Six months of treatment with oral IMR-687 safely and effectively reduced the number of vaso-occlusive crises (VOCs) and other disease-associated pain crises in adults with sickle cell disease (SCD), updated data from a Phase 2a clinical trial show.
Most benefits were observed when patients were given the highest doses, its researchers noted, and combining the therapy with hydroxyurea did not appear to provide additional benefits.
“I am encouraged by the incremental data from this readout, especially in light of the COVID-19 pandemic challenges,” Biree Andemariam, MD, the trial’s lead investigator, said in a press release. Andemariam is the director of the New England Sickle Cell Institute at UConn Health, and an associated professor at the University of Connecticut School of Medicine.
“This includes a favorable safety profile of IMR-687, lower rate of VOCs/SCPCs [sickle cell-related pain crises] and VOC-related hospitalizations in the Population A1 monotherapy arm, and improvements in several biomarker results across both the monotherapy and combination groups,” she added.
Andemariam also noted that the drops in “clinically utilized biomarkers of inflammation and cardiac stress” seen in the monotherapy group suggest that “higher doses of IMR-687 may have novel anti-inflammatory and cardiovascular benefits in sickle cell disease.”
Rahul Ballal, PhD, the president and CEO of Imara, developing the therapy, said these results “start an important year of data readouts” for his company.
Imara plans to report updates on the Phase 2a trial’s separate but open-label extension (NCT04053803) by late June, and to present detailed data from the main study (NCT03401112) at an upcoming medical meeting.
IMR-687 works by blocking phosphodiesterase 9 (PDE9), an enzyme found in red blood cells that normally destroys a signaling molecule called cyclic guanosine monophosphate (cGMP), whose levels are typically lower in people with SCD.
By suppressing PDE9 and increasing the levels of cGMP, IMR-687 is thought to reactivate the production of fetal hemoglobin in red blood cells, ultimately easing SCD symptoms and lessening complications. Fetal hemoglobin is a form of hemoglobin, mostly present in newborns, that transports oxygen more efficiently than its adult counterpart.
IMR-687 received orphan drug, fast track, and rare pediatric disease designations of from the U.S. Food and Drug Administration, as well as orphan drug status from the European Commission as a potential SCD treatment. These are meant to accelerate the therapy’s development and review.
The Phase 2a clinical trial evaluated IMR-687’s safety, tolerability, pharmacokinetics (its movement into, through, and out of the body), pharmacodynamics (its effects on the body), and its efficacy against a placebo in 93 adults, ages 18 to 55, with SCD.
The study was divided into four sub-studies: two testing IMR-687 alone (group A and A1) and the other two (group B and B1) evaluating the therapy in combination with hydroxyurea — an approved treatment to reduce the frequency of pain crises and the need for blood transfusions in SCD patients.
Participants were randomly assigned to receive either 50 mg or 100 mg of IMR-687, or a placebo, once daily for four or 12 weeks, after which those on IMR-687 had their doses doubled until week 16 or 24.
Previous interim data from group A showed that the therapy was generally safe and resulted in an increase in the levels of fetal hemoglobin and the number of red blood cells containing fetal hemoglobin, or F-cells, when given at the highest doses (100 mg and 200 mg).
Newly announced results focused on data from the total 18 patients from group A1 and the 14 from group B1.
Participants of both groups received either a placebo for 24 weeks, or 50 mg (group B1) or 100 mg (group A1) of IMR-687 for four weeks, after which the dose was doubled until week 24 (about six months). Group B1 was also treated with hydroxyurea.
Results showed that IMR-687’s safety profile was consistent with that reported in previous analyses, with the most common adverse events (side effects) including SCD with crisis, nausea, and headache.
In group A1, a smaller proportion of IMR-687-treated patients experienced VOCs/SCPCs than did those on a placebo (58% vs. 83%) — reflecting a 25% drop. The rate of VOC-related hospitalizations was also twice as lower in the IMR-687 group than in the placebo group (33% vs. 66%).
Notably, no meaningful changes were observed in the levels of hemoglobin and fetal hemoglobin, and in the number of F-cells after six months of IMR-687 treatment, even though an increase in fetal hemoglobin levels was seen when the dose was doubled after four weeks.
Initiation of the highest dose (200 mg) was also associated with greater reductions in the levels of biomarkers of hemolysis (red blood cell destruction), inflammation, and cardiac stress.
Dose-dependent reductions in hemolysis markers were also observed among group B1 participants receiving the combination therapy, but the levels of inflammation and cardiac stress biomarkers increased slightly, compared with values before treatment.
Moreover, despite an overall increase in fetal hemoglobin levels and F-cells in patients given the combination therapy, their rates of VOCs/SCPCs and VOC-related hospitalizations were similar to those on hydroxyurea plus a placebo.
Overall trial data showed that IMR-687 was generally well-tolerated as a single therapy and in combination with hydroxyurea at all dose levels, the release also noted, and that the two treatment regimens showed a similar pharmacokinetic profile.
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