PDE9 Inhibitor Shows Promise as Monotherapy and With Hydroxyurea in Sickle Cell Disease

Data from two new studies indicated that daily dosing of the oral phosphodiesterase type 9 (PDE9) inhibitor IMR-687, at doses up to 200 mg, was safe and well-tolerated as a monotherapy or in combination with hydroxyurea in patients with sickle cell disease (SCD). Biree Andemariam, MD, of the University of Connecticut Health Center, presented results of the phase IIa study at EHA2021 Virtual, the annual congress of the European Hematology Association.

In preclinical studies, IMR-687 has been shown to increase intracellular cyclic guanosine monophosphate (cGMP) levels by activating the nitric oxide-cGMP pathway, increasing fetal hemoglobin expression, and reducing hemolysis and sickling of red blood cells, Dr. Andemariam explained.

Ninety-three patients with SCD were randomized to receive placebo or IMR-687 (at a 50 mg dose escalated to 100 mg, or a 100 mg dose escalated to 200 mg) once daily for four to six months. In an open-label expansion study, 24 patients received IMR-687 200 mg once daily with or without hydroxyurea (n=7 and n=14 patients, respectively).

There were no treatment-related serious adverse events (AEs) or treatment-related grade 3 or higher AEs. There were also no clinically relevant changes in laboratory safety data, ECG results, or vital signs. “Importantly, there were no cases of neutropenia,” Dr. Andemariam added. “Overall, IMR-687 was generally well-tolerated as a monotherapy as well as in combination with hydroxyurea.”

AEs leading to treatment discontinuation occurred in 10% of patients on placebo and 8% of patients on IMR-687. Common AEs included headache, nausea, and abdominal pain.

Treatment with IMR-687 reduced the average annualized rate of vaso-occlusive crises (VOCs) by 40% compared with placebo. The median annualized rate of VOCs was 0 for the pooled IMR-687 group compared with 1.87 per year for the placebo group (p=0.048), while the mean annualized rate of VOC-related hospitalizations was 0.84 among patients who received IMR-687 and 1.36 among those who received placebo.

The time to first VOC was almost twice as long with IMR-687 compared with placebo (median = 169 vs. 87 days; p=0.029). The researchers also looked at characterization of pain from VOC episodes, finding that IMR-687 at doses of 100 mg/200 mg showed a significant reduction in pain episode severity. In the open-label expansion study, there was a low VOC rate that was maintained in patients who remained on IMR-687 long term, as well as in patients who switched to IMR-687 after placebo.

“The data point to a clinically relevant improvement in key outcome measures with IMR-687 treatment,” Dr. Andemariam concluded.

Pharmacokinetic and pharmacodynamic data showed increases in F cells correlated with hemoglobin F and with IMR-687 exposure. More than one-third of patients (36%) increased their hemoglobin F by more than 3% at month eight with minimal change in total hemoglobin.

Dr. Andemariam added that higher doses of IMR-687 up to 400 mg are being investigated in ongoing phase IIb studies.

Study authors report relationships with Imara, which sponsored this trial.

Reference

Andemariam B, Bronte L, Gordeuk V, et al. The safety, pharmacokinetics & pharmacodynamic effects of IMR-687, a highly-selective PDE9 inhibitor, in adults with sickle cell disease: Phase-2A placebo-controlled & open-label extension studies. Abstract S263. Presented at the EHA 2021 Virtual Congress, June 9-17, 2021.