Ojjaara (momelotinib) / GSK - LARVOL DELTA

Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. (PubMed, Blood Adv) - "Pacritinib inhibited ACVR1 with greater potency (IC50 = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 >1000; Cmax:IC50 <0.01). Among patients on PERSIST-2 who were not TI at baseline based on Gale criteria, a significantly greater proportion became TI on pacritinib compared to best available therapy (37% vs. 7%, P=0.001), and significantly more had a ≥50% reduction in transfusion burden (49% vs. 9%, P<0.0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition."

Journal • Anemia • Hematological Disorders • Myelofibrosis • ACVR1 • IRAK1

Preliminary data from the Phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, in combination with momelotinib showed clinical responses in patients with relapsed/refractory myelofibrosis (ASH 2025) - P1/2 | "Nuvisertib (NUVI, TP-3654), an oralinvestigational highly selective PIM1 kinase inhibitor, alone and in combination with ruxolitinib (RUX)showed spleen size reduction and bone marrow (BM) fibrosis improvement in JAK2V617F and MPLW515LMF mouse models. NUVI + MMB combo appeared to be well tolerated. Preliminary data showed early clinicalactivity including 60% TSS50 response and absolute symptom improvement, 40% SVR25 response,cytokine modulation and anemia improvement in R/R MF pts with anemia. Preliminary data supportsfurther development of NUVI + MMB combo for pts with MF."

Clinical • Combination therapy • P1/2 data • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia • ACVR1 • PIM1

A phase 2 study of canakinumab in patient with myelofibrosis: Results from part 1 (ASH 2025) - "Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) for which the only approved therapies are JAKinhibitors which improve splenomegaly and disease-related symptoms. Given the encouraging impact onMF symptoms, blood counts and reassuring safety profile, the study was amended to enroll pts on astable dose of a JAK inhibitor (ruxolitinib, fedratinib, momelotinib, or pacritinib) who have the potential tobenefit from additional therapy. Part 2 is currently enrolling at multiple sites and updated clinical andcorrelative data will be presented at the meeting."

Clinical • P2 data • Cardiovascular • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytopenia • CRP • IL1B

AN EVOLVING LANDSCAPE – HOW CHANGING CONDITIONING REGIMES CAN IMPROVE MYELOFIBROSIS TRANSPLANT OUTCOMES (EBMT 2026) - "The average age at transplant was 55 years, with a male predominance.Seven patients received Fludarabine/Busulphan/Antithymocyte globulin (Flu/Bu/ATG) conditioning (Fludarabine 30mg/m2 for 5 days, Busulphan 3.2mg/kg for 2 days and rabbit ATG 2.5mg/kg for 2 days), seven received Fludarabine/Cyclophosphamide (Flu/Cy) (Fludarabine 25mg/m2 for 5 days and Cyclophosphamide 1g/m2 for 2 days), and two received Fludarabine/Melphalan (Flu/Mel) (Fludarabine 25mg/m2 for 5 days and Melphalan 100mg/m2 on one day)...Therapies included Ruxolitnib, Momelotinib, splenic irradiation and Hydroxycarbamide amongst others.Cytogenetics were abnormal in four patients (two in each regimen group), normal in nine, and unknown in three... Although limited by a small sample size, these findings indicate that the Flu/Bu/ATG conditioning regimen may be associated with improved outcomes. This supports its adoption as the preferred approach, in line with BSH guidelines."

Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Infectious Disease • Myelofibrosis • Pneumonia • Respiratory Diseases • Transplantation • CALR • JAK2

ALLOGENEIC STEM CELL TRANSPLANTATION IN MYELOFIBROSIS: SINGLE CENTRE EXPERIENCE (EBMT 2026) - "All transplants used peripheral blood as stem cells source and received antifungal and antiviral prophylaxis (letermovir for CMV-seropositive since available), as well as graft-versus-host disease (GVHD) prophylaxis with different regimens...Four received radiotherapy and 2 splenectomy.Seven patients received pre-transplant ruxolitinib; two responded to treatment: one had initial response that later lost, and the other one switched to momelotinib because of secondary anemia.Regarding donor type: 40% (6/15) were from matched related donors, 40% (6/15) mismatch unrelated, 13.3% (2/15) matched unrelated and 6.6% (1/15) haploidentical.Most commonly conditioning regimen was fludarabine-busulfan. Four patients received TBF (thiotepa, busulfan and fludarabine) and the rest other regimens (BuCy, FluMel).For GVHD prophylaxis, cyclosporine A was mainly used in combination with other immunosuppressants (methotrexate, mycophenolate mofetil)... Our cohort supports that AHSCT in..."

