OB756 Showcases Favorable Tolerability in JAK Inhibitor–Naive Myelofibrosis

The investigative JAK2 inhibitor OB756 was found to be well tolerated and to elicit meaningful clinical activity in the form of rapid and durable spleen reduction in Chinese patients with myelofibrosis who did not have prior exposure to JAK inhibition, according to data from a phase 1/2 study (CTR20201950) presented during the 2024 ASH Annual Meeting.

In the phase 1 portion of the research, no dose-limiting toxicities were reported when the agent was administered at twice daily doses ranging from 8 mg to 32 mg. Investigators ultimately identified 16 mg and 20 mg twice daily as the recommended phase 2 dose (RP2D) according to p-STAT3 inhibited percentage in an Imax model.

Of 66 evaluable patients, 54.5% achieved a spleen volume reduction (SVR) of at least 35% (SVR35) at the end of cycle 6. Moreover, 59.1% of patients achieved SVR35 at the time of the last follow-up; at the end of cycle 12, 50.0% had achieved SVR35. SVR occurred early, with 7 of 28 patients experiencing a reduction of greater than 5 cm from baseline by week 1 of treatment. Additionally, a 50% or higher reduction in total symptom score (TSS50) was achieved by 51.4% of 55 patients at the end of cycle 3, 64.2% of 53 patients at the end of cycle 6, and 87.5% of 8 patients at the end of cycle 20.

“OB756 can be a promising treatment option for patients with myelofibrosis, but we still need to wait for the final data analysis results after all patients complete follow-up,” Yile Zhou, MD, of the Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, in Hangzhou, China, said in a poster presentation of the data.

In preclinical studies, OB756 was found to hinder cell proliferation and encourage cell apoptosis by acting on the JAK/STAT-signaling pathway. The open-label, multicenter, phase 1/2 study enrolled patients with primary myelofibrosis, post–polycythemia vera (post-PV) myelofibrosis, and post–essential thrombocytopenia (post-ET) myelofibrosis who were at least 18 years of age and whose disease was intermediate-1/2 or higher per the International Prognostic Scoring System (IPSS).

The trial utilized a 3+3 design for the dose-escalation portion of the research. OB756 was to be evaluated twice daily at the following 6 dosage levels: 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, and 48 mg. The number of patients enrolled per dose level in phase 1 were as follows: 1 patient in the 8-mg group, 3 in the 16-mg group, 4 in the 24-mg group, and 1 in the 32-mg group.

The primary end point of phase 1 was to identify the maximum tolerated dose and the RP2D of OB756. For the second phase, investigators set out to determine the proportion of patients who achieved SVR35 from baseline at week 24. The key secondary end points in phase 2 included TSS50 from baseline at week 24, platelet and anemia improvements, and safety.

A total of 296 patients with myelofibrosis were assessed for eligibility between November 3, 2020, and May 16, 2024; 75 patients were enrolled and received the JAK2 inhibitor (phase 1, n = 9; phase 2, n = 66). The median age of patients included in the phase 2 portion of the research was 58 years (range, 55-69), and more than half were male (57.6%). Most patients had primary myelofibrosis (71.2%), and the remaining patients had post-PV disease (21.2%) or post-ET disease (7.6%). Regarding IPSS, 28.8% of patients had intermediate-1 disease, 39.4% had intermediate-2 disease, and 31.8% had high-risk disease. The median spleen volume was 1780.2 mL (range, 1132.5-2728.7). Moreover, 6.1% of patients had a history of red blood cell transfusion. Patients had EOG status of 0 (24.2%), 1 (68.7%), or 2 (6.1%). Most patients had JAK2 mutation (87.1%); other participants had CARL (12.1%) or MPL (1.6%) mutations. The mean MPN System Assessment Form TSS was 13.5 (range, 0-71). The mean number of days from diagnosis to enrollment was 298.5 (range, 4-4020).

Treatment with OB756 boosted hemoglobin levels to at least 20 g/L in 15.0% of patients who had a baseline level of up to 100 g/L.

The most common treatment-emergent adverse effects included anemia (grade 1/2, 36.4%; grade ≥3, 34.8%), thrombocytopenia (27.3%; 22.7%), fibrinogenopenia (28.8%; 1.5%), increased alanine aminotransferase (19.7%; 0%), elevated serum creatinine (18.2%; 0%), hypertriglyceridemia (16.7%; 0%), reduced white blood cells (10.6%; 4.5%), increased aspartate aminotransferase (13.6%; 0%), weight gain (13.6%; 0%), decreased lymphocytes (7.6%; 4.5%), elevated γ-glutamyltransferase (10.6%; 0%), and sinus bradycardia (10.6%; 0%).

Disclosures: Dr Zhou did not declare any relevant conflicts of interest.

Reference

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. Blood. 2024;144(suppl 1):1808. doi:10.1182/blood-2024-212216