Momelotinib Shows Superiority Over Danazol in Symptomatic and Anemic Myelofibrosis

Srdan Verstovsek, MD, PhD

Momelotinib demonstrated significant improvements in symptoms, spleen size, and anemia measures compared with danazol in patients with symptomatic and anemic myelofibrosis who previously received treatment with a JAK inhibitor, meeting the primary and key secondary end points of the phase 3 MOMENTUM trial (NCT04173494).¹

The data, which were presented during the 2022 EHA Congress, showed that total symptom score (TSS) response rate at week 24 with momelotinib (n = 130) was 24.6% (95% CI, 17.49%-32.94%) vs 9.2% (95% CI, 3.46%-19.02%) with danazol (n = 65; P = .0095). Patients needed to achieve at least a 50% reduction in TSS compared with baseline to establish superiority.

Momelotinib was also found to be superior to danazol in terms of spleen response rate at week 24, at both the 25% and 35% reduction thresholds. Specifically, 40.0% (95% CI, 31.51%-48.95%) of those who received momelotinib achieved at least a 25% reduction in spleen volume vs 6.2% (95% CI, 1.70%-15.01%) of those who were given danazol (P < .0001). Moreover, 23.1% (95% CI, 16.14%-31.28%) of those in the momelotinib arm achieved at least a 35% reduction in spleen volume vs 3.1% (95% CI, 0.37%-10.68%) in the danazol arm (P = .0006).

Regarding transfusion independence rate at week 24, momelotinib demonstrated noninferiority to danazol. Thirty-one percent of patients in the investigative arm achieved transfusion independence at that time point vs 20% of those in the control arm (P = .0064).

“Momelotinib induced rapid and sustained improvements in hemoglobin levels consistent with its differentiated mechanism of action as the first and only JAK1 and JAK2 inhibitor that decreases hepcidin through ACVR1 inhibition,” Srdan Verstovsek, MD, PhD, lead study author, United Energy Resources Inc. Professor of Medicine, and hematologic oncologist at the University of Texas MD Anderson Cancer Center, said in a presentation on the data. “These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis—especially in those with anemia.”

Myelofibrosis is driven by dysregulated JAK/STAT signaling that commonly manifests as bone marrow fibrosis, anemia, splenomegaly, and debilitating symptoms, according to Verstovsek. Although available JAK inhibitors can provide spleen and symptom improvements, they can induce, worsen, or fail to address anemia in patients with this disease.

Momelotinib may overcome this challenge because it inhibits not only disease drivers JAK1 and JAK2, but the iron regulator SVR1, which reduces hepcidin and improves iron metabolism, promoting erythropoiesis, Verstovsek explained. As such, this agent “addresses the 3 main hallmarks of myelofibrosis—namely, symptoms, splenomegaly, and anemia.”

The clinical benefit of momelotinib has been illustrated in many prior studies, including the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) studies. In SIMPLIFY-1, momelotinib met the trial’s primary end point of noninferiority to ruxolitinib (Jakafi), when it was found to reduce spleen volume; the splenic response rates with momelotinib (n = 215) and ruxolitinib (n = 217) were 26.5% and 29.0%, respectively (P = .0011).

“Furthermore, its ability to improve anemia was evidenced by a higher week-24 transfusion independence rate, increase in hemoglobin levels, and roughly half the transfusion burden compared with ruxolitinib,” Verstovsek added. “Although momelotinib did not demonstrate noninferiority in reducing symptoms by 50% in SIMPLIFY-1, patients [who received] momelotinib did experience a 28% symptom response rate at week 24.”

In SIMPLIFY-2, additional symptom responses were observed with momelotinib in patients who previously received ruxolitinib without washout, with a TSS response rate of 26% (n =27/103). “However, [spleen] volume reductions of at least 35% immediately following ruxolitinib treatment without the washout was not achieved [in this trial], necessitating a third redesigned phase 3 study to fully understand the [clinical benefit of] momelotinib,” Verstovsek said.

MOMENTUM enrolled patients with symptomatic (TSS ≥10) and anemic (hemoglobin <10 g/dL) myelofibrosis who previously received a JAK inhibitor. A total of 195 patients with taper and washout over at least 3 weeks and dosed with a JAK inhibitor therapy were randomized 2:1 to receive momelotinib at a daily dose of 200 mg or danazol at a daily dose of 600 mg.

