A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

Abstract

NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK–signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1–2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.

Emerging treatments for classical myeloproliferative neoplasms

“…63 Pacritinib and momelotinib are discussed here; other drugs of interest include NS018 64 and INCB039110. 65 None are currently being evaluated in PV or ET.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…NS-018 is a JAK2-selective inhibitor with an IC 50 of <1 nM and it has 30- to 50-fold greater selectivity for JAK2 than for other JAK family kinases (JAK1, JAK3, TYK2), and can also inhibit SRC-family kinases. NS-018 potently decreases viability of cell lines expressing constitutively activated JAK2, suppresses endogenous erythroid colony formation by primary cells from PV patients, reduces leukocytosis and splenomegaly, improves BM fibrosis, and prolongs survival in a mouse model of JAK2 V617F-driven MF without causing peripheral anemia or thrombocytopenia [157]. Still, Ruxolitinib remains superior in clinical use and will be challenging to improve upon.…”

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

“…Fourteen of 36 evaluable patients (39%) had International Working Group for Myelofibrosis Research and Treatment-defined 78 clinical improvement in splenomegaly (sustained for $8 weeks). 77 The rates of anemia and thrombocytopenia were 15% and 27% in phase 1, 77 and 21% and 14% in phase 2 (preliminary results), respectively. 75 Enrollment in the phase 2 portion was restricted to patients for whom prior JAK2 inhibitor therapy had failed.…”

“…In vitro, this agent is 4.3-fold more selective for JAK2 V617F than wild-type JAK2, which translated to reduction of leukocytosis and splenomegaly, improvement in BM fibrosis, and prolonged survival in a mouse model of MF without a decrease in circulating RBCs or platelet counts. 76 In the phase 1 portion of the ongoing trial, 77 a $50% reduction in palpable splenomegaly was achieved in more than half the patients, 48% of whom had previously been exposed to JAK inhibitors. Fourteen of 36 evaluable patients (39%) had International Working Group for Myelofibrosis Research and Treatment-defined 78 clinical improvement in splenomegaly (sustained for $8 weeks).…”