Molotinib shows strong efficacy in JAK-exposed myelofibrosis patients

Real-world results of molotinib in patients with myelofibrosis (MF) support the drug's efficacy and ability to improve symptoms, reduce spleen size, increase hemoglobin (Hb) levels and reduce infusion dependence in Janus kinase (JAK) inhibitor-naïve patients and patients exposed to JAK inhibitors, as demonstrated in several clinical trials.

MF is a myeloproliferative neoplasm characterized by marked bone marrow scarring, extramedullary hematopoiesis, recurrent splenomegaly, and anemia due to progressive reduction in the production of red blood cells (RBCs). JAK inhibitors, such as ruxolitinib, are first-line drugs for the treatment of MF; however, drug resistance remains a major obstacle for many patients. Additionally, ruxolitinib was highly associated with anemia or worsening of existing anemia, leading to the development of other novel JAK inhibitors, including molotinib.

Molotinib is an adenosine triphosphate competitive small moleculeJAK inhibitor targeting JAK1, JAK2, JAK3 and TYK2. On September 15, 2023, it was approved by the US Food and Drug Administration for the treatment of patients with anemia and high/intermediate risk MF, including primary and secondary polycythemia vera or essential thrombocythemia. In multiple clinical trials, molotinib has been shown to have superior efficacy than another drug used to treat MF, namely ruxolitinib (Jakafi; Incyte Corp). This was observed in the phase 3 SIMPLIFY trial (NCT01969838), where the therapeutic index of molotinib treatment increased 50% to 83.3% from baseline to week 24, while the therapeutic index of ruxolitinib decreased from 88.9% to 44.4%.

In the real-world, multicenter, retrospective MOMGEMFIN study, researchers evaluated the safety and efficacy of molotinib in adult patients with primary or secondary MF anemia treated between March 2023 and July 2024. Anemia is defined as a hemoglobin value less than 11 g/dL in men and less than 10 g/dL in women. Transfusion dependence was defined as requiring 3 or more units of red blood cells within 12 weeks, or at least one unit per month. The evaluation of the spleen complied with the 2013 ELN (IWG-MRT) criteria.

The patient cohort is mainly divided intoGroup 2: JAK inhibitor-exposed patients (76.6%) and JAK inhibitor-naïve patients (23.4%). Among patients previously treated with a JAK inhibitor, ruxolitinib was the most commonly used (99%), with a median treatment duration of 16.8 months. Notably, 58.8% of these patients switched to molotinib immediately or within a week after stopping previous treatment.

In theJAK inhibitor-exposed group, the overall response rate (ORR) was 70.6% at 3 months and 85.7% at 6 months. In contrast, the ORR in JAK inhibitor novice patients was significantly lower, 16.6% at 3 months and 25% after 6 months. Additionally, the study considered patients based on anemia status, specifically those who were transfusion dependent. In transfusion-dependent patients, study results showed that molotinib not only improved hemoglobin levels but also increased transfusion independence rates.

The study also highlighted treatment safety, with 10.3% of patients reporting adverse events such as thrombocytopenia, the majority of which were grade 1 or 2.3. The results of the MOMGEMFIN study support the potential of molotinib as an effective treatment option for patients with anemic MF, particularly those with prior exposure to JAK inhibitors. These key real-world data deepen clinical understanding of the role of molotinib in the management of MF in diverse patient populations with varying treatment histories.

References:https://www.pharmacytimes.com/view/momelotinib-shows-strong-efficacy-in-jak-exposed-myelofibrosis-patients