Daily use of levosimendan capsules appear to preserve respiratory strength in people with amyotrophic lateral sclerosis (ALS) while in a supine, or lying flat, position, a sub-analysis of the Phase 2 LEVALS trial reports.
Treatment did not show significant benefit against placebo when patients were sitting up, its primary goal. But study researchers said a supine position might be a “more sensitive measure of diaphragmatic strength.”
The study, “Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial,” appeared in the Journal of Neurology, Nurosurgery & Psychiatry.
Despite advances in non-invasive ventilation, effective treatment of respiratory dysfunction in people with ALS remains an unmet need. Levosimendan, a potential therapy developed by Orion Corporation, is a calcium sensitizer and potassium channel opener. Outside the U.S., it is widely approved under the brand name Simdax as an intravenous medicine for acute heart failure.
Levosimendan is also able to sensitize skeletal muscles to calcium, including those responsible for breathing, and as such may preserve respiratory strength. This has been supported by clinical studies, where an oral formulation of the therapy was seen to improve diaphragm function of healthy people.
Better respiratory function was reported in ALS patients who took part in a Phase 2b trial (NCT01709149) of another calcium sensitizer, called tirasemtiv. (Of note, tirasemtiv is no longer being developed by Cytokinetics after disappointing Phase 3 results.)
The LEVALS Phase 2 trial (NCT02487407) recruited 66 patients (71.2% men, 92.4% white, and 83.3% with spinal-onset ALS) at 11 sites in the U.K., Germany, Ireland, and the Netherlands. Their median disease duration was 21.2 months.
Of these, 59 patients participated the double-blind period and 50 entered the study’s six-month open-label extension. Initially, all were randomized to three crossover periods of two weeks each, during which they were given either 1 mg of levosimendan or a placebo daily, or 1 mg of the potential therapy or placebo twice a day. In the extension, all patients started on 1 mg daily capsules for two weeks, with 44 of them moving on to a 2 mg daily dose at that time. The mean duration of treatment was 147.9 days (about 2.8 years).
The primary endpoint, or goal, was slow vital capacity (SVC) while seated. SVC measures the maximum volume of air that can be slowly inhaled or exhaled in a given position.
Secondary endpoints included changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) — a tool to monitor disability progression — hand grip strength, overnight arterial oxygen saturation, the Clinical Global Impression of Change (CGI-C), as assessed by patients and researchers, a visual analogue scale of fatigue, and two quality of life scales.
Trial results showed no significant benefit for levosimendan over placebo in SVC while seated. Yet, as with early results, a post-hoc analysis of supine SVC — the maximum air volume slowly inhaled or exhaled when lying flat on the back — found differences favoring both dosing regimens, especially when 1 mg was given two times a day.
Specifically, there no evidence of deterioration in supine respiration in treated patients compared to those given placebo. People with bulbar-onset ALS and those with baseline supine SVC values below 75% showed greater benefits.
“Seeing differences between the treatments in supine but not sitting SVC is supported by the finding that in patients with ALS, supine vital capacity is a more sensitive measure of diaphragmatic strength than that measured in the upright position,” the researchers said.
No differences between treatment and placebo groups were also found in ALSFRS-R, fatigue, overnight oxygen saturation, hand grip, CGI-C, quality of life, or sniff nasal pressure. Lung function, quality of life, and ALSFRS-R scores declined during the extension phase.
Adverse events (AEs) were reported by 71% of patients taking levosimendan 1 mg daily, 85% of those on levosimendan 2 mg daily, and 53% of those on placebo. Most AEs were mild, with headache (10%) and falls (9%) the most common.
In turn, 42 (84%) patients reported AEs during follow-up (the extension study), with falls (28%), swallowing problems (12%) and respiratory failure (also 12%) being the most frequent.
Headaches and heart rate increases were more common with levosimendan, especially with the 2 mg daily dose.
Serious AEs were experienced by four patients on levosimendan 1 mg daily or on placebo, and by two people on the 2 mg daily dose. Nineteen (38%) experienced such AEs during follow-up. Two cases — bradycardia (a slower-than-normal heart rate) and cardiac arrest in the double-blind part, and acute myocardial infarction during the open-label extension — were considered related to treatment.
Thirteen patients stopped treatment during the primary study due to an adverse event, most commonly increased heart rate. Six discontinued during follow-up, five due to such serious AEs as respiratory failure and acute myocardial infarction.
Five patients died during the study, all but one during the open-label part. No death was considered related to treatment.
Two of this study’s nine authors are Orion employees.