Significant spleen volume reduction and improved safety profile with jaktinib over hydroxyurea in patients with intermediate and high-risk myelofibrosis

In China, limited treatment options are available for the treatment of intermediate or high-risk patients with myelofibrosis (MF). To address this unmet clinical need, the phase III ZGJAK016 trial was set up to assess the efficacy and safety of jaktinib, a JAK and ACR1 inhibitor, for the treatment of these patients. Results showed a significant spleen volume reduction and better safety profile in patients receiving jaktinib over hydroxyurea and highlight the potential of jaktinib as a valuable treatment alternative for intermediate or high-risk MF patients.

While the FDA has approved three small JAK inhibitor (JAKi) molecules, i.e., ruxolitinib, fedratinib, and pacritinib, for the treatment of myelofibrosis (MF), only ruxolitinib has received approval for this indication in China. The MF treatment guidelines in China recommend ruxolitinib or hydroxyurea as first-line therapies for managing splenomegaly. However, the increase in MF-associated anaemia and constitutional symptoms among patients in China highlight the need for new drugs that can effectively manage symptomatic splenomegaly. Jaktinib is a novel JAK and ACR1 inhibitor that has demonstrated promising activity in reducing MF-related splenomegaly, anaemia, and constitutional symptoms in a phase II study. Building upon these encouraging results, the phase III ZGJAK016 trial was initiated to evaluate the efficacy of jaktinib compared to hydroxyurea in participants with intermediate or high-risk MF.

 Study design

This phase III study enrolled adult patients (≥18 years) with intermediate-2 or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPSS), and no prior or  ≤10 days’ treatment with a JAK inhibitor. In total, 70 patients were randomly assigned (2:1) to receive jaktinib (100 mg bid, N= 47) or hydroxyurea (0.5 g bid, N= 23) for at least 24 days, followed by an extension period with jaktinib or the initially assigned treatment. The primary endpoint was the proportion of patients with a spleen volume reduction of ≥35% (SVR35) from baseline at week 24, measured by MRI/ computed tomography (CT) images and assessed by independent review comittee (IRC). Key secondary endpoints included SVR35 at week 24 assessed by investigator, best spleen response (defined as achieving SVR35 at any time), the proportion of patients with a ≥50% reduction in myeloproliferative neoplasm-symptom assessment form total symtpom score (MPN-SAF TSS), improvement of anaemia and safety.

Results

The study met its primary endpoint, with an improved/significantly higher IRC-assessed SVR35 rate with jaktinib vs. hydroxyurea at 24 weeks (34% vs. 4%, respectively; p ≤ 0.0001). The investigator-assessed SVR35 results were consistent with those of IRC-assessed (p= 0.0011). The medium maximum percentage change in spleen volume from baseline assessed by IRC was -46.6% vs. -18.5% in the jaktinib and  hydroxyurea groups, respectively, while the best spleen response was 80.9% vs. 26.1%. The subgroup analysis showed a consistent benefit with jaktinib over hydroxyurea in IRC-assessed SVR35 across all preset subgroups. Furthermore, there were more patients with a ≥50% MPN-SAF TSS reduction from baseline to week 24 in the jaktinib group (MPN-SAF TSS: 63.8% vs. 43.5% at week 24 in the jaktinib and hydroxyurea groups, respectively). Additionally, the haemoglobin levels increased from baseline in the jaktinib group and decreased in the hydroxyurea one. Among seven jaktinib-treated and five hydroxyurea-treated patients who required red blood cells (RBC) transfusion at baseline, five and two achieved a ≥50% decrease in RBC transfusion unit by week 24, respectively. In transfusion-independent patients with baseline haemoglobin ≤100 g/L, 39.3% and 15.4% of patients treated with jaktinib and hydroxyurea had a ≥20 g/L haemoglobin increase.

Grade ≥3 treatment-emergent adverse events (TEAEs) were observed in 51.1% vs. 60.9% of patients in the jaktinib and hydroxyurea groups, respectively. Jaktinib showed a better safety profile in terms of haematological and non-haematological TEAEs. Grade ≥3 haematological TEAEs included thrombocytopenia (17% vs. 39.1% in the jaktinib and hydroxyurea groups, respectively), anaemia (25.5% vs. 43.5%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). No grade ≥3 non-haematological TEAEs were observed in any of the groups. Most common non-haematological TEAEs of any grade included respiratory tract infection (21.3% vs. 21.7%), increased blood bilirubin (12.8% vs. 26.1%), fever (12.8% vs 21.7%) and diarrhoea (10.6% vs 21.7%).

Conclusions

Jaktinib met its primary endpoint and showed a statistically significant improvement in IRC-assessed SV35 rate at week 24 over hydroxyurea in patients with DIPSS intermediate-2 or high-risk MF. The spleen response benefit observed with jaktinib over hydroxyurea was consistent across all subgroups. Furthermore, jaktinib exhibited a favourable trend in symptom response compared to hydroxyurea. Importantly, jaktinib also displayed a better safety profile, including a reduced incidence of cytopenias, when compared to hydroxyurea. These promising results suggest that jaktinib could become a new treatment option for MF patients with DIPSS intermediate-2 or high-risk, offering improved efficacy and safety outcomes.

Reference

Zhang Y, Zhou H, Zhuang J, et al. A randomised double-blind phase 3 study of jaktinib versus hydroxyurea in patients with intermediate-2 or high risk myelofibrosis. Presented at EHA 2023; Abstract S212.