From January 22, 2021, to August 31, 2022, a total of 105 participants were randomized across 38 centers, with 71 patients allocated to the gecacitinib 100 mg BID group and 34 to the HU 500 mg BID group. All participants were included in both the Full Analysis Set and the Safety Set.

Baseline characteristics were generally balanced between the two groups, with the exception of a higher proportion of patients with grade 3 bone marrow fibrosis (59.2% vs 44.1%) observed in the gecacitinib group, Table 1. The average age of the patient was 63.1 years (SD: 8.76), ranging from 41 years to 79 years, and 44 of them (41.9%) were male. The majority were diagnosed with PMF (73.3%). The proportions of intermediate-2 risk vs high risk were 89.5% vs 10.5% by DIPSS. The mean disease duration at baseline was 1.4 years. Hemoglobin levels below 100 g/L at baseline were reported in 66.2% of the gecacitinib group and 64.7% of the HU group. JAK2V617F mutation was present in 59.2% of the gecacitinib vs 58.8% in the HU group. 42.3% of the gecacitinib group had received prior HU therapy, compared with 50.0% in the HU group.

The median follow-up time was 17.5 months in the gecacitinib group and 15.9 months in the HU group. In total, 91 of the 105 patients (86.7%) completed the 24-week main study period, with 65 (91.5%) from the gecacitinib group and 26 (76.5%) from the HU group, as depicted in Fig. 1. Reason for treatment discontinuation in the gecacitinib group (n = 6) were hematologic adverse event (n = 2), death (n = 1), patient withdrawal (n = 1), and other reasons (n = 2). In the HU group (n = 8), reasons included non-hematologic AE (n = 3), hematologic adverse event (n = 1), patient withdrawal (n = 2), and other reasons (n = 2). A total of 85 patients (81.0%) entered the extension phase, with 60 (84.5%) from the gecacitinib group and 25 (73.5%) from the HU group, with 17 patients (50.0%) crossed over from HU to gecacitinib treatment. No patients underwent bone marrow transplantation in the study.

*One patient who discontinued the main study period early due to a ≥25% increase in spleen volume entered the extension period and crossed over to gecacitinib. †As of February 15, 2023, five patients (four in the gecacitinib group and one in the HU group) completing the main study period did not yet enter the extension period. HU hydroxyurea, AE adverse event.

The gecacitinib group exhibited a 24-week SVR35 rate of 64.8% (46/71), significantly higher than the HU group’s 26.5% (9/34), with a difference of 36.5% (95% CI: 19.0–53.9%; P = 0.0002; Table 2). Among evaluable patients at week 24, most patients treated with gecacitinib had a spleen volume reduction, Fig. 2A. Across all predefined subgroups, gecacitinib’s 24-week SVR35 efficacy rates surpassed those of HU, Supplementary Fig. 1.

A Percentage change in spleen volume compared to baseline at week 24. B Proportion of patients achieving SVR35 (≥35% reduction in spleen volume) at each visit. C Proportion of patients achieving the best spleen response. HU hydroxyurea, CMH test stratified Cochran–Mantel–Haenszel test (Note: patients without week 24 spleen volume data [8 from the gecacitinib group and 10 from the HU group] are not included on the waterfall plot).

At 12 weeks, the gecacitinib group exhibited a rapid spleen response with an SVR35 compared to the HU, 53.5% (38/71) vs 20.6% (7/34), P = 0.0017, Fig. 2B and Table 2. The gecacitinib group reached an 81.7% (58/71) best overall spleen response rate, markedly greater than the HU group’s 32.4% (11/34; P < 0.0001), Fig. 2C and Table 2. The median percentage of the largest spleen volume reduction from baseline was 51.7% in gecacitinib-treated patients vs 30.0% in the HU group.

At week 24, 62.0% (44/71; 95% CI: 49.7–73.2%) of gecacitinib patients reported a TSS50, compared to 50.0% (17/34; 95% CI: 32.4–67.6%) in the HU group, P = 0.2065; Fig. 3A and Table 2. Besides, more patients achieved TSS50 in the gecacitinib group than in the HU Group at each visit, starting from week 6, Fig. 3B.

A Percentage change in TSS compared to baseline at week 24. B Proportion of patients achieving TSS50 (≥50% reduction in TSS) at each visit. HU hydroxyurea (Note: patients without week 24 TSS data or with TSS 0 at baseline [9 from the gecacitinib group and 10 from the HU group] are not included on the waterfall plot).

In the gecacitinib group, 47.9% (34/71) achieved both SVR35 and TSS50 responses at week 24, compared with 20.6% (7/34) in the HU group (post-hoc analysis). Moreover, the gecacitinib group showed a 63.4% (45/71) achievement of both SVR35 and TSS50 at any timepoint during the study, vs the 26.5% (9/34) in the HU group (post-hoc analysis).

