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DRUG:

Inrebic (fedratinib)

i
Other names: TG 101348, TG101348, SAR302503, SAR-302503, TG-101348, SAR 302503
Company:
BMS
Drug class:
JAK2 inhibitor, FLT3 inhibitor
Related drugs:
7d
Fedratinib in Combination with Nivolumab (clinicaltrials.gov)
P2, N=30, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Active, not recruiting
Enrollment closed • Combination therapy
|
Opdivo (nivolumab) • Inrebic (fedratinib)
7d
MCC-20963: Fedratinib in Myelodysplastic /Myeloproliferative Neoplasms (MDS/MPNs) and Chronic Neutrophilic Leukemia (CNL) (clinicaltrials.gov)
P2, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting
Enrollment closed
|
ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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Inrebic (fedratinib)
24d
Spatial-transcriptomic profiling: a new lens for understanding myelofibrosis pathophysiology. (PubMed, Cell Commun Signal)
Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches...Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape...These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.
Review • Journal
|
TP53 (Tumor protein P53) • JAK2 (Janus kinase 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • TNFA (Tumor Necrosis Factor-Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • TGFB1 (Transforming Growth Factor Beta 1) • CALR (Calreticulin)
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TP53 mutation • TET2 mutation • SRSF2 mutation
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
29d
Maintenance Fedratinib to Prevent Post-Transplant Relapse in Myeloproliferative Neoplasms (clinicaltrials.gov)
P1/2, N=12, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=46 --> 12
Enrollment closed • Enrollment change • Post-transplantation
|
Inrebic (fedratinib)
1m
Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2. (PubMed, Mol Oncol)
Analyses of sotorasib- and MRTX1133-resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2-mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer.
Journal
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KRAS (KRAS proto-oncogene GTPase) • JAK2 (Janus kinase 2)
|
KRAS mutation • KRAS G12C • KRAS G12D
|
Mekinist (trametinib) • Lumakras (sotorasib) • MRTX1133 • Inrebic (fedratinib)
1m
How I individualize selection of JAK inhibitors for patients with myelofibrosis. (PubMed, Blood)
Ruxolitinib and fedratinib can cause myelosuppression and are recommended for patients with myeloproliferative MF. Approval of 2 less myelosuppressive JAKi, pacritinib and momelotinib, provided essential treatment options for patients with severe thrombocytopenia and anemia, respectively...Judicious treatment decisions of JAKi can be made with in-depth understanding of the pivotal clinical trials on JAKi and their therapeutic attributes and should be guided by the dominant clinical manifestations and the type/degree of cytopenia(s). This article reviews our clinical approach to treatment with JAKi and their sequencing in MF patients by presenting 3 clinical vignettes.
Journal
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ACVR1 (Activin A Receptor Type 1)
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
2ms
Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis (clinicaltrials.gov)
P2, N=20, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2026
Trial primary completion date
|
cyclophosphamide • melphalan • fludarabine IV • Inrebic (fedratinib)
3ms
Momelotinib: Mechanism of action, clinical, and translational science. (PubMed, Clin Transl Sci)
While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.
Review • Journal
|
JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • ACVR1 (Activin A Receptor Type 1) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
3ms
Maintenance Fedratinib to Prevent Post-Transplant Relapse in Myeloproliferative Neoplasms (clinicaltrials.gov)
P1/2, N=46, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Nov 2025 --> Aug 2025 | Trial primary completion date: Nov 2024 --> Aug 2025
Trial completion date • Trial primary completion date • Post-transplantation
|
Inrebic (fedratinib)
3ms
Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19. (PubMed, Cancer Chemother Pharmacol)
The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.
PK/PD data • Journal
|
CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
|
Inrebic (fedratinib)
3ms
Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms. (PubMed, Front Oncol)
Our study identifies JAK1 and JAK2 resistance variants against the type I JAK2 inhibitors ruxolitinib, fedratinib, and lestaurtinib. The sensitivity of these resistant variants towards the type II JAK2 inhibitor CHZ-868 indicates that this mode of type II JAK2 inhibition is a potential therapeutic approach against ruxolitinib refractory leukemia. This also proposes the development of potent and specific type II JAK2 inhibitors using ruxolitinib-resistance variants as a prototype.
Journal
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JAK1 (Janus Kinase 1) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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Jakafi (ruxolitinib) • CHZ868 • lestaurtinib (CEP-701) • Inrebic (fedratinib)
4ms
Enrollment change • Trial withdrawal • Metastases
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
|
Tibsovo (ivosidenib) • Idhifa (enasidenib) • Inrebic (fedratinib)
4ms
MoReLife - real-life data support the potential of momelotinib as a safe and effective treatment option for cytopenic myelofibrosis patients. (PubMed, Ann Hematol)
Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. 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.
