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Aim: To estimate projected US-based cost and time burden for patients with myelofibrosis and anemia treated with momelotinib compared with danazol. Methods: Cost and time burden were calculated based on the transfusion status of patients in the MOMENTUM trial and estimates extracted from previous studies. Results: Reductions in transfusion associated with momelotinib are projected to result in cost and time savings compared with danazol in transfusion-dependent and transfusion-independent/requiring patients with myelofibrosis, respectively: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and annual time savings (173 and 35 h per person). Conclusion: Fewer transfusions with momelotinib are projected to result in cost and time savings in patients with myelofibrosis and anemia compared with danazol. Plain Language Summary Estimated cost & time savings in patients with the blood cancer myelofibrosis Myelofibrosis is a rare blood cancer often associated with bone marrow damage, too few of some types of blood cells and symptoms including tiredness, night sweating, itching and feelings of fullness and pain because of increased spleen size. Patients with anemia (too few red blood cells) may require regular blood transfusions and this is one sign that myelofibrosis is getting worse. MOMENTUM was a Phase III clinical trial showing that the drug momelotinib was safe and effective in patients with myelofibrosis who were previously treated with a type of drug called a JAK inhibitor. In particular, the trial showed that momelotinib reduced the need for transfusions compared with danazol, another drug typically used to treat patients with anemia. Based on this transfusion information from MOMENTUM and other publicly available information about estimated medical costs and patients' time spent in receiving transfusions, the analysis described here shows that a reduction in the number of transfusions with momelotinib compared with danazol is estimated to lead to cost savings as well as reduced patient time spent in transfusion-related travel, preparing and waiting for transfusions and receiving and recovering from transfusions. Tweetable Abstract Reductions in transfusions associated with momelotinib are projected to result in savings in medical and transfusion-related costs and time burden relative to danazol in patients with myelofibrosis and anemia. Article highlights Momelotinib is a JAK1, JAK2 and ACVR1 inhibitor that targets both the complex drivers of iron-restricted anemia and chronic inflammation in MF, thereby improving constitutional symptoms and splenomegaly while also maintaining or improving Hb levels across the continuum of JAK inhibitor–naive and previously JAK inhibitor–treated patients. Transfusion dependency and moderate-to-severe anemia are critical negative prognostic factors in MF and lead to significantly higher rates of HCRU and costs in affected patients compared with non-TD patients. MOMENTUM is a randomized, double-blind study comparing momelotinib and danazol in symptomatic patients with MF and anemia who previously received JAK inhibitor therapy. Projected differences in cost and time burden associated with momelotinib relative to danazol were based on patient transfusion data from the MOMENTUM trial and cost estimates from studies using the IBM MarketScan Commercial Database and Medicare fee-for-service database as well as time burden estimates from the 2022 Knoth et al. study. Reductions in transfusions associated with momelotinib are projected to result in savings in medical and transfusion-related costs and patient time savings relative to danazol in patients with baseline TD and TI/TR status, respectively, using a terminal TI rate: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and time savings (173 and 35 h per person). Projected savings in total annual medical costs with momelotinib relative to danazol were also shown using a rolling TI rate in patients with baseline TD and TI/TR status ($23,780 and $39,305). Projected savings in transfusion-related costs and patient time savings with momelotinib relative to danazol were also observed for patients aged ≥65 years. The results of this analysis demonstrate that momelotinib not only addresses a high unmet need in patients with MF-associated anemia but may also provide medical cost and time savings for patients by reducing their transfusion dependency. [ABSTRACT FROM AUTHOR]

Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1–2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2–12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions. [ABSTRACT FROM AUTHOR]

Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF. [ABSTRACT FROM AUTHOR]

Introduction: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. Methods: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. Results: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. Conclusion: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. Trial Registration: ClinicalTrials.gov: NCT02101268. Plain Language Summary: Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia. [ABSTRACT FROM AUTHOR]

Abstract Myelofibrosis (MF), a complex hematological malignancy, presents a diverse array of symptoms, including anemia, constitutional symptoms, bone marrow insufficiency, and splenomegaly. The latter, often necessitating blood transfusions, poses an essential obstacle to MF management. While conventional approaches predominantly involve the use of JAK inhibitors, the potential for exacerbating anemia introduces complexity to the treatment. Nonetheless, Momelotinib stands out as a promising pharmaceutical compound with the potential to revolutionize the field. Momelotinib is an ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes. By targeting MF's hematological and fibrotic aspects, Momelotinib influences iron metabolism by regulating hepcidin. This results in reduced hepcidin expression and increased iron availability, ultimately leading to improved anemia and reduced dependency on blood transfusion. This study aims to provide a concise overview of the pathogenesis of MF and elucidate the mechanism of action of Momelotinib. Subsequently, our review offers a practical summary encompassing the effects of Momelotinib in monotherapy, combined comparative drug therapy, and its associated side effects. Additionally, we explore the application of Momelotinib in other cancer types and investigate predictors for treatment success. Furthermore, we examine the utilization of Momelotinib in patients with liver and kidney failure.

