FDA Approves Momelotinib for Myelofibrosis With Anemia

FDA

The FDA has approved momelotinib (Ojjaara) for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.^1,2

The regulatory decision is supported by findings from the phase 3 MOMENTUM trial (NCT04173494) and data for a subpopulation of adult patients with anemia enrolled in the phase 3 SIMPLIFY-1 trial (NCT01969838).

“With momelotinib we have the potential to establish a new standard of care for myelofibrosis patients with anemia,” Ruben A. Mesa, MD, FACP, president and executive director at Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, stated in a press release. “Addressing key manifestations of myelofibrosis, including anemia, constitutional symptoms and splenomegaly, makes a significant difference in the treatment regimen for these patients who have limited options to address these aspects of the disease.”

MOMENTUM

The double-blind, active-controlled phase 3 trial enrolled 195 patients with a confirmed diagnosis of primary myelofibrosis, post-polycythemia vera (PV) myelofibrosis, or post–essential thrombocytopenia (ET) myelofibrosis who were at least 18 years of age and who received a prior approved JAK inhibitor for at least 90 days.^2,3

Patients were symptomatic, which was defined as a total symptom score (TSS) of at least 10 at screening; were anemic, defined as having a hemoglobin of less than 10 g/dL; a platelet count of more than 25 x 109 cells/L; and had splenomegaly at baseline. Patients required to have an ECOG performance status of 0 to 2. They 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 receive 200 mg of momelotinib once daily (n = 130) or 300 mg of danazol twice daily for 24 weeks (n = 65).1 Subsequently, those in the danazol arm switched to open-label treatment with momelotinib.

The primary end point of the trial was achievement of a Myelofibrosis Symptom Assessment Form (MFSAF v4.0) TSS reduction of 50% or more at week 24 vs baseline. Symptoms were measured using a patient diary, which was completed throughout the treatment period, and captured disease-related symptoms like fatigue, night sweats, itching, abdominal discomfort, pain under the ribs or left side, felling of fullness after beginning to eat, and bone pain.

Other end points comprised transfusion independence (TI), spleen volume response (SVR), MFSAF v4.0 Total Symptom Score change from baseline, and percentage of patients with no transfusions.

The median age for patients was 71 years (range, 38-86), with 79% of patients aged 65 years and older. More than half of patients were male (63%), and the majority were White (81%). Moreover, 64% of patients had primary myelofibrosis, 19% had post–polycythemia vera myelofibrosis, and 17% had post–essential thrombocytopenia myelofibrosis. In terms of risk, 5% had intermediate-1 risk disease, 57% had intermediate-2 risk disease, and 35% had high-risk disease. In the 8 weeks before study treatment, 79% of patients had received red blood cell (RBC) transfusions, with a median of 4 RBC units (interquartile range, 1-6).

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

Data showed that 25% of those in the momelotinib arm experienced a MFSAF v4.0 TSS reduction of 50% or more compared with 9% of those in the danazol arm, with a treatment difference of 16% (95% CI, 6%-26%; P < .01). Thirty percent of patient who were given momelotinib achieved TI vs 20% of those who received danazol, which translated to a noninferiority treatment difference of 14% (95% CI, 2%-25%; P = .023).

Additionally, 39% of those in the momelotinib arm experienced a SVR of at least 25% vs 6% of those in the danazol arm (difference, 33%; 95% CI, 23%-44%; P < .0001); 22% vs 3% of patients, respectively, achieved a SVR reduction of at least 35% (difference, 18%; 95% CI, 10%-27%; P = .001). The percentage of patients in the momelotinib arm with no transfusions during the 24-week treatment period was 35%; this rate was 17% in the danazol arm (difference, 17%; 95% CI, 8%-26%; P = .001). The MFSAF v4.0 TSS change from baseline with momelotinib was -9.4 vs -3.1 with danazol (difference, -6.2; 95% CI, -10 to -2.4; P = .001).

Of those who received momelotinib, 72% were exposed to the agent for at least 24 weeks and 52% were exposed for at least 48 weeks.

The most common toxicities reported in 5% or more of patients who received the agent were thrombocytopenia (all grade, 28%; ≥3, 22%), diarrhea (22%; 0%), hemorrhage (22%; 2%), fatigue (21%; 2%), fatigue (21%; 2%), nausea (16%; 2%), bacterial infection (15%; 8%), abdominal pain (13%; 1%), viral infection (12%; 5%), pruritus (11%; 2%), elevated liver enzymes (10%; 2%), pyrexia (10%; 2%), cough (8%; 0%), paresthesia (8%; 1%), dizziness (8%; 2%), and vomiting (8%; 1%).

Thirty-five percent of patients experienced serious toxicities, and adverse effects (AEs) were fatal for 12% of patients. Moreover, 34% of patients of patients experienced AEs that required dose reduction or interruption. Eighteen percent of patients experienced AEs that resulted in treatment discontinuation.

SIMPLIFY-1

The double-blind, active-controlled, phase 3 trial enrolled patients with myelofibrosis who did not have prior exposure to a JAK inhibitor (n = 432). Participants were given momelotinib at a once-daily dose of 200 mg or ruxolitinib (Rituxan) at an adjusted dose twice daily for 24 weeks. Subsequently, those in the ruxolitinib arm were able to switch to open-label momelotinib.

In the subgroup of patients with anemia at baseline, defined as having a hemoglobin that is less than 10 g/dL (n = 181). This group had a median age of 68 years (range, 25-86), with more than half aged 65 years (67%) and male (59%). Most patients were White (81%). Sixty-three percent, 13%, and 24% of patients had primary myelofibrosis, post-PV myelofibrosis, and post-ET myelofibrosis, respectively. Moreover, 4% of patients had intermediate-1 risk disease, 25% had intermediate-2 risk disease, and 71% had high-risk disease. More patients in the ruxolitinib arm were TI at baseline vs those in the momelotinib arm, at 44% and 29%, respectively.

The primary efficacy end point was reduction in SVR by 35% or more. Data showed that 31.4% (95% CI, 21.8%-42.3%) of those in the momelotinib arm (n = 86) achieved a SVR reduction of at least 35% vs 32.6% (95% CI, 23.4%-43.0%) of those in the danazol arm (n = 95).

In this anemic subset who received momelotinib, 78% were exposed to the agent for at least 24 weeks and 61% were exposed for at least 48 weeks. The most common AEs observed in at least 20% were 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%).

Serious AEs occurred in 28% of patients and 1 fatal AE was reported. Twenty-one percent of patients required dose interruptions or reduction due to toxicities. Nineteen percent of patients had an AE that led to treatment discontinuation.

References

1. 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 September 15, 2023. 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
2. Momelotinib (Ojjaara) Prescribing information. GlaxoSmithKline; 2023. Accessed September 15, 2023. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Ojjaara/pdf/OJJAARA-PI-PIL.PDF
3. 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