Journal
|
ACVR1 (Activin A Receptor Type 1)
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
4ms
The Role of the JAK-STAT Pathway in Childhood B-Cell Acute Lymphoblastic Leukemia. (PubMed, Int J Mol Sci)
Understanding the mechanisms underlying the malfunction of the JAK-STAT pathway holds potential for research on drugs targeting its components. Available drugs that interfere with the JAK-STAT pathway include fludarabine, ruxolitinib, and fedratinib.
Review • Journal
|
ABL1 (ABL proto-oncogene 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
|
Jakafi (ruxolitinib) • fludarabine IV • Inrebic (fedratinib)
4ms
Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2. (PubMed, Adv Ther)
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.
Journal
|
JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • ACVR1 (Activin A Receptor Type 1)
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
4ms
Enrollment change
|
cyclophosphamide • melphalan • fludarabine IV • Inrebic (fedratinib)
4ms
FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN). (PubMed, Ann Hematol)
Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.
P2 data • Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1)
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Opdivo (nivolumab) • Jakafi (ruxolitinib) • Inrebic (fedratinib)
5ms
Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity. (PubMed, J Med Chem)
Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.
Journal
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JAK2 (Janus kinase 2)
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
6ms
CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov)
P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Apr 2027 --> May 2026 | Trial primary completion date: Apr 2025 --> May 2026
Trial completion date • Trial primary completion date • Combination therapy
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • ezobresib (BMS-986158)
7ms
Disseminated Histoplasmosis in a Patient with Myelofibrosis on Ruxolitinib: A Case Report and Review of the Literature on Ruxolitinib-Associated Invasive Fungal Infections. (PubMed, J Fungi (Basel))
Later, the patient received fedratinib, a relatively JAK2-selective inhibitor, without relapse of histoplasmosis. Although uncommon, a high index of suspicion for opportunistic IFIs is needed in patients receiving JAK inhibitors. Furthermore, the paucity of data regarding the optimal management of IFIs in patients treated with JAK inhibitors underscore the need for well-designed studies to evaluate the epidemiology, pathobiology, early diagnosis, and multimodal therapy of IFIs in patients with hematological malignancies receiving targeted therapies.
Review • Journal
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JAK2 (Janus kinase 2)
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Jakafi (ruxolitinib) • Inrebic (fedratinib)
7ms
Combination of Fedratinib and Decitabine for Myeloproliferative Neoplasms (MPN)- Accelerated Phase (AP)/Blast Phase (BP) (clinicaltrials.gov)
P1, N=2, Terminated, Joseph Jurcic | N=13 --> 2 | Trial completion date: Dec 2025 --> Apr 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Apr 2024; Closed by Sponsor
Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Combination therapy
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decitabine • Inrebic (fedratinib)
7ms
miR-146a-/- mice model reveals that NF-κB inhibition reverts inflammation-driven myelofibrosis-like phenotype. (PubMed, Am J Hematol)
Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias...Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib...Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
Preclinical • Journal
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IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • COL1A1 (Collagen Type I Alpha 1 Chain) • IL1B (Interleukin 1, beta) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1)
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JAK2 V617F
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • BMS-345541 • Inrebic (fedratinib)
7ms
Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management. (PubMed, Am J Hematol)
Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • CSF3R (Colony Stimulating Factor 3 Receptor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • SETBP1 (SET Binding Protein 1) • ETNK1 (Ethanolamine Kinase 1)
|
KRAS mutation • NRAS mutation • ASXL1 mutation • TET2 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • CSF3R T618I • CSF3R mutation • ETNK1 mutation
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hydroxyurea • Inrebic (fedratinib)
7ms
A Post-Marketing Surveillance Study to Assess the Safety of Fedratinib in Korean Patients With Myelofibrosis (clinicaltrials.gov)
P=N/A, N=137, Recruiting, Bristol-Myers Squibb | Trial completion date: Sep 2029 --> Dec 2027
Trial completion date
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Inrebic (fedratinib)
7ms
Momelotinib in myelofibrosis. (PubMed, Expert Opin Pharmacother)
Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. 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.