Early crossover was permitted to patients on the danazol arm who had confirmed disease progression; those patients then went on to receive open-label momelotinib at a daily dose of 200 mg.

Participants were stratified by TTS, palpable spleen length, number of red blood cell (RBC) units transfused in the 8 weeks before randomization, and study site. “Note that this study was entirely conducted during the COVID-19 pandemic,” Verstovsek said.

The primary end point of the trial was TTS response rate at week 24, and key secondary end points included transfusion independence and splenic response rates at week 24.

Accrual for the study began in April 2020, with the last participants enrolled in June 2021. The database lock for the analysis presented during the meeting was December 2021.

At this time, 195 patients were enrolled to the trial and underwent randomization; 130 patients comprised the momelotinib arm and 65 comprised the danazol arm. In the investigative and control arms, 72.3% and 58.5% of patients, respectively, completed treatment.

Of the 130 patients who received momelotinib, 27.7% discontinued treatment; the most common reasons for discontinuation included toxicity (n = 16), patient decision (n = 6) and insufficient efficacy (n = 6). In the danazol arm, 41.5% of patients discontinued treatment, the most common reasons being toxicity (n = 11), patient decision (n = 5), death (n = 3), and insufficient efficacy (n = 3). Most patients on the momelotinib (70.8%) and danazol (61.5%) arms entered the momelotinib open-label extension.

Baseline characteristics were noted to be balanced across the treatment arms and to be consistent with the advanced myelofibrosis patient population. The median age of participants was 71.0 years in the investigative arm and 72.0 years in the control arm, and most patients were male, White, had primary myelofibrosis, and had intermediate-2 disease risk. The majority of patients had JAK2V617F mutation positivity, and an ECOG performance status of 1.

“Mean baseline TSS was around 27 on a scale of 0 to 70, and mean hemoglobin was about 8 g/dL,” Verstovsek said. “About half of the patients were transfusion dependent at baseline, and all received prior JAK inhibitor treatment with ruxolitinib; 9 also received prior fedratinib [Inrebic]. The mean duration of prior JAK inhibitor therapy was 2.5 years.”

MOMENTUM had a strict definition of transfusion independence, according to Verstovsek. To be deemed independent, patients could not have received RBC transfusions in the 12 weeks before week 24 and hemoglobin levels during those 12 weeks needed to be at least 8 g/dL.

“For those randomized to the active comparator, danazol, the proportion of transfusion independent patients increased from 15% at baseline to 20% at week 24; however, a greater proportion of momelotinib-randomized patients achieved transfusion independence at week 24, at a rate of 31%—despite a lower baseline rate of 13%,” Verstovsek noted.

These data correlate with laboratory assessments of mean hemoglobin levels, with plots showing a rapid increase of mean hemoglobin from baseline to week 24 in both treatment arms, he added, although this was observed at a higher degree with momelotinib, with an approximate 1.5-g/dL initial increase.

“At week 24, all danazol-treated patients crossed over [to open-label momelotinib], and that’s important to highlight,” Verstovsek said. “From which point, their mean hemoglobin levels increased over time, converging with the momelotinib-randomized group.”

Moreover, a trend toward improved overall survival was observed with momelotinib vs danazol; overall, the hazard ratio was 0.734 (95% CI, 0.382-1.409; P = .3510). Up to week 24, the hazard ratio for OS between the investigative and control arms was 0.506 (95% CI, 0.238-1.076; P = .0719), meeting significance. “And remember, at week 24, all patients on danazol moved onto momelotinib,” Verstovsek noted.

Regarding safety, the most common non-hematologic adverse effects of any grade reported with momelotinib included diarrhea (22.3%), nausea (16.2%), and asthenia (13.1%). With danazol, the most common all-grade non-hematologic toxicities included blood creatinine increase (15.4%), dyspnea (13.8%), and peripheral edema (13.8%).

Anemia was the most common grade 3 or 4 hematologic abnormality and was noted to occur more frequently in those who received danazol vs momelotinib, at 75.4% and 60.8%, respectively. Rates of grade 3/4 thrombocytopenia and neutropenia were comparable between the treatment arms.

Reference

1. Verstovsek S, Vannucchi A, Gerds AT, 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. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S195.