Clinical • Chronic Graft versus Host Disease • Essential Thrombocythemia • Graft versus Host Disease • Hematological Disorders • Hepatology • Immunology • Myelofibrosis • Polycythemia Vera • Transplantation • ASXL1 • CALR • JAK2 • TP53

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy (ASH 2022) - P1/2 | "TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors."

Clinical • P1/2 data • Hematological Disorders • Immunology • Myelofibrosis • CALR • IL18 • MMP9 • PIM1 • TIMP1

Post-FDA Approval Experience With Momelotinib in JAK Inhibitor-Naïve Myelofibrosis: Focus on Anemia Response and Treatment-Emergent Nephropathy and Peripheral Neuropathy. (PubMed, Am J Hematol) - "Real-world experience using momelotinib as first-line JAK2 inhibitor therapy in myelofibrosis. Anemia response was moderate (23%) while treatment-emergent adverse events included nephropathy (29%) and peripheral neuropathy (20%)."

FDA event • Journal • Anemia • Hematological Disorders • Myelofibrosis • Pain • Renal Disease

Pacritinib Is a Potent ACVR1 Inhibitor with Significant Anemia Benefit in Patients with Myelofibrosis (ASH 2022) - "The subgroup of BAT that received erythroid support (erythropoiesis stimulating agents, danazol, thalidomide or analogs, or corticosteroids) was also analyzed...The inhibitory activity of pacritinib, momelotinib, fedratinib, and ruxolitinib against ACVR1 was assessed using a HotSpot assay (Reaction Biology Corporation)... Baseline characteristics of patients who were not TI (SIMPLIFY criteria) were similar between pacritinib (n=42) and BAT (n=44), including median hemoglobin (8.7 vs. 8.6 g/dL), median platelet count (43 vs. 41 x109/L), and percentage who received prior JAK2 inhibitor therapy (55% vs."

Clinical • Anemia • Hematological Disorders • Myelofibrosis • Thrombocytopenia • ACVR1 • IRAK1

SURVIVAL IMPACT AND KINETICS OF HEMOGLOBIN IMPROVEMENT WITH MOMELOTINIB IN PATIENTS WITH MYELOFIBROSIS AND MODERATE TO SEVERE ANEMIA: POST HOC ANALYSES OF SIMPLIFY-1 AND MOMENTUM (EHA 2025) - "SIMPLIFY-1 and MOMENTUM were randomized, double-blind, phase 3 trials of momelotinib (n=215) vs ruxolitinib (n=217) in JAK inhibitor-naive patients and momelotinib (n=130) vs danazol (n=65) in JAK inhibitor-experienced patients, respectively. Anemia severity at BL dictates the probability and kinetics of achieving Hb >10 g/dL with momelotinib. Patients with BL moderate anemia were numerically more likely to achieve this threshold and faster than those with BL severe anemia, underscoring the benefits of earlier anemia intervention with momelotinib to maximize clinical outcomes. Regardless of anemia severity, patients who achieved Hb >10 g/dL by week 24 with momelotinib had numerically longer OS than those who did not, validating achievement of Hb levels above this threshold as a positive prognostic factor."

Clinical • Retrospective data • Anemia • Hematological Disorders • Myelofibrosis • ACVR1 • JAK1 • JAK2

Bone Marrow Fibrosis Changes Do Not Correlate with Efficacy Outcomes in Myelofibrosis: Analysis of More Than 300 JAK Inhibitor-Naïve Patients Treated with Momelotinib or Ruxolitinib (ASH 2022) - "These data represent the most extensive analysis to date of the correlation of BMF changes with other outcome measures in JAKi-naïve patients with MF. Of particular note, anemia improvement was not linked with BMF changes. These findings bring into question the use of BMF assessment at W24 as a surrogate for clinical benefit."

Clinical • Anemia • Hematological Disorders • Immunology • Myelofibrosis • ACVR1

MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. (ASCO 2022) - P3 | "Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia."