Review • Journal
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ACVR1 (Activin A Receptor Type 1)
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
7ms
A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non-small cell lung cancer by upregulating JAK2 and MCM8. (PubMed, Gene)
The JAK2 inhibitor fedratinib attenuated the oncogenic outcomes induced by DAZL overexpression, whereas silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and half-maximal inhibitory concentration of cisplatin. In conclusion, DAZL was identified as a novel cancer-germline gene that enhances the translation of JAK2 and MCM8 to promote NSCLC progression and resistance to cisplatin, respectively. These findings suggest that DAZL is a potential therapeutic target in NSCLC.
Journal
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JAK2 (Janus kinase 2)
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cisplatin • Inrebic (fedratinib)
8ms
Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms (clinicaltrials.gov)
P2, N=25, Recruiting, University of Washington | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Nov 2026
Trial completion date • Trial primary completion date • Combination therapy
|
azacitidine • Jakafi (ruxolitinib) • decitabine • Vonjo (pacritinib) • Inrebic (fedratinib)
8ms
Enrollment closed • Combination therapy
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • ezobresib (BMS-986158)
10ms
ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. (PubMed, Cancers (Basel))
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...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.
Review • Journal
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ACVR1 (Activin A Receptor Type 1) • BMP6 (Bone Morphogenetic Protein 6) • ACVR2B (Activin A Receptor Type 2B)
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Jakafi (ruxolitinib) • Reblozyl (luspatercept-aamt) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib) • zilurgisertib (INCB00928)
11ms
Identification of basement membrane-related signatures for estimating prognosis, immune infiltration landscape and drug candidates in pancreatic adenocarcinoma. (PubMed, J Cancer)
RO-90-7501, Scriptaid, TG-101348, XMD-892, and XMD-1150 may be valuable small molecule drugs to treat PAAD. In conclusion, we develop a novel BM-related gene signature provide new insights and targets for the diagnosis, outcome estimation, candidate drugs and therapy management of PAAD patients.
Journal
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MUC16 (Mucin 16, Cell Surface Associated) • WNT7A (Wnt Family Member 7A)
|
Inrebic (fedratinib)
11ms
Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices. (PubMed, Am J Hematol)
The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib-resistance/intolerance, respectively. Splenectomy remains a viable option for drug-resistant symptomatic splenomegaly and cytopenia.
Review • Journal
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JAK2 (Janus kinase 2) • ACVR1 (Activin A Receptor Type 1)
|
Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
11ms
Cost in the United States of FDA-approved small molecule protein kinase inhibitors used in the treatment of neoplastic and non-neoplastic diseases. (PubMed, Pharmacol Res)
The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.
FDA event • Review • Journal
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FGFR2 (Fibroblast growth factor receptor 2)
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FGFR2 fusion
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Tagrisso (osimertinib) • Imbruvica (ibrutinib) • imatinib • lapatinib • Mektovi (binimetinib) • Lytgobi (futibatinib) • Tukysa (tucatinib) • nintedanib • Ayvakit (avapritinib) • Inrebic (fedratinib) • Tavalisse (fostamatinib)
11ms
SOCS2 inhibits hepatoblastoma metastasis via downregulation of the JAK2/STAT5 signal pathway. (PubMed, Sci Rep)
The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.
Journal
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SOCS2 (Suppressor Of Cytokine Signaling 2)
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SOCS2 expression
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Inrebic (fedratinib)
12ms
Tagraxofusp Shows Promising Anti-Tumoral Efficacy in Preclinical in Vitro Models of Myelofibrosis, Both As a Single Agent and in Combination with Janus Kinase Inhibitors (ASH 2023)
The role of the JAK/Signal transducer and activator of transcriptions (STAT) pathway in MF has led to the recent approval of three different JAK2 inhibitors (ruxolitinib, pacritinib, and fedratinib) for MF treatment. Our studies showed high sensitivity of MF cell lines to tagraxofusp as a single agent, which is expected given phase 2 results demonstrated clinical efficacy of single-agent tagraxofusp in R/R MF (Yacoub et al. ASH 2021). In addition, synergism was observed in combination with JAK inhibitors.
