Jaktinib and momelotinib for the treatment of myelofibrosis—Birds of a feather?

Myeloproliferative neoplasms (MPNs) are characterized molecularly by constitutional JAK–STAT activation1 and morphologically by trilineage myeloproliferation.2 MPNs are subclassified into essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), and MPN, unclassifiable (MPN-U), based on presence or absence of erythrocytosis, thrombocytosis, and/or bone marrow fibrosis.3 Myelofibrosis (MF) is an operational designation used to include PMF and post-ET or post-PV myelofibrosis.4 Prognosis in ET and PV is relatively good with expected survival exceeding 35 years, in patients aged 40 years or younger.5 Unfortunately, the same is not true for MF; using contemporary risk models,6, 7 10-year survival in PMF was estimated at 0–15% for high/very high, 30–40% for intermediate, and 50–80% for low/very low risk disease. Importantly, in addition to shortened survival, quality-of-life (QoL) in patients with MF is severely compromised by anemia, marked splenomegaly, and constitutional symptoms, which is often accompanied by cachexia.8 It is currently believed that the latter triad of symptoms are mediated by inflammatory cytokines and JAK–STAT-enabled myeloproliferation.9 Despite the promise of targeted therapy from the discovery of gain-of-function mutations involving JAK2 and related MPN-driver mutations (i.e., CALR and MPL),1 current drug therapy in MF remains palliative, without demonstration of disease-modifying activity, and the only treatment of relevance, in terms of cure or prolongation of survival, being allogeneic hematopoietic stem cell transplant (AHSCT).10 However, nonspecific inhibition of JAK–STAT by ATP-competitive small molecule JAK2 inhibitors (JAKi) has proven effective in the broad suppression of inflammatory cytokines, with favorable effects on MF-associated constitutional symptoms and splenomegaly, which has led to FDA approval of ruxolitinib (2011), fedratinib (2019), and pacritinib (2022).8 In addition, a fourth JAKi, momelotinib, is currently under FDA review. Momelotinib has distinguished itself, from ruxolitinib and fedratinib, by being less detrimental to erythropoiesis while sustaining the JAK2 inhibitor class effect of reducing spleen size and alleviating symptoms, in patients with MF.11 Momelotinib inhibits both JAK1 and JAK2, and, in addition, Activin A Receptor type 1 gene (ACVR1) and FLT3-ITD.11-13 It is currently believed that momelotinib's inhibition of JAK2 is responsible for its therapeutic activity on splenomegaly and symptoms, through non-specific inhibition of JAK–STAT,14 while the ACVR1 target might play a role in the drug's salutary effect on erythropoiesis.15 Mechanistically, ACVR1 inhibition is believed to interfere with SMAD signaling and regulation of transcription of genes that contribute to hepcidin expression, ineffective erythropoiesis, and terminal erythroid differentiation.16, 17 In the first-in-human phase-1/2 study of momelotinib in MF, serially published in 201318 and 2018,19 response rates were 54% for anemia and 40% for clinically vetted reduction in spleen size. The value of momelotinib in improving MF-associated anemia was subsequently confirmed in both phase-215 and phase-3 studies.20, 21 Of note, momelotinib treatment-emergent peripheral neuropathy was reported in 44% of 100 consecutive patients treated at the Mayo Clinic.22 Jaktinib is a derivative of momelotinib, by way of deuteration, with the objective to improve drug pharmacokinetics.23 Accordingly, it is reasonable to expect jaktinib to have similar efficacy and side effect profile to that of momelotinib.24 In a healthy volunteer study of 126 subjects, jaktinib, at dose levels of 25–400 mg was found to be well tolerated.25 In a previously published phase-2 study of ruxolitinib-naïve MF,26 118 patients with dynamic international prognostic scoring system (DIPSS)-plus high/intermediate risk MF received jaktinib, including 104 randomized to jaktinib 100 mg BID or 200 mg QD, with additional 14 patients enrolled in the 100 BID cohort. Spleen volume reduction from baseline ≥35% (SVR35) at week 24 was reported in 55% of the patients in the 100 mg BID arm and 31% in the 200 mg QD 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. The study also reported 36% anemia response in patients with baseline hemoglobin ≤10 g/dL, defined as ≥2 g/dL increase in hemoglobin level persisting for at least 12 weeks; anemia response rates were 43% versus 28% in the BID versus QD groups. Similarly, ≥50% improvement in symptoms score was achieved in 70% versus 58%, in the BID