Gecacitinib Demonstrates Safety, Efficacy Over Hydroxyurea in Patients With Myelofibrosis and Anemia

Gecacitinib (Jaktinib; Suzhou Zelgen Biopharmaceuticals) demonstrated superior efficacy and safety compared with hydroxyurea (HU), according to study results from the phase 3 ZGJAK016 trial (NCT04617028). The data, published in Blood Cancer Journal, suggests that gecacitinib may be a promising treatment for patients with myelofibrosis (MF) and anemia.^1,2

Hemoglobin deficiency and red blood cell anemia | Image Credit: © loran4a - stock.adobe.com

MF is a myeloproliferative neoplasm (MPN) that is characterized by increasingly reduced red blood cell production, resulting in severe bone marrow scarring, extramedullary hematopoiesis, frequent splenomegaly, and anemia. Janus kinase inhibitors (JAKi) are the first line treatment for MF; however, these therapies are associated with worsening anemia, and some patients become refractory. HU, a non-alkylating antineoplastic agent, is another frequently used treatment for cytoreduction in MPNs. According to some data, combination therapy with HU and JAKis, namely ruxolitinib (Jakafi; Incyte Corp) can improve clinical response rate.^3-5

Gecacitinib is a novel inhibitor targeting both JAK and ACVR1 which demonstrated capabilities in alleviating inflammation and splenomegaly, as well as reducing the occurence of anemia and transfusion dependency. It does this through inhibition of the pathways JAK1, JAK2, JAK3, and TYK2, as well as ACVR1 activity, which allows for the downregulation of hepcidin expression, improvement iron metabolism imbalance, and increased hemoglobin.²

In the randomized, double-blind, double-simulated, parallel-controlled, multicenter phase 3 study, investigators aimed to determine efficacy of gecacitinib versus HU in participants with intermediate-2 or high-risk MF. The trial included over 100 patients with MF who were randomly assigned in a 2:1 ratio to receive either gecacitinib (100 mg twice a day) or HU (500 mg twice a day). The primary end point was ≥35% reduction in spleen volume (SVR35) from baseline at week 24, with secondary end points including best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile.^1,2

According to the study results, at 24 weeks, SVR35 was reached by 64.8% of patients on gecacitinib compared to 26.5% on HU (P = 0.0002). Patients in the gecacitinib arm achieved superior best spleen response rates of 81.7% compared with 32.4% for patients receiving HU (P < 0.0001). TSS50 rates were 62.0% for the gecacitinib and 50% for the HU arms. Among non-transfusion-dependent patients with baseline hemoglobin (HGB) of ≤ 100 g/L, 31.0%, those receiving gecacitinib showed a ≥20 g/L increase in HGB, compared with 15.0% (3/20) in HU group.²

The most common grade ≥ 3 treatment-emergent adverse events (TEAEs), which were less frequent in patients receiving gecacitinib versus HU. This 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%).²

These findings underscore gecacitinib's potential as a groundbreaking therapy for patients with MF, particularly those who also suffer from anemia. As the first JAK and ACVR1 inhibitor to demonstrate such robust results, it represents a promising advancement in the pursuit of more effective and safer therapies for myelofibrosis.

REFERENCES

1. Jaktinib versus hydroxycarbamide in subjects with intermediate-2 or high-risk myelofibrosis. Updated November 11, 2023. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT04617028?id=%22NCT04617028%22&rank=1

2. Zhang Y, Suo S, Zhuang J, et al. Evaluation of gecacitinib vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis: final analysis results from a randomized phase 3 study. Blood Cancer Journal. December 18, 2024. doi:10.1038/s41408-024-01202-8

3. Gerlach A. Pelabresib and ruxolitinib achieve primary end point in phase 3 MANIFEST-2 trial. Pharmacy Times. December 5, 2024. Accessed December 20, 2024. https://www.pharmacytimes.com/view/pelabresib-and-ruxolitinib-achieve-primary-end-point-in-phase-3-manifest-2-trial

4. De Melo Campos P. Primary myelofibrosis: current therapeutic options. Revista Brasileira de Hematologia e Hemoterapia. April 27, 2017. doi:10.1016/j.bjhh.2016.04.003

5. Pugliese N, Giordano C, Nappi D, et al. Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis. Cancer Med. April 17, 2019. doi:10.1002/cam4.2147