Phase 3 Trial of Oral Levosimendan as Respiratory Treatment for ALS Recruiting in US, Europe and Australia

A new Phase 3 trial evaluating levosimendan (also known as ODM-109), an oral treatment by Orion for breathing problems in amyotrophic lateral sclerosis (ALS), has recruited its first patients, the Finnish pharmaceutical company announced.

The trial, called REFALS (NCT03505021), aims to investigate the potential benefits of prolonged treatment with levosimendan on respiratory muscles in ALS patients. The therapy is expected to help halt the deterioration in patients’ ability to breath and delay the need for ventilation support.

REFALS aims to recruit 450 patients at sites in North America, Europe, and Australia. They will be randomly assigned to receive either levosimendan, administered in 1 mg oral capsules, or placebo once to twice a day for 48 weeks (11 months). Enrollment information is available here.

The trial’s primary goal is to determine the changes in lung function, measured by the supine slow vital capacity — the maximum volume of air that can be slowly inhaled or exhaled when in a supine (lying face upward) position — after 12 weeks of treatment. This is important because signs of respiratory insufficiency often appear when lying down.

Additional objectives include changes in the Revised ALS Functional Rating Scale ALSFRS-R function, a validated instrument for monitoring disability progression in ALS patients, including respiratory function and survival.

Levosimendan is a calcium sensitizer and potassium channel opener. It is widely approved — although not in the U.S. — under the trade name Simdax as an intraveneous medicine for acute worsening of severe chronic heart failure. The therapy is also able to sensitize skeletal muscles, like those responsible for breathing, to calcium.

In the previous Phase 2 trial LEVALS (NCT02487407),66 ALS patients were randomized to treatment with levosimendan (1 mg and 2 mg daily doses) or placebo for two weeks separated by a wash-out period (19-23 days). After completing the third treatment period, patients continued to an open-label follow-up part for six months.

Treatment with levosimendan was found to be generally well-tolerated, with most common adverse events including headache and an increased heart rate.

These side effects led to discontinuations, mainly due to increased heart rate, in one patient on the 1 mg dose and 10 receiving 2 mg of levosimendan. The placebo group had two discontinuations.

LEVALS’ primary endpoint was changes in slow vital capacity when sitting at nine months, but the study failed to reach differences among the groups. However, levosimendan treatment led to promising signals in supine slow vital capacity.

Results were presented at the 28^thInternational Symposium on ALS/MND in December 2017 in the poster titled,“Oral levosimendan (ODM-109):
Key placebo-controlled results from the phase 2 study in ALS patients with SVC between 60-90% predicted at screening.”

If the Phase 3 trial is positive, Orion plans to file for marketing authorisation for oral administration of levosimendan in ALS in the United States and Europe; it has been designated an orphan drug in both countries.