One of six transfusion-dependent gecacitinib patients at baseline became independent post-treatment, whereas none in the HU group archived this; P = 0.4386; Table 2. Among patients who were non-transfusion-dependent and had HGB ≤ 100 g/L at baseline, 31.0% (13/42) in the gecacitinib group experienced an increase of at least 20 g/L in HGB post-treatment, compared to 15.0% (3/20) in the HU group; Table 2. Among the 11 gecacitinib patients requiring RBC transfusions at baseline, seven and six patients, respectively, showed a reduction in transfusion frequency and units by ≥50% from baseline; in the HU group, these numbers were three and two out of five patients, P > 0.9999 and P = 0.4795 respectively; Table 2. Gecacitinib demonstrated a positive effect compared to HU, as indicated by the mean absolute change in HGB relative to baseline at each visit, particularly at week 24 (1.27 g/L vs −3.50 g/L), Fig. 4A and Table 2. A steady increase in mean HGB levels over time has been observed in patients with baseline levels < 100 g/L, while mean HGB levels have remained stable in patients with baseline levels ≥ 100 g/L, showing only a minor overall decrease, Fig. 4B. Using a mixed-effects model for repeated measures, a significant difference in HGB change from baseline between the two treatment groups during the main study period was observed (P = 0.0118).

A Change in hemoglobin (HGB) relative to baseline at each visit. B Mean hemoglobin levels in patients by baseline levels of <100 g/L or ≥100 g/L (main study period). GCA gecacitinib, HU hydroxyurea, BL HGB baseline hemoglobin level.

Even with lower initial platelet levels (mean [SD]: 349.70 [267.67] × 109/L vs 407.24 [372.18] × 109/L), gecacitinib group exhibited less fluctuation in platelet levels at each visit, and from week 4 onward, the mean platelet levels surpassed those of the HU group (−93.28 × 109/L vs −182.56 × 109/L) (Fig. 5 and Table 2).

Change in platelet relative to baseline at each visit. HU hydroxyurea, BL baseline.

At week 24, one patient of each group achieved partial remission; furthermore, 70.4% (50/71) of patients in the gecacitinib group experienced clinical improvement, vs 41.2% (14/34) in the HU group, Table 2.

In the gecacitinib group, progressive splenomegaly, defined as an increase of ≥25% from the nadir, including baseline measurements, was observed at a rate of 25.4% (18/71; Supplementary Table 1). In comparison, the incidence in the HU group was 11.8% (4/34). Within the gecacitinib group, three (4.2%) experienced leukemic transformation (Supplementary Table 2). In contrast, no patients in the HU group exhibited these leukemic events. Notably, among the HU group, 17 of 34 patients subsequently crossed over to receive gecacitinib, with 14 of these patients demonstrating no signs of progressive disease at the time of crossover. Censoring prior to crossover for patients who had not yet experienced disease progression may be associated with a smaller number of patients with progressive disease in the HU group.

A total of 12 patients, with 8 in the gecacitinib group and 4 in the HU group died. The OS rate of the gecacitinib group at 18 months was 85.4%, compared to 79.5% in the HU group, with median OS not reached in either group, Supplementary Fig. 2.

Efficacy was durable with continued gecacitinib. At week 48 in the interim analysis population, patients in the gecacitinib group showed a 66.0% (31/47) SVR35 rate, a 59.6% (28/47) TSS50 rate, an 85.1% (40/47) best overall spleen response rate, and a 46.4% (13/28) rate of ≥20 g/L HGB increase among non-transfusion-dependent patients with baseline HGB ≤ 100 g/L. Among patients with SVR35, 74.7% maintained a response for at least 48 weeks.

The average drug exposure during the main study period was 173.5 (SD: 30.7) days for the gecacitinib group and 154.9 (57.9) days for the HU group. Adverse event occurrence was 98.6% in the gecacitinib group, with ≥grade 3 AEs in 49.3%; the HU group reported 100% occurrence with 64.7% at ≥grade 3. The incidence of serious AEs was 26.8% for gecacitinib and 41.2% for HU.

AEs leading to dose reduction or treatment interruption were reported in 25.4% of gecacitinib patients, with 7.0% discontinuing treatment permanently; corresponding rates for HU were 32.4% and 11.8%, Supplementary Table 3.

The common grade ≥ 3 treatment-emergent adverse events (TEAEs, occurring in ≥20%) were anemia (26.8% in gecacitinib vs 44.1% in HU), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%). Common non-hematological TEAEs of any grade, including upper respiratory tract infection (15.5% vs 17.6%), blood bilirubin increase (12.7% vs 20.6%), fever (12.7% vs 17.6%), and diarrhea (14.1% vs 17.6%), were also favorable with gecacitinib, Table 3.

Adverse drug reactions (ADRs) of special interest showed lower cytopenia rates in the gecacitinib group (56.3% vs 76.5%) with respective anemia rates of 26.8% and 52.9%. Infectious pneumonia occurred in 5.6% of gecacitinib patients vs 2.9% in HU, and peripheral neuropathy was reported in 2.8% of gecacitinib patients, with no cases in the HU group. Opportunistic infection-related AEs were reported in 9.9% for gecacitinib and 8.8% for HU, with 1.4% and 2.9% being drug-related, respectively.

By the cutoff date, five deaths were reported during the study or within 28 days after treatment discontinuation. The causes of death included septicemia, infectious pneumonia, multiple organ failure, gastrointestinal bleeding, and adenocarcinoma of the cardia, all of which occurred in the gecacitinib group. One death occurred during the main study period and was considered drug-unrelated by the investigator, while four deaths occurred in the extension period, one (infectious pneumonia) was deemed drug-related, and three were considered unrelated.