Myelofibrosis (MF), a complex hematological malignancy, presents a diverse array of symptoms, including anemia, constitutional symptoms, bone marrow insufficiency, and splenomegaly. The latter, often necessitating blood transfusions, poses an essential obstacle to MF management. While conventional approaches predominantly involve the use of JAK inhibitors, the potential for exacerbating anemia introduces complexity to the treatment. Nonetheless, Momelotinib stands out as a promising pharmaceutical compound with the potential to revolutionize the field. Momelotinib is an ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes. By targeting MF's hematological and fibrotic aspects, Momelotinib influences iron metabolism by regulating hepcidin. This results in reduced hepcidin expression and increased iron availability, ultimately leading to improved anemia and reduced dependency on blood transfusion. This study aims to provide a concise overview of the pathogenesis of MF and elucidate the mechanism of action of Momelotinib. Subsequently, our review offers a practical summary encompassing the effects of Momelotinib in monotherapy, combined comparative drug therapy, and its associated side effects. Additionally, we explore the application of Momelotinib in other cancer types and investigate predictors for treatment success. Furthermore, we examine the utilization of Momelotinib in patients with liver and kidney failure. Highlights: MF is a complex hematological malignancy that has the potential to transform into acute myeloid leukemia in 20 % of cases Anemia occurs in approximately one-third of MF patients Momelotinib is a novel ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes just FDA approved on September 15 A comprehensive applied review of this novel agent is lacking [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes. MF presents in primary and secondary forms, with common symptoms including splenomegaly, anemia, and thrombocytopenia. Diagnostic criteria involve bone marrow examination and mutation studies. Current treatments are limited, with allogeneic stem cell transplant as the only curative option. Recent FDA approval of Momelotinib (MMB) offers new promise for MF patients with anemia. MMB, a JAK1/2 and ACVR1 inhibitor, effectively reduces spleen size, improves hemoglobin levels, and decreases transfusion dependency. The MOMENTUM trial compared MMB to danazol in JAK inhibitortreated MF patients with anemia, showing MMB's superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB's non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements. MMB's unique dual inhibition mechanism addresses anemia by suppressing hepcidin production, thus enhancing erythropoiesis. These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population. [ABSTRACT FROM AUTHOR]

A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL. [ABSTRACT FROM AUTHOR]

Introduction: The hallmark discovery of hyperactivation of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was a sentinel moment in the history of myeloproliferative neoplasms (MPNs). This finding paved the way for the development of JAK inhibitors, which now represent the foundation of myelofibrosis therapy. With four JAK inhibitors now approved for myelofibrosis, awareness of their clinical efficacy and safety data and recognition of their unique pharmacologic attributes are of critical importance. Additionally, ruxolitinib represents an integral part of the therapeutic arsenal for polycythemia vera. Areas covered: This review provides a broad overview of the published literature supporting JAK inhibitor therapy for MPNs. Primarily focusing on myelofibrosis, each of the four available JAK inhibitors is reviewed in detail, including pharmacology, efficacy, and safety data. Failure of JAK inhibitors and future directions in JAK inhibitor therapy are also discussed. Expert opinion: JAK inhibitors revolutionized the treatment of MPNs and have dramatically improved patient outcomes. However, data informing selection between currently available JAK inhibitors is limited. These agents are not curative and eventually fail most patients with myelofibrosis. Combining JAK inhibitors with novel targeted agents appears to be the most promising path to further improve outcomes. [ABSTRACT FROM AUTHOR]

Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies. • Although clinical trials in patients with myelofibrosis have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline, whether 50% constitutes a meaningful benefit has not been established. • To our knowledge, this report is the first to publish a meaningful change threshold for 2 momelotinib phase III trials (SIMPLIFY-1 and SIMPLIFY-2) in the symptomatic population of intermediate- or high-risk patients with myelofibrosis using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. • This study demonstrates clinically meaningful symptom benefits with momelotinib, provides valuable insight into the percent and absolute thresholds of change considered meaningful in patients with myelofibrosis, and verifies the appropriateness of the threshold used in historical studies. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients. Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies. [ABSTRACT FROM AUTHOR]

