Myelofibrosis (MF) is a rare but debilitating haematological malignancy, with a poor prognosis and very limited therapeutic options. Currently, there are three approved therapies for MF: Incyte/Novartis’s Jakafi/Jakavi (ruxolitinib), Bristol Myers Squibb’s Inrebic (fedratinib), and CTI BioPharma’s Vonjo (pacritinib), all of which are JAK inhibitors (JAKi). The standard of care for treating MF is Jakafi/Jakavi, which demonstrates superlative efficacy in reducing splenomegaly (enlarged spleen) and constitutional symptoms such as night sweats, weight loss, fever, among others, both of which are cardinal presentations of MF.
Importantly, JAK inhibitors are intrinsically myelosuppressive and prolonged use often causes dose-limiting anaemia and thrombocytopenia, therefore leaving patients with no effective treatments after JAKi therapy failure. Aiming to mitigate this issue is a novel JAK/ALK2 inhibitor, Sierra Oncology’s (GSK) momelotinib, currently being evaluated in the pivotal Phase III MOMENTUM trial to investigate the agent’s efficacy for treating splenomegaly and constitutional symptoms, without the deleterious effects of traditional JAK inhibitors of anaemia and thrombocytopenia. An abstract on the MOMENTUM trial was provided at this year’s ASCO conference, published on 2 June.
Intermediate- to high-risk MF patients who have failed previous JAKi therapy and are anaemic (baseline haemoglobin <10g/dL) were randomised 2:1 to receive either momelotinib 200mg daily plus a placebo, or danazol (a common and inexpensive androgen used to treat anemia) plus a placebo. Primary endpoints included a total symptom score (TSS) improvement of greater than 50% (TSS ≥50%) at week 24. Key secondary endpoints included red blood cell transfusion independence (TI) and a splenic response rate (SRR) (≥35% reduction in spleen volume size). Results from thrombocytopenic patients (baseline platelets ≤150×109/L) were specifically analysed as thrombocytopenic patients receive suboptimal dosages of Jakafi/Jakavi with inferior efficacy, and patients with platelets ≤50×109/L are ineligible for Jakafi/Jakavi and Inrebic, highlighting an unmet need in this patient population.
Momelotinib demonstrated superior efficacy to danazol for all endpoints, with 29.6% of patients on momelotinib achieving TSS ≥50% (vs. 11.6%), 32.1% achieving TI (vs. 18.6%), and 22.2% achieving SRR ≥35% (vs. 4.7%). Reportedly, similar treatment effects were observed in patients with platelets ≤100×109/L and ≤50×109/L. Overall, these results show momelotinib is effective at controlling anemia and is effective in patients with low platelets. Results from the MOMENTUM trial should secure FDA approval by the end of the year, and momelotinib may present as the new standard of care for thrombocytopenic patients with anaemia.
Vonjo was granted accelerated approval by the FDA in February 2022 for the treatment of intermediate- to high-risk MF patients with platelets ≤50×109/L. Until now, Vonjo’s clinical and commercial viability was secured by virtue of being the only agent effective in this patient population. However, momelotinib is now well positioned to provide fierce competition to Vonjo. Given momelotinib’s additional anaemia efficacy and potentially noninferior splenomegaly and symptom efficacy, GlobalData forecasts momelotinib to capture a higher patient share than Vonjo in thrombocytopenic MF patients. Full results on momelotinib’s efficacy in patients with platelets ≤50×109/L are eagerly awaited for a direct comparison between the two agents.
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GSK agreed to acquire Sierra Oncology in April 2022 for a total of $1.9 billion, with the goal to realise momelotinib’s commercial and clinical potential by utilising GSK’s global launch capabilities and established haematology marketing presence. This will increase GSK’s oncology portfolio before the company’s upcoming demerger. According to an upcoming patient-based forecast, GlobalData projects momelotinib to reach a peak annual sales of $630 million by 2031, providing lucrative returns on investment for GSK.