Ojjaara (momelotinib) / GSK - LARVOL DELTA

Momelotinib's unique polypharmacology supports indication expansion beyond myelofibrosis (ASH 2025) - "Furthermore, cellular reporter assays demonstrated that momelotinib inhibited NF-kB activity stimulated by pro-inflammatory cytokines, including canonical (TNFα, IL-1β) and non-canonical (RANKL, LIGHT) activators. These findings confirm momelotinib's unique polypharmacology and therapeutic potential in pro-inflammatory diseases beyond MF, namely Vacuoles E1 X-chromosome Autoinflammatory Somatic syndrome (VEXAS), lower-risk myelodysplastic syndrome (LR-MDS), and graft-versus-host disease (GvHD) where these pathways are significantly impaired and there continues to be a high medical need."

Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Myelodysplastic Syndrome • Myelofibrosis • ACVR1 • IL1B • IRAK1 • JAK1 • TNFA

Enhanced antileukemic activity of momelotinib in combination with venetoclax and azacitidine compared to gilteritinib-based combination (ASH 2025) - "Despite extensive genomic insights, conventional chemotherapies, specifically anthracyclines and cytarabine , have remained the cornerstone of treatment for the past four decades...In contrast, selective inhibitors of JAK-STAT (ruxolitinib) or FLT3 (gilteritinib or quizartinib) alone failed to demonstrate comparable synergy, highlighting the distinct polypharmacological profile of momelotinib in mediating the cytotoxic response...Notably, while the efficacy of gilteritinib-based regimens was restricted to FLT3-mutant AML, the momelotinib combination demonstrated activity across both FLT3 mutant and FLT3 wild-type contexts. Altogether these preclinical data support clinical evaluation of momelotinib in combination with venetoclax and azacitidine as a potential effective treatment in AML."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ACVR1 • FLT3 • IRAK1

An evolving landscape – how changing conditioning regimes can improve myelofibrosis transplant outcomes. (ASH 2025) - "Of the 16 cases, seven received Fludarabine/Busulphan/Antithymocyte globulin (Flu/Bu/ATG) conditioning (Fludarabine 30mg/m 2 day -9 to day -5, Busulphan 3.2mg/kg on day -4 and day -3 and rabbit ATG 2.5mg/kg on day -2 and day -1), seven underwent Fludarabine/Cyclophosphamide (Flu/Cy) conditioning (Fludarabine 25mg/m 2 day -6 to day -2 and Cyclophosphamide 1g/m 2 on day -3 and day -2), and two received Fludarabine/Melphalan (Flu/Mel) (Fludarabine 25mg/m 2 day -6 to day -2 and Melphalan 100mg/m 2 on day -2)...Therapies included Ruxolitnib, Momelotinib, splenic irradiation, Hydroxycarbamide, Danazol, Interferon, Cyclophosphamide, Anagrelide, Thalidomide, Panobinostat and Navitoclax...Although limited by a small sample size, these findings indicate that the Flu/Bu/ATG conditioning regimen may be associated with improved outcomes, thereby supporting its adoption as the preferred approach for patients undergoing allogeneic stem cell transplantation for myelofibrosis as per BSH..."

Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Infectious Disease • Myelofibrosis • Pneumonia • Respiratory Diseases • Transplantation • ASXL1 • CALR • JAK2 • SF3B1 • U2AF1

Prescribing patterns in MDS/MPN syndromes (ASH 2025) - "Additionally, the prescribing patterns of Hydroxyurea, Hypomethylating Agents (HMA)- Azacitidine/Decitabine and JAK inhibitors Ruxolitinib/Cedazuridine/Pacritinib/Momelotinib/Fedratinib were analyzed in these patients. In this real-world analysis, our data demonstrate that over 90% of patients diagnosed with MDS/MPN overlap syndromes do not receive any treatment in routine clinical practice. The most prescribed medication in this cohort of patients with MDS/MPN was hydroxyurea, followed by hypomethylating medications (decitabine and azacitidine). Being untreated was associated with a significant decrement in survival, with untreated patients having up to twice the risk of death than those treated."

