IMR-687 Continuing to Lower VOCs and Hospitalizations in SCD Patients
IMR-687 (tovinontrine), an experimental oral therapy for sickle cell disease (SCD), reduced the rate of painful vaso-occlusive crisis (VOC), lowered hospitalization due to VOCs, and extended the time to a first VOC in SCD patients, according to new data from an open-label extension of a Phase 2 clinical trial.
Another investigational SCD therapy, called IMR-261, also reduced VOCs in a mouse model of the disease. Both IMR-687 and IMR-261 are being developed by Imara.
These data will be presented at the American Society of Hematology (ASH) Annual Meeting set for Dec. 11–14.
“We look forward to reporting updated 12-month VOC data from our Phase 2a open-label extension trial of tovinontrine (IMR-687) in adults with sickle cell disease,” Rahul Ballal, PhD, president and CEO of Imara, said in a press release. “In addition, we are excited to share this first look at IMR-261, a new asset in our development pipeline.”
People with SCD produce a faulty form of hemoglobin (Hb), the protein that transports oxygen in red blood cells throughout the body. Defective hemoglobin causes red blood cells to become sickle-shaped, leading to their destruction (hemolysis) and the blocking of small blood vessels, causing a painful vaso-occlusive crisis.
One treatment strategy is to increase the production of fetal hemoglobin (HbF), a form of hemoglobin created during fetal development that is a more efficient oxygen transporter than adult Hb.
IMR-687 is designed to increase the levels of cyclic guanosine monophosphate (cGMP), an important signaling molecule shown to trigger the expression of fetal hemoglobin. According to Imara, increasing HbF in red blood cells can reduce hemolysis and sickling of red blood cells, ultimately lowering the incidence of VOCs.
Data from a now complete, placebo-controlled Phase 2a study (NCT03401112) showed that 50–200 mg of oral IMR-687 once daily for up to six months reduced the mean annualized VOC rate by 40% compared with placebo.
The therapy also lowered the mean annualized rate of VOC-related hospitalizations by 38%, and lengthened the time to the first VOC — a median of 169 days versus 87 days in the placebo group. Patients also reported improvement in the severity of VOC pain and saw an increase in red blood cells containing HbF (F-cells).
One year of data from the trial’s open-label extension (OLE) study (NCT04053803) — assessing the long-term safety and efficacy of IMR-687 in adults with SCD for up to four years — is being presented at the meeting in the poster, “Treatment with IMR-687, a Highly Selective PDE9 Inhibitor, Increases HbF and Reduces VOCs in Adults with Sickle Cell Disease in a Long-Term, Phase 2a, Open-Label Extension Study.”
In the OLE study, the initial dose of IMR-687 was 200 mg daily, and participants were evaluated every four to six months for VOCs, the levels of HbF, Hb, and F-cells, as well as safety.
As of May 2021, the cutoff date for this analysis, 24 patients were enrolled in the OLE, of whom 17 had a treatment interruption between the Phase 2a trial and the OLE and seven did not. Of these, 17 received IMR-687 alone, and seven were treated with a combination of IMR-687 and hydroxyurea, an approved medicine to reduce VOCs.
Patients randomized to treatment with IMR-687 in the Phase 2a trial had a low mean annualized VOC rate of 1.34 per year, which was maintained in the OLE study at 1.85 per year. Those on placebo in this trial had a VOC rate of 4.71 per year, which fell to 2.89 per year in the OLE study upon switching to IMR-687 — representing a reduction in VOC rate of 39%.
Of the 15 people assessed at eight months, seven (47%) saw an increase in F-cells of 6% or more, and four out of 11 had an increase in HbF of 3% or more. Data on those who completed one year in the OLE will be presented at the meeting.
IMR-687 continued to be well-tolerated in the OLE, with no treatment-related serious adverse events. The most common side effects were headache (21%), back pain (17%), and nausea (13%). Three participants (13%) were hospitalized due to VOC.
“Consistent with the parent study, preliminary results from the ongoing Phase 2a OLE study demonstrate that daily dosing of 200 mg IMR-687 was well-tolerated with longer-term treatment as a monotherapy or in combination with HU [hydroxyurea],” the researchers wrote. “Based on these encouraging data, a Phase 2b study (NCT04474314) is ongoing to further explore IMR-687 at doses up to 400 mg daily as a disease-modifying therapy for SCD.”
This Phase 2b trial is due to conclude in August.
Preclinical data on Imara’s newest SCD experimental therapy — IMR-261 — is also being presented in the poster, “IMR-261, a Novel Oral Nrf2 Activator, Induces Fetal Hemoglobin in Human Erythroblasts, Reduces VOCs, and Ameliorates Ineffective Erythropoiesis in Experimental Mouse Models of Sickle Cell Disease and Beta-Thalassemia.”
IMR-261 is a clinic-ready activator of nuclear factor erythroid 2–related factor 2 or Nrf2, a protein associated with the enhanced expression of HbF. The therapy is also being assessed for beta-thalassemia, a condition similar to SCD characterized by reduced hemoglobin production.
To test whether IMR-261 could induce fetal hemoglobin expression, human red blood cell precursors called erythroblasts were derived from blood marrow progenitor cells isolated from SCD or healthy individuals. IMR-261 was shown to enhance HbF expression and increase the proportion of F-cells in a dose-dependent manner.
In a mouse model of SCD, HbF induction was also tested by administering 12.5 mg/kg or 37.5 mg/kg IMR-261 twice a day for four weeks. Both doses significantly increased HbF relative to controls, but only the higher dose led to a significant increase in F-cells. In addition, IMR-261 at both doses increased the number of red blood cells and total hemoglobin, and decreased the number of immature red blood cells.
Researchers then tested the ability of IMR-261 to reduce VOCs, induced in the SCD mice via exposure to the pro-inflammatory signaling protein TNF-alpha. IMR-261 was dosed at 37.5 mg/kg twice daily for five days before triggering VOCs.
Compared to control animals, mice treated with IMR-261 had a significantly reduced presence of red blood cells in blocked blood vessels. IMR-261 also reduced bilirubin and free-heme, both markers of red blood cell destruction.
“In human erythroblasts, IMR-261 significantly increased HbF and %F-cells,” the researchers wrote. “In vivo [living] SCD models show that IMR-261 significantly induced HbF and %F-cells, improved hemolytic markers, and decreased VOCs.”
They concluded that these data “suggest that IMR-261 is a promising, novel, oral therapy that warrants clinical testing in SCD.”
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