Preclinical • Combination therapy
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CD123 (Interleukin 3 Receptor Subunit Alpha) • IL3RA (Interleukin 3 Receptor Subunit Alpha)
|
CD123 positive • JAK2 V617F • CD123 expression • IL3RA expression • IL3RA positive
|
Jakafi (ruxolitinib) • Elzonris (tagraxofusp-erzs) • Vonjo (pacritinib) • Inrebic (fedratinib)
12ms
Trial completion • Phase classification
|
Jakafi (ruxolitinib) • Inrebic (fedratinib)
12ms
Phase classification • Combination therapy
|
Jakafi (ruxolitinib) • Inrebic (fedratinib) • ezobresib (BMS-986158)
12ms
FEDRATINIB MAY BE THE FIRST CHOICE FOR PATIENTS AFFECTED BY MYELOFIBROSIS AND CONCURRENT LYMPHOPROLIFERATIVE DISORDER OR DEVELOPED AFTER ANOTHER JAK INHIBITOR THERAPY (SIE 2023)
The first-in-class JAK inhibitor ruxolitinib (RUX) can control the disease, splenomegaly, and systemic symptoms. The data presented in this report allows us to suggest FED in the first line for patients harboring indolent lymphoid clones, closely monitoring potential progressions, and as a second line JAKi in case of the development of LPD during RUX therapy. Understanding the underlying biological processes could help treat these patients at best in the future.
Clinical
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JAK2 (Janus kinase 2) • CALR (Calreticulin)
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JAK2 mutation • CALR mutation
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Jakafi (ruxolitinib) • Inrebic (fedratinib)
1year
Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults. (PubMed, Cancer Chemother Pharmacol)
These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).
Journal
|
JAK2 (Janus kinase 2)
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Inrebic (fedratinib)
1year
Fedratinib Treatment Reduces the Inflammatory Cytokine Profile and Decreases Exhausted T Cells Correlating with Clinical Response in Patients with Myelofibrosis: Biomarker Analysis from the Phase 3 FREEDOM2 Trial (ASH 2023)
Here, we report the multiplatform biomarker analysis including immune changes from phase 3 (FREEDOM2) trial in patients with MF previously exposed to ruxolitinib (Rux) and treated with fedratinib vs. best available therapy (BAT) (primary efficacy: 35.8% vs 6% responders at the end of cycle 6 (EOC6) in fedratinib vs BAT, respectively). To our knowledge, this is the first comprehensive study detailing cytokine and immune changes in patients with MF in a clinical trial. In addition, our data for the first time demonstrates the impact of fedratinib on the immune system and its ability to reduce exhausted T cells, highlighting the immune modulatory mechanism of fedratinib. Notably, the cytokine and immune changes correlated with the primary endpoint and were not observed in the BAT arm demonstrating superior efficacy of fedratinib in previously RUX exposed patients.
Clinical • P3 data • PD(L)-1 Biomarker • IO biomarker
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JAK2 (Janus kinase 2) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD4 (CD4 Molecule) • MMP2 (Matrix metallopeptidase 2) • TIMP1 (Tissue inhibitor of metalloproteinases 1) • IL18 (Interleukin 18) • CALR (Calreticulin) • CEACAM8 (CEA Cell Adhesion Molecule 8) • IL16 (Interleukin 16)
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PD-1 expression • JAK2 V617F
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Jakafi (ruxolitinib) • Inrebic (fedratinib)
1year
Type 1/like Calr Mutation in Momelotinib-Treated Patients with Myelofibrosis Is the Most Prominent Predictor of Drug Survival and Longevity without Transplant (ASH 2023)
FDA-approved JAKi for the treatment of MF include ruxolitinib, fedratinib, and pacritinib. CALR-1 mutation is the most important risk factor for both drug survival and longevity without AHSCT, in momelotinib-treated patients with MF. Such information might help identify MF patients who might benefit from treatment with momelotinib and in whom AHSCT might be deferred or not.
Clinical
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JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CALR (Calreticulin)
|
ASXL1 mutation • SRSF2 mutation • CALR mutation
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)
1year
Comparison of the Enzymatic and Cellular Profiles of Clinical JAK2 Inhibitors for the Treatment of Myelofibrosis (ASH 2023)
Introduction: Three Janus kinase 2 (JAK2) inhibitors (JAKinibs) have been approved by the FDA for the treatment of myelofibrosis (MF): ruxolitinib, fedratinib, and pacritinib; a fourth one, momelotinib, is currently under FDA review. JAKinibs clinically evaluated for treatment of MF exhibit distinct kinase inhibition profiles and cellular activities. Amongst the agents tested in this study, ruxolitinib was the most potent and selective JAK2 inhibitor. At concentrations several fold above clinically relevant concentrations, ruxolitinib had no observable effects on the health of cells not reliant on JAK/STAT mediated signaling.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • JAK1 (Janus Kinase 1) • CD34 (CD34 molecule) • ACVR1 (Activin A Receptor Type 1) • TYK2 (Tyrosine Kinase 2)
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Jakafi (ruxolitinib) • Vonjo (pacritinib) • Inrebic (fedratinib) • Ojjaara (momelotinib)