SCDAA 46th Annual National Convention

Abstract 

Authors:
Dr. Regina Graul- Ironwood pharmaceuticals, Dr. Bina Tejura- Ironwood pharmaceuticals, Dr. José Trevejo- Ironwood pharmaceuticals, Dr. Courtney Walls- Ironwood pharmaceuticals, Ms. Meghan Bratton- Ironwood pharmaceuticals, Dr. Jennifer Chickering- Ironwood pharmaceuticals, Ms. Oluwafunke Ojo- Ironwood pharmaceuticals,Dr. Joshua Field- Froedtert and Medical College of Wisconsin

BACKGROUND: STRONG-SCD is an ongoing randomized, double-blind, placebo-controlled, Phase 2 study of the sGC stimulator, olinciguat (IW-1701), in patients with stable sickle cell disease. Olinciguat is an oral sGC stimulator that enhances NO-sGC-cGMP signaling. Intracellular cyclic guanosine monophosphate (cGMP) produced by soluble guanylate cyclase (sGC) in response to nitric oxide (NO) binding plays an important role in regulating vascular tone, smooth-muscle proliferation, fibrosis, and inflammation. Low NO bioavailability in SCD has been proposed to contribute to marked vascular inflammation, cellular adhesion, and vasoconstriction, which may propagate vaso-occlusive crisis and other complications of SCD. In preclinical studies in relevant animal models, olinciguat decreased biomarkers of intravascular inflammation, leukocyte-endothelial cell interactions, and neutrophil extravasation both alone and in combination with hydroxyurea.
METHODS: The clinical program with olinciguat includes completed Phase 1 single ascending and multiple ascending dose (MAD) studies in healthy volunteers and STRONG-SCD, the ongoing Phase 2 study. STRONG-SCD is a multicenter, randomized, double-blind, placebo-controlled study evaluating 12 weeks of treatment with olinciguat in SCD patients (NCT03285178). Its primary objective is to assess the safety and tolerability of 3 dose levels of olinciguat. Exploratory objectives include evaluation of plasma biomarkers of disease progression, as well as health-related patient-reported outcomes. In particular, daily symptoms of SCD will be assessed via eDiary using the Sickle Cell Disease Symptom Assessment Form (SCD-SAF). The SCD-SAF is a fit-for-purpose instrument designed to reflect the most important and relevant SCD symptoms that impact patients with SCD. The STRONG-SCD study is enrolling patients 16-70 years old with HbSS, HbSC, HbSβ0-thalassemia, or HbSβ+-thalassemia who have had 1 to 10 pain crises in the past year and who meet all protocol defined eligibility criteria. Patients may be on stable therapy of hydroxyurea and other approved SCD medications. An independent data monitoring committee will review safety data. Target enrollment is 88 patients across sites in the US.
RESULTS: Multiple doses of olinciguat were well tolerated across the dose levels tested in the Phase 1 single and multiple ascending dose studies, with olinciguat showing target engagement as evidenced by reductions in blood pressure and increases in circulating cGMP concentrations. The most common adverse event (AE) reported was headache (22% in pooled treatment groups compared to 5% in placebo). Patients for the STRONG-SCD are still being enrolled.
CONCLUSION: Results of preclinical and clinical data supported the clinical development of olinciguat in SCD, with the STRONG SCD study initiated in initiated in 2017. Completion is expected in 2019.