FDA Grants Momelotinib Fast Track Designation in Myelofibrosis

Barbara Klencke, MD

The FDA has granted momelotinib a fast track designation for use as a treatment of patients with intermediate- or high-risk myelofibrosis who previously received a JAK inhibitor.¹

Sierra Oncology, the developer of the JAK1/JAK2/ACVR1 inhibitor, announced that it will launch the phase III MOMENTUM trial, which will evaluate momelotinib compared with danazol in symptomatic, anemic patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia, in the fourth quarter of 2019.

"Fast track designation for momelotinib highlights the serious and significant unmet needs of patients with myelofibrosis who have previously received a JAK inhibitor,” Barbara Klencke, MD, chief development officer of Sierra Oncology, stated in a press release. “These patients typically suffer from uncontrolled constitutional symptoms, progressively worsening anemia often resulting in transfusion dependency, and enlarged spleens. Fast track also recognizes the absence of FDA-approved treatments for these patients and that momelotinib has the potential to address their unmet needs.”

In the double-blind, phase III MOMENTUM trial, an estimated 180 patients with myelofibrosis who are symptomatic, anemic, and have been previously treated with a JAK inhibitor will be randomized 2:1 to receive either momelotinib or danazol. Following 24 weeks of therapy, patients on the danazol arm will be permitted to cross over to the momelotinib arm.

The primary endpoint is total symptom score (TSS) response rate of momelotinib compared with danazol at week 24 (99% power; P <.05). Secondary and exploratory endpoints include transfusion-independence response (TI-R) rate at week 24 (>90% powered; P <.05), splenic response rate at week 24 (>90% powered; P <.05), duration of TSS response to week 48, and measures of anemia benefit that include transfusion-dependence response (TD-R) rate. There will also be patient-reported outcome measures of fatigue and physical function.

Prior data with momelotinib have demonstrated mixed findings in this patient population.

Most recently, an open-label, phase II study presented at the 2018 ASH Annual Meeting looked at the impact of momelotinib on blood hepcidin in patients with myelofibrosis. Results showed that daily treatment with momelotinib led to a transient decrease in blood hepcidin.² Moreover, in patients with a TI-R, hepcidin suppression was linked with increased iron availability and markers of erythropoiesis. At baseline, TI-R associated with reduced inflammation, lower hepcidin, and increased markers of erythropoiesis and bone marrow function.

Secondly, in the phase III SIMPLIFY-1 trial, momelotinib achieved the primary endpoint of noninferiority compared with ruxolitinib (Jakafi) in the percentage of patients with myelofibrosis who had >35% reduction in spleen volume at 24 weeks. Results showed that this was achieved in 26.5% of those on momelotinib compared with 29% of those on ruxolitinib (95% CI, -11.2%-5.6%; P = .011).³

However, noninferiority for momelotinib was not demonstrated for a secondary endpoint of response rate in total symptom score (TSS) at week 24. This was specifically defined as the percentage of patients reaching >50% reduction in their symptoms, and was evaluated by the modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score diary.

Additional secondary endpoints were met, however, which were related to anemia. There was a greater improvement with momelotinib in the red blood cell (RBC) transfusion rate through week 24, RBC transfusion independence rate at 24 weeks, and RBC transfusion dependence rate at 24 weeks.

However, in the open-label phase III SIMPLIFY 2 trial, the agent was not found to be superior compared with best available therapy (BAT) in patients with myelofibrosis who previously received ruxolitinib for the reduction of spleen size by >35% compared with baseline.⁴

A total 156 patients were recruited on the trial to receive momelotinib (n = 104) and BAT (n = 52), which was ruxolitinib in 46 (89%) of 52 patients. Seventy-three (70%) of patients on the momelotinib arm and 40 (77%) of patients receiving BAT completed the 24-week treatment phase. Results showed that 7 (7%) on momelotinib and 3 (6%) of 52 on BAT had a reduction in the spleen volume by >35% compared with baseline (proportion difference [Cochran-Mantel-Haenszel method], 0.01; 95% CI, 0.09-0.10); P = .90).

Regarding safety, the most common grade ≥3 adverse events (AEs) were anemia (14% on momelotinib vs 14% on BAT), thrombocytopenia (7% vs 6%, respectively), and abdominal pain (1% vs 6%). Moreover, peripheral neuropathy occurred in 11% of those on momelotinib, one of which was grade 3, and in no patients on BAT. Serious AEs occurred in 35% and 23% of the momelotinib- and BAT-treated patients, respectively. AEs that led to death occurred in 6 patients on momelotinib, which were acute myeloid leukemia (n = 2), respiratory failure (n = 2), cardiac arrest (n = 1), and bacterial sepsis (n = 1). This is in comparison to 4 deaths on the BAT arm: sepsis (n = 2), lung adenocarcinoma (n = 1), and myelofibrosis (n = 1).

"We look forward to continuing to work closely with the FDA as we launch and conduct the MOMENTUM phase III trial of momelotinib, with the goal of bringing this important therapy to patients expeditiously,” said Klencke in the press release.

References

1. Sierra Announces Momelotinib Granted FDA Fast Track Designation. Sierra Oncology. Published June 5, 2019. https://bit.ly/2WvP8Ah. Accessed June 5, 2019.
2. Oh ST, Taplaz M, Gerds AT, et al. Hepcidin suppression by momelotinib is associated with increased iron availability and erythropoiesis in transfusion-dependent myelofibrosis patients. Blood. 2018;132:4282. doi: 10.1182/blood-2018-99-111349.
3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus Kinase Inhibitor—naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi: 10.1200/JCO.2017.73.4418.
4. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. doi: 10.1016/S2352-3026(17)30237-5.