Atypical Chronic Myeloid Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Retromomelo: Real-world use of momelotinib – the french experience from the FIM group (ASH 2025) - "A majority of patients (84%) had received prior ruxolitinib therapy, and 54% were transfusion dependent at baseline. In this real-world cohort of patients with myelofibrosis, momelotinib demonstrated meaningful clinical benefit in reducing spleen size and improving anemia, even in heavily pretreated patients. Treatment discontinuation was frequent but primarily due to disease progression or intolerance rather than unexpected safety concerns. Gastrointestinal adverse events were mostly low grade; however, their persistence may have contributed to momelotinib discontinuation in a non-negligible number of cases, highlighting the importance of early symptomatic management at treatment initiation."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Dermatology • Musculoskeletal Pain • Myelofibrosis • Myeloproliferative Neoplasm • Pruritus • Thrombocytosis • ACVR1 • CALR

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

Selinexor alone and in combination with JAK inhibitors suppresses pro-inflammatory cytokine secretion from primary myelofibrosis cells ex vivo (ASH 2025) - P3 | "In combination with ruxolitinib (RUX), SEL has shown rapid, deep, and sustained spleenand symptom responses including disease modifying potential in patients with JAK inhibitor(JAKi)–naïve myelofibrosis (MF), with associated reductions in proinflammatory cytokines(Tantravahi SK, et al...JAKis used in MF therapy, including RUX, momelotinib (MOM), and pacritinib(PAC), have limited impact on cytokine modulation... XPO1 inhibition is a potentially fundamental mechanism that addresses keyinflammatory and pathobiological features of MF. Here we demonstrate that SEL effectivelysuppresses ex vivo NF-κB–regulated pro-inflammatory cytokine production in PBMCs derivedfrom patients with MF, both as a single agent and in combination with JAKi, further validating thepotential of disease modification. The combinatory activity of XPO1 inhibition and JAK/STATinhibitors supports the clinical use of SEL plus RUX in JAKi-naïve MF, which is being evaluated inthe ongoing Phase..."

Combination therapy • IO biomarker • Preclinical • Fibrosis • Immunology • Myelofibrosis • CALR • IL6 • JAK2 • TLR8 • XPO1

The selective PI3Kδ inhibitor roginolisib synergizes with ruxolitinib against progenitor cells from naïve and JAK inhibitor-refractory/resistant patients with myelofibrosis (ASH 2025) - P1/2 | "We also evaluated combinations of suboptimal IOA-244 (0.5-1 µM) and Momelotinib (Mome, 5-50nM) doses. At the maximal dose, reductions were statistically significant (p<0.05)for IL-10 (-53%), IL-18 (-41.3%), IL-1β (-52.5%), IL-2 (-49.2%), IL-6 (-76.1%), IL-8 (-58.8%), TNF (-44.3%), CCL1(-67.9%), CCL4 (-39.8%), and CXCL10 (-84.2%).CONCLUSIONS. These findings support efficacy of IOA-244, a selective PI3Kδ inhibitor, in primary MFcells, especially when combined with JAK2 inhibitors, providing a rationale for the ongoing phase 2 HEMA-MED clinical trial (NCT06887803)."

Clinical • Hematological Malignancies • Myelofibrosis • CALR • CD34 • CXCL10 • CXCL8 • IL10 • IL18 • IL1B • IL2 • IL6 • PIK3CD

Selective degradation of oncogenic signaling nodes by momelotinib-based protacs exerts potent anti-leukemic response in B-ALL, AML, and MF while sparing normal cells (ASH 2025) - "While these results are promising, in vivo studies are currently underway to evaluate thetherapeutic efficacy of this novel PROTAC in leukemic models. These findings provide a proof of conceptto deplete the oncogenic kinases and key signaling nodes to target intrinsic resistance for enhancedtherapeutic outcome."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Targeted Protein Degradation • ABL1 • BCR • CALR • FLT3 • IRAK1

