Orion has been granted Orphan Drug Designation for the development of ODM-109 in ALS by the FDA, with the Phase 3 trial expected to include US based sites. Previous studies of levosimendan done in Europe failed to meet endpoints, however the higher dose cohort did slightly better than the lower dose group overall. This announcement shows that skeletal muscle targeting treatments continue to show interest among drug developers working to advance effective treatments for ALS.
Earlier this month Orion Pharmaceuticals announced a Phase 3 clinical trial of their oral medication levosimendan (ODM-109), in people with ALS. Researchers designed the Phase 3 trial to include 450 people with ALS. The primary purpose of the trial is to determine whether ODM-109 significantly improves respiratory function in people with ALS. Efficacy will be determined by measuring differences between slow vital capacity (SVC) at baseline and after 12 weeks of treatment. The trial is not yet open for recruitment, however, when it does start accepting patients we will update our listing of the trial in our database. Subscribe to our clinical trial mailing list to receive notice of when that occurs.
Orion Pharmaceuticals disclosed results from a complex 66-participant Phase 2 clinical trial of this compound in the middle of 2017. The Phase 2 trial was also designed to determine whether ODM-109 improved respiratory function as measured by SVC. The Phase 2 trial was designed as a crossover trial in which enrolled participants were randomized into ODM-109 or placebo groups, treated for two weeks, then washed out for three weeks. After crossover, this treatment and washout period was repeated twice (total of 3 treatment periods). The trial then entered an open label period lasting six months. Two different doses of drug were testing, 1mg and 2mg, neither of which met statistical endpoints, although the higher dose did produce slightly better p values. The Phase 2 trial took place between 2015-2017 at ALS/MND research centers located in Germany, Ireland, Netherlands and the United Kingdom. The principal investigators reported that the earlier Phase 2 study missed all endpoints.
However the company believes that there were positive enough trends to warrant moving forward with larger 450-participant Phase 3 study. Two-thirds of people with ALS who enroll in this pivotal clinical trial will take capsules containing 2mg of levosimendan daily for the nearly year-long study. The other third will receive a placebo. There is no crossover design, nor is it known if Orion will offer another Open Label Extension arm as they did in the Phase 2 trial. This study will also include sites in the United States, whereas the previous study was entirely conducted in the EU. The enrollment criteria in this trial remain nearly identical to the Phase 2 trial. Riluzole usage is allowed, enrollees should have a high baseline SVC and be within the first 4 years of symptom onset. However, concomitant use of the recently FDA-approved ALS treatment edaravone will not be allowed in this Phase 3 trial.
According to preclinical research, Orion believes that levosimendan helps muscles contract more easily by sensitizing skeletal muscle’s contractile apparatus to calcium signaling. This makes their proposed mechanism of action similar those those being developed by Cytokinetics, who has been advancing skeletal muscle activators across ALS clinical trials for the past decade. Cytokinetics recently announced that their lead molecule in ALS, tirasemtiv, failed to achieve its endpoints in its own Phase 3 pivotal trial. Nevertheless, Cytokinetics has initiated a Phase 2 clinical trial to test a second-generation skeletal muscle activator called reldesemtiv (CK-2127107 or CK-107), which they believe will be much better tolerated than tirasemtiv and produce fewer side effects.
Levosimendan, marketed by Orion or its partners as Simdax, was approved to be marketed as a treatment for a type of congestive heart failure in 2000 by the EMA, and later in other countries. To date, levosimendan use as a treatment for any disorder has not been granted by the FDA, however in addition to this trial in ALS, there is an ongoing trial sponsored by Tenax Therapeutics to use levosimendan in cardiac disorders.