Pain Crises New Main Goal in Ongoing Ardent Trial of IMR-687
The trial’s new main goal is the annual rate of vaso-occlusive crises (VOCs) — painful crises resulting from blood vessel blockage by “sickle-shaped” red blood cells. This had been a key secondary goal.
This alteration followed a recommendation made by the U.S. Food and Drug Administration (FDA). The U.S. agency reviewed Imara’s draft statistical analysis plan (SAP), after which it advised the company to swap trial goals. The original main goal — an increase of at least 3% in the production of fetal hemoglobin after about six months of treatment — is now a key secondary goal.
Fetal hemoglobin is a form of hemoglobin — the protein in red blood cells that transports oxygen throughout the body — produced during fetal development. It is more effective at transporting oxygen than its adult counterpart.
Additional goals include assessing the effects of treatment on other VOC-related measures, red blood cells’ destruction (hemolysis) markers, and patients’ quality of life.
“We welcome the FDA’s recommendations and are in the process of changing the primary endpoint of the Ardent trial to be annualized rate of VOCs and moving HbF [fetal hemoglobin] response to be a key secondary endpoint,” Rahul Ballal, PhD, Imara’s president and CEO, said in a press release.
“A reduction in VOC rate is an established approval endpoint, and we are engaging the FDA further on this and related topics, including possible streamlined paths to registration,” he added.
Participants are being randomly assigned to receive either a low (200 mg or 300 mg) or high (300 mg or 400 mg) dose, based on their body weight, of IMR-687 or a placebo, given once daily for one year.
With this revision in the trial’s design, data from the first interim analysis is now expected by April 2022. According to Imara, the trial’s final data should be available in the second half of 2022.
“In light of this endpoint revision, the previously planned fourth quarter interim analysis will no longer occur,” Ballal said. “That interim analysis had been designed to have a focus on safety and pharmacodynamic biomarkers, including HbF, but did not include a review of VOCs. The first review of data from the Ardent trial, including annualized VOC rate, will be conducted when all subjects have completed assessment at Week 24 or terminated early, and is planned for the first quarter of 2022, subject to our upcoming discussions with the FDA.”
IMR-687 (tovinontrine) is a highly selective oral inhibitor of phosphodiesterase 9 (PDE9), an enzyme that destroys an important active signaling molecule called cyclic guanosine monophosphate (cGMP).
cGMP levels are often low in SCD patients, a reduction associated with impaired blood flow and increased inflammation.
By blocking PDE9 and boosting cGMP levels, IMR-687 is expected to restart the production of fetal hemoglobin, which in turn is anticipated to ease SCD symptoms.
Data from the first and second analyses of a previous Phase 2a trial (NCT03401112) showed that IMR-687 lowered the levels of several disease biomarkers and increased the number of red blood cells containing fetal hemoglobin.
After six months of treatment with IMR-687, the number of VOCs and other disease-related pain crises were reduced. Trial data also indicated the therapy was generally well-tolerated and safe.
“We reported promising data from our Phase 2a and open label extension clinical trials in SCD that demonstrated reduced annualized rates of VOCs in patients treated with tovinontrine versus placebo,” Ballal said.
Patients who completed the Phase 2a trial were invited to join an open-label extension study (NCT04053803), in which all will receive IMR-687 for up to four years. The study’s aim is to evaluate the therapy’s long-term safety and tolerability.
One-year data from the extension study recently presented at the American Society of Hematology (ASH) annual meeting showed that IMR-687 safely and sustainably lowered the number of VOCs while increasing the production of fetal hemoglobin and the number of red blood cells containing it. The extension study is expected to conclude by March 2025.