Targeting the JAK-STAT pathway in myelofibrosis: could momelotinib be the answer we’ve been looking for?
Increased understanding of disease biology and technological advancement has led to the existence of targeted therapies, such as JAK inhibitors (1, 2). Momelotinib is a novel JAK inhibitor currently being investigated for myelofibrosis, a rare bone marrow cancer in which clonal proliferation of a haematopoietic stem cell eventually results in normal bone marrow being replaced with fibrotic scar tissue [figure 1].
So far, data indicates that it could be a game-changer for this disease, in which prognosis is usually poor and treatment is often palliative. Due to its unique anaemia-alleviating mechanism, studies such as the SIMPLIFY-1 trial (3) have highlighted momelotinib’s astonishing potential in improving treatment outcomes for patients with myelofibrosis.
There is currently a lack of safe and effective therapies that exist for this disease. Allogeneic stem cell transplants are the only way to cure myelofibrosis, but with only a minority of patients with myelofibrosis eligible for the procedure due to the increased risk of severe complications in older patients, treatment is palliative and is usually aimed at symptom control. Most patients have intermediate-2 or high-risk disease (International Prognostic Scoring System), giving a very poor prognosis and short survival time (4).
In 2016, the National Institute of Health and Care Excellence (NICE) recommended the use of ruxolitinib, thus allowing NHS patients to receive this ground-breaking new drug. Ruxolitinib is the only JAK inhibitor both to be approved by the European Medicines Agency and recommended in the British Society of Haematology myelofibrosis guidelines as first line therapy for symptomatic splenomegaly (enlarged spleen) and/or myelofibrosis-related constitutional symptoms (e.g., weight loss, night sweats, and fever).
Its introduction changed the treatment landscape of myelofibrosis, ultimately improving patients’ quality of life. However, a study (5) found that over half of the patients stopped treatment within the first 2-3 years of ruxolitinib therapy due to adverse events, such as worsening anaemia and thrombocytopenia (low platelet count), and treatment resistance. Furthermore, following drug discontinuation or dose reduction, there was rapid reoccurrence of splenomegaly and constitutional symptoms, and patients generally experienced poor overall survival (median 11.1 months). This highlights an urgent need for more tolerable and effective treatments, particularly after discontinuation of ruxolitinib, which may increase mortality burden and constitute additional risk factors.
Ruxolitinib has nevertheless paved the way for research into further JAK inhibitors for myelofibrosis, such as momelotinib. Momelotinib is currently undergoing Phase III trials to evaluate its safety and efficacy compared to existing treatment options. Previous studies (6, 7) found that momelotinib has an unexpected additional therapeutic mechanism via ACVR1 inhibition, which alleviates anaemia and thus reduces transfusion dependency by increasing the amount of iron available for red blood cell production [figure 2].
This finding was particularly encouraging. Anaemia is a significant concern in myelofibrosis, as progressive and severe anaemia is strongly associated with poor prognosis and reduced survival. It is a characteristic symptom that eventually results in most patients being transfusion-dependent, and the inherent mechanism of ruxolitinib further suppresses bone marrow activity.
The SIMPLIFY-1 trial (3), published in the Journal of Clinical Oncology in 2017, was a 24-week, multicentre, randomised, double-blind, double-dummy, phase III trial, aimed to compare the safety and efficacy of momelotinib with ruxolitinib, in patients who had not been treated with a JAK inhibitor before. The study enrolled 432 patients with myelofibrosis and randomised participants 1:1 to receive either momelotinib or ruxolitinib. Participants who were assigned ruxolitinib could cross over to momelotinib after the study period.
The SIMPLIFY-1 trial found that momelotinib (vs. ruxolitinib):
Further updates to this study were recently presented at the 2020 American Society of Haematology’s Annual Meeting (8). These remarkable results strongly support momelotinib’s potential as a new, long-term treatment option for myelofibrosis patients [figure 3].
Its maintenance of haemoglobin levels may greatly improve patients’ quality of life through sustained transfusion independence, spleen volume reduction, and constitutional symptom control. The ACVR1 inhibition could mean that patients who are not able to receive ruxolitinib due to severe anaemia or thrombocytopenia, or cannot continue with ruxolitinib, are able to receive momelotinib instead, allowing clinicians to personalise treatment accordingly.
Crucially, this drug may have the ability to transform patient management, quality of life, and treatment outcomes for an extended period of time, which arguably has been long overdue in myelofibrosis.
 |
| Figure 1 – The aetiology, clinical presentation, and treatment of myelofibrosis |
So far, data indicates that it could be a game-changer for this disease, in which prognosis is usually poor and treatment is often palliative. Due to its unique anaemia-alleviating mechanism, studies such as the SIMPLIFY-1 trial (3) have highlighted momelotinib’s astonishing potential in improving treatment outcomes for patients with myelofibrosis.
There is currently a lack of safe and effective therapies that exist for this disease. Allogeneic stem cell transplants are the only way to cure myelofibrosis, but with only a minority of patients with myelofibrosis eligible for the procedure due to the increased risk of severe complications in older patients, treatment is palliative and is usually aimed at symptom control. Most patients have intermediate-2 or high-risk disease (International Prognostic Scoring System), giving a very poor prognosis and short survival time (4).
In 2016, the National Institute of Health and Care Excellence (NICE) recommended the use of ruxolitinib, thus allowing NHS patients to receive this ground-breaking new drug. Ruxolitinib is the only JAK inhibitor both to be approved by the European Medicines Agency and recommended in the British Society of Haematology myelofibrosis guidelines as first line therapy for symptomatic splenomegaly (enlarged spleen) and/or myelofibrosis-related constitutional symptoms (e.g., weight loss, night sweats, and fever).
