Roginolisib in Combination with JAK Inhibitors in Patients with Myelofibrosis Who are Unresponsive to Approved JAK Inhibitors (Study HEMA-MED) – A Trial in Progress

Background and Significance: Inhibition of both the phosphoinositide 3-kinase delta (PI3Kδ) pathway and Janus kinase (JAK) signaling decreases proliferation of cells from patients with myelofibrosis (MF). Roginolisib is a novel oral conformation-selective PI3Kδ inhibitor and when combined with JAK inhibitors it shows efficacy in primary progenitor cells isolated from MF patients. The biologically effective dose (BED) previously established at the daily 80 mg dose and corresponding to ≥ 90% target inhibition was well tolerated during the first-in-human (FiH) dose study. This dose of roginolisib was combined with approved JAK inhibitors in MF patients who no longer responded to JAK inhibition. Study Design and Methods: The HEMA-MED trial (NCT06887803) is a prospective, multi-center Phase 1/2 study. The primary objective of this study is to evaluate the tolerability of roginolisib when combined with an approved JAK inhibitor in MF patients. Secondary objectives include: (a) changes in peripheral blood Tregs; (b) splenic response rate (SRR); (c) proportion of patients with a reduction in Total Symptom Score (TSS) as measured by Myelofibrosis Symptom Assessment Form (modified MFSAF version 4). Key Inclusion criteria: (1) diagnosis of primary MF; (2) prior treatment with approved JAK inhibitors for ≥ 3 months and on a stable dose for ≥ 1 month prior to starting the add-on treatment. Furthermore, patients must show an unsatisfactory spleen reduction; (3) active symptoms of MF as demonstrated by the presence of a TSS of ≥ 10; (4) platelet count ≥ 50 × 10 9 /L and haemoglobin ≥ 8 g/dL. The study is actively enrolling at 17 sites in Italy, Spain and United Kingdom. Conclusion: Given the safety profile of roginolisib as monotherapy in patients of the FiH study, the combination of a JAK inhibitor (eg, ruxolitinib) and roginolisib is expected to provide a well-tolerated treatment in patients with MF who are no longer responding to JAK inhibition. Keywords: myelofibrosis, roginolisib, IOA-244, PI3Kdelta, JAK1/2 inhibition, ruxolitinib, momelotinib, resistance mechanism