Cytokinetics Updates Phase 3 COURAGE-ALS Trial of Reldesemtiv

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by Marta Figueiredo PhD |

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Most of the initial amyotrophic lateral sclerosis (ALS) patients enrolled in Cytokinetics’ COURAGE-ALS Phase 3 trial testing its experimental therapy reldesemtiv have moderate-to-fast progressing disease at study entry.

An analysis shows that, as intended, COURAGE-ALS is increasing the proportion of patients with rapidly progressing disease compared with the recently completed FORTITUDE-ALS Phase 2 trial (NCT03160898).

“The analysis of patients enrolled to date in COURAGE-ALS shows that the great majority of patients have middle and fast pre-study disease progression rates, which was our objective after observing in FORTITUDE-ALS that the treatment effect of reldesemtiv was greater in patients with faster disease progression,” Fady I. Malik, MD, PhD, Cytokinetics’ executive vice president of research and development, said in a press release.

“While we are not excluding slow progressors, by adjusting the inclusion criteria to enrich the population for faster rates of progression, we may be able to increase the sensitivity of detecting a potential treatment effect of reldesemtiv,” Malik said. “We look forward to continuing COURAGE-ALS.”

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These and FORTITUDE-ALS findings highlighting associations between strength measures and motor and functional outcomes in ALS patients were presented recently through three posters at the 32nd International Symposium on ALS/MND, held virtually Dec. 7–10.

Developed by Cytokinetics in collaboration with Astellas, reldesemtiv is an orally available small molecule designed to slow the progressive muscle weakness seen in ALS and other neuromuscular diseases by increasing the muscle’s contractile response to weak nerve signals.

While in the previous FORTITUDE-ALS Phase 2 trial reldesemtiv did not meet the main goal of significantly slowing ALS patients’ lung function decline, additional analyses suggested that those with shorter disease duration and moderate-to-fast progression at study start experienced the greatest benefits.

These findings informed the design of the ongoing global COURAGE-ALS Phase 3 trial (NCT04944784), which is evaluating the safety and effectiveness of reldesemtiv against a placebo in about 555 adults with ALS.

Eligible patients must have developed symptoms of muscle weakness within the two years prior to enrollment and show moderate lung function loss and mild functional disability — defined as an ALS Functional Rating Scale Revised (ALSFRS-R) score of no more than 44 at enrollment.

Recruitment, which began in August, is ongoing at sites in North America, Australia, and Europe. More information is available here.

Participants will be assigned randomly to receive an oral tablet of either reldesemtiv (300 mg) or a placebo, twice daily over 24 weeks (nearly six months), after which all will be given the experimental therapy for another 24 weeks.

Those on standard ALS therapies, such as Radicava (edaravone) and riluzole, can continue treatment during the trial.

The trial’s main goal is assessing changes in functional disability, as measured with the ALSFRS-R, over the initial 24-week period. Secondary goals include a combined score of changes in total ALSFRS-R scores, time to respiratory insufficiency, and death, as well as changes in lung function, quality of life, and handgrip strength.

In the poster, “Update of COURAGE-ALS: a Phase 3, double-blind, randomized, placebo-controlled, study to evaluate efficacy and safety of reldesemtiv in patients with ALS (abstract CLT-15), Stacy Rudnicki, MD, Cytokinetics’ vice president of clinical research, presented initial features of the first 27 patients enrolled in the trial.

Similar to what was done previously in FORTITUDE-ALS, patients were divided into slow, moderate, and fast progression categories based on their disease duration and ALSFRS-R total score at study’s start.

A decline of up to 0.37 points per month was classified as a slow progression rate, while a drop of more than 0.67 points per month was considered fast progression. Patients with an ALSFRS-R monthly decline between 0.37 and 0.67 points were classified as having moderate progression.

Results showed that most of the patients enrolled initially were moderate progressors (48.2%) or fast progressors (37%). That suggests the adjusted eligibility criteria in COURAGE-ALS is “achieving the intended goal of increasing the proportion of patients with middle to fast disease progression rates, as compared to FORTITUDE-ALS,” Cytokinetics stated in the release.

The other two posters concerned analyses of potential associations between frequently used outcome measures using data from the FORTITUDE-ALS study, which involved 458 ALS patients.

In the poster, “Grip strength is more than a number: the relationship between grip strength and fine motor and arm function in FORTITUDE-ALS” (abstract CLT-36), Andrew Wolff, MD, Cytokinetics’ senior vice president and senior fellow of clinical research and development, showed how handgrip strength relates to functionality and quality of life.

Reduced grip strength was associated strongly with worse fine motor function — as assessed with the ALSFRS-R — and moderately associated with greater patient-reported difficulty in using arms and hands, as assessed with the ALS Assessment Questionnaire.

Fine motor function, involving precise movement of hand and finger muscles, was evaluated via the ALSFRS-R through questions concerning the patients’ ability to write, cut food, and dress themselves, or tend to their hygiene.

These findings highlight that “grip strength, which is frequently included as an outcome measure in ALS clinical trials and may be assessed as part of routine care for people with ALS, has clinical relevance due to its correlation to fine motor function and patient reported quality of life,” Cytokinetics stated.

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Bill Jacobsen, MD, a neurologist at the Gregory W. Fulton ALS and Neuromuscular Disease Center, in Phoenix, presented data supporting that overall muscle strength is linked to functionally and quality of life. Jacobsen also is an assistant professor at the Barrow Neurological Institute, also in Phoenix.

The poster was titled, “Relationship between quantitative strength changes and functional outcomes in the Phase 2 FORTITUDE-ALS Trial” (abstract CLT-10).

The researchers found that, similar to handgrip strength, reduced upper limb strength was moderately to strongly associated with worse fine motor function, and moderately linked to patient-perceived worse ability to use the upper limbs.

Weaker associations were observed for lower extremity muscle strength, but combining upper and lower muscle strength conferred even stronger links than those observed with individual muscle groups.

These results suggest that “extremity muscle strength is moderately to strongly related to physical function and quality of life,” Cytokinetics stated in the release.