Clinical features and outcomes of myelofibrosis patients with MPL mutations (ASH 2025) - "Treatment regimensincluded JAK inhibitors, most commonly Ruxolitinib (n=31), Momelotinib (n=4), Fedratinib (n=2), andPacritinib (n=1). Anemia-directed therapies included erythropoietin-stimulating agents (ESA) in 21patients, Danazol (n=9), and Luspatercept (n=2)...A significant subset of patients progressed to accelerated-phase disease or AML (n=11, 15%).Despite this, only one-fifth underwent hematopoietic stem cell transplantation. These results highlightedthe need for improved risk stratification and the development of targeted therapeutic strategies for thisrare and understudied population."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • ASXL1 • CALR • JAK2 • SRSF2 • U2AF1

An independent, multi-center analysis of the post-approval utilization and efficacy of pacritinib and momelotinib in patients with myelofibrosis (ASH 2025) - "Early JAK inhibitors(ruxolitinib (RUX) and fedratinib) result in myelosuppression that often exacerbates disease-relatedanemia and thrombocytopenia. The magnitude ofthese differences warrants further investigation. Overall, this real-world study highlights clinical nuancesin JAK inhibitor selection and emphasizes the opportunity to personalize treatment approach."

Clinical • Myelofibrosis • Thrombocytopenia • CALR

Impact of hemoglobin improvement with momelotinib on survival in patients with myelofibrosis and anemia: Post hoc analyses of the simplify-1 and momentum trials (ASH 2025) - P3 | "The presentpost hoc analyses were conducted using a narrower definition restricting achievement of Hb ≥10 g/dL toweek 24 ± a 2-week window, to further evaluate the OS impact of achieving Hb ≥10 g/dL at week 24 withmomelotinib. SIMPLIFY-1 (NCT01969838; JAK inhibitor–naive patients) and MOMENTUM (NCT04173494; JAKinhibitor–experienced patients) were phase 3, randomized, double-blind trials of momelotinib vsruxolitinib or danazol, respectively. These post hoc analyses confirm and expand on previous evidence that, in patients withmoderate to severe anemia regardless of JAK inhibitor exposure, achieving Hb ≥10 g/dL at week 24 withmomelotinib is associated with longer survival. Early intervention with momelotinib to achieve Hbimprovements may support optimal outcomes, as evidenced by the results in JAK inhibitor–naive andmoderately anemic patients compared with JAK inhibitor–experienced or severely anemic patients.Overall, achieving Hb ≥10 g/dL at week 24 per the..."

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

Association between momelotinib exposure and hemoglobin improvement in patients with myelofibrosis and anemia: An exposure-response and time-to-event analysis (ASH 2025) - P3 | "The current analysis aims to characterize therelationship between momelotinib exposure and Hb improvement, as well as the time needed to achievean improvement of ≥1 g/dL, in the MOMENTUM patient population, in which all patients had Hb <10 g/dLat baseline. MOMENTUM (NCT04173494) was a randomized phase 3 trial of momelotinib vs danazol insymptomatic (Total Symptom Score ≥10) and anemic (Hb <10 g/dL), JAK inhibitor–experienced patientswith MF. In JAK inhibitor–experienced patients with baseline Hb <10 g/dL, higher momelotinibexposure was associated with greater anemia-related benefits, including maintenance of increased Hbfrom baseline and faster time to Hb improvement of ≥1 g/dL. The benefits were more pronounced in thehigher quartiles of AUCss (Q3-Q4), highlighting the fact that initiation and maintenance of the full 200-mgdaily dose of momelotinib in line with prescribing information is necessary to ensure optimal outcomes inthis patient population."

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

Survival outcomes in ruxolitinib-treated patients with myelofibrosis following crossover to momelotinib: Application of the response to ruxolitinib at 6 months (RR6) prognostic model to SIMPLIFY-1 (ASH 2025) - P=N/A, P3 | "Among comparable ruxolitinib-treated cohorts with similar RR6 risk distributions,ruxolitinib-randomized patients in SIMPLIFY-1 who crossed over to momelotinib achieved better OS vspatients following ruxolitinib discontinuation in RUXOREL-MF, suggesting that momelotinib may mitigaterisk following ruxolitinib discontinuation and confer a potential survival benefit even in patients with ahigher risk of impaired survival."

