According to results from a multicenter, phase 1/2 trial, novel small molecule Janus kinase 2 (JAK2) inhibitor OB756 was found to be well-tolerated and demonstrated meaningful clinical activity, including fast and lasting spleen reduction, among patients with myelofibrosis (MF) who were Janus kinase inhibitor-naive.

These results will be presented by Yile Zhou, MD, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

The investigators conducted a multicenter, phase 1/2 trial of OB756 across 17 sites in China. This study included a phase 1 dose-escalation cohort and phase 2 dose-expansion cohort. The primary end points of this study were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in phase 1, and the proportion of pts with ≥ 35% spleen volume reduction (SVR35) from baseline at week 24 in phase 2. The main secondary end point included symptom response (≥ 50% reduction in total symptom score, TSS50) from baseline at week 24, platelet and anemia improvement, and safety in phase 2.

Patients enrolled in this study were adults with international prognostic scoring system (IPSS) intermediate 1/2 or higher risk. They received escalating doses of oral OB756 at 4 dose cohorts, ranging from 8 to 32 mg of each 28-day cycle, and a modified “3 + 3” design was used in phase 1. In phase 2 study, patients were treated with OB756 with RP2D of 16mg or 20mg twice daily for 28-day cycles until progressive disease or intolerance. Over the study dates of November 3, 2020 and May 16, 2024, 296 patients were assessed for eligibility, 75 patients were enrolled and treated with OB756.

In the phase 2 portion of the trial, 47 were patients with primary MF, 14 were patients with post-PV MF, and 5 were patients with post-ET MF, with IPSS assessment of intermediate-1 risk in 19 patients, intermediate-2 risk in 27 patients, and high-risk in 21 patients. Baseline median spleen volume was 1780.2 ml. A total of 36 patients achieved SVR35 at EOC6, and 7 reduced spleen more than 5cm from baseline at week 1. In addition, patients had SVR35 during study period and EOC12 were 39 and 12, respectively. As far as  secondary end points, 31/55 (51.4%), 34/53 (64.2%), and 7/8 (87.5%) pts achieved TSS50 at EOC3, EOC6, and EOC20, respectively. OB756 had quick spleen reduction and durable SVR. OB756 treatment increased hemoglobin level to ≥20 g/L in 15.0% (3/20) of pts with hemoglobin ≤100 g/L at baseline.

The most frequent treatment-emergent adverse events recorded were grade 1 or 2. The most frequent grade ≥3 hematological treatment-related adverse events were found to be generally manageable, and were thrombocytopenia and anemia. Occurrence of other grade ≥ 3 non-hematologic were noted to be low. . Investigators reported no mortalities related to either disease progression or treatment with OB756.

“OB756 is well-tolerated and showed meaningful clinical activity in patients with MF, especially for quick and durable spleen reduction,” concluded Zhou and colleagues. “OB756 also showed few non-hematological TEAEs, and may be a new treatment option for MF patients.”

Source:

Zhou Y, Huang J, Wen B, et al. A Novel JAK2 Inhibitor OB756 in Treatment of Janus Kinase Inhibitor-Naive Patients with Myelofibrosis: A Phase 1/2, Open-Label, Multicenter Study. Dec 7-10, 2024; San Diego, CA. Abstract: 1808