versus QD treatment groups. Grade ≥3 hematologic adverse events in the particular study26 included thrombocytopenia (17% BID vs. 12% QD dosing arms) and neutropenia (3% vs. 12%); non-hematological AEs of any grade included elevated serum creatinine (20% vs. 31%), elevated alanine transaminase (24% vs. 21%), and elevated bilirubin (24% vs. 14%). Drug-related neuropathy was reported in 10 (8%) patients, mostly in the BID treatment group.26 In the current edition of AJH, Zhang et al. have followed up on their above-described study,26 this time focusing on ruxolitinib-intolerant (n = 51)27 or ruxolitinib-relapsed/refractory (n = 34)27 MF. Among the ruxolitinib-intolerant group (median follow-up 10.7 months),27 44 patients were evaluable for efficacy on jaktinib 100 mg BID dosing; at week 24, SVR35 was 43.2%, anemia response in patients who were not transfusion-dependent but with baseline hemoglobin <10 g/dL was 41.9%, and symptom response was 61.8%; treatment-emergent adverse events included thrombocytopenia (22.2% grade ≥3), neutropenia (15.6% grade ≥3), increased serum creatinine (22.2% grade ≤2), increased bilirubin (2.2% grade ≤2), increased transaminase (17.8% grade ≤2), and shingles (any grade 11%). All the patients in the ruxolitinib-relapsed/refractory group (n = 34) received jaktinib 100 mg BID (median follow-up 7.2 months); at week 24, SVR35 was 32.4%, anemia response in patients who were not transfusion-dependent but with baseline hemoglobin <10 g/dL was 50%, and symptom response was 46.4%; treatment-emergent adverse events included thrombocytopenia (32.4% grade ≥3), neutropenia (8.8% grade ≥3), increased serum creatinine (15.6% grade ≤2), increased bilirubin (32.4 grade ≤2), and increased transaminase (20.6% grade ≤2). In a more recent report presented at the 2023 European Hematology Association annual meeting, Zhang et al. presented interim analysis from a phase-3 study (NCT04617028) comparing jaktinib 100 mg BID (n = 47) against hydroxyurea 500 mg BID (n = 23), in DIPSS high- or intermediate-risk and JAKi-naïve MF (previous JAKi treatment for less than 10 days was allowed) with baseline platelet count ≥100 × 109/L28; on assessment at week 24, SVR35 was 72.3% versus 17.4% and symptom burden response was 63.8% versus 43.5%, for jaktinib vs hydroxyurea, respectively; one of 4 jaktinib-treated and none of 3 hydroxyurea-treated patients achieved transfusion independence; among transfusion independent patients with baseline hemoglobin ≤10 g/dL, 39.3% for jaktinib and 15.4% for hydroxyurea experienced a ≥2 g/dL increase in hemoglobin level; grade ≥3 treatment-emergent side effects on the jaktinib treatment arm included anemia (25.5%), thrombocytopenia (17%), and neutropenia (2.1%); the corresponding rates for the hydroxyurea treatment arm were 43.5%, 39.1% and 21.7%. Taken together, it is clear that jaktinib is therapeutically active in ruxolitinib-naïve, intolerant, or relapsed/refractory MF.26-28 It also seems apparent that the drug has efficacy, and safety profile that is similar to that of momelotinib, which is not surprising considering their common chemical structure, save for differences in kinetic isotope effect. Whether or not deuteration of momelotinib translates into clinically relevant improvement in pharmakokinetic or toxicity profile requires a head-to-head comparison, which will also address the added value of twice-daily (jaktinib) vs once-daily (momelotinib) dosing. In as much as we consider momelotinib to have an edge over ruxolitinib and fedratinib,11 in addressing all three QoL offenders in MF (anemia, splenomegaly, and constitutional symptoms), the same is likely to hold true for jaktinib. Zhang et al. have done a remarkable job in rapidly moving the clinical trials with jaktinib forward, but the follow-up period is currently too short to allow accurate assessment of durability of response and toxicity, especially in terms of peripheral neuropathy and consequences of immune suppression. Similarly, the above-discussed jaktinib studies are deficient in important laboratory correlative studies, including monitoring of changes in cytogenetic abnormalities, mutations, and cytokine profiles, as well as assessment of their impact on response and survival; the importance of such details was recently underlined in the context of momelotinib therapy for MF.29-31 Regardless, the prospect of a momelotinib-like JAKi being available outside of the monopolies of the US drug market is appealing to the global community for the possibilities of more affordable drug pricing and easier access.32, 33 None. None. No data available.