JAK inhibitors are the current standard of care in myelofibrosis, but many do not address and may worsen anemia; thus, anemia-related responses have traditionally been overlooked as efficacy end points in pivotal clinical trials, leading to a lack of consistency and analytic detail in their reporting. Here we apply our experiences in the phase III trials of momelotinib, a JAK1/JAK2/ACVR1 inhibitor and the first therapy indicated by the US FDA for myelofibrosis patients with anemia, to highlight how application of different criteria impacts the anemia-related benefits reported for any potential treatment in myelofibrosis. We advocate for a convention of a new expert consensus panel to bring consistency and transparency to the definition of anemia-related response in myelofibrosis. Anemia (too few healthy red blood cells) is common in patients with myelofibrosis. While it is becoming more common to measure the anemia benefits associated with potential treatments for myelofibrosis in clinical trials, different definitions of anemia benefit are available. This Perspective reviews these definitions, the differences between them, and why consistency and clarity in measuring anemia benefit matter. The definitions used in clinical trials of momelotinib, a treatment for patients with myelofibrosis and anemia, are also explained to show how the anemia benefit observed in these trials could have changed if different definitions were used. Definitions of anemia benefit may include the number of red blood cell transfusions a patient receives, the amount of hemoglobin (a red blood cell protein) in their blood, or a combination thereof. Considerations such as timing, the types of patients included, and other factors are not consistent across definitions and not always clearly reported. Results when different definitions of anemia benefit were followed in the momelotinib clinical trials show that the amount of benefit observed with treatments changes depending on which definition is used. More consistency and clarity in the definitions of anemia benefit in myelofibrosis clinical trials are needed, suggesting that a new panel of experts should come together to discuss this topic. Klencke et al. discuss the need for consensus in anemia-related response end points in myelofibrosis clinical trials, highlighting the varying definitions, key considerations, and resulting impacts on reported anemia benefits [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes. MF presents in primary and secondary forms, with common symptoms including splenomegaly, anemia, and thrombocytopenia. Diagnostic criteria involve bone marrow examination and mutation studies. Current treatments are limited, with allogeneic stem cell transplant as the only curative option. Recent FDA approval of Momelotinib (MMB) offers new promise for MF patients with anemia. MMB, a JAK1/2 and ACVR1 inhibitor, effectively reduces spleen size, improves hemoglobin levels, and decreases transfusion dependency. The MOMENTUM trial compared MMB to danazol in JAK inhibitor-treated MF patients with anemia, showing MMB’s superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB’s non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements. MMB’s unique dual inhibition mechanism addresses anemia by suppressing hepcidin production, thus enhancing erythropoiesis. These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population.

Abstract Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor–naive patients from SIMPLIFY‐1 (NCT01969838), a double‐blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1‐grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

Simple Summary: The human activin receptor type I (ACVR1) is a complex protein that regulates production of hepcidin on hepatocytes and red blood cells. Hepcidin is a small peptide that regulates iron metabolism and plasma iron levels. High hepcidin levels are associated with anemia, which is a hallmark of myelofibrosis. Myelofibrosis is a cancer of the bone marrow, characterized by fibrosis and anemia, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact prognosis in myelofibrosis. Ruxolitinib and fedratinib (JAK inhibitors) may exacerbate anemia in myelofibrosis patients. Momelotinib and pacritinib are potent ACVR1 inhibitors that are preferable to treat cytopenic patients with myelofibrosis. In September 2023, momelotinib was approved as a treatment for anemic patients with myelofibrosis based on the phase 3 clinical trials SIMPLIFY-1 and MOMENTUM, which demonstrated the marked anemia benefits of momelotinib. Other ACVR1 inhibitors (e.g., zilurgisertib) are evaluated in early phase clinical trials as treatments for anemia in MF patients. Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients. [ABSTRACT FROM AUTHOR]

Dahniel Sastow,1 Douglas Tremblay2 1Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: Douglas Tremblay, Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, Box 1079, New York, NY, 10029, USA, Email Douglas.tremblay@mssm.eduAbstract: Myelofibrosis (MF) is a hematologic malignancy characterized by abnormal proliferation of myeloid cells and the release of pro-inflammatory cytokines, leading to progressive bone marrow dysfunction. The introduction of ruxolitinib just over a decade ago marked a significant advancement in MF therapy, with JAK inhibitors now being the first-line treatment for reducing spleen size and managing symptoms. However, early JAK inhibitors (ruxolitinib and fedratinib) are often associated with cytopenias, particularly thrombocytopenia and anemia, which limit their tolerability. To address these complications, pacritinib has been developed and recently approved for patients with thrombocytopenia, while momelotinib is in development for those with anemia. Although JAK inhibitors have significantly improved the quality of life of MF patients, they have not demonstrated the ability to reduce leukemic transformation and their impact on survival is debated. Numerous drugs are currently being developed and investigated in clinical trials, both as standalone therapy and in combination with JAK inhibitors, with promising results enhancing the benefits of JAK inhibitors. In the near future, MF treatment strategies will involve selecting the most suitable JAK inhibitor based on individual patient characteristics and prior therapy. Ongoing and future clinical trials are crucial for advancing the field and expanding therapeutic options for MF patients.Keywords: myelofibrosis, emerging therapy, momelotinib, anemia, JAK inhibitors

