A Phase 2b clinical trial that is investigating the safety and effectiveness of IMR-687 in people with sickle cell disease (SCD) has dosed its first participant, according to the potential therapy’s developer, Imara.
Patients will be assigned randomly to receive one of two doses of IMR-687, or a placebo, once-a-day for one year.
The trial’s main goal is to assess the percentage of patients having an increase of at least 3% in the production of fetal hemoglobin driven by IMR-687 after 24 weeks of treatment. Secondary goals include assessing the effects of treatment on the levels of different biomarkers associated with fetal hemoglobin, rate of red blood cells’ destruction (hemolysis), incidence of vaso-occlusive crises, and quality of life.
After completing the study, patients will have the option to enroll in an extension study in which all will receive IMR-687. Imara plans to conduct a preliminary analysis of the study when 33 patients complete 24 weeks of treatment.
“Dosing of the first patient in the Ardent clinical trial represents a critical step forward as we advance IMR-687 into Phase 2b testing, a clinical trial that will test higher doses and longer durations of IMR-687,” Rahul Ballal, PhD, president and CEO of Imara, said in a press release.
“Specifically, the 300 mg and potentially 400 mg dose levels to be administered in the Ardent trial are designed to provide meaningful exposure to IMR-687 that could be up to two-fold higher than administered in our ongoing Phase 2a clinical trial. We believe that this increased exposure could have a meaningful impact on the therapeutic effect of IMR-687,” Ballal said.
IMR-687 is a selective, oral inhibitor of phosphodiesterase 9 (PDE9). This enzyme, found in red blood cells, normally destroys cyclic guanosine monophosphate (cGMP), an important signaling molecule whose levels are usually diminished in people with SCD and beta-thalassemia.
By blocking PDE9 and increasing the levels of cGMP, IMR-687 is expected to reactivate the production of fetal hemoglobin, the protein that carries oxygen in a developing baby, but is largely lost after birth.
Compared to the version of the protein found in adults, fetal hemoglobin is more effective at transporting oxygen throughout the body. As such, by increasing the levels of fetal hemoglobin in red blood cells, IMR-687 is expected to ease the symptoms caused by defects in the adult form of the protein in people with SCD and beta-thalassemia.
Before launching Ardent, Imara initiated a Phase 2a trial (NCT03401112) to investigate the safety and pharmacological properties of IMR-687 in adults with SCD.
In this trial, two groups of patients — those receiving IMR-687 alone (group A) or IMR-687 alongside hydroxyurea (group B) — were assigned randomly to receive either IMR-687 at a starting dose of 50 or 100 mg, or a placebo, for an initial period of four or 12 weeks.
Following this initial period, participants receiving IMR-687 had their doses doubled until week 24.
Findings from the first analysis of the study, which was based on data from 19 patients from group A, showed that when given at the highest dose IMR-687 lowered the levels of several disease biomarkers and increased the number of red blood cells containing fetal hemoglobin, or F-cells. Treatment was well-tolerated.
In turn, results from a second analysis, which included data from 18 patients from group A who completed the study, showed that when given at the highest dose, IMR-687 increased the number of F-cells by an average of 155%, and levels of fetal hemoglobin by 1.7%.
In addition, a safety analysis based on data from 57 patients, showed that the drug continued to be safe and well-tolerated when used alone or in combination with hydroxyurea.
The company anticipates reporting top-line results from this study before the end of the year. An open-label extension study (NCT04053803) enrolling patients who completed this Phase 2a trial also is ongoing to assess the long-term safety and tolerability of IMR-687.
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