Phase 1/2 Study of SB1518, a Novel JAK2/FLT3 Inhibitor, In the Treatment of Primary Myelofibrosis

Abstract 3082

Mutation of Janus Associated Kinase 2 (JAK2) at amino acid 617 and the resulting constitutively active JAK2V617F enzyme has been linked to the pathogenesis of myeloproliferative neoplasms (MPN). SB1518 is a potent ATP-competitive inhibitor of both JAK2 (IC₅₀ = 23 nM) and its JAK2^V617F mutant (IC₅₀ = 19 nM) that is selective for JAK2 inhibition compared to JAK1 and JAK3 (58 and 24 fold, respectively). Flt3 inhibition (IC₅₀ = 22nM) is also observed.

In the phase 1 portion of this study, target inhibition was evaluated by assessment of the activation state of JAK-STAT pathways as measured by phosphorylation of the STAT3, STAT5 and JAK proteins in PBMCs and whole blood. Inhibition of STAT3 and STAT5 phosphorylation was observed at all dose levels of SB1518 from 100–600 mg daily, and the steady state plasma concentrations at all dose levels were well in excess of the IC₅₀ for the target enzymes JAK2 and FLT3. 400 mg orally daily was selected as the recommended Phase 2 dose based on the response rate (reduction in splenomegaly) and safety and tolerability with long-term administration.

Objectives of the Phase 2 portion of the study are to determine the spleen reduction response rate, the duration of spleen response and assess the safety and tolerability of 400 mg SB1518 when administered orally once daily continuously in 28-day cycles. Thirty-three patients with PMF have been enrolled and 32 are evaluable for safety. All patients entered the study with splenomegaly: median span below the left costal margin was 18cm. All had been previously treated: median number of prior systemic therapies was 1. The most common related adverse events have been diarrhea 81% (6% G3), nausea 41% (all G1,2), vomiting 22% (all G1,2), fatigue 9% (all G1,2) and abdominal pain, extremity pain and insomnia 6% (all G1,2) and rash 6% (3% G3). Neutropenia and thrombocytopenia were uncommon (no G3/4 events). Eighteen patients experienced adverse events requiring either study drug interruption and/or dose reduction, the majority reported GI symptoms, in particular diarrhea, as a contributing factor. Three deaths have been reported, two due to disease progression and one due to hemorrhage, none were related to study drug. To date, 23 patients (69.9%) remain on study drug; the median duration on study drug is 3.7 months (range 0.4–4.6 months). Ten patients have discontinued study drug, 1 due to AE, 2 withdrew consent, 1 for disease progression, 5 for lack of response and 1 due to death. 25 patients have completed 12 weeks on study, 17/25 patients were evaluable for response at 12 weeks by MRI. Thirty patients have had response evaluated by physical examination. Significant reductions in spleen size have been observed by both MRI and physical exam. Twelve and 24 week spleen reduction data will be presented for all patients. Bone pain, night sweats, pruritus, fatigue and abdominal pain are being evaluated monthly and a trend for reduction in MF-associated symptoms within the first 12 weeks of treatment has been observed.

SB1518 shows promising clinical efficacy with reductions in both splenomegaly and MF-associated symptoms in patients with symptomatic MF and baseline splenomegaly. SB1518 has been well tolerated at the Phase 2 dose of 400mg daily in patients with CIMF.