Purpose This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent pathophysiology and supportive care are discussed. Emerging therapies are also briefly described. Summary MPNs are a heterogeneous group of diseases characterized by acquired abnormalities of hematopoietic stem cells (HSCs), resulting in the generation of transformed myeloid progenitor cells that overproduce mature and immature cells within the myeloid lineage. Mutations in JAK2 and other driver oncogenes are central to the genetic variability of these diseases. Cytoreductive therapies such as hydroxyurea, anagrelide, interferon, and therapeutic phlebotomy aim to lower the risk of thrombotic events without exposing patients to an increased risk of leukemic transformation. However, no comparisons can be made between these therapies, as reduction of thrombotic risk has not been used as an endpoint. On the other hand, Janus kinase (JAK) inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib (an investigational agent at the time of writing) directly target the constitutively activated JAK–signal transducer and activator of transcription (JAK-STAT) pathway of HSCs in the bone marrow. Mutations of genes in the JAK-STAT signaling pathway provide a unifying understanding of MPNs, spur therapeutic innovations, and represent opportunities for pharmacists to optimize mitigation strategies for both disease-related and treatment-related adverse effects. Conclusion Treatment options for MPNs span a wide range of disease mechanisms. The growth of targeted therapies holds promise for expanding the treatment arsenal for these rare, yet complex diseases and creates opportunities to optimize supportive care for affected patients. [ABSTRACT FROM AUTHOR]

Abstract Background Myelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods Longitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data. Results Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of

Simple Summary: Myelofibrosis is an aggressive bone marrow cancer whose clinical presentation can be extremely heterogenous. Two distinct phenotypes, myeloproliferative and myelodepletive or cytopenic, have increasingly been recognized in recent years. The two phenotypes represent the two ends of the disease spectrum and are characterized by opposing trends for a wide range of clinical variables (e.g., peripheral blood counts, spleen volume) and molecular profiles that result in significantly different prognoses and outcomes. The myeloproliferative phenotype is usually associated with normal/higher peripheral blood counts and larger spleen volume, higher mutant JAK2 allele burden, fewer "non-driver mutations", and superior overall survival. The myelodepletive phenotype is associated with progressive anemia and/or thrombocytopenia, modest splenomegaly, more high molecular risk mutations, lower mutant JAK2 allele burden, and inferior outcomes. Management of myelofibrosis is largely dictated by clinical needs, including the degrees of splenomegaly, symptoms and cytopenias, as well as prognostic risk assessment. Ruxolitinib and fedratinib are more efficacious in the myeloproliferative phenotype, whereas momelotinib and pacrtitinib can address the unmet needs of the myelodepletive phenotype. Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum. [ABSTRACT FROM AUTHOR]

Ruxolitinib has been the cornerstone of pharmacologic therapy for myelofibrosis for over a decade. However, the last several years have witnessed the regulatory approval of other Janus kinase (JAK) inhibitors for myelofibrosis, i.e. fedratinib, pacritinib, and US approval of momelotinib is widely anticipated in 2023. Due to the multifaceted clinical presentation of myelofibrosis, a watertight definition of ruxolitinib failure has remained elusive, as "progression" on ruxolitinib can take many forms and management is highly nuanced. Yet, the availability of other JAK inhibitors and potential future availability of non-JAK inhibitor agents for myelofibrosis make a consensus on management of ruxolitinib failure critically important. This consensus paper summarizes a discussion between multiple academic and community physician experts, a pharmacist and an advanced practice provider around the issues to be considered for the optimal care of patients with myelofibrosis whose disease is refractory to or does not respond adequately to ruxolitinib, or who exhibit intolerance to ruxolitinib. The panel identified several areas of consensus, as well as some areas where more data to inform evidence-based practice are needed. In some situations, maintaining ruxolitinib while adding another agent, e.g. to address anemia, is appropriate, whereas in others, switching to a different drug has merit. [ABSTRACT FROM AUTHOR]

Cytopenic myelofibrosis is increasingly recognized as a phenotype of myelofibrosis presenting with low blood counts, lower driver mutation allele burden, increased likelihood of arising de novo, i.e. primary myelofibrosis, greater genomic complexity, worse survival, and higher rates of leukemic transformation compared to the more traditional 'myeloproliferative' phenotype. Both anemia and thrombocytopenia are very common, often coexist, and can be worsened by treatment. Several JAK inhibitors with different kinome profiles are now available for routine clinical use. Additionally, ancillary therapies can also provide some, albeit non-durable, benefit. In this review, we discuss the prevalence and clinical significance of cytopenias in myelofibrosis. We then discuss the various Janus kinase (JAK) inhibitors and ancillary therapies available with a special focus on their use in cytopenic populations, ability to improve cytopenias, and notable adverse events. Articles included were selected through literature searches using the PubMed database. Pacritinib and momelotinib are new treatment options for patients with cytopenic myelofibrosis. These JAK inhibitors are less myelosuppressive and allow for cytopenia stabilization or improvement while providing additional benefits. It is likely that their use will expand and these newer JAK inhibitors will become backbones for future combinations with novel, 'disease modifying' agents. [ABSTRACT FROM AUTHOR]

Background: Myelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods: Longitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data. Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings. [ABSTRACT FROM AUTHOR]

Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.

