Cytokinetics is preparing a global Phase 3 trial that will enroll more than 500 people with early amyotrophic lateral sclerosis (ALS) to test its investigational therapy reldesemtiv in slowing progressive muscle weakness, the company announced.
Details from the trial design were shared at the 31st International Symposium on ALS/MND, being held virtually Dec. 9–11. A presentation, titled “A Phase 3, Multi-Center, Double-Blind, Randomized, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Reldesemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS): COURAGE-ALS Trial Design,” was given by Jeremy Shefner, MD, PhD, of the Barrow Neurological Institute.
Reldesemtiv is a fast skeletal muscle troponin activator designed to slow the progressive muscle weakness seen in ALS and other neuromuscular diseases by increasing the muscle’s response to weak nerve signals.
The upcoming Phase 3 trial, Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS – dubbed COURAGE-ALS – will build upon the results of the recently completed FORTITUDE-ALS Phase 2 trial (NCT03160898), which evaluated reldesemtiv in 458 patients diagnosed with ALS less than two years before entering the study.
The researchers used the insights gained from FORTITUDE-ALS — with respect to dose level, the appropriate patient population, and adverse events — to design the new COURAGE-ALS trial, which will continue to evaluate reldesemtiv as an ALS treatment.
COURAGE-ALS will recruit approximately 555 patients who are within two years of their first symptom of muscle weakness. Participants will have moderate lung function loss and an ALS Functional Rating Scale Revised (ALSFRS-R) score of no more than 44 at the time of screening.
As in FORTITUDE-ALS, patients can continue to receive their standard ALS therapies of Radicava (edaravone) and/or riluzole.
At the study’s start, the participants will be randomly assigned to receive 300 mg of oral reldesemtiv, or a placebo, twice daily over 24 weeks (nearly six months). For each patient given a placebo, two will receive the active treatment. A second 24-week or nearly six-month period will follow, in which all patients will receive 300 mg of oral reldesemtiv twice daily.
The primary goal of COURAGE-ALS is to measure changes in the participants’ ALFRS-R scores over the first 24 weeks. Secondary measures include changes in slow vital capacity (SVC) — a measure of respiratory function — grip strength, total ALFRS-R scores, and a composite measure of respiratory insufficiency and survival.
Additional exploratory endpoints will include the participants’ first, and any substantial use of home medical equipment, and an assessment of hand muscle strength, measured with hand-held dynamometry, a portable measurement device. Another exploratory endpoint will be ALS progression, as measured by the Milano Torino Staging (MiToS) system, found to reliably predict the course of ALS up to 18 months.
A data monitoring committee will conduct two interim analyses during the study. A futility study — meant to determine if the trial can meet its goals — will take place 12 weeks after one-third or more of the planned sample size has been randomly assigned to receive the medication or the placebo. A second analysis will assess both futility and whether the trial needs more participants.
Cytokinetics did not announce any timeline for the trial in its ALS/MND symposium presentation. But Shefner, who also served as the lead researcher for FORTITUDE-ALS, said the new study will build upon the previous three-month-long trial, completed in March 2019.
In FORTITUDE-ALS, participants 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. Those receiving the standard ALS therapy riluzole before enrolling could continue doing so during the trial.
That study’s main goal was to measure changes in patients’ percent predicted slow vital capacity or SVC. Secondary endpoints included changes in the ALSFRS-R, which measures a patient’s ability to perform activities of daily living, and muscle strength.
Although changes in SVC and other measures did not meet statistical significance in that trial, reldesemtiv did slow lung function decline and investigators observed positive trends in SVC, ALSFRS-R, and muscle strength.
A follow-up analysis revealed that participants with shorter symptom duration and faster progression rates saw the greatest benefits, experiencing significant changes in their ALSFRS-R scores compared with those on a placebo.
The results also demonstrated that epidermal growth factor (eGFR) signaling declined with increasing doses of reldesemtiv – a trend that reversed following discontinuation of the medicine. Inhibition of eGFR signaling is thought to protect neurons from degeneration, researchers note.
Reldesemtiv has been designated an orphan drug for ALS treatment both in the U.S. and in the European Union. Those designations are awarded to certain therapies that are designed to treat rare diseases, defined as a condition that affects fewer than 200,000 people in the U.S. In the European Union, a disease is defined as rare when it affects fewer than 1 in 2,000 people. Orphan drug designation provides assistance for the development of such therapies and a period of market exclusivity if they are approved for use.
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