Its introduction changed the treatment landscape of myelofibrosis, ultimately improving patients’ quality of life. However, a study (5) found that over half of the patients stopped treatment within the first 2-3 years of ruxolitinib therapy due to adverse events, such as worsening anaemia and thrombocytopenia (low platelet count), and treatment resistance. Furthermore, following drug discontinuation or dose reduction, there was rapid reoccurrence of splenomegaly and constitutional symptoms, and patients generally experienced poor overall survival (median 11.1 months). This highlights an urgent need for more tolerable and effective treatments, particularly after discontinuation of ruxolitinib, which may increase mortality burden and constitute additional risk factors.
Ruxolitinib has nevertheless paved the way for research into further JAK inhibitors for myelofibrosis, such as momelotinib. Momelotinib is currently undergoing Phase III trials to evaluate its safety and efficacy compared to existing treatment options. Previous studies (6, 7) found that momelotinib has an unexpected additional therapeutic mechanism via ACVR1 inhibition, which alleviates anaemia and thus reduces transfusion dependency by increasing the amount of iron available for red blood cell production [figure 2].
 |
| Figure 2 – Momelotinib’s mechanism of action. Adapted from https://www.sierraoncology.com/momelotinib-overview/ |
This finding was particularly encouraging. Anaemia is a significant concern in myelofibrosis, as progressive and severe anaemia is strongly associated with poor prognosis and reduced survival. It is a characteristic symptom that eventually results in most patients being transfusion-dependent, and the inherent mechanism of ruxolitinib further suppresses bone marrow activity.
The SIMPLIFY-1 trial (3), published in the Journal of Clinical Oncology in 2017, was a 24-week, multicentre, randomised, double-blind, double-dummy, phase III trial, aimed to compare the safety and efficacy of momelotinib with ruxolitinib, in patients who had not been treated with a JAK inhibitor before. The study enrolled 432 patients with myelofibrosis and randomised participants 1:1 to receive either momelotinib or ruxolitinib. Participants who were assigned ruxolitinib could cross over to momelotinib after the study period.
The SIMPLIFY-1 trial found that momelotinib (vs. ruxolitinib):
- Showed a comparable spleen volume reduction, defined as ≥35% reduction from baseline at week 24 (27% vs. 29%)
- Was worse at symptom control, defined as >50% total symptom score reduction from baseline (28% vs. 42%)
- Caused more serious adverse events (23% vs. 18%)
- Caused fewer cases of anaemia (5.6% vs. 23%)
- Reduced the median rate of red cell transfusions (0 units/month vs. 0.4 units/month)
- Increased transfusion independence at week 24 (67% vs. 49%)
- Reduced transfusion dependence at week 24 (30% vs. 40%)
Further updates to this study were recently presented at the 2020 American Society of Haematology’s Annual Meeting (8). These remarkable results strongly support momelotinib’s potential as a new, long-term treatment option for myelofibrosis patients [figure 3].
 |
| Figure 3 – SIMPLIFY-1 trial updates |
Its maintenance of haemoglobin levels may greatly improve patients’ quality of life through sustained transfusion independence, spleen volume reduction, and constitutional symptom control. The ACVR1 inhibition could mean that patients who are not able to receive ruxolitinib due to severe anaemia or thrombocytopenia, or cannot continue with ruxolitinib, are able to receive momelotinib instead, allowing clinicians to personalise treatment accordingly.
Crucially, this drug may have the ability to transform patient management, quality of life, and treatment outcomes for an extended period of time, which arguably has been long overdue in myelofibrosis.
References
1. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;17(1):78.
2. ExchangeCME. JAK/STAT Signaling Transduction Pathways. YouTube. 2019 [Available from: https://www.youtube.com/watch?v=zPj_P1ztf8I]
3. Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, 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):3844-50.
4. Tang D, Taneja A, Rajora P, Sly I, Davison NJ. Overall Survival in Patients with Myelofibrosis Who Have Discontinued Ruxolitinib: A Literature Review. Blood. 2019;134(Supplement_1):3457-.
5. Mascarenhas J, Mehra M, He J, Potluri R, Loefgren C. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. Journal of Medical Economics. 2020;23(7):721-7.
6. Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Advances. 2020;4(18):4282-91.
7. Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823-30.
8. Verstovsek S, Egyed M, Lech-Marańda E, Sacha T, Dubruille V, Oh ST, et al. Robust Overall Survival and Sustained Efficacy Outcomes during Long Term Exposure to Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients. Blood. 2020;136(Supplement 1):51-2.
1. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;17(1):78.
2. ExchangeCME. JAK/STAT Signaling Transduction Pathways. YouTube. 2019 [Available from: https://www.youtube.com/watch?v=zPj_P1ztf8I]
3. Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, 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):3844-50.
4. Tang D, Taneja A, Rajora P, Sly I, Davison NJ. Overall Survival in Patients with Myelofibrosis Who Have Discontinued Ruxolitinib: A Literature Review. Blood. 2019;134(Supplement_1):3457-.
5. Mascarenhas J, Mehra M, He J, Potluri R, Loefgren C. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. Journal of Medical Economics. 2020;23(7):721-7.
6. Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Advances. 2020;4(18):4282-91.
7. Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823-30.
8. Verstovsek S, Egyed M, Lech-Marańda E, Sacha T, Dubruille V, Oh ST, et al. Robust Overall Survival and Sustained Efficacy Outcomes during Long Term Exposure to Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients. Blood. 2020;136(Supplement 1):51-2.
Comments
Post a Comment