Clinical • Hematological Disorders • Myelofibrosis

Momelotinib-mediated transcriptional reprogramming induces synthetic lethal interaction with calcineurin-NFAT signaling (ASH 2025) - "Consistent with priorfindings, gilteritinib significantly depleted genes involved in DNA and purine synthesis, while the loss ofP53 and BAX conferred resistance to both gilteritinib and venetoclax...Using a high-risk murine AML model (Flt3ITD/ITD:Tet2-/-), which is refractory to existing targetedtherapies, the combination of momelotinib and calcineurin inhibitors (such as cyclosporine or tacrolimus)resulted in a curative response...This selectivity is likely due to the context-dependent interaction of AP-1, NF-κB, STATs,and NFAT transcription factors in leukemic cells compared to normal cells. Given the profound anti-leukemic efficacy, durable responses, and notable therapeutic window, these findings provide acompelling rationale for clinical evaluation of momelotinib and calcineurin inhibitor combinations in AML."

Synthetic lethality • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • FLT3 • JAK1 • JAK2 • TET2 • TP53

It's not yet time to abandon ruxolitinib in anemic myelofibrosis: Predictive factors of erythroid response to standard anemia-directed therapies combined with ruxolitinib (ASH 2025) - "However, on-target RUX-associated anemia represents a major therapeutic limitation,negatively affecting quality of life, prognosis, and treatment duration.Novel JAK1/2 inhibitors, such as momelotinib and pacritinib, also target ACVR1 and may ameliorateanemia both in RUX-naïve and -exposed pts. However, there is a number of standard anemia-directedtherapies (ADT), including erythropoietin (EPO), danazol, steroids and immunomodulatory agents (e.g.thalidomide), that have been used for a long time to manage anemia in MF...Proactive anemia management with EPO, initiated early before the establishment of TDA, isassociated with better RUX survival and favorable safety profile. These results support a personalizedapproach integrating early prognostic assessment with optimized anemia management strategies, inorder to maximize treatment benefits."

Biomarker • Anemia • Myelofibrosis • ACVR1 • CALR

Molecular predictors of anemia response to momelotinib in patients with myelofibrosis: Real-world outcomes from the momgemfin study. (ASH 2025) - "TheJAK2 driver mutation was associated with a better response to MMB with the exception of those with aU2AF1 co-mutation. Transfusion dependence negatively impacted overall survival, consistent withpublished data."

Clinical • Real-world • Real-world evidence • Anemia • Myelofibrosis • ASXL1 • CALR • IDH1 • IDH2 • SF3B1 • SRSF2 • TET2 • U2AF1

Prognostic impact of persistent and treatment-emergent cytopenia in 879 myelofibrosis patients treated with ruxolitinib: The "RUX-MF" study (ASH 2025) - P | "Also,hemoglobin (Hb) improvement during the first 24 weeks of momelotinib therapy was linked to prolongedOS (Palandri F. et al, EHA 2025).Here, we evaluated the trajectory of cytopenia during the first 6 months of RUX therapy, aiming toinvestigate the prognostic impact of: (1) treatment-emergent (TE) and persistent cytopenia; (2) TE anemiaversus TE thrombocytopenia; and (3) Hb improvement in patients with baseline anemia.MethodsThis sub-analysis of the RUX-MF study (NCT06516406) included 879 patients treated with RUX for ≥6months. Achieving Hb >10 g/dL was validated as a favorable prognostic marker duringJAK inhibitors therapy. These results underscore the prognostic heterogeneity of cytopenia during RUXtherapy and the need for individualized therapeutic strategies."

Clinical • Myelofibrosis • Thrombocytopenia

Preliminary experience from the ODYSSEY trial: Efficacy and safety of momelotinib in combination with luspatercept in patients with transfusion-dependent myelofibrosis (ASH 2025) - P2 | "WhileJAK inhibitors are the current standard of care in transplant-ineligible patients with intermediate- or high-risk MF, some such as ruxolitinib cause or worsen anemia...In cohort 2, previous or currentruxolitinib or fedratinib is permitted (no washout required), while discontinuation of other MF-directedtherapy is required ≥28 days before enrollment in both cohorts... ODYSSEY builds on the established anemia-related benefits of momelotinib andluspatercept in patients with MF and may highlight momelotinib as a potentially optimal JAK inhibitorbackbone for combination with emerging agents in patients with MF and anemia."