[Display omitted] • This work first proved that momelotinib was a suitable warhead for the design of JAK1 PROTACs. • This work provides a new case study about JAK1 subtype-selective PROTACs. • Compound 10c may serve as a novel lead compound for antitumor drug discovery. • This work highlights the potential of JAK1-directed protein degradation as an antitumor therapeutic approach. Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor—momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC 50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery. [ABSTRACT FROM AUTHOR]

Abstract The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib’s unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib may lead to its approval. Graphical abstract

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, debilitating constitutional symptoms and bone marrow failure. Disease-related anemia is common and associated with an inferior quality of life and survival. Unfortunately, few therapies exist to improve hemoglobin in myelofibrosis patients. Momelotinib is a JAK1/JAK2 inhibitor that also antagonizes ACVR1, leading to downregulation of hepcidin expression and increased availability of iron for erythropoiesis. In clinical testing, momelotinib has demonstrated a unique ability to improve hemoglobin and reduce transfusion burden in myelofibrosis patients with baseline anemia, while producing reductions in spleen size and symptom burden. This review explores the preclinical rationale, clinical trial data and future role of momelotinib in the evolving therapeutic landscape of myelofibrosis. [ABSTRACT FROM AUTHOR]

Classic Philadelphia-negative myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), classified as primary (PMF), or secondary to PV or ET. All MPN, regardless of the underlying driver mutation in JAK2/CALR/MPL, are invariably associated with dysregulation of JAK/STAT pathway. The discovery of JAK2V617F point mutation prompted the development of small molecules inhibitors of JAK tyrosine kinases (JAK inhibitors–JAKi). To date, among JAKi, ruxolitinib (RUX) and fedratinib (FEDR) are approved for intermediate and high-risk MF, and RUX is also an option for high-risk PV patients inadequately controlled by or intolerant to hydroxyurea. While not yet registered, pacritinib (PAC) and momelotinib (MMB), proved to be effective particularly in thrombocytopenic and anemic MF patients, respectively. In most cases, JAKi are effective in reducing splenomegaly and alleviating disease-related symptoms. However, almost 50% lose response by three years and dose-dependent toxicities may lead to suboptimal dosing or treatment discontinuation. To date, although not being disease-modifying agents, JAKi represent the therapeutic backbone particularly in MF patient. To optimize therapeutic strategies, many trials with drug combinations of JAKi with novel molecules are ongoing. This review critically discusses the role of JAKi in the modern management of patients with MPN. [ABSTRACT FROM AUTHOR]

Given its rarity, multi-faceted clinical presentation and the relative paucity of approved therapies, the management of myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can be challenging. Janus kinase (JAK) inhibitors, the only approved agents at present, have brought many clinical benefits to patients, with prolongation of survival also demonstrated for ruxolitinib. However, these agents have clear limitations. Optimal management of anemia in MF remains a major unmet need. Neither ruxolitinib nor fedratinib is recommended for use in patients with severe thrombocytopenia, i.e. platelets <50 × 109/L, who have a particularly poor prognosis. The search for the optimal partner for JAK inhibitors to address some of the shortcomings of these agents (e.g. limited ability to improve bone marrow fibrosis, cytopenias and induce molecular responses) and achieve meaningful 'disease modification' continues. This has led to the development of a number of rational, preclinically synergistic combinations for use either upfront or in the setting of sub-optimal response to JAK inhibition. Finally, the outlook for patients whose disease progresses on JAK inhibitor therapy continues to be grim, and agents with alternative mechanisms of action may be needed in this setting. In this article, we use a case-based approach to illustrate challenges commonly encountered in clinical practice and our management of the same. Fortunately, there has been enormous growth in drug development efforts in the MF space in the last few years, some of which appear poised to bear fruit in the very near future. [ABSTRACT FROM AUTHOR]

The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib's unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib may lead to its approval. [ABSTRACT FROM AUTHOR]

Sarah Bassiony, Claire N Harrison, Donal P McLornan Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UKCorrespondence: Donal P McLornanDepartment of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Tower, Great Maze Pond, London, SE1 9RT, UKTel +44 20 7188 2742Email donal.mclornan@nhs.netAbstract: Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond.Keywords: myelofibrosis, JAK inhibitors, momelotinib

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB. [ABSTRACT FROM AUTHOR]

