Inrebic (fedratinib)

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.

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

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.

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.

P=N/A, N=137, Recruiting, Bristol-Myers Squibb | Trial completion date: Sep 2029 --> Dec 2027

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.

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.

P2, N=25, Recruiting, University of Washington | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Nov 2026

P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

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.

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.

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.

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.

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.

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.

P3, N=38, Completed, Celgene | Active, not recruiting --> Completed | Phase classification: P3b --> P3

P1/2, N=216, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2 --> P1/2

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.

These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).

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.

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.

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.

In combination with Janus kinase inhibitors (JAKi), ruxolitinib (RUX) or fedratinib (FED), BET inhibitors (BETi) have been shown to reduce inflammatory signals and disease burden in preclinical models of MF. 2023) were observed as expected. Conclusions Preliminary data suggest combination treatment with BMS-986158 and JAKi in MF may modulate JAK2 VAF, BM microenvironment, circulatory cytokines, and other SF, providing evidence of early disease modifying potential of these drug combinations.

While Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) and fedratinib (FED) may address symptoms and splenomegaly, they do not manage and may exacerbate anemia. Treatments for anemia include erythropoiesis-stimulating agents (ESAs), often in combination with RUX or FED, and androgens such as danazol; however, these have shown limited efficacy... In RUX/BAT-treated pts with MF who required RBC transfusions, continued treatment with RUX/BAT in most pts resulted in poor treatment outcomes compared with MMB. Specifically, treatment with MMB demonstrated an ability to deliver higher SVR, TI, and TSS response rates. The lower SVR35 rate in both arms, similar to the overall ITT population, was likely a result of lack of washout from prior JAK inhibitor treatment.

Hydroxyurea was the most commonly used drug in patients with MF prior to the approval of ruxolitinib (RUX), a first-in-class Janus kinase 1/2 inhibitor (JAKi) that is widely approved for symptomatic patients with MF. In addition to RUX, the JAKis fedratinib and, more recently, pacritinib have also been approved by the US Food and Drug Administration... In patients with MF, RUX was the most commonly used agent in all lines of therapy. The greatest reduction in duration of MF treatment occurred from 1L to 2L. Most patients remained on 1L therapy through Week 24 and did not initiate 2L therapy until Week 156.

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.

CD24 expression was high in granulocytes from MPN transformed into AML and in the JAK inhibitors ruxolitinib and fedratinib-resistant HEL cells (Nat Cancer 4:108). This treatment improved thrombocytosis, decreased platelet-neutrophil complexes, restored normal clearance of mutated senescent neutrophils and reduced emperipolesis levels which, in turn, decreased active TGF-β, ultimately improving myelofibrosis. This study reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions that may increase thrombosis and myelofibrosis risk, and postulate CD24 as a candidate target for innate immune checkpoint in myeloid malignancies.

Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

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.

Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous cells, desirable in vitro metabolic stability in mouse microsome, and sufficient in vivo exposure via intraperitoneal administration. Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft model.

Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [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.

P=N/A, N=137, Recruiting, Bristol-Myers Squibb

The first-in-class JAKi ruxolitinib (RUX) can control the disease, splenomegaly, and systemic symptoms. Our limited series suggests carefully evaluating patients affected by MPN and treated with JAKi, with the key role of FED in these cases instead of RUX.

However, early JAK inhibitors (ruxolitinib and fedratinib) are often associated with cytopenias, particularly thrombocytopenia and anemia, which limit their tolerability. To address these complications, pacritinib has been developed and recently approved for patients with thrombocytopenia, while momelotinib is in development for those with anemia...In the near future, MF treatment strategies will involve selecting the most suitable JAK inhibitor based on individual patient characteristics and prior therapy. Ongoing and future clinical trials are crucial for advancing the field and expanding therapeutic options for MF patients.

We found that fedratinib, trametinib and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

In the base case scenario for MF prevalence estimation, only patients with ≥1 diagnosis of ICD-10-GM D47.4 or treatment with Janus kinase (JAK) inhibitors (fedratinib, ruxolitinib) and no documented diagnosis of ET or PV at any time following the first MF diagnosis were counted. To our knowledge, this is the first study investigating the epidemiology of MF based on German claims data. Prevalence rates of MF were generally higher than previously reported, which may be explained by improved diagnostics, increased offerings for preventive checkups, and the classification change of prefibrotic MF by the World Health Organization (WHO) in 2016. Diagnostic coding routines in Germany should reflect subtypes of MF (prefibrotic, post-ET, post-PV, primary MF) per the current WHO classification.

The Janus kinase inhibitors (JAKis) ruxolitinib and fedratinib are approved for the treatment of MF based on reduction of symptomatology and splenomegaly, however, not all patients respond. Clinical trial, Myelofibrosis