S854 IMR‐687, A HIGHLY SELECTIVE PHOSPHODIESTERASE 9 INHIBITOR (PDE9I), DEMONSTRATES PRELIMINARY EVIDENCE OF ACTIVITY ON RED AND WHITE CELL BIOMARKERS IN A PH‐2A INTERIM ANALYSIS
Authors: B. Andemariam, K. Johnson, V. Gordeuk, J. Howard, J. Kanter, P. Eleftheriou, R. Ballal, S. Parulkar, S. Foo, S. Parasuraman, J. McArthur, N. Svenstrup, T. Creighton, C. O’Rourke
Journal: HemaSphere (2019)

Background: IMR‐687 is a novel phosphodiesterase 9 (PDE9) inhibitor in clinical development as a once a day, oral therapy for the treatment of sickle cell disease (SCD). IMR‐687 inhibition of PDE9 increases intracellular cGMP levels, increases fetal hemoglobin (HbF) expression, and reduces sickling and hemolysis of RBCs in vitro and in murine systems. IMR‐687 does not induce neutropenia, is not teratogenic, and does not impact fertility or reproduction in rodent and rabbit models. Aims: The objectives of this study are to evaluate the safety, tolerability, PK, and PD of IMR‐687 administered once daily for 16 to 24 weeks in 2 populations of subjects with SCD: those not on hydroxyurea (HU) (Pop A) and those receiving a stable dose of HU according to standard of care (Pop B). Methods: IMR‐SCD‐102 is a Phase 2a, randomized, double‐blind, placebo‐controlled study of IMR‐687 in adult patients with sickle cell anemia (homozygous HbSS or sickle‐β0 thalassemia). Subjects in Pop A receive either IMR‐687 or placebo for a total of 24 weeks. On Day 1, subjects are randomized 1:1:1 to receive oral IMR‐687 50 mg, IMR 687 100 mg, or placebo daily for the first 12 weeks. Each subject's dose is doubled at week 13 following the Safety Review Committee (SRC) approval of each subject's clinical safety data. Subjects in Pop B are randomized 2:1 and receive the 50 mg dose of IMR‐687 or placebo, with dose escalation to 100 mg (or placebo) after 4 weeks &amp; SRC review. The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ‐Me®), is also administered at baseline, 13 weeks, and at the end of the study. As pre‐specified in the protocol, an interim analysis was performed once at least 18 subjects in Pop A had ≥4 weeks of available data for soluble adhesion markers (sP‐Sel, sVCAM) and myeloperoxidase (MPO). 3‐month RBC data (absolute reticulocytes, % reticulocytes, Hb, %F cells, and HbF) was available for a subset of 13 of these Pop A subjects. Pop B subjects were not analyzed in the interim analysis. Results: Blinded safety measures were available for 27 patients. No clinically significant changes in white blood cell counts (including neutrophil count) were noted and no evidence of neutropenia was seen. There were no treatment‐related SAEs. Blinded white cell markers in Pop A (n = 19) along with red cell markers and quality of life measure (ASCQ‐Me®) (n = 13) were analyzed. At 5 weeks, in the 100 mg dose group, there was a trend to reduced sP‐Sel, sVCAM and MPO compared to placebo. At 13 weeks, in the 100 mg dose group, there was a two‐fold increase in the percent F cells along with a trend toward an increase in hemoglobin. A corresponding decrease in absolute reticulocyte count and % reticulocytes with a trend towards improved pain measured by ASCQ‐Me® was also observed in the 13‐week analysis. Summary/Conclusion: This interim analysis demonstrates that daily dosing of IMR‐687 was safe and well tolerated. Preliminary efficacy data show promising changes in WBC and RBC markers with an increase in percentage F‐cells in conjunction with reduced hemolysis and cellular adhesion factors. While there was only a trend toward an increase in HbF in the IMR‐687 100 mg dose group, the 3‐month time point is likely too early to observe the full effect on HbF as maximum level of HbF may not be ascertained for 6 months or more after F cell increases. The clinical data generated in this pre‐specified interim analysis support further investigation of IMR‐687 as a potential disease modifying therapy for SCD. image