IMR-687 safely increases the levels of fetal hemoglobin and the number of fetal hemoglobin-producing cells in people with sickle cell disease (SCD), according to early data from an ongoing Phase 2a clinical trial.
The findings support the continuation of IMR-687’s clinical development as a potential disease modifying therapy for SCD, investigators said.
Results will be shared in an oral presentation titled, “IMR-687, A Highly Selective Phosphodiesterase 9 Inhibitor (PDE9I), Increases F-Cells and Fetal Hemoglobin in a Ph-2A Interim Analysis,” at the 25th Annual European Hematology Association (EHA) Congress, taking place virtually June 11–21.
The presentation will be given by Biree Andemariam, MD, director of the New England Sickle Cell Institute at UConn Health and lead investigator of the trial; it will become available for on-demand viewing starting at 2:30 a.m. ET on June 12, and will be accessible until Oct. 15.
PDE9 normally destroys cyclic guanosine monophosphate (cGMP), a signaling molecule with a key role in many cellular functions and whose levels often are diminished in people with SCD or beta-thalassemia.
By blocking PDE9 and increasing the levels of cGMP, IMR-687 reactivates the production of fetal hemoglobin, the protein that carries oxygen in a developing baby but is largely lost following birth. Compared to the version of hemoglobin found in adults, fetal hemoglobin is more effective at transporting oxygen throughout the body.
Ultimately, by increasing the levels of fetal hemoglobin in red blood cells, IMR-687 is expected to alleviate the symptoms of both SCD and beta-thalassemia — caused by defects in the adult form of the protein.
An ongoing Phase 2a trial (NCT03401112) is assessing the safety, tolerability, pharmacokinetic and pharmacodynamic properties of IMR-687 in SCD patients. Pharmacokinetics assesses how a medication is processed in the body, while pharmacodynamics studies the effects a of compound in the body.
The trial achieved its target enrollment in January, with top-line data expected later this year, Imara said in a press release.
The study comprises two distinct patient populations: participants on IMR-687 alone (group A), and participants receiving both the experimental therapy and hydroxyurea, an approved treatment for pain crises associated with SCD (group B).
During the trial, patients in group A will be selected randomly to receive either IMR-687 — at a dose of 50 or 100 mg — or a placebo daily for the first 12 weeks. At week 13, each participant’s dose will be doubled, and treatment continues up until week 24 (about six months).
In turn, patients in group B will be assigned randomly to receive a 50 mg dose of IMR-687 or a placebo. After four weeks, their dose will be increased to 100 mg, or maintained in the case of those receiving the placebo.
Findings from the first analysis, which focused on 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 safe and well-tolerated. No treatment-related serious adverse events (side effects) were reported.
The second analysis included data from 18 patients from group A who completed the study. Results showed that when given at the highest doses (100 mg and 200 mg), IMR-687 increased levels of F-cells by an average of 155%, and levels of fetal hemoglobin by an average of 1.7%.
More than half (60%) of the patients in the high-dose group had an increase in the levels of fetal hemoglobin that exceeded the pre-established 1% treatment response threshold (mean increase 3.1%).
Patients from group A receiving the lower 50 mg dose of IMR-687 did not experience increased levels of F-cells until they started receiving the medication at 100 mg on week 13. However, none of the patients in this group experienced an increase in fetal hemoglobin up until week 25.
Based on data from 57 participants, safety assessments showed that IMR-687 was generally safe and well-tolerated, not leading to significant changes in white blood cell counts or other vital signs in any group.
No treatment-related serious adverse events, or adverse events leading up to treatment discontinuation, were reported.
In patients from group B, safety analyses also revealed that IMR-687 was well-tolerated when given alongside hydroxyurea. No signs of drug-drug interactions were observed.
“The clinical data generated in this pre-specified interim analysis support further clinical development and testing of higher doses of IMR-687 as a potential disease modifying therapy for SCD,” the researchers wrote.
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