Reldesemtiv Effects Maintained When Used on Top of Rilutek or Radicava, New Trial Analysis Shows

Treatment with oral reldesemtiv appears to slow the deterioration of function — including breathing capacity and muscle strength — in amyotrophic lateral sclerosis (ALS) patients, regardless of whether or not they were taking additional medications such as Radicava (edaravone) or Rilutek (riluzole), a new analysis of the FORTITUDE-ALS trial shows.

If such results are confirmed in a larger trial, reldesemtiv therapy will likely be useful for further slowing disease progression in combination with existing ALS medicines, the researchers said.

A separate analysis also indicates that depression worsens among people with ALS as they experience greater difficulties, and a decline in their quality of life.

These new results were presented at the 30^th International Symposium on ALS/Motor Neurone Disease (MND), held Dec. 4-6 in Perth, Australia.

Being developed by Cytokinetics in collaboration with Astellas, reldesemtiv is a fast skeletal muscle troponin activator (FSTA). It is intended to slow the decline in muscle and physical function of people with muscle impairment and weakness caused by debilitating diseases such as ALS and spinal muscle atrophy (SMA).

Among the presented works, the poster “Responder and subgroup analyses for FORTITUDE-ALS, a phase 2 trial of reldesemtiv in patients with ALS” (abstract CLT-21) described the effects of reldesemtiv with and without the use of two approved ALS medicines, Mitsubishi Tanabe‘s Radicava and Sanofi‘s Rilutek, as studied in the FORTITUDE-ALS trial.

The study, now completed, was a Phase 2 trial (NCT03160898) that assessed the effects of reldesemtiv on respiratory function and other muscle parameters in people with ALS diagnosed less than two years prior to the study’s start.

A total of 458 patients were randomly assigned to receive increasing doses of reldesemtiv — 150, 300 or 450 mg — or a placebo, given orally twice a day for 12 weeks.

Results presented earlier this year showed that, at the end of the 12-week treatment, participants taking reldesemtiv did not accumulate as much disability as those on placebo — with larger effects becoming evident over time. The level of disability was measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), a measure of overall disability, and slow vital capacity (SVC), a standard lung function test.

Despite a consistent trend toward slower disease progression, the differences in functional outcomes between patients on reldesemtiv and those on placebo did not reach statistical significance. Thus, the trial did not achieve its primary goal, or endpoint.

What the new analysis shows is that reldesemtiv’s effect on overall disability, respiratory function, and muscle strength — measured by handheld dynamometry, or HHD — is maintained whether or not patients also were being treated with Radicava or Rilutek, or both.

About half of the study’s participants — 56.5% — were taking Rilutek only, while 4.2% were taking Radicava alone; 20.6% were receiving both therapies.

“The results from these subgroup analyses add to the growing body of evidence regarding the effects of reldesemtivin patients with ALS,” Jeremy Shefner, MD, PhD, the trial’s lead investigator and a professor at the Barrow Neurological Institute and the University of Arizona, said in a press release.

“As the treatment landscape evolves in ALS, these data demonstrate how we may be able to further slow the decline of disease progression when adding new mechanism therapies like reldesemtiv on top of existing treatment regimens,” Shefner said.

“Should these effects of reldesemtiv be confirmed in a Phase 3 trial, reldesemtiv will likely be useful with other approved agents,” the researchers said.

Another post-hoc analysis of the trial focused on the interaction between quality of life and depression in people with ALS not taking reldesemtiv. The data from that analysis was showcased in the poster “Quality of life and depression measurements in FORTITUDE-ALS” (abstract CLT-22).

Here, the researchers analyzed data from 115 participants in the trial’s placebo group. To measure the quality of life of these patients, both during the 12 weeks of treatment and at follow-up four weeks later, participants were asked to complete the survey ALSAQ-5. The survey questioned their difficulty in standing, using their arms, eating, and speaking, and also asked about their feelings of hopelessness about the future.

Depression also was assessed using the BDI-FS scale, which questions patients about hopelessness and suicidal thoughts, among other topics.

The analysis showed that both the participants’ quality of life and depressive feelings got worse throughout the trial, and were correlated to some extent. This suggests that as patients’ physical function declines, their depression worsens.

Age, sex, and the place in the body at which the disease emerged were not related to depression worsening. However, in patients taking Radicava, depression did not aggravate as fast, the analysis showed.