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

Introduction

IMR-687 (tovinontrine) is a highly selective phosphodiesterase 9 (PDE9) inhibitor being developed as an orally administered therapy for patients with sickle cell disease (SCD) and beta-thalassemia. IMR-687 increases intracellular cGMP levels and has been shown in preclinical studies to increase fetal hemoglobin (HbF) expression and reduce hemolysis and sickling of RBCs, which can lead to painful vaso-occlusive crisis (VOC). In a Phase 2a, randomized, double-blind, placebo-controlled study of adult patients with SCD (N=93) (NCT03401112), IMR-687 was generally well-tolerated as a monotherapy and in combination with hydroxyurea (HU) (European Hematology Association Annual Congress 2021, Abstract S263). IMR-687 treatment with 50-200 mg once daily (N=63) for up to 6 months, as compared with placebo (N=30), resulted in a 40% lower mean annualized rate of VOCs, 38% lower mean annualized rate of VOC-related hospitalizations, and increased median time to first VOC (169 days vs 87 days, respectively, p=0.029). Improvements were also observed in patient-reported outcomes regarding pain episode severity (ASCQ-Me) and percentage of RBCs containing HbF (F-cells).

Methods

A Phase 2a open-label extension (OLE) study (NCT04053803) is ongoing to assess the long-term safety and benefit of IMR-687 administered to adult subjects with SCD for up to 4 years. Secondary long-term pharmacokinetic (PK) and pharmacodynamic (PD) parameters are also being examined. The use of background HU is permitted. The Safety Review Committee meets regularly and ad hoc as necessary.

Subjects were eligible upon completion of the Phase 2a parent study (16 or 24 weeks depending on the assigned treatment arm and without early withdrawal) and if they met all inclusion and exclusion criteria. For subjects without treatment interruption, baseline values from the parent study were used, as appropriate. The dose of IMR-687 initially administered in the OLE study was 200 mg as a once daily oral dose. The dose of IMR-687 is planned to be increased to 300 or 400 mg daily, depending on the subject's weight.

Subjects are evaluated every 4-6 months for safety, PK and PD parameters (including HbF, F-cells, hemoglobin [Hb] and other biomarkers) as well as incidence of VOCs.

Results

As of a data cut-off of 12-May-2021, 24 subjects were enrolled in the OLE study, 17 of which had a treatment interruption between the parent and OLE studies, and 7 subjects had direct roll-over to the OLE study. Seventeen of the OLE subjects were treated with IMR-687 monotherapy and 7 subjects were treated with combination IMR-687 + HU.

IMR-687 continued to be well-tolerated in the OLE study (N=24). There were no treatment-related serious adverse events (SAEs), and the most common (≥10%) AEs were headache (21% of subjects), back pain (17%) and nausea (13%). There were 3 (13%) subjects with VOC-related hospitalizations.

Annualized VOC rate was analyzed for 18 subjects treated for at least 200 days in the OLE study. Subjects who were previously in the active treatment arm in the parent study (N=13) maintained a low mean annualized VOC rate while continuing IMR-687 in the OLE study (1.35/yr [parent] and 1.85/yr [OLE]); subjects previously treated with placebo (N=5) had a 39% reduction in VOC rate when switched to IMR-687 (4.71/yr [parent] vs 2.89/yr [OLE]) (Figure 1). Of 15 subjects with evaluable PD data at 8 months, 7 (47%) subjects had a ≥ 6% absolute increase in F-cells, and 4 of 11 (36%) subjects had a ≥ 3% absolute increase in HbF (Figure 2). Updated data for subjects completing 12 months in the OLE study will be presented.

Conclusions

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. IMR-687 treatment reduced the annualized rate of VOCs and increased HbF (%) and F-cells (%). 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.

Figure 1

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Figure 1

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