Inrebic (fedratinib) / BMS - 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

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

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

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

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

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

Sodium butyrate induces apoptosis enhanced by JAK2 inhibitor Fedratinib in NK/T-cell lymphoma cell. (PubMed, Clin Transl Oncol) - "NaB effectively promotes apoptosis and inhibits the JAK/STAT signaling pathway in NKTCL, which is further promoted by the JAK2 inhibitors fedratinib. Furthermore, NaB induces EBV reactivation and lytic infection in NKTCL, suggesting its ability to transition EBV from a latent to a lytic form."

Journal • Epstein-Barr Virus Infections • Hematological Malignancies • Infectious Disease • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial (ASH 2022) - P2, P3b | "Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size."

Clinical • Anemia • CNS Disorders • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Myelofibrosis • Myeloproliferative Neoplasm • Novel Coronavirus Disease • Oncology • Polycythemia Vera • Thrombocytopenia • Thrombocytosis

A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia (ASH 2023) - P2 | "The JAK1/JAK2 inhibitor, ruxolitinib, has shown clinical benefit in pts with MDS/MPN and pts harboring CSF3R mutations. Fedratinib demonstrates promising clinical efficacy in MDS/MPN and CNL pts with proliferative features. The safety profile is consistent with prior experience. Fedratinib's unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population."

Clinical • P2 data • Anemia • Atypical Chronic Myeloid Leukemia • Chronic Myeloid Leukemia • Chronic Neutrophilic Leukemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Neutropenia • Thrombocytosis • BRD4 • CSF3R • FLT3 • MYC

Efficacy and Safety of Fedratinib in Patients with Myelofibrosis and Low Baseline Platelet Counts in the Phase 3 Randomized FREEDOM2 Trial (ASH 2024) - P2, P3 | "Introduction Fedratinib (FEDR), a Janus kinase inhibitor (JAKi), demonstrated spleen volume reduction (SVR) and symptom reduction in the phase 3, randomized, open-label FREEDOM2 trial (NCT03952039) vs best available therapy (BAT) in patients (pts) with myelofibrosis (MF) previously treated with ruxolitinib (Harrison CN, et al. Safety was consistent with previous trials. Together, these data suggest a platelet sparing effect of second-line FEDR vs BAT, and support FEDR as a promising second-line treatment option for pts with MF with low or high BL PLT."

Clinical • P3 data • Anemia • Hematological Disorders • Myelofibrosis • Thrombocytopenia

BMS-986158, a Potent BET Inhibitor, in Combination with Ruxolitinib or Fedratinib in Patients (pts) with Intermediate- or High-Risk Myelofibrosis (MF): Updated Results from a Phase 1/2 Study (ASH 2023) - P1/2 | "The reductions observed in JAK2 VAF provide promising preliminary data of potential disease modification. Dose expansion with BMS-986158+RUX in 1L MF has opened and is actively enrolling patients."

Clinical • Combination therapy • P1/2 data • Anemia • Cardiovascular • Hematological Disorders • Hepatology • Herpes Zoster • Hypertension • Leukopenia • Myelofibrosis • Neutropenia • Thrombocytopenia • Varicella Zoster • CD34 • JAK2

A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia (ASH 2024) - P2 | "The JAK1/JAK2 inhibitor, ruxolitinib, has shown clinical benefit in pts with MDS/MPN and pts harboring CSF3R mutations. The safety profile is consistent with prior experience. Fedratinib's unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population."

Clinical • P2 data • Anemia • Atypical Chronic Myeloid Leukemia • Chronic Myeloid Leukemia • Chronic Neutrophilic Leukemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Neutropenia • Oncology • Thrombocytosis • BRD4 • CALR • CSF3R • FLT3 • MYC

IO-202, a Novel Anti-LILRB4 Antibody, with Azacitidine for Hypomethylating Agent-Naive Chronic Myelomonocytic Leukemia: Phase 1b Expansion Cohort Results (ASH 2024) - P1 | "Five patients had prior therapies including 4 with hydroxyurea and 1 with fedratinib. Translational data suggest LILRB4 expression as a biomarker for response to therapy, supporting the mechanism of action for IO-202. In light of the paucity of effective therapies for CMML, these data support a future pivotal study of IO-202 + AZA in HMA-naïve CMML."

P1 data • Anemia • Chronic Myelomonocytic Leukemia • Dermatology • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Pruritus • ASXL1 • LILRB4 • RUNX1 • SRSF2 • TET2

Fedratinib for patients with myelofibrosis - Authors' reply. (PubMed, Lancet Haematol) - No abstract available

Journal • Myelofibrosis

Esculentoside a attenuates airway inflammation in asthma by regulating mitochondrial apoptosis via the JAK2/STAT3 pathway. (PubMed, Allergol Immunopathol (Madr)) - ": EsA ameliorates OVA-induced airway inflammation in mice, likely by suppressing the JAK2/STAT3 signaling pathway and attenuating mitochondrial-dependent apoptosis. These findings suggest that EsA holds therapeutic potential as a novel anti-asthmatic agent targeting inflammatory and mitochondrial pathways."

