Jaktinib (JAK1/2 inhibitor): A momelotinib derivative with similar activity and optimized dosing schedule

The seminal description of JAK2V617F in 2005 has had substantial impact on the science and practice of myeloproliferative neoplasms (MPN). JAK2 and related MPN-driver mutations (i.e., CALR and MPL) are gain-of-function variants that lead to constitutive JAK–STAT activation, which has since been exploited in the development of multiple JAK2 inhibitors that are not necessarily specific to the oncogenic mutations themselves. Fortunately, their nonspecific inhibition of JAK2 produces broad suppression of inflammatory cytokines and accordingly has had favorable effects on constitutional symptoms and splenomegaly, associated with myelofibrosis (MF) and related MPNs. The demonstration of benefit in quality of life (QOL), by way of effective control of splenomegaly and constitutional symptoms, has so far allowed FDA approval of three smallmolecule JAK2 inhibitors: ruxolitinib (2011), fedratinib (2019), and pacritinib (2022). However, none of these drugs were shown to induce morphologic or molecular remissions, and are therefore unlikely to modify the natural history of the disease. Furthermore, these drugs have had limited value in resolving red cell transfusion dependency in patients with MF. Jaktinib and momelotinib are also small-molecule JAK2 inhibitors that are currently under investigation and not FDA approved as yet, but appear poised to address this significant unmet need (i.e., anemia) in MF, at least in some patients. In 2009, we reported preclinical observations on momelotinib that included selective activity against JAK1 and JAK2 and less so against JAK3 and in vitro growth inhibition of cell lines harboring JAK2V617F or MPLW515L, as well as erythroid colonies from patients with polycythemia vera. This was followed by the first-in-human phase-1/2 study in MF, serially published in 2013 and 2018 (NCT00935987); results included responses in anemia (54%), resolution of red cell transfusion need (68%), and clinically vetted reduction in spleen size (40%). Adverse events (AEs) included grade-3/4 thrombocytopenia (34%) and neutropenia (8%), grade-1/2 diarrhea (48%), nausea (39%), vomiting (24%), dizziness (40%), peripheral neuropathy (30%), and flushing (11%); in addition, increases in liver function tests and pancreatic enzymes were documented in 15%–18% and 11%–13%, respectively. In 2015, we reported additional observations from the original phase-1/2 study including treatment-emergent peripheral neuropathy in 44% of the 100 consecutive patients treated at the Mayo Clinic. More recently, we reported the 12-year survival data on JAK inhibitor-naïve patients, which was similar to the long-term survival data from patients treated with ruxolitinib or risk-matched MF patients not receiving JAK2 inhibitor therapy. The value of momelotinib in improving MF-associated anemia, ascribed to its inhibitory activity on activin receptor type 1, was subsequently confirmed in both phase-2 and phase-3 studies. New drug application for momelotinib has recently been accepted by the US FDA, with a Prescription Drug User Fee Act action date of 16 June 2023. The regulatory submission was based on a recently completed phase-3 study in MF (MOMENTUM) where momelotinib surpassed danazol in a number of study endpoints including drug-induced red cell transfusion independence, reduction in spleen size, and alleviation of constitutional symptoms. Jaktinib is a deuterated form of momelotinib, which involves replacement of one or more hydrogen atoms with deuterium, a non-radioactive isotope of hydrogen; the particular drug modification is purported to improve the pharmacokinetics of the drug, without altering its pharmacodynamics, and thus affecting dose and/or dosing schedule. In a recently published healthy volunteer study of 126 subjects, jaktinib was evaluated in the context of single (25–400 mg) and multiple (up to 200 mg daily) ascending dose levels and was found to be well tolerated; frequently-reported side effects included neutropenia, diarrhea, dizziness, and headache. In the current issue of AJH, Zhang and colleagues from China present results from a phase-2 multicenter study of jaktinib, in dynamic international prognostic scoring system (DIPSS)-plus high/ intermediate risk MF (NCT03886415). The study included 104 patients randomized to jaktinib 100 mg twice-daily or 200 mg once-daily, with additional 14 patients enrolled to the 100 twice-daily cohort. MRI/CT adjudicated spleen volume reduction from baseline ≥35% (SVR35) at week 24 was reported in 55% of the patients in the 100 mg twice-daily arm and 31% in the 200 mg once-daily arm (p = .02), with median duration of response not reached for the former versus 11 months for the latter; among patients achieving SVR35, 64% sustained their response for ≥1 year. Anemia response, defined as ≥2 g/dL increase in hemoglobin level persisting for at least 12 weeks, was reported in 36% of a combined group of 59 informative cases (baseline hemoglobin ≤10 g/ dL); anemia response rates were 43% versus 28% in the twice-daily versus once-daily groups; two of six patients requiring red cell transfusions at baseline became transfusion independent. The ≥50% improvement in symptoms score was achieved in 70% versus 58%, in the twice-daily versus once-daily treatment groups. Grade ≥3 hematologic adverse events included thrombocytopenia (17% twice-daily dosing arm vs. 12% once-daily dosing arm) and neutropenia (3% vs. 12%); nonhematological AEs of any grade included elevated serum creatinine Received: 29 August 2022 Accepted: 30 August 2022