Patients with intermediate-2 or high-risk myelofibrosis who received the novel JAK/ACVR1 inhibitor jaktinib experienced a statistically significant improvement in the proportion of patients with a spleen-volume reduction of at least 35% from baseline (SVR35) at week 24 vs those who were treated with hydroxyurea, according to findings from the phase 3 study ZGJAK016 (NCT04617028). These results were presented at the 2023 EHA Congress and met the primary end point of the trial.

At the April 28, 2022, data cutoff, findings from the interim analysis of the study showed that the 24-week independent review committee (IRC)-assessed SVR35 rate was 72.3% (95% CI, 57.4%-84.4%) in the jaktinib arm (n = 47) compared with 17.4% (95% CI, 5.0%-38.8%) in the hydroxyurea arm (n = 23; P ≤ .0001). Additionally, the best spleen response rates were 80.9% vs 26.1%, respectively (P ≤ .0001). The median maximum percentage change in spleen volume from baseline per IRC assessment were –46.6% vs –18.5%, respectively.

“Three small molecule JAK inhibitors have been approved for myelofibrosis by the FDA, including ruxolitinib [Jakafi], fedratinib [Inrebic], and pacrritinib [Vonjo],” Jie Jin, MD, PhD, a professor of medicine in the Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, in Hangzhou, China, said during the presentation. “Currently in China, ruxolitinib is the only one that is available. Therefore, the treatment [options for] myelofibrosis in China is limited.”

ZGJAK016 was a double-blind, active-controlled, multicenter trial that enrolled adult patients with DIPSS intermediate-2 or high-risk myelofibrosis with an ECOG performance status of 1 or 0. Eligible patients also needed to have a palpable spleen of at least 5 cm below the left costal margin, a platelet count of at least 100 ´ 109/L, and no prior or a maximum of 10 days of treatment with a JAK inhibitor.

Following a 28-day screening period, enrolled patients were randomly assigned 2:1 to receive either jaktinib 100 mg twice daily plus a hydroxyurea placebo or hydroxyurea 0.5 g twice daily plus a jaktinib placebo for four 6-week cycles. At week 24, the extension period began, and patients who achieved SPV35 remained on their initially assigned treatment and those who did not received jaktinib 100 mg twice daily until criteria for termination. Patients were stratified by DIPSS risk status (intermediate-2 vs high-risk).

The primary end point of the study was SVR35 at week 24, measured by MRI or CT imaging and assessed by IRC. Key secondary end points included investigator-assessed SVR35 at week 24, best spleen response rate (defined as achieving SVR35 at any time), proportion of patients with reduction in MPN-SAF Total Symptom Score (TSS) of at least 50%, improvement in terms of anemia, and safety.

The baseline characteristics were well-balanced between the 2 arms; the median age was 63 years (range, 46-76) in the jaktinib arm compared with 62 years (range, 42-74) in the hydroxyurea arm. Most patients in both arms were women (61.7% vs 60.9%), had intermediate-2 DIPSS risk status (89.4% vs 87.0%), did not previously receive a JAK inhibitor (97.9% vs 91.3%), were JAK2 V617F positive (59.6% vs 69.6%), and had primary myelofibrosis (70.2% vs 73.9%). The median spleen volumes upon central review were 1389.7 cm3 (range, 433.6-5070.5) and 1249.1 cm3(range, 579.6-3011.4), respectively. Additionally, the median platelet count and hemoglobin levels were similar between the 2 arms.

Most patients in the jaktinib arm completed 24 weeks of treatment (89.4%) and entered the extension period (83.0%). In the control arm, these rates were 69.6% and 69.6%, respectively. One patient in the hydroxyurea arm also received open-label jaktinib without unblinding. Four patients died on the jaktinib arm compared with 1 on the hydroxyurea arm; no death was determined to be treatment related.

Additional findings from the study showed that the SVR35 benefit was observed with jaktinib over hydroxyurea across all prespecified subgroups. The greatest differences in SVR35 rate in favor of jaktinib were observed among patients with a baseline MPN-SAF TSS greater than the median (72.0% [95% CI, 35.5%-85.9]), those with a DIPSS risk status of intermediate-2 (66.2% [95% CI, 42.2%-80.4%]), and those whose disease harbored a JAK2 V617F mutation (63.4% [95% CI, 35.0%-81.2%]).

More patients in the jaktinib arm experienced a reduction in MPN-SAF TSS from baseline compared with the hydroxyurea group at every time point examined in the interim analysis. This included week 6 (55.3% vs 34.8%), week 12 (59.6% vs 43.5%), week 18 (66.0% vs 39.1%), and week 24 (63.8% vs 43.5%).

Hemoglobin levels were increased from baseline in the jaktinib arm and decreased in the hydroxyurea arm. Among patients who received jaktinib who required a red blood cell transfusion (n = 7), 5 achieved a decreased in red blood cell transfusion unit of at least 50% by week 24 compared with 2 who received hydroxyurea and required a transfusion (n = 5).

Safety findings demonstrated that nearly all patients in the jaktinib and hydroxyurea arms experienced an any-grade treatment-emergent adverse effect (TEAE), at 97.9% and 100%, respectively. Most patients in both arms experienced a TEAE of grade 3 or higher severity (51.1% vs 60.9%).

Serious TEAEs were present in 27.7% of patients in the jaktinib arm compared with 47.8% in the hydroxyurea arm. TEAEs leading to dose reduction or interruption (23.4% vs 34.8%), as well as those leading to treatment discontinuation (8.5% vs 17.4%), were reported in both arms.

In the jaktinib arm, the most common any-grade TEAEs included thrombocytopenia (40.4%), anemia (38.3%), respiratory tract infections (21.3%), leukopenia (14.9%), fever (12.8%), and reduced blood bilirubin (12.8%). Common grade 3 or higher TEAEs consisted of anemia (25.5%), thrombocytopenia (17.0%), leukopenia (2.1%), neutropenia (2.1%), and decreased lymphocyte count (2.1%).

Comparatively in the hydroxyurea arm, the most common any-grade TEAEs included thrombocytopenia (52.2%), anemia (52.2%), leukopenia (30.4%), neutropenia (26.1%), decreased lymphocyte count (26.1%), and decreased blood bilirubin (26.1%). Grade 3 or higher TEAEs included anemia (43.5%), thrombocytopenia (39.1%), leukopenia (21.7%), neutropenia (21.7%), and decreased lymphocyte count (13.0%).

“At the time of this prespecified interim analysis, jaktinib has demonstrated an improved trend in symptom response vs hydroxyurea,” Jin said. “[Additionally], there were [fewer] cytopenias in the jaktinib group than the hydroxyurea [arm]. Our interim results demonstrate that jaktinib could be a new treatment option for patients with myelofibrosis [who are] DIPSS intermediate-2 or high-risk.”