Interventions in JAK/STAT signalling pathway

Momelotinib is a potent inhibitor of JAK1, JAK2, and activine A-receptor type I (ACVR1), with clinical activity against each of the 3 hallmark features of myelofibrosis: anaemia, constitutional symptoms, and splenomegaly. Its clinical activity was observed in 2 previously conducted phase 3 trials across the continuum of intermediate-/high-risk myelofibrosis patients, either JAK inhibitor-naïve (SIMPLIFY-1) or previously JAK inhibitor-treated (SIMPLIFY-2). Updated overall survival (OS) data were presented.

Dysregulation of JAK/STAT signalling is central to the pathogenesis of myelofibrosis. “Currently approved JAK inhibitors (ruxolitinib and fedratinib) are intrinsically myelosuppressive,” Dr Srdan Verstovsek (MD Anderson Cancer Center, Texas, USA) stated. “OS following JAK inhibitor discontinuation is short, indicating a substantial unmet medical need for safe and efficacious treatments in myelofibrosis patients previously treated with ruxolitinib.”

Previously reported data from SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) suggested that momelotinib provides similar splenic response compared to ruxolitinib, improvement of constitutional symptoms, reduced transfusion burden and improved anaemia, and a favourable safety profile [1,2].

Robust OS data were found in both JAK inhibitor-naïve and previously ruxolitinib-treated patients, namely:

• median OS in SIMPLIFY-1 (53.1 months and not reached) consistent with OS advantage in myelofibrosis provided by JAK inhibition; and
• median OS in SIMPLIFY-2 (34.3 and 37.5 months) represent the best reported OS in this previously ruxolitinib-treated setting [3]

In addition, sustained transfusion independence and splenic response were observed. The durability of activity and survival data are consistent with the clinical and biological profile of momelotinib, characterised by a potential to improve splenomegaly, constitutional symptoms, and anaemia in combination with low myelosuppressive potential and lack of cumulative toxicity [1-3]. This data demonstrated potential ability of momelotinib to durably address the unmet needs of patients with intermediate-/high-risk myelofibrosis.

1. Mesa RA, et al. J Clin Oncol. 2017 Dec 1;35(34):3844-50.
2. Harrison CN, et al. Lancet Haematol. 2018 Feb;5(2):e73-e81.
3. Verstovsek S, et al. Robust Overall Survival and Sustained Efficacy Outcomes during Long Term Exposure to Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 54.

Posted on 18 February, 20214 September, 2023