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Phase 3 Update: Levosimendan Fails to Ease Breathing Problems in ALS Patients

Orion Corporation’s oral therapy levosimendan (ODM-109) failed to preserve lung function and overall functionality in people with amyotrophic lateral sclerosis (ALS), data from the Phase 3 REFALS clinical trial show.

“We would like to express our warmest thanks to the patients, carers and investigators for participating in the REFALS trial. The results were not what we wished and particularly we are disappointed on behalf of the ALS patients and their caregivers,” Outi Vaarala, MD, PhD, the senior vice president and head of research and development at Orion, said in a press release. “There are very limited treatment options for ALS at the moment and there is a high unmet need for new innovative therapies,” Vaarala added, noting that REFALS “still provides great resources to aid ongoing ALS research.

Levosimendan is a small molecule that works by increasing calcium sensitivity in both heart and skeletal muscle fibres, potentially improving their function.

Originally developed for the treatment of acute heart failure, levosimendan is sold as Simdax in nearly 60 countries — not in the U.S. — as an intravenous (administered into the bloodstream) medicine for that indication.

Since levosimendan also can improve the activity of skeletal muscle cells, such as those responsible for controlling breathing, Orion thought of assessing whether oral levosimendan could help preserve lung function and delay the need for ventilation support in ALS patients. Data from the previous, placebo-controlled Phase 2 LEVALS trial (NCT02487407) showed that oral levosimendan was safe and resulted in promising benefits in patients’ lung function when in a supine position (lying down with the face and torso facing up).

This potential benefit was relevant since signs of respiratory insufficiency often appear when lying down.

REFALS was designed to assess whether oral levosimendan was superior to placebo in helping maintain lung function and subsequently preserve overall functionality in people with ALS.

Fully enrolled since July 2019, the trial evaluated the safety and effectiveness of oral levosimendan in 492 ALS patients, recruited across 104 sites in the U.S., Canada, Europe, and Australia. Participants were assigned randomly to receive orally either 1 mg of levosimendan or a placebo once to twice a day, for up to 48 weeks (11 months).

The trial’s main goal was to assess changes in patients’ lung function by measuring their supine slow vital capacity — the maximum volume of air they could slowly inhale or exhale when in a supine position — after 12 weeks of treatment.

Secondary goals included changes in the ALS Functional Rating Scale-Revised — a validated measure to monitor disability progression in ALS patients — combined with survival at 48 weeks.

According to Orion’s press release, results showed that the trial met neither of these goals and that no new safety concerns were identified.

Orion plans to present REFALS’ final data at a future scientific meeting.

All patients completing the trial had the option to continue or begin levosimendan treatment in the REFALS-ES (NCT03948178) extension study, meant to investigate the therapy’s long-term safety and effectiveness.

Due to the results of the REFALS study, the continuation of REFALS-ES is under review.

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