Would you like to take some more ruxolitinib after your fedratinib?

In Europe, ruxolitinib and fedratinib are the only JAK2 inhibitors available in local pharmacies. According to trial data, myelofibrosis patients should mostly receive ruxolitinib as first-line treatment and fedratinib in case of failure or intolerance (depending on their profile). Is it possible to reverse the choice of these drugs? Commentary on: Palandri et al. Ruxolitinib after Fedratinib failure in patients with myelofibrosis: a real-world case series. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19654.

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).

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). 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. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. 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.

Cost in the United States of FDA-approved small molecule protein kinase inhibitors used in the treatment of neoplastic and non-neoplastic diseases.

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia. Moreover, the remaining 11 drugs target non-neoplastic diseases including psoriasis, rheumatoid arthritis, and ulcerative colitis. The cost of drugs was obtained from www.pharmacychecker.com using the FDA label to determine the dosage and number of tablets required per day. This methodology excludes any private or governmental insurance coverage, which would cover the entire cost or more likely a fraction of the stated price. 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.

Deucravacitinib is an allosteric TYK2 protein kinase inhibitor FDA-approved for the treatment of psoriasis.

Psoriasis is a heterogeneous, inflammatory, autoimmune skin disease that affects up to 2% of the world's population. There are many treatment modalities including topical medicines, ultraviolet light therapy, monoclonal antibodies, and several oral medications. Cytokines play a central role in the pathogenesis of this disorder including TNF-α, (tumor necrosis factor-α) IL-17A (interleukin-17A), IL-17F, IL-22, and IL-23. Cytokine signaling involves transduction mediated by the JAK-STAT pathway. There are four JAKS (JAK1/2/3 and TYK2) and six STATS (signal transducer and activators of transcription). Janus kinases contain an inactive JH2 domain that is aminoterminal to the active JH1 domain. Under basal conditions, the JH2 domain inhibits the activity of the JH1 domain. Deucravacitinib is an orally effective N-trideuteromethyl-pyridazine derivative that targets and stabilizes the TYK2 JH2 domain and thereby blocks TYK2 JH1 activity. Seven other JAK inhibitors, which target the JAK family JH1 domain, are prescribed for the treatment of neoplastic and other inflammatory diseases. The use of deuterium in the trimethylamide decreases the rate of demethylation and slows the production of a metabolite that is active against a variety of targets in addition to TYK2. A second unique aspect in the development of deucravacitinib is the targeting of a pseudokinase domain. Deucravacitinib is rather specific for TYK2 and its toxic effects are much less than those of the other FDA-approved JAK inhibitors. The successful development of deucravacitinib may stimulate the development of additional pseudokinase ligands for the JAK family and for other kinase families as well.

Real-world outcomes with fedratinib therapy in patients who discontinued ruxolitinib for primary myelofibrosis.

Aim: Fedratinib is an oral selective JAK2 inhibitor approved in the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF). Methods: This observational study assessed adult US patients who received ruxolitinib for primary MF (Flatiron Health database: 1