NDA for Momelotinib Submitted to the FDA for Myelofibrosis

The FDA has received a new drug application for momelotinib as treatment of patients with myelofibrosis.

A new drug application (NDA) has been submitted to the FDA for the ACVR1 / ALK2, JAK1 and JAK2 inhibitor, momelotinib, which is in development for the treatment of patients with myelofibrosis, according to Sierra Oncology, Inc.1

The basis of the submission of the NDA comes from results from several phase 2 and phase 3 studies examining momelotinib in this patient population, including the recently completed MOMENTUM study (NCT04173494).

Findings of the MOMENTUM trial met its primary and key secondary end points and showed momelotinib to demonstrate 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.2,3

“We are thrilled to submit this NDA on behalf of myelofibrosis patients and look forward to working with the FDA over the coming months,” stated Stephen Dilly, MBBS, PhD, president and chief executive officer of Sierra Oncology, Inc, in the press release. “We are immensely grateful to the patients and investigators who participated in momelotinib trials over the years, making it possible to achieve this milestone.”

The potent, selective and orally bioavailable ACVR1 / ALK2, JAK1, JAK2 inhibitor is currently under investigation for the treatment of patients with myelofibrosis who are symptomatic, anemic, and previously treated with an approved JAK inhibitor. Since the studies began in 2009, over 1,200 subjects have received momelotinib, including about 1,000 patients treated for myelofibrosis, several of whom remain on treatment for over 12 years.

To date, momelotinib is the first and only JAK inhibitor to demonstrate positive data for symptoms, splenic response, and anemia in patients with myelofibrosis.

MOMENTUM, a randomized, double-blind, active control, phase 3 trial, examined the differentiated clinical benefits of momelotinib with the intended goal of comparing it to danazol (DAN) in these patients. Key goals of the clinical study were to compare the efficacy and safety of momelotinib vs danazol in treating and reducing disease related symptoms, the need for blood transfusions, and splenomegaly, in adults with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.


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

Patients receiving danazol who had confirmed disease progression were permitted early crossover, and then went on to receive open-label momelotinib at a dose of 200 mg daily.In the trial, patients were stratified by total symptom score (TTS), palpable spleen length, number of red blood cell (RBC) units transfused in the 8 weeks before randomization, and study site.

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

Data were presented during the 2022 American Society of Clinical Oncology by Ruben A. Mesa, MD, PhD, director, Mays Cancer Center at The University of Texas Health San Antonio, MD Anderson Cancer Center San Antonio, TX and at the 2022 European Hematology Association by Srdan Verstovsek, MD, PhD, the United Energy Resources, Inc., professor of Medicine, chief of the Section for Myeloproliferative Neoplasms and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center in Houston .

Baseline characteristics were shown to be balanced across the treatment arms and consistent with the advanced myelofibrosis patient population. The median age of patients was 71 years in the investigative arm and 72 years in the control arm. Further, a majority of patients were male, White, had primary myelofibrosis (60% and 70.8%, respectively), and most had a JAK2V617F mutation (74.6% and 78.5%, respectively).

Findings revealed that in 130 patients who received momelotinib, the TSS response rate at week 24 was 24.6% (95% CI, 17.49%-32.94%) vs 9.2% (95% CI, 3.46%-19.02%) in patients given danazol (n = 65; P = .0095). To establish superiority, participants needed to achieve at least a 50% reduction in TSS compared with baseline.

Baseline rates of transfusion independence were 13.1% with momelotinib and 15.4% with danazol. Momelotinib was also found to be superior when compared to danazol in regard to spleen response rate at week 24, at both the 25% and 35% reduction thresholds. A total of 40% (95% CI, 31.51%-48.95%) of patients who received momelotinib reached a 25% or higher reduction in spleen volume vs 6.2% (95% CI, 1.70%-15.01%) of the patients administered danazol (P < .0001).

A trend toward improved overall survival (OS) up to week 24 was seen with momelotinib vs danazol at 0.734 (95% CI, 0.382-1.409; P = .3510), and the hazard ratio for OS between the investigative and control arms up to week 24 was 0.506 (95% CI, 0.238-1.076; P = .0719), meeting significance.

Additionally, 23.1% (95% CI, 16.14%-31.28%) of patients given momelotinib achieved at least a 35% reduction in spleen volume compared to 3.1% (95% CI, 0.37%-10.68%) of patients in the danazol arm (P = .0006).

In regard to safety, the most common grade 3 or higher treatment emergent adverse events (TEAEs) were thrombocytopenia (22% vs 12%) and anemia (8% vs 11%). Grade 3 or higher infections occurred in 15% of patients given momelotinib and 17% of patients given danazol. Peripheral neuropathy occurred in 5 (4%) of patients in the momelotinib arm and 1 (2%) in the danazol arm. TEAEs led to study drug discontinuation in 18% of patients in the momelotinib arm and 23% of patients in the danazol arm.

These findings support the use of momelotinib as an effective treatment in patients with myelofibrosis.

References:
  1. Sierra oncology announces submission of new drug application for momelotinib to US food & drug administration. News release. Sierra Oncology, Inc. June 17, 2022. Accessed June 17, 2022. https://bwnews.pr/3xywqr5
  2. Mesa RA, Gerds AT, Vannucchi 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
  3. Verstovsek S, Vannucchi A, Gerds 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. Presented at EHA 2022; June 9-12, 2022. Abstract S195.