FDA Grants Fast Track Designation to Momelotinib for Intermediate/High-Risk Myelofibrosis

Srdan Verstovesk, MD, PhD

Srdan Verstovesk, MD, PhD

The FDA has granted a fast track designation to momelotinib for the treatment of patients with intermediate/high-risk myelofibrosis who have previously received a JAK inhibitor.¹

Momelotinib is a selective inhibitor of JAK1, JAK2, and ACVR1 that has demonstrated benefit towards improving anemia in patients with myelofibrosis. The agent will be investigated further in a randomized, phase III trial beginning later in the year.

"We are very pleased that momelotinib has been granted Fast Track designation by the FDA, which further reflects the collaborative and constructive dialogue we have had with the Agency concerning the advancement of momelotinib towards potential registration," said Nick Glover, PhD, president & CEO of Sierra Oncology, in a statement.

The FDA’s fast track designation facilitates the expedited development and review of agents that have the potential to address an unmet medical need. Sierra Oncology will be able to communicate with the FDA more frequently throughout the development and review process.

"Fast Track designation for momelotinib highlights the serious and significant unmet needs of patients with myelofibrosis who have previously received a JAK inhibitor. These patients typically suffer from uncontrolled constitutional symptoms, progressively worsening anemia often resulting in transfusion dependency, and enlarged spleens. Fast Track also recognizes the absence of FDA-approved treatments for these patients and that momelotinib has the potential to address their unmet needs," Barbara Klencke, MD, the chief development officer of Sierra Oncology, said in a statement. "We look forward to continuing to work closely with the FDA as we launch and conduct the MOMENTUM Phase III trial of momelotinib, with the goal of bringing this important therapy to patients expeditiously."

The randomized, double-blind phase III MOMENTUM trial is being initiated in Q4 2019 to support potential registration for momelotinib.²Investigators, led by chief investigator Srdan Verstovesk, MD, PhD, are planning to enroll 180 patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis. Eligible patients must be symptomatic, anemic, and must have received prior treatment with a JAK inhibitor.

Patients will be randomized 2:1 to either momelotinib or danazol, which is currently recommended in guidelines for treating anemia in myelofibrosis. However, all patients randomized to danazol will have the option to crossover to receive momelotinib after 24 weeks of treatment.

The primary endpoint of the trial is the total symptom score response rate at 24 weeks, and secondary endpoints include transfusion independence rate at 24 weeks, splenic response rate at 24 weeks, duration of total symptom score at 48 weeks, and patient-reported outcomes for fatigue and functionality.

"I have been involved in the development of momelotinib for many years, and I am very pleased to be named Chief Investigator of the MOMENTUM Phase III study,” Verstovsek, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas, said in a statement. “In my opinion, a good proportion of myelofibrosis patients in the second line setting would be candidates for momelotinib treatment due to its potential ability to improve both quality of life and anemia in a significant number of patients. As a myelofibrosis clinician, I can attest that we desperately need more treatment options that offer an array of distinct benefits for our patients. I look forward to momelotinib potentially becoming an important addition to the armamentarium in the treatment of myelofibrosis."

Previous phase III trial findings for momelotinib had more disappointing results. In the phase III SIMPLIFY-1 trial,³which looked at momelotinib in comparison with ruxolitinib (Jakafi) in patients with myelofibrosis who had never received a JAK inhibitor before, momelotinib was found to noninferior to ruxolitinib for spleen response at 24 weeks, but not for symptom response.

At week 24, a ≥35% reduction in spleen volume was achieved by 26.5% of the momelotinib arm compared with 29% in the ruxolitinib group. A ≥50% reduction in the total symptom score was achieved by 28.4% and 42.2% of patients with momelotinib and ruxolitinib treatment, respectively, which did not meet noninferiority. The rates of transfusion, transfusion independence, and transfusion dependence were all improved with momelotinib compared with ruxolitinib.

Common hematologic abnormalities were similar between either arm. The rate of grade ≥3 infections was slightly increased with momelotinib compared with ruxolitinib (7% vs 3%).

The SIMPLIFY-2 trial looked at momelotinib in comparison with best available therapy in patients with myelofibrosis who had a suboptimal response to ruxolitinib or a hematologic toxic effect.⁴A ≥35% reduction in spleen volume was observed in 7% of patients in the momelotinib arm versus 6% in the best available therapy group.

In terms of safety, the most common grade ≥3 adverse events (AEs) were anemia (14% in each group), thrombocytopenia (7% with momelotinib vs 6% with best available therapy), and abdominal pain (1% vs 6%, respectively). Eleven percent of patients who received momelotinib had peripheral neuropathy versus 0 in the best available therapy group. Serious AEs were reported in 35% of patients who received momelotinib and in 23% in the best available therapy arm. Six patients receiving momelotinib died from AEs compared with 4 in the best available therapy arm.

References

1. Sierra Announces Momelotinib Granted FDA Fast Track Designation [news release]. Vancouver: Sierra Oncology, Inc; June 5, 2019. https://bit.ly/2WvP8Ah. Accessed June 5, 2019.
2. Sierra Announces FDA Regulatory Clarity for Momelotinib & Design of the MOMENTUM Phase 3 Clinical Trial. Vancouver: Sierra Oncology, Inc; June 4, 2019. https://bit.ly/2IjEB0Z. Accessed June 4, 2019.
3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus Kinase Inhibitor—naïve patients with myelofibrosis.J Clin Oncol. 2017;35(34):3844-3850. doi: 10.1200/JCO.2017.73.4418.
4. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.Lancet Haematol.2018;5(2):e73-e81. doi: 10.1016/S2352-3026(17)30237-5.