung function, as assessed with supine slow vital capacity, as well as its secondary goal slowing functional decline, measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), combined with extended survival.

Of note, supine slow vital capacity refers to the maximum volume of air patients could slowly inhale or exhale when in a supine position (lying horizontally face up).

In an oral presentation, “Determinants of clinical response to levosimendan in the REFALS phase 3 study in people with ALS,” Merit Cudkowicz, MD, a REFALS investigator and the director of the Healey & AMG Center for ALS, presented data supporting the existence of a subgroup of ALS patients showing better responses to levosimendan.

REFALS included a broad ALS patient population, reflecting what is typically seen in ALS trials, said Cudkowicz, who is also the chair of neurology at Massachusetts General Hospital in Boston.

Patients’ mean age was 59.2 years, 61.9% were men, and they had been living with the disease for a median of 24.3 months (about two years). About 20% had bulbar onset ALS, when the disease first affects muscles involved in speaking, swallowing, and breathing.

Researchers conducted subgroup analysis to evaluate whether patients’ characteristics at the study’s start (baseline) determined their response to treatment.

Results showed that some subgroups of levosimendan-treated patients did significantly better in terms of maintaining their ALSFRS-R scores than those given a placebo. These included patients with shorter disease duration (less than about two years), faster disease progression, worse lung function, and greater heart rate changes.

Notably, among the subgroups of patients with faster disease progression and worse lung function, significant therapeutic effects were only observed at 48 weeks, rather than throughout the study.

These findings highlighted that while levosimendan “did not significantly improve the respiratory function or overall functionality in the broad population of people with ALS, there was a trend to treatment effects in a subgroup of participants,” Cudkowicz said.

In particular, “short duration of disease, worse respiratory function, and faster progression of ALS suggested better response to levosimendan,” she said, adding that this type of subgroup analysis “may be of value in identifying patient groups with the stronger treatment effect for future trial designs.”

Cudkowicz emphasized that it is particularly important to look for subgroups in ALS patients, given the severe nature of the disease and the absence of good treatment.

“We never want to miss a group of people that might be benefiting from the treatment,” Cudkowicz concluded.

In a poster titled, “Correlation of laboratory safety variables with disease course in the REFALS phase 3 study of levosimendan in people with ALS,” researchers also presented trial data regarding potential biomarkers of ALS disease course.

An analysis of potential associations between the levels of several molecules and disease progression, as assessed with the ALSFRS-R and supine slow vital capacity, revealed that muscle-related biomarkers — creatinine, creatinine clearance, creatine kinase, and cardiac troponin T — were significantly associated with disease progression.

The levels of neurofilament light chain, a biomarker of nerve damage, were generally stable over time, but higher levels at treatment start were found to predict faster ALS progression.

In addition, higher levels of cardiac troponin T were predictive of faster disease progression, specifically in patients with bulbar onset.

Further studies are needed to confirm the predictive value of these biomarkers, the researchers noted.