Gecacitinib (Jaktinib; Suzhou Zelgen Biopharmaceuticals) has shown superior efficacy and safety compared to hydroxyurea (HU) in patients with myelofibrosis (MF) and anemia, according to results from the phase 3 ZGJAK016 trial. The findings, published in Blood Cancer Journal, suggest that gecacitinib could be a promising treatment option for this patient population.
Myelofibrosis is a myeloproliferative neoplasm characterized by reduced red blood cell production, leading to bone marrow scarring, extramedullary hematopoiesis, splenomegaly, and anemia. While Janus kinase inhibitors (JAKi) are often the first-line treatment, they can worsen anemia or become ineffective over time. Hydroxyurea, a non-alkylating antineoplastic agent, is another common treatment for cytoreduction in MPNs.
Gecacitinib, a novel inhibitor targeting both JAK and ACVR1, has demonstrated the ability to alleviate inflammation and splenomegaly, while also reducing anemia and transfusion dependency. It achieves this by inhibiting JAK1, JAK2, JAK3, and TYK2 pathways, as well as ACVR1 activity, which downregulates hepcidin expression, improves iron metabolism imbalance, and increases hemoglobin levels.
Phase 3 Trial Results
The randomized, double-blind, double-simulated, parallel-controlled, multicenter phase 3 study compared gecacitinib to HU in patients with intermediate-2 or high-risk MF. Over 100 patients were randomized in a 2:1 ratio to receive either gecacitinib (100 mg twice daily) or HU (500 mg twice daily). The primary endpoint was a ≥35% reduction in spleen volume (SVR35) from baseline at week 24. Secondary endpoints included best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile.
At 24 weeks, 64.8% of patients on gecacitinib achieved SVR35 compared to 26.5% on HU (P = 0.0002). Gecacitinib also demonstrated superior best spleen response rates of 81.7% compared to 32.4% for HU (P < 0.0001). TSS50 rates were 62.0% for gecacitinib and 50% for HU. Among non-transfusion-dependent patients with baseline hemoglobin ≤100 g/L, 31.0% of those receiving gecacitinib showed a ≥20 g/L increase in hemoglobin, compared with 15.0% in the HU group.
Safety Profile
The most common grade ≥3 treatment-emergent adverse events (TEAEs) were less frequent in the gecacitinib arm compared to the HU arm. These included anemia (26.8% vs 44.1%), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%).
These findings highlight gecacitinib's potential as a significant advancement in the treatment of myelofibrosis, especially for patients with anemia. As the first JAK and ACVR1 inhibitor to demonstrate these results, it represents a promising step towards more effective and safer therapies.