Clinical • P3 data • Anemia • Hematological Disorders • Infectious Disease • Myelofibrosis • Pain • Thrombocytopenia • ACVR1 • JAK1 • JAK2

Association between hemoglobin (Hb) improvement and patient-reported outcomes (PROs) in patients (pts) with myelofibrosis (MF) and anemia: Post hoc pooled analysis of momelotinib (MMB) phase 3 trials. (ASCO 2024) - P3 | " The pooled treatment-agnostic analysis set included pts with anemia (baseline [BL] Hb <10 g/dL) from 3 phase 3 trials: S1 (JAK inhibitor [JAKi] naive; MMB vs ruxolitinib), S2 (JAKi experienced; MMB vs best available therapy), and MOMENTUM (JAKi experienced; MMB vs danazol). In these trial populations, Hb improvement at wk 24 was associated with improved HRQOL and symptoms in pts with MF and anemia. These results highlight the value of treatments with anemia-related benefits in improving the pt experience in MF."

P3 data • Patient reported outcomes • Retrospective data • Anemia • Hematological Disorders • Myelofibrosis

Impact of Transfusion Burden on Health‑Related Quality of Life and Functioning in Patients With Myelofibrosis: Post Hoc Analysis of SIMPLIFY‑1 and ‑2 (SOHO 2023) - "Design: The pooled analysis set comprised both arms of the intent-to-treat populations of SIMPLIFY-1 (JAK inhibitor-naïve, momelotinib vs ruxolitinib; N=432) and SIMPLIFY-2 (JAK inhibitor-experienced, momelotinib vs best available therapy; N=156). Among patients with myelofibrosis in the SIMPLIFY studies, TD patients had lower functioning and HRQOL than TI patients across SF-36v2 domains, suggesting that transfusion dependence negatively affects multiple aspects of QOL. Baseline TD patients who became TI at W24 had greater improvement across most domains than those who remained TD, with mean changes near/above the minimally important differences. These analyses support further research into the impact of transfusions on QOL in myelofibrosis."

Clinical • HEOR • Retrospective data • Myelofibrosis • Oncology • ACVR1 • JAK1 • JAK2

Momelotinib (MMB) Long-Term Safety: Pooled Data from Three Phase 3 Randomized-Controlled Trials (RCTs) (ASH 2022) - " Adult pts with high- and intermediate-risk MF were randomized to receive MMB or ruxolitinib (RUX; S1); MMB or best available therapy, which was RUX in 89% (S2) of patients; and MMB or danazol (MOMENTUM). We report the largest trial safety database to date for a JAK inhibitor in MF. MMB demonstrated a consistent safety profile without unexpected long-term or cumulative toxicity."

Clinical • P3 data • Acute Myelogenous Leukemia • Anemia • Genetic Disorders • Infectious Disease • Myelofibrosis • Neutropenia • Non-melanoma Skin Cancer • Pain • Skin Cancer • Solid Tumor • Thrombocytopenia • ACVR1 • JAK1 • JAK2

Momelotinib Long-Term Safety and Survival in Myelofibrosis: Integrated Analysis of Phase 3 Randomized-Controlled Trials. (PubMed, Blood Adv) - "Patients in the control arms (danazol in MOMENTUM; ruxolitinib in SIMPLIFY-1; best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol. Incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in myelofibrosis demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity."

Journal • P3 data • Infectious Disease • Myelofibrosis • Neutropenia • Pain • Thrombocytopenia • ACVR1 • JAK1 • JAK2

Impact of transfusion burden on health-related quality of life (HRQOL) and functioning in patients (pts) with myelofibrosis (MF): Post hoc analysis of SIMPLIFY-1 (S1) and -2 (S2). (ASCO 2023) - P3 | "To characterize the relationship between transfusion burden and pt-reported outcomes (PROs), we report an exploratory post hoc analysis of the phase 3 S1 and S2 trials of the JAK1/JAK2/ACVR1 inhibitor momelotinib (MMB) in pts with MF. The pooled analysis set comprised both arms of the intent-to-treat populations of S1 (JAK inhibitor naive, MMB vs ruxolitinib [RUX]; N = 432) and S2 (JAK inhibitor exposed, MMB vs best available therapy [88% RUX]; N = 156)... Among pts with MF in S1 and S2, TD pts had lower functioning and HRQOL than TI pts across SF-36v2 domains, suggesting that transfusion dependence has detrimental effects on multiple aspects of QOL. Among BL TD pts, those who became TI at W24 had greater improvement across most domains than those who remained TD, with mean changes for TD-TI pts near or above the minimally important difference (2 or 3, based on domain) for groups with low BL NBS. These analyses highlight transfusion dependence as a key pt-centered..."