IO biomarker • Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • BAX • BCL2 • CASP3 • IL13 • IL4

TIPP: A Novel Iodoacetamide Reaction-Induced Protein Precipitation Approach for Proteome-Wide Ligand-Target Identification. (PubMed, Anal Chem) - "The feasibility of the developed TIPP method was evaluated by identifying target proteins of various ligand compounds, including MTX, TG101348, and staurosporine...The developed method has similar efficiency and good complementarity with the traditional method, and can be combined with the traditional method to increase the coverage of target identification. Therefore, TIPP is expected to become a powerful strategy to achieve comprehensive ligand-target identification by complementing other drug target identification methods."

Journal

Fedratinib reveals chemotherapeutic potential in esophageal squamous cell cancer. (PubMed, Front Pharmacol) - "Similarly, ectopic expression of survivin, vimentin, or cyclin D1 partially rescued the phenotypic changes induced by fedratinib. Fedratinib exerts antitumor effects against ESCC in vitro, in vivo, and in patient-derived organoid models by suppressing the JAK2-STAT3 signaling axis and its downstream effectors, vimentin, survivin, and cyclin D1."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • BIRC5 • CCND1 • VIM

FRACTION: Fedratinib in Combination With Nivolumab (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Trial primary completion date: Dec 2025 ➔ Mar 2026

Trial primary completion date • Myelofibrosis

Fedratinib in chronic kidney disease: antifibrotic potential and renal safety signals from integrated network toxicology and pharmacovigilance. (PubMed, Ren Fail) - "Fedratinib exhibits therapeutic duality: inhibition of SRC and JAK2 attenuates fibrosis by inhibiting JAK-STAT/TGFβ/Smad3 pathways, while off-target binding to AKT1/EGFR drives renal injury and vitamin B1 depletion-related toxicity with black-box encephalopathy warning. Evidence suggests for CKD patients with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 or age ≥70 years, a 50% dose reduction (200 mg/day) with renal function and thiamin monitoring (<30 nmol/L) may optimize risk-benefit profile."

Adverse events • Journal • Chronic Kidney Disease • CNS Disorders • Fibrosis • Immunology • Nephrology • Renal Disease • SMAD3 • TGFB1

Ernest Beutler Lecture and Prize (ASH 2025) - "The ensuing years have also shown benefit of ruxolitinib on survival for MF. Subsequently, three additional JAK inhibitors — each with their own incremental benefits — have been approved (fedratinib in 2019, pacritinib in 2022, and momelotinib in 2023). A new generation of more mutant selective JAK2 inhibitors (INCB160058, AJ1-11095) is currently in early clinical trials...Radek C. Skoda will describe how the JAK2-V617F mutation drives hematopoiesis causing MPNs and recent advances in understanding of how this mutation activates the JAK2 kinase, opening new ways to find candidate drugs preferentially targeting the mutated JAK2 protein.Dr. Ruben Mesa will summarize how the single-agent JAK inhibitors significantly helped decrease the burden of MPNs and the role of current agents, the next generation of new inhibitors, and combination approaches, as well as the impact JAK inhibitors have had on non-neoplastic inflammatory disorders."

Atopic Dermatitis • Chronic Graft versus Host Disease • Dermatitis • Dermatology • Essential Thrombocythemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • Vitiligo • CALR • TET2

Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Suspended ➔ Recruiting

Enrollment open • Myelofibrosis • Transplantation

Fedora preliminary analysis of a Phase II study evaluating the tolerability, safety and activity of fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis. (ASH 2025) - "The combination of the JAK2 inhibitor fedratinib and ropeg interferon alfa-2b appearstolerable and safe. Symptom score responses and spleen reductions were observed and encouragingreductions in JAK2 allele burden seen in a proportion."

Clinical • P2 data • Myelofibrosis • Myeloproliferative Neoplasm • Ocular Inflammation • Ophthalmology • Uveitis

Current treatments, practical management, and emerging investigational therapies for myelofibrosis. (PubMed, Expert Rev Hematol) - "Equally, there is a major focus on next generation JAK inhibitors and mutant calreticulin antibodies. There is also increasing conversation around the need for novel endpoints, as the limitations of symptom assessment, in particular, become apparent and candidate biomarkers of disease modification emerge."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

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

XPO1 inhibition by selinexor blocks nucleo-cytoplasmic trafficking of multiple members of the NF-kb family in MPN cell lines and primary myelofibrosis cells (ASH 2025) - P3 | "The patient was previously treated with ruxolitinib, fedratinib, and ilginatinib/NS018, with adverse events and lack of response. Selinexor induced G0/G1 cell cycle arrest at 16 hours in HEL cells. Preliminary data showed that exposure of HEL cells to selinexor led to pronounced nuclear sequestration of several NF-κB family members. Cells with nuclear localization of RELA increased from 39.4% in DMSO-treated controls to 93.2% following selinexor treatment."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Polycythemia Vera • CD33 • CD34 • JAK2 • NFKBIA • NRAS • PTPRC • RELA • RUNX1 • SRSF2 • TET2