Jean-Jacques Kiladjian, MD, PhD

JAK inhibitors (JAKi) designed for the treatment of myelofibrosis (MF) address the splenic response and constitutional symptoms associated with the disease, but the agents are inherently myelosuppressive and can exacerbate anemia and thrombocytopenia. Anemia is a common concern at presentation, and it generally progresses over time. In fact, dose reductions are common, and some patients never receive a JAKi, due to low platelet counts or severe anemia. Severe anemia can significantly impact a patient's quality of life and is typically managed with repeated blood transfusions.

Hepcidin levels, a hormone that controls iron homeostasis, play an important role in the anemia of myelofibrosis. High levels of hepcidin restrict iron availability, suppressing the body's ability to make new red blood cells.

 Data show that both anemia and elevated hepcidin levels are strong prognostic indicators of survival in myelofibrosis.

Momelotinib is an investigational therapy that may address anemia as well as the splenomegaly and constitutional systems through a unique mechanism of action.

 Similar to other currently approved treatments, momelotinib inhibits 

 leads to a decrease in hepcidin levels, potentially improving anemia and transfusion requirements.

In multiple late-stage clinical trials momelotinib has been evaluated and is currently under investigation in the phase 3 MOMENTUM study (NCT04173494). The prior SIMPLIFY-1 trial (NCT01969838) was designed to evaluate momelotinib's potential in JAKi-naïve patients compared to ruxolitinib (Jakafi) and SIMPLIFY-2 (NCT02101268) explored its potential in patients who were previously treated with JAKis compared to best available therapy.

 Both previously completed studies had a 24-week randomized treatment phase and a long-term extension of open-label momelotinib. The primary endpoint for both studies was splenic response; secondary endpoints were total symptom score and transfusion independence.

Retrospective analyses of the SIMPLIFY-1 and SIMPLIFY-2 studies were recently presented at the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition. One analysis sought to understand the effects of baseline platelet count and momelotinib efficacy. A second long-term follow-up analysis was conducted to understand the potential overall survival benefit in patients who remained on momelotinib following the initial 24-week trial period. 

Baseline Platelet Count May Not Impact Momelotinib Activity

In this retrospective analysis, patients were stratified into three groups: patients with baseline platelets ≤150 × 109/L, between 150-300 × 109/L and >300 × 109/L.

In SIMPLIFY-1, patients whose baseline platelet counts were below ≤150 × 109/L, momelotinib achieved substantially higher transfusion independence rates (62% vs. 42%) and splenic response rates (23% vs. 4%) and showed a similar symptomatic response (28% vs. 33%) relative to ruxolitinib. Patients with platelet counts between 150-300 × 109/L showed a similar splenic (35% vs. 32%) and symptom response rates (33% vs. 41%) and a higher transfusion independence rate (72% vs. 54%). In patients with platelet counts >300 × 109/L, ruxolitinib achieved higher splenic (44% vs. 19%) and symptom response rates (46% vs. 23%) at week 24. However, the final transfusion independence remained higher with momelotinib (63% vs. 51%).

In SIMPLIFY-2, momelotinib's response rates for the three response parameters remain consistent with the overall intent-to-treat response rates in patients whose baseline platelets were ≤150 × 109 /L. Additionally, momelotinib's symptomatic and anemia benefit were also preserved in patients whose baseline platelet counts were <50 and >50-100 x 109/L. In both studies, rates of treatment-emergent adverse events on momelotinib were generally similar.

This retrospective analysis of the data from the two phase 3 SIMPLIFY studies demonstrate that momelotinib's safety and activity profile do not appear to be affected by baseline platelet counts. Ruxolitinib's activity declined in patients with lower baseline platelet counts. Therefore, the relative benefit-risk profile of momelotinib and ruxolitinib may be influenced by baseline platelet count and is generally comparable or favorable in JAKi-naïve patients with baseline platelet counts ≤ 300 x 109 /L. These retrospectiveefficacy analyses complement previous findings highlighting the ability to initiate and maintain near-maximal momelotinib dose intensity irrespective of baseline platelet count, suggesting that this durable dosing contributes to the compound's efficacy profile.

In addition to this retrospective analysis, a long-term study of the SIMPLIFY-1 and SIMPLIFY-2 trials found robust overall survival (OS) benefits in both patients initially treated with, as well as those who crossed over to, momelotinib. In SIMPLIFY-1, the median OS was 53 months in patients who crossed over from ruxolitinib to momelotinib and has not been reached in patients initially treated with momelotinib (HR, 0.99, 

 =.97). In SIMPLIFY-2, the median OS was 34.3 months in patients initially treated with momelotinib and 37.5 months in the patients that crossed over from the best available therapy to momelotinib (HR, 0.96, 

This analysis demonstrates a robust OS benefit for momelotinib in both JAK inhibitor-naïve and patients who were previously treated with ruxolitinib. In particular, the median OS of 34.3 and 37.5 months, observed in the two treatment arms of SIMPLIFY-2, compare favorably with OS previously reported in patients who have received JAK inhibitors in earlier lines of treatment.

Cumulatively, these studies provide strong support for the potential of momelotinib as a new treatment option for patients with myelofibrosis. Its activity profile could allow patients and physicians to individualize treatment decisions based on factors such as anemia or pretreatment platelet counts and ultimately improve treatment outcomes.Moreover, the OS data demonstrate momelotinib’s potential as a long-term, sustainable treatment option. 

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Articles

JAK inhibitors designed for the treatment of myelofibrosis address the splenic response and constitutional symptoms associated with the disease, but the agents are inherently myelosuppressive and can exacerbate anemia and thrombocytopenia. 

Data Support Momelotinib as a Differentiated Approach to Treating Myelofibrosis

Jean-Jacques Kiladjian, MD, PhD, professor of clinical pharmacology at Paris Diderot University, discusses the 5-year follow-up results from the RESPONSE trial, where more than 65% of patients with polycythemia vera (PV) still remained on treatment with ruxolitinib (Jakafi).

In addition, more than 74% of patients who achieved a primary response maintained this response, Kiladjian says. Of the patients who achieved a complete hematologic response, 54% maintained that response as well.

Kiladjian says he was pleased to see that molecular response was achieved in these patients as the mean

Videos

Jean-Jacques Kiladjian, MD, PhD, discusses the 5-year follow-up results from the RESPONSE trial, where more than 65% of patients with polycythemia vera still remained on treatment with ruxolitinib.

Updated Findings With Ruxolitinib in Polycythemia Vera

Jean-Jacques Kiladjian, MD, PhD, head of clinical investigation at Saint Louis Hospital in Paris, discusses the Ruxopeg trial, a phase I/II trial investigating the combination of ruxolitinib (Jakafi) with pegylated interferon alfa-2a in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF).

Jean-Jacques Kiladjian, MD, PhD, head of clinical investigation at Saint Louis Hospital in Paris, discusses the Ruxopeg trial, a phase I/II trial investigating the combination of ruxolitinib (Jakafi) with pegylated interferon alfa-2a in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis.

Jean-Jacques Kiladjian, MD, PhD | Authors

Articles

Data Support Momelotinib as a Differentiated Approach to Treating Myelofibrosis

Updated Findings With Ruxolitinib in Polycythemia Vera

Evaluating Ruxolitinib With Pegylated Interferon Alfa-2a in Myelofibrosis