Purpose of Review: Ruxolitinib is the first FDA-approved JAK inhibitor for the treatment of myeloproliferative neoplasms and is an effective means of controlling symptom burden and improving splenomegaly. However, a majority of patients will develop disease progression with long-term use. Fedratinib, momelotinib, and pacritinib are three newer-generation JAK inhibitors being prospectively evaluated and we will discuss their roles in the treatment of myeloproliferative neoplasms. Recent Findings: Fedratinib has a role in both JAK-inhibitor naive intermediate-/high-risk myelofibrosis patients and in patients that have previously received ruxolitinib. It has recently received FDA approval for these indications as well. Momelotinib does not appear to have an advantage over ruxolitinib with regards to improving splenomegaly in intermediate-/high-risk JAK-inhibitor naive myelofibrosis. However, increased rates of transfusion independence have been noted with momelotinib. Pacritinib has been studied in myelofibrosis patients with significant baseline anemia and thrombocytopenia; these trials support the use of pacritinib in myelofibrosis patients with significant thrombocytopenia. Summary: While ruxolitinib is effective in reducing the symptom burden and splenomegaly of patients with myeloproliferative neoplasms, a majority of patients will ultimately progress on therapy. Newer-generation JAK inhibitors including fedratinib, momelotinib, and pacritinib are being prospectively evaluated to determine their appropriate roles in the management of myeloproliferative neoplasms. In addition, both combination therapies with JAK inhibitors and novel investigational therapies are being actively explored. [ABSTRACT FROM AUTHOR]

Over the last decade, the Janus kinase1/2 (JAK1/2) inhibitor ruxolitinib has emerged as a cornerstone of myelofibrosis (MF) management. Ruxolitinib improves splenomegaly and symptoms regardless of driver mutation status, and confers a survival advantage in patients with intermediate-2/high risk MF. However, cytopenias remain problematic, and evidence for a robust anti-clonal effect is lacking. Furthermore, the median duration of spleen response to ruxolitinib in clinical trials is approximately 3 years, and ruxolitinib does not appear to affect the risk of leukemic transformation. There is no therapy approved specifically for patients whose disease 'progresses' on ruxolitinib, defining which remains challenging. The recent regulatory approval of the JAK2 inihibitor fedratinib partially fulfills this unmet need, but much remains to be done. Other JAK inhibitors and a plethora of novel agents are being studied in the ruxolitinib 'failure' setting, as well as 'add-on' therapies to ruxolitinib in patients having a 'sub-optimal' response. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation, orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efficacy in patients with myelofibrosis. We hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting JAK/STAT3 and HDAC simultaneously might enhance the efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL, and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of the extrinsic apoptotic pathway. We identified a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2 expression, activated caspase 3, and significantly inhibited cell viability and clonogenic survival. [ABSTRACT FROM AUTHOR]

Opinion Statement: Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation. [ABSTRACT FROM AUTHOR]

Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p  = .350; ruxolitinib, p  = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p  = .126; ruxolitinib, p  = .407)/symptom (momelotinib, p  = .617; ruxolitinib, p  = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1-grade BMF improvement (momelotinib, p  = .395; ruxolitinib, p  = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors., Competing Interests: Stephen T. Oh reports consulting fees from AbbVie, Blueprint Medicines, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, CTI BioPharma, Disc Medicine, Incyte, Kartos Therapeutics, PharmaEssentia, and Sierra Oncology. Srdan Verstovsek reports consulting fees from Bristol Myers Squibb/Celgene, Incyte, Novartis, and Sierra Oncology and research funding from AstraZeneca, Blueprint Medicines, Bristol Myers Squibb/Celgene, CTI BioPharma, Genentech, Gilead, Incyte, Italfarmaco, Novartis, NS Pharma, PharmaEssentia, and Promedior. Vikas Gupta reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Constellation Biopharma, Novartis, Pfizer, and Sierra Oncology; honoraria from Bristol Myers Squibb/Celgene, Constellation Biopharma, and Novartis; and participation on a data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb/Celgene, Pfizer, and Roche. Uwe Platzbecker reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Janssen, and Novartis; honoraria from Amgen, Jazz Pharmaceuticals, and Takeda; and participation on a data safety monitoring board or advisor board for AbbVie and Novartis. Timothy Devos reports consulting fees from AOP Health, Bristol Myers Squibb/Celgene, Incyte, and MorphoSys and honoraria from Novartis and Sobi. Jean‐Jacques Kiladjian reports honoraria from Novartis and participation on a data safety monitoring board or advisory board for AbbVie, AOP Orphan, Bristol Myers Squibb, Incyte, and Novartis. Donal P. McLornan reports grants or contracts from CPI and honoraria from AbbVie, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, and Novartis. Andrew Perkins reports honoraria from AbbVie, Novartis, CTI BioPharma, Sierra Oncology, and Kartos Therapeutics. Maria Laura Fox reports consulting fees from AbbVie, GSK, Novartis, and Sierra Oncology; payment or honoraria from Bristol Myers Squibb and Novartis; and travel support from AbbVie. Mary Frances McMullin reports consulting fees from AbbVie, Bristol Myers Squibb, CTI, Novartis, and Sierra Oncology and honoraria from AbbVie, AOP, Incyte, Novartis, and Pfizer. Adam J. Mead reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Galecto, Gilead, Incyte, Karyopharm, Novartis, Pfizer, Sensyn, and Sierra Oncology; travel fees from Bristol Myers Squibb/Celgene; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb/Celgene. Jiri Mayer reports research support from Sierra Oncology. Tomasz Sacha reports honoraria from Angelini Pharma, Bristol Myers Squibb/Celgene, Novartis, Pfizer, and Roche. Jun Kawashima reports employment at Sierra Oncology and stock or stock options at Gilead Sciences and Sierra Oncology. Mei Huang reports employment and stock options at Sierra Oncology. Bryan Strouse reports employment at Sierra Oncology. Ruben Mesa reports grants or contracts from AbbVie, Celgene, CTI Biopharma, Constellation Biopharma, Genotech, Incyte, Promedior, Samus Therapeutics, and the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174) and consulting fees from Constellation Biopharma, La Jolla, Novartis, and Sierra Oncology. Miklos Egyed declares no conflict of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Myelofibrosis should be diagnosed according to the WHO classification (2022, 5th Ed.) and International Consensus Conference 2022 criteria. Testing for driver mutations in the three genes JAK2, CALR, and MPL is recommended to ensure a definitive diagnosis. Ruxolitinib is the only JAK inhibitor currently approved in Japan, but momelotinib is under regulatory review. The MOMENTUM study showed similar spleen volume reduction at 24 weeks and MFSAF-TSS reduction as the COMFORT study of ruxolitinib. Momelotinib acts on ACVR1 and, therefore, improves anemia through suppression of hepcidin. Anemia and/or transfusion dependency are known to be associated with overall survival duration. Consequently, supportive care measures such as ESA and danazol in lieu of transfusion should be considered in addition to JAK inhibitor selection. Mean survival after discontinuation of JAK inhibitors is 11 to 14 months. Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.

