FDA Extends Review Period for Momelotinib NDA in Myelofibrosis

The FDA has extended the review period for the new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis.1 The regulatory agency pushed the decision date back by 3 months, to September 16, 2023, to allow for more time to review recently submitted findings.

The application was based on data from the phase 3 MOMENTUM trial (NCT04173494), in which momelotinib significantly improved symptoms, spleen size, and anemia vs danazol in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor.²

Specifically, more patients who received momelotinib (n = 130) experienced a reduction in tumor symptom score (TSS) of 50% or higher at week 24 vs those who were given danazol (n = 65), at 25% and 9%, respectively (proportion difference, 16%; 95% CI, 6%-26%; P = .0095), which met the primary end point of superiority with momelotinib. Moreover, more patients on the investigative arm achieved transfusion independence (TI) at week 24 than those on the control arm, at 30% (95% CI, 22%-39%) and 20% (95% CI, 11%-32%), respectively (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016); TI rates from baseline to week 24 increased by 17% with momelotinib compared with 5% with danazol.

Momelotinib also demonstrated superiority over danazol with regard to splenic response rates at week 24. Thirty-nine percent of patients who received momelotinib experienced a reduction of 25% or more in spleen volume from baseline to week 24 vs 6% in those given danazol (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011).

In a recent news release, GlaxoSmithKline, the drug developer, stated that they were “confident in the momelotinib NDA” and that they “look forward to working with the FDA as they finalize their review.”¹

The international, double-blind, randomized, controlled MOMENTUM trial enrolled patients with a confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post–essential thrombocytopenia myelofibrosis who were at least 18 years of age and who received a prior approved JAK inhibitor for at least 90 days.²

Patients were symptomatic, defined as a TSS of at least 10 at screening; were anemic, defined as a hemoglobin of less than 10 g/dL; a platelet count of more than 25 x 10⁹ cells/L; and had splenomegaly at baseline. Moreover, patients had an ECOG performance status of 0 to 2, and could have had high-risk, intermediate2-risk, or intermediate-1 risk disease by Dynamic International Prognostic Scoring System criteria.

Study participants were randomly assigned 2:1 to momelotinib at 200 mg once daily or danazol at 300 mg twice daily.

The primary end point of the trial was week-24 TSS response rate, which was defined as the proportion of participants achieving a reduction in mean TSS of at least 50% over the 28 days prior to the end of week 24 vs baseline. Important secondary end points comprised week-24 TI rate, 25% splenic response rate at week 24, change in TSS from baseline to week 24, 35% splenic response rate at week 24, and rate of zero transfusions at week 24. Other end points focused on anemia, transfusions, survival, and safety.

A total of 195 patients were enrolled in the trial and were treated. Of those in the momelotinib and danazol arms, 72% and 58% of patients, respectively, completed treatment. The most common reason for early discontinuation in these arms was toxicity (12% vs 17%), followed by patient decision (5% vs 8%).

Data from the study were published in The Lancet and have a data cutoff date of December 3, 2021.

In all patients, the median baseline age was 71 years (interquartile range, 66-76), and most were male (63%) and White (81%). Moreover, the majority of patients had primary myelofibrosis (64%), intermediate-2 risk disease (57%), and harbored a JAK2 mutation (76%). Fourteen of the patients were TI and 50% were dependent. The mean duration of prior JAK inhibition in these patients was 2.6 years, and all patients previously receives ruxolitinib (Jakafi). Five percent of patients had prior fedratinib (Inrebic). The mean TSS at baseline was 27.2, mean hemoglobin was 8.0 g/dL, and the mean platelet count was 144.7 x 10⁹ cells/L.

Additional findings indicated that in the group of patients who were transfusion dependent at baseline (n = 168), 26% and 15% of those in the momelotinib and danazol arms, respectively, achieved TI by the end of week 24.

Momelotinib also proved to be superior to danazol with regard to mean TSS change from baseline to end of week 24, at –11.5 vs –3.9, respectively (least squares mean difference, –6.2; 95% CI, –10.0 to –2.4; P = .0014). This was also true for the rate of zero transfusions to week 24, at 35% (95% CI, 27%-44%) and 17% (95% CI, 9%-28%), respectively (P = .0012). There was also a higher rate of zero transfusions at week 24 in those with hemoglobin at least 8 g/dL vs those with less than 8 g/dL (49% vs 21%) with momelotinib and with danazol (24% vs 9%).

Currently, momelotinib is not approved in any market.¹

References

1. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed June 16, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/
2. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0