Clinical • Combination therapy • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • ACVR1 • JAK1 • TGFB1

Post-FDA approval experience with momelotinib in JAK inhibitor-naïve myelofibrosis: Focus on anemia response and treatment-emergent nephropathy and peripheral neuropathy (ASH 2025) - "In routine practice, momelotinib therapy might alleviate anemia in about a quarter of JAKi-naive patientswith MF but is associated with non-trivial rates of treatment-emergent peripheral neuropathy andnephropathy. The latter appeared to be reversible on treatment discontinuation. Our novel observationregarding association of anemia response with SH2B3 mutation requires validation in a larger group ofinformative cases."

Anemia • Hematological Malignancies • Leukemia • Myelofibrosis • Pain • Renal Disease • ACVR1 • ASXL1 • IDH2 • IL2 • IL6 • JAK1 • JAK2 • SF3B1 • SH2B3 • SRSF2 • TET2 • TNFA • ZRSR2

Momelotinib inhibition of JAK/STAT in a mouse JAKV617F myelofibrosis model showed concurrent activation of p-ERK and p-AKT which was reversed by combination therapy using LP-182, a novel MEK/PI3K/mTOR inhibitor (ASH 2025) - "Introduction: Most cases of myelofibrosis (MF) arise from constitutive activation of the JAK/STAT signalingpathway in hematopoietic stem cells (HSCs) with resultant activation of bone marrow stromal cells drivingfibrosis. Treatment of in vitro SET-2 cells revealed IC50 for proliferation of LP-182, MMB andLP-182+MMB was 14.4, 0.13 and 0.07mm, respectively. MRI was used to quantify changes in spleenvolumes over time in a mouse JAK2-mutant MF mouse model. Treatment cohorts consisted of vehicle(n=11), LP-182 (400 mg/kg, PO, n=5), momelotinib (MMB, 50 mg/kg, PO, n=7) and combination (LP-182+MMB, n=4) OD for 28 days."

Combination therapy • Preclinical • Fibrosis • Immunology • Myelofibrosis • JAK2

Clonal architecture inferred from routine NGS data predicts outcome and response to JAK-inhibitors in myelofibrosis (ASH 2025) - "216 ptsreceived ruxolitinib (86.4%), 15 fedratinib (6%), 19 momelotinib (7.6%). This study highlights the impact of clonal architecture profile on response to JAKi in MF pts,particularly the role of mutations in epigenetic regulators when acquired as first-hit event. These findingswere generated using an inferential method based on VAF calculation from routine bulk sequencing, thatcan be easily implemented in practice and used to guide therapeutic strategies."

Biomarker • Next-generation sequencing • Hematological Malignancies • Leukemia • Myelofibrosis • ASXL1 • DNMT3A • IDH2 • KRAS • NRAS • SF3B1 • SRSF2 • TET2 • U2AF1 • ZRSR2

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

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

Leveraging real-world workshop insights for improving education design: Patient-centered care of myelofibrosis with JAK inhibitors (ASH 2025) - "As a resultof this education, relative improvements were observed in selecting guideline- and expert-concordantanswers to pre/post quesitons on: 1) individualizing front-line therapy with ruxolitinib dosing (30%baseline vs 71% post education; P <.001); 2) optimal use of front-line pacritinib for patients with MF andlow platelet count (20% baseline vs 62% post education; P <.001); 3) sequencing JAKi for second-linetherapy (eg, pacritinib, momelotinib, fedratinib) based on patient characteristics (34% baseline vs 69%post education; P <.001) and, 4) recognizing and effectively managing treatment-related AEs in patientsreceiving JAKi therapies (37% baseline vs 69% post education; P <.001). HCP confidence, knowledge, and competence in personalizing JAKi therapy for patients withMF was improved following participation in this multimodal educational program. This educationalinitiative demonstrated that integrating quantitative and qualitative insights from..."

Clinical • Real-world • Real-world evidence • Hematological Disorders • Myelofibrosis • Thrombocytopenia