Introduction: Myelofibrosis is a clonal myeloproliferative neoplasm associated with the proliferation of hematopoietic stem cells, increased bone marrow fibrosis, extramedullary hematopoiesis, hepatosplenomegaly, abnormal cytokine production, and constitutional symptoms. These and many other factors contribute to the development of anemia in myelofibrosis patients., Areas Covered: This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat., Expert Opinion: Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer. [Display omitted] • Concordant AXL-STAT3 enhances M2-like polarization and phenotypic diversity of TAMs • AXL-dependent IL-11 secretion by lung cancer cells and fibroblasts activates STAT3 in TAMs • TAMs promote vasculogenic network via IL-11/AXL-STAT3 manner to upregulate CD44 expression • AXL-STAT3 targeting attenuates M2 polarization and recruitment of TAMs in a mouse model Hung et al. discuss that advanced lung adenocarcinoma (LAC) tumors harbor M2-polarized TAMs with concordant AXL-STAT3 signaling. LAC cells and fibroblasts secrete IL-11 in an AXL-dependent manner. Thus, IL-11 binds to GP130 complex and triggers pSTAT3 activation in M2-polarized macrophages. AXL-STAT3 targeting disrupts intercellular communication and suppresses tumor growth. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging worldwide epidemics, projected to become the leading cause of liver transplants. The strongest genetic risk factor for NAFLD/NASH susceptibility and progression is a single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), rs738409, encoding the missense mutation I148M. This aminoacidic substitution interferes with the normal remodeling of lipid droplets in hepatocytes. It is also thought to play a key role in promoting liver fibrosis by inhibiting the release of retinol from hepatic stellate cells. Reducing PNPLA3 levels in individuals homozygous for 148M may be an effective treatment for the entire spectrum of NAFLD, based on gene dosage analysis in the human population, as well as the protective effect of another naturally occurring SNP (rs2294918) in PNPLA3 which, when co-inherited, reduces PNPLA3 mRNA levels to 50% and counteracts disease risk. By screening a clinical compound library targeting specific signaling pathways active in primary human hepatocytes, we identified momelotinib, a drug evaluated in clinical trials to treat myelofibrosis, as a potent down-regulator of PNPLA3 expression, across all genotypes. We found that momelotinib treatment yielded >80% reduction in PNPLA3 mRNA in human primary hepatocytes and stellate cells, as well as in vivo via acute and chronic treatment of WT mice. Using a human multilineage 3D spheroid model of NASH homozygous for the PNPLA3 mutant protein, we additionally show that it decreases PNPLA3 mRNA as well as intracellular lipid content. Furthermore, we show that the effects on PNPLA3 coincide with changes in chromatin accessibility within regulatory regions of the PNPLA3 locus, consistent with inhibition occurring at the level of transcription. In addition to its primary reported targets, the JAK kinases, momelotinib inhibits several non-JAK kinases, including ACVR1. Using a combination of targeted siRNA knockdowns and signaling pathway perturbations, we show that momelotinib reduces the expression of the PNPLA3 gene largely through the inhibition of BMP signaling rather than the JAK/STAT pathway. Overall, our work identified momelotinib as a potential NASH therapeutic and uncovered previously unrecognized connections between signaling pathways and PNPLA3. These pathways may be exploited by drug modalities to “tune down” the level of gene expression, and therefore offer a potential therapeutic benefit to a high at-risk subset of NAFLD/NASH patients.

