Health Canada Slated to Review New Drug Submission for Momelotinib in Myelofibrosis

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Health Canada has accepted for review the new drug submission seeking the approval of momelotinib in patients with myelofibrosis, according to a recent announcement from GlaxoSmithKline.¹ The submission is based on findings from the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials.

Specifically, SIMPLIFY-1 data showed that of the 86 patients who received momelotinib, 31.4% (95% CI, 21.8%-42.3%) experienced a spleen volume response (SVR) reduction of 35% or higher vs 32.6% (95% CI, 23.4%-43.0%) of the 95 patients who received danazol.²

Moreover, findings from MOMENTUM indicated that a tumor symptom score (TSS) of at least 50% was observed in 25% of the 130 patients given momelotinib per the Myelofibrosis Symptom Assessment Form (MFSAF v4.0), representing a treatment difference of 16% (95% CI, 6%-26%; P < .01).^2,3 The MFSAF v4.0 TSS change from baseline in the momelotinib and danazol arms were -9.4 and -3.1, respectively, equating to a difference of -6.2 (95% CI, -10 to -2.4; P = .001).

Thirty percent of those in the momelotinib arm achieved transfusion independence (TI) compared with 20% of those in the danazol arm, translating to a noninferiority treatment difference of 14% (95% CI, 2%-25%; P = .023). A SVR of 25% or higher was achieved by 39% of those given momelotinib vs 6% of those who received danazol, equating to a difference of 33% (95% CI, 23%-44%; P < .0001). A SVR reduction of at least 35% was reported in 22% of those on the momelotinib arm vs 3% of those on the danazol arm, translating to a difference of 17% (95% CI, 8%-26%; P = .001).

A Deeper Dive Into SIMPLIFY-1

The SIMPLIFY-1 trial included those with myelofibrosis who previously received a JAK inhibitor (n = 432). They were given momelotinib at a once-daily dose of 200 mg or ruxolitinib (Jakafi) at an adjusted dose twice daily for the duration of 24 weeks. Patients who received ruxolitinib were allowed to cross over to receive momelotinib.

In the 181 patients who had baseline anemia, the median age was 68 years (range, 25-86) with 67% of patients aged 65 years. Moreover, 59% of patients were male and 81% were White. In terms of disease, 63% of patients had primary myelofibrosis, 13% had post–polycythemia vera (PV) myelofibrosis, and 24% had post–essential thrombocytopenia (ET) myelofibrosis. With regard to disease risk, most patients had high-risk disease (71%) followed by intermediate-2 risk disease (25%) and intermediate-1 risk disease (4%). Forty-four percent of those in the ruxolitinib arm were TI at baseline compared with 29% of those on the momelotinib arm. The primary end point of the study was achievement of a SVR of 35% or higher.

With regard to safety, the most frequent adverse effects (AEs) to be reported in at least 20% of patients included dizziness (any grade, 24%; grade ≥3, 1%), fatigue (22%; 0%), bacterial infection (21%; 8%), hemorrhage (21%; 1%), thrombocytopenia (21%; 11%), diarrhea (20%; 1%), nausea (20%; 0%), abdominal pain (18%; 1%), cough (14%; 0%), hypotension (14%; 2%), pain in extremity (12%; 0%), pyrexia (12%; 1%), rash (12%; 0%), renal and urinary tract infection (12%; 1%), elevated liver enzymes (11%; 4%), headache (11%; 0%), peripheral edema (11%; 0%), arrhythmia (8%; 2%), paresthesia (8%; 0%), pneumonia (8%; 8%), vomiting (8%; 0%), back pain (7%; 1%), viral infection (6%; 0%), and vitamin B1 deficiency (6%; 0%).

