Orion Presents Data on How Levosimendan Works in ALS and Disease Biomarkers

Researchers with Orion Corporation presented new data on levosimendan‘s mechanism of action, and potential biomarkers of amyotrophic lateral sclerosis (ALS) progression.

The data were recently presented in four posters at the 30^th International Symposium on ALS/MND, held Dec. 4–6, in Perth, Australia.

Levosimendan, a small molecule that acts by increasing calcium sensitivity in both heart and skeletal muscle fibers, was originally developed by Orion to treat acute heart failure. Sold under the brand name Simdax, it is approved in nearly 60 countries — although not in the U.S. — as an intravenous (administered into the bloodstream) medicine for this indication.

Since levosimendan can also improve the activity of skeletal muscle cells, such as those responsible for controlling breathing, Orion is evaluating the potential of oral levosimendan in preserving lung function and delaying the need for ventilation support in ALS patients.

In the poster, “Mechanism of action of the cardiovascular drug levosimendan in the management of amyotrophic lateral sclerosis,” (abstract TST-43, page 244) researchers reviewed published data on the therapy’s mechanisms of action to identify those relevant to ALS.

Data from preclinical and clinical studies showed that levosimendan improves lung muscle ability to contract, as well as blood circulation in the brain, while reducing endoplasmic reticulum stress, cell death, and mitochondrial damage. It was also shown to have antioxidant and anti-inflammatory effects.

The endoplasmic reticulum is involved in the production, folding, modification, and transport of proteins, while mitochondria are the cells’ powerhouses, supplying vital energy.

All these processes have been suggested or shown to be associated with ALS development, highlighting that besides its main effect on skeletal muscle function, levosimendan may also act on other underlying mechanisms of the disease.

“While the direct activity of levosimendan on skeletal muscle is clearly the main effect of interest in relation to ALS, a number of other … effects of the drug raise some intriguing possibilities in the context of this disease,” the researchers wrote. “These effects should be confirmed in models more relevant to ALS.”

The study presented in the poster “Biomarker analysis in oral levosimendan phase 2 clinical trial LEVALS,” (abstract BIO-11, page 212) focused on the identification of biomarkers of ALS progression through the analysis of data from the LEVALS study and the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

The previous LEVALS Phase 2 trial (NCT02487407) involved 66 ALS patients who were randomly assigned to levosimendan or a placebo daily for three two-week periods, separated by a treatment-free period (19–23 days). After completing the third treatment period, patients continued with or started on treatment for six months in an open-label extension study.

To identify potential biomarkers of disease progression, the researchers analyzed patients’ laboratory data, as well as ALS Functional Rating Scale-Revised (ALSFRS-R) and slow vital capacity (SVC) scores during the LEVALS trial and extension study.

ALSFRS-R is a validated measure of functional declines, while SVC measures the maximum volume of air that can be slowly inhaled or exhaled in a given position and is used to assess lung function.

Results showed that the levels of a muscle biomarker (creatinine) significantly dropped over time in ALS patients, in agreement with muscle function decline.

Levels of another muscle marker (creatine kinase), an energy-associated enzyme and tissue damage indicator (lactate dehydrogenase), and proteins associated with liver function (alkaline phosphatase, albumin, and gamma-glutamyl transferase) were also significantly associated with ALSFRS-R and/or SVC scores.

When researchers compared these data with that of a matching “placebo” group from the PRO-ACT database, they found that levosimendan-treated patients showed trends of improvement in several of these markers.

These findings suggest that some of them could be potential biomarkers of ALS progression and treatment response.

“Such routine markers may have additional value in managing patients with ALS and in future clinical trials,” the researchers wrote.

The company presented two other posters with updated data on the REFALS Phase 3 trial (NCT03505021) — including the characteristics of the complete study population on enrollment — and levosimendan’s pharmacokinetics (uptake, distribution, and elimination in the body) in people with ALS.

REFALS, fully enrolled since July 2019, is evaluating the effectiveness of oral levosimendan in preserving lung function and overall functionality in almost 500 ALS patients. Participants are being treated with either levosimendan (1–2 mg) or a placebo daily for up to 48 weeks.

Those who complete the REFALS trial will have the opportunity to continue or begin levosimendan treatment in the REFALS-ES (NCT03948178) extension study, which will assess the therapy’s long-term safety and effectiveness in these patients.