Clinical • HEOR • Retrospective data • Anemia • Hematological Disorders • Myelofibrosis • ACVR1 • JAK1 • JAK2

MOMENTUM: PHASE 3 RANDOMIZED STUDY OF MOMELOTINIB (MMB) VERSUS DANAZOL (DAN) IN SYMPTOMATIC AND ANEMIC MYELOFIBROSIS (MF) PATIENTS PREVIOUSLY TREATED WITH A JAK INHIBITOR (EHA 2022) - P3 | "Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%); mean duration of prior JAKi was 134 weeks. MMB may address a critical unmet need, particularly in MF pts with anemia. NCT04173494."

Clinical • P3 data • Anemia • Hematological Disorders • Infectious Disease • Myelofibrosis • Pain • Thrombocytopenia • ACVR1

Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, Showed Durable Clinical Response and Sustained Hematological Improvement in Relapsed/Refractory Myelofibrosis Patients (ASH 2024) - P1/2 | "Preliminary data of TP-3654 in relapsed/refractory MF pts showed clinical activity including SVR25, symptom improvement correlating with cytokines reduction, BM fibrosis reduction, and Hgb and PLT responses. Current monotherapy and preclinical data support the development of TP-3654 in combination with JAK inhibitors ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively); enrollment ongoing in all 3 arms."

Clinical • Anemia • Fatigue • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Musculoskeletal Pain • Myelofibrosis • Oncology • Pain • PIM1

Updated Results from the Momentum Phase 3 Study of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated with a JAK Inhibitor (ASH 2022) - P3 | "In these initial analyses of response duration, OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT (symptomatic and anemic MF pts) and in those with low PLT. MMB may address a critical unmet need, particularly in MF pts with anemia, including those with severe thrombocytopenia."

Clinical • P3 data • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelofibrosis • Neutropenia • Novel Coronavirus Disease • Oncology • Pain • Thrombocytopenia • ACVR1 • JAK1 • JAK2

The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study (ASH 2022) - "MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04). Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF."

Clinical • HEOR • P3 data • Anemia • Fatigue • Hematological Disorders • Immunology • Inflammation • Musculoskeletal Pain • Myelofibrosis • Oncology • Pain • Pruritus • ACVR1 • JAK2

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. (PubMed, Lancet) - P3 | "Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia."

Journal • P3 data • Acute Kidney Injury • Anemia • Infectious Disease • Myelofibrosis • Nephrology • Oncology • Pneumonia • Polycythemia Vera • Renal Disease • Respiratory Diseases • Thrombocytopenia • ACVR1 • JAK1 • JAK2

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. (PubMed, Lancet Haematol) - P2, P3 | "Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia."

Journal • P3 data • Anemia • Gastrointestinal Disorder • Infectious Disease • Myelofibrosis • Oncology • Pneumonia • Polycythemia Vera • Respiratory Diseases • Thrombocytopenia

Long-term survival adjusted for treatment crossover in patients (pts) with myelofibrosis (MF) treated with momelotinib (MMB) vs danazol (DAN) in the MOMENTUM trial. (ASCO 2024) - P2, P3 | "Consistent with the original unadjusted survival analysis, RPSFT models adjusting for the effects of treatment crossover showed prolonged OS and LFS in pts initially randomized to MMB vs those initially randomized to DAN; HRs in favor of MMB were lower after crossover adjustment. While these RPSFT analyses maintain the significance level of the original unadjusted analysis (P>.05), these results support the trend of long-term survival benefits with MMB vs DAN in JAKi–experienced pts with MF and anemia."

Clinical • Anemia • Hematological Disorders • Leukemia • Myelofibrosis • ACVR1 • JAK1 • JAK2

Transfusion-related cost offsets and time burden in patients with myelofibrosis on momelotinib vs. danazol from MOMENTUM. (PubMed, Future Oncol) - " 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). Fewer transfusions with momelotinib are projected to result in cost and time savings in patients with myelofibrosis and anemia compared with danazol."

Journal • Hematological Disorders • Myelofibrosis

The Immunoregulatory and Hematopoietic Effects of Momelotinib in a Murine Bone Marrow Failure Model. (PubMed, J Clin Lab Anal) - "MMB treatment exacerbated peripheral blood cell reduction and impaired bone marrow hematopoiesis in the immune-mediated AA mouse model. Although MMB modulated T lymphocyte subsets, it did not significantly improve hematopoietic stem and progenitor cell function. These findings highlight the need for further research to explore the potential and limitations of JAK inhibitors like MMB in the treatment of immune-mediated bone marrow failure."

Journal • Preclinical • Aplastic Anemia • Hematological Disorders • CD4 • CD8 • FASLG