Taking a Closer Look at MOMENTUM

The MOMENTUM study included those with primary myelofibrosis, post–PV myelofibrosis, or post­–ET myelofibrosis (n = 195). Patients were symptomatic and had high-risk, intermediate-2 risk, or intermediate-1 risk disease according to Dynamic International Prognostic Scoring System criteria. They were required to be at least 18 years of age and have an ECOG performance status no greater than 2.

They were randomized in a 2:1 fashion to received 200 mg of momelotinib once daily or 300 mg of danazol twice daily for 24 weeks. Patients in the control arm were permitted to cross over to receive momelotinib. The primary end point of the study was a MFSAF v4.0 TSS reduction of 50% or more at week 24 compared with baseline. Other important end points comprised TI achievement, SVR, MFSAF v4.0 TSS change from baseline, and the percentage of patients who did not receive transfusions.

The median age of the study participants was 71 years (range, 38-86), with 79% at least 65 years of age. Moreover, 63% of patients were male and 81% were White. When broken down by disease type, most patients had primary myelofibrosis (64%), followed by post-PV myelofibrosis (19%) and post-ET myelofibrosis (17%). In terms of risk, most patients had intermediate-2 risk disease (57%), followed by high-risk disease (35%) and intermediate-1 risk disease (5%). Most patients (79%) received red blood cell (RBC) transfusions in the 8 weeks before initiating treatment on the study with a median of 4 RBC units received (interquartile range, 1-6).

At baseline, 13% of patients in the investigative arm were TI compared with 15% of those in the control arm. The median hemoglobin count was 8 g/dL at baseline, and the median platelet count was 96 × 109/L (range, 24-733). The median palpable spleen length was 11 cm below the left costal margin at baseline, and the median central spleen volume measured by MRI or CT was 2105 cm3 (range, 609-9717).

The most common all-grade toxicities reported in the momelotinib arm to be experienced by 5% or more of patients included thrombocytopenia (28%), diarrhea (22%), hemorrhage (22%), fatigue (21%), nausea (16%), bacterial infection (15%), abdominal pain (13%), viral infection (12%), pruritus (11%), elevated liver enzymes (10%), pyrexia (10%), cough (8%), paresthesia (8%), dizziness (8%), and vomiting (8%).

The most common grade 3 or higher adverse effects (AEs) with momelotinib included thrombocytopenia (22%), bacterial infection (8%), viral infection (5%), hemorrhage (2%), fatigue (2%), nausea (2%), pruritus (2%), elevated liver enzymes (2%), pyrexia (2%), dizziness (2%), paresthesia (1%), abdominal pain (1%), and vomiting (1%).

Other Regulatory Decisions With Momelotinib

The FDA approved momelotinib (Ojjaara) for use in adult patients with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis, and anemia in September 2023.4 The decision was based on MOMENTUM data. More recently, in January 2024, the European Commission granted marketing authorization for momelotinib (Omjjara) for the treatment of adult patients with disease-related splenomegaly or symptoms and moderate-to-severe anemia, including those who have primary myelofibrosis, post-PV myelofibrosis, or post-ET myelofibrosis and who were naive to JAK inhibition or who have received prior ruxolitinib.5 This decision was based on SIMPLIFY-1 and MOMENTUM data.

References

• GSK Canada’s submission for momelotinib for the treatment of myelofibrosis accepted for review by Health Canada. News release. GlaxoSmithKline. January 30, 2024. Accessed February 5, 2024. https://ca.gsk.com/en-ca/media/press-releases/gsk-canada-s-submission-for-momelotinib-for-the-treatment-of-myelofibrosis-accepted-for-review-by-health-canada/

1. Momelotinib (Ojjaara) Prescribing information. GlaxoSmithKline; 2023. Accessed February 5, 2024. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Ojjaara/pdf/OJJAARA-PI-PIL.PDF
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
3. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed February 5, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
4. GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anemia. News release. GlaxoSmithKline. November 13, 2023. Accessed February 5, 2024. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-positive-chmp-opinion-recommending-momelotinib-for-myelofibrosis-patients-with-anaemia/