FDA Approval Sought for Momelotinib in Myelofibrosis

A new drug application (NDA), which is seeking the approval of momelotinib for the treatment of patients with myelofibrosis, has been submitted to the FDA.¹

The NDA is supported by findings from several phase 2 and phase 3 studies, including the pivotal phase 3 MOMENTUM trial (NCT04173494), in which the agent was found to result in significant improvements in symptoms, spleen size, and anemia measures vs danazol in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor.²

A higher proportion of patients who received momelotinib (n = 130) vs danazol (n = 65) achieved at least a 50% reduction in total symptom score (TSS) over the 28 days immediately prior to the end of week 24 compared with baseline, at 24.6% (95% CI, 17.49%-32.94%) and 9.2% (95% CI, 3.46%-19.02%), respectively (P = .0095).

Moreover, a higher proportion of patients in the momelotinib arm achieved a reduction in spleen volume of 25% or higher from baseline vs those in the danazol arm, at 40.0% (95% CI, 31.51%-48.95%) and 6.2% (95% CI, 1.70%-15.01%), respectively (P < .0001); 23.1% (95% CI, 16.14%-31.28%) and 3.1% (95% CI, 0.37%-10.68%), respectively, achieved a reduction in spleen volume of 35% or higher from baseline (P = .0006).

Regarding transfusion independence rate at week 24, momelotinib showcased noninferiority to danazol. Specifically, 31% of patients in the investigative arm vs 20% of those in the control arm achieved transfusion independence by week 24 (P = .0064).

“Today is truly momentous for everyone at Sierra Oncology and the patients we serve. This team designed a targeted study to address the highest unmet need and delivered incredible results in the midst of a pandemic,” Stephen Dilly, MBBS, PhD, president and chief executive officer of Sierra Oncology, stated in a press release. “We are thrilled to submit this NDA on behalf of myelofibrosis patients and look forward to working with the FDA over the coming months.”

The global, double-blind, phase 3 MOMENTUM trial enrolled patients with symptomatic and anemic myelofibrosis who previously received a JAK inhibitor; these patients were required to have a TSS of 10 or higher and hemoglobin of less than 10 g/dL.

A total of 195 participants were randomized 2:1 to receive momelotinib at 200 mg daily plus placebo or danazol at 600 mg daily plus placebo. Patients in the control arm were permitted to crossover to momelotinib early if disease progression was confirmed.

Key stratification factors included TSS, palpable spleen length, transfused units in the previous 8 weeks, and study site.

The primary end point was TSS response rate at week 24, and key secondary end points included transfusion independence rate at week 24 and splenic response rate at week 24.

Of the 195 patients enrolled and randomized, 72.3% of patients assigned to momelotinib completed treatment vs 58.5% of those assigned to danazol. In the investigative arm, 27.7% of patients discontinued because of toxicity (n = 16), patient decision (n = 6), insufficient efficacy (n = 6), death (n = 4), leukemic transformation (n = 2), loss to follow-up (n = 1), or disease progression (n = 1). In the control arm, 41.5% of patients discontinued, the most common reasons being toxicity (n = 11), patient decision (n = 5), and death (n = 3). Four patients crossed over to receive momelotinib early.

Additionally, 70.8% of those on the momelotinib arm and 61.5% of those on the danazol arm entered the momelotinib open-extension portion of the trial, where they received momelotinib at a daily dose of 200 mg.

The median age of participants across the arms was 71.5 years, 64.3% were male, and 79.6% were White. Most patients had primary myelofibrosis, fell into the intermediate-2 DIPSS risk category, had JAK2V617F positivity, and an ECOG performance status of 1. The mean TSS at baseline in the momelotinib arm was 28.0 vs 25.7 in the danazol arm. In the investigative and control arms, the mean hemoglobin at baseline was 8.1 g/dL and 7.9 g/dL, respectively.

Additional data from the trial presented during the 2022 ASCO Annual Meeting showed that the hazard ratio for overall survival with momelotinib was 0.734 (95% CI, 0.382-1.409; P = .3510) overall, and 0.506 (95% CI, 0.238-1.076; P = .0719) up to week 24.

Regarding safety, grade 3 or higher adverse effects (AEs) were experienced by 53.8% of those in the momelotinib arm vs 64.6% of those in the control arm; serious AEs occurred in 34.6% and 40.0% of patients, respectively.

The most common any-grade non-hematologic AEs observed in the momelotinib and danazol arms, respectively, were diarrhea (22.3% vs 9.2%) nausea (16.2% vs 9.2%), blood creatinine increase (7.7% vs 15.4%), asthenia (13.1% vs 9.2%), dyspnea (7.7% vs 13.8%), peripheral edema (7.7% vs 13.8%), acute kidney injury (4.6% vs 12.3%), fatigue (6.2% vs 10.8%), pruritus (10.8% vs 10.8%), and weight decrease (10.8% vs 6.2%).

The most common grade 3 or higher non-hematologic toxicities reported in the investigative arm were acute kidney injury (3.1%), dyspnea (2.3%), and nausea (2.3%). In the control arm, the most common grade 3 or higher AEs were acute kidney injury (9.2%), nausea (3.1%), blood creatinine increase (3.1%), and fatigue (3.1%).

The most common hematologic abnormalities reported in the momelotinib arm were anemia (any-grade, 99.2%; grade ≥3, 60.8%), thrombocytopenia (any-grade, 76.2%; grade ≥3, 27.7%), and neutropenia (any-grade, 29.2%; grade ≥3, 12.3%). In the control arm, any-grade anemia occurred in all patients and was grade 3 or higher in 75.4%; all-grade thrombocytopenia occurred in 61.5% of patients and was grade 3 or higher in 26.2%; and all-grade neutropenia occurred in 26.2% of patients and was grade 3 or higher in 9.2%.

References

1. Sierra Oncology announces submission of new drug application for momelotinib to US Food & Drug Administration. News release. June 17, 2022. Accessed June 17, 2022. https://bwnews.pr/3xCxI4q
2. Mesa R, Gerds AT, Vannucci A, et al. MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16)7002. doi:10.1200/JCO.2022.40.16_suppl.7002