Purpose of Review: Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies.Recent Findings: The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias.Summary: Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future. [ABSTRACT FROM AUTHOR]

Abstract: Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open‐label, parallel‐group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200‐mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least‐squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration–time curve from time 0 to ∞ [AUC∞] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC∞ was increased (GMR, 197%; 90%CI, 129%–301%), and M21 AUC∞ was decreased (GMR, 52%; 90%CI, 34%–79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced. [ABSTRACT FROM AUTHOR]

Abstract: Momelotinib is a potent and selective small‐molecule inhibitor of JAK1/2 that is under investigation for the treatment of myeloproliferative neoplasms. In a phase 1/2 study in myelofibrosis patients, once‐daily dosing of a 300‐mg momelotinib capsule was selected for further development based on a favorable benefit:risk profile. A tablet formulation was recently developed for further clinical evaluation. In this study, the relative bioavailability of the tablet formulation versus the initial capsule formulation and the effect of food and omeprazole on the pharmacokinetics of a single‐dose momelotinib tablet were evaluated in healthy subjects. The momelotinib tablet, 200 mg, provided plasma exposure equivalent to the 300‐mg capsule. Plasma exposure of momelotinib increased less than dose‐proportionally from 100 to 800 mg. Food intake modestly increased Cmax (38% and 28% increase for low‐ and high‐fat meals, respectively) and AUCinf (16% and 28% increase for low‐ and high‐fat meals, respectively) for the momelotinib tablet. Omeprazole reduced the exposure of the momelotinib tablet by 36% for Cmax and 33% for AUCinf. Neither the food effect nor the omeprazole effect on momelotinib exposure was considered clinically meaningful because of the safety and efficacy profile of momelotinib. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic recurrent skin disease dominated by T-helper 2 inflammation. Momelotinib (MMB) is a novel JAK1/JAK2 inhibitor suppressing the signal transduction of multiple pro-inflammatory cytokines. Recent studies indicated that JAK inhibitor could play a therapeutic role in AD disease. In this study, we evaluated the efficacy of MMB as a novel JAK1/JAK2 inhibitor in DNCB-induced AD mice and TSLP-activated dendritic cells. Our data showed that topical application of MMB reduced the skin severity scores and total serum IgE levels, and alleviated the histological indexes including epidermal thickness measurement and mast cell number. Also, it was demonstrated that MMB down-regulated the mRNA expression of IL-4, IL-5, IFN-γ and TSLP, and inhibited the phosphorylation of STAT1, STAT3 and STAT5 in skin lesions. Moreover, MMB reduced the expression of CD80, CD86, MHCII and mRNA of OX40L in TSLP-activated dendritic cells. In general, our study suggests that MMB can improve the symptoms of AD and topical application of MMB can become a promising new therapy strategy for AD.

Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100 mg and 200 mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10 × 10 9 /L, platelet count ≤400 × 10 9 /L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200 mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET). [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a chronic malignancy of the blood-forming system caused by hyperactivation of JAK2/STAT signaling pathway. Small-molecule inhibitors of JAK2 can variably ameliorate MF-related symptoms caused by chronic inflammation and hepatosplenomegaly. Anemia is a significant problem and adverse prognostic factor in over a third of MF patients and is often worsened by JAK2 inhibitors. The JAK1/2 inhibitor momelotinib unexpectedly resulted in reduction of anemia in MF patients during Phase I/II trials. Current Phase III trials will be the basis for seeking regulatory approval of momelotinib during 2017. Studies to determine how momelotinib improves anemia are underway, potentially leading to expanded momelotinib use and/or development of other targeted therapies for treating anemia in MF and related diseases. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy. However, more recently, the discovery of JAK2 mutations has also led to the development of small-molecule JAK1/2 inhibitors, the first of which, ruxolitinib, has been approved for the treatment of MF in the United States and Europe. In this article, we report on old and new therapeutic strategies that proved effective in early preclinical and clinical trials, and subsequently in the daily clinical practice, for patients with MF, particularly concerning the topics of anaemia, splenomegaly, iron overload, and allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Introduction: JAK inhibitors (JAKis), used in the treatment of myelofibrosis, have entered standard treatment, providing significant improvements in spleen size and symptom burden. Although splenomegaly provides a reduction and some improvement in cytopenia, there is still a way to go. Novel JAKis are being investigated to overcome barriers to treatment access, such as therapeutic challenges, intolerance, and unresponsiveness., Areas Covered: This review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate. MEDLINE and clinicaltrials.gov were screened to identify all completed or active studies on this topic. The outcomes of the preclinical studies and clinical trials are presented and discussed for each drug., Expert Opinion: In patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS). More phase 3 studies are needed to provide more precise evidence. The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs.