The results were presented at the 24th Congress of the European Hematology Association (EHA), held recently in Amsterdam, the Netherlands.
“We are encouraged by this interim Phase 2a analysis that reinforces our belief in the potential of IMR-687 as a single oral, once-a-day therapeutic,” Rahul D. Ballal, CEO of Imara, said in a press release.
“IMR-687 uniquely targets both red cell and white cell aspects of the disease, and we are working to expeditiously advance this novel therapy through clinical development, with a goal of delivering it to patients with SCD [sickle cell disease] who are in need of innovative treatment options,” Ballal added.
The highly potent therapy is an oral inhibitor of the phosphodiesterase 9 (PDE9) enzyme found in red blood cells. Inhibition of PDE9 in preclinical studies with cells and animal models showed that IMR-687 increases fetal hemoglobin. This, in turn, prevents the assembly of sickled hemoglobin in red blood cells, reducing red cell sickling and blood vessel occlusion — a cause of debilitating pain, organ damage, and early mortality in people with the disease.
In a first-in-human Phase 1 clinical trial (NCT02998450) with healthy adult volunteers, IMR-687 proved to be well-tolerated. The therapy has recently been granted fast track designation by the U.S. Food and Drug Administration (FDA).
The Phase 2 trial (NCT03401112), still recruiting participants at several trial centers in the U.S. and the U.K., is testing IMR-687’s safety and tolerability. It also aims to assess the therapy’s pharmacokinetics, or its processing inside the body, and the pharmacodynamics — sometimes described as what a drug does to the body — of increasing doses of IMR-687 in adult patients with sickle cell disease.
Patients are divided into two groups: those also undergoing treatment with hydroxyurea (group B), and those who are not (group A). Hydroxyurea is a medicine used to lessen the frequency of pain crises in people with SCA.
Those in group A are randomly selected to receive either IMR-687 — at doses of 50 mg or 100 mg — or a placebo daily for the first 12 weeks. At week 13, each participant’s dose is doubled, and treatment continues until 24 weeks.
Participants in group B are randomly selected to receive a 50 mg dose of IMR-687 or placebo. After four weeks, their dose is increased to 100 mg, or they maintain the placebo.
The interim analysis was conducted on group A, which included 19 participants. Results after five weeks showed that patients treated with high doses of IMR-687 had a trend for lower levels of disease biomarkers in their blood, compared with those in the placebo group. The blood biomarkers included the soluble P selectin (sPsel), soluble vascular cell adhesion molecule-1 (sVCAM), and myeloperoxidase (MPO).
At week 13, this same group experienced an increase of 110% in F-cells — red blood cells that have fetal hemoglobin and often increase before fetal hemoglobin rises. At this time point, researchers detected a decrease in the number of reticulocytes (immature red blood cells), and a trend toward lessening of pain, as measured by the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me).
Safety data from 27 patients showed that IMR-687 was generally well-tolerated, without marked changes in white blood cell counts, including lower counts of neutrophils (a condition called neutropenia). No treatment-related serious adverse events were detected.
“These initial Phase 2a data demonstrate the potential of IMR-687 to significantly impact key biomarkers associated with the pathology of this serious disease,” said Biree Andemariam, MD, lead investigator for the trial.
“In the laboratory we saw that IMR-687 inhibition of PDE9 increases intracellular cGMP levels, increases fetal hemoglobin expression, reduces sickling and hemolysis of red blood cells, and does not induce neutropenia. The interim Phase 2a data reflect trends that could be indicative of meaningful clinical translation of these important measures in SCD,” added Andemariam, an associate professor at UConn School of Medicine and director of the New England Sickle Cell Institute at UConn Health.
Imara said it expects to announce additional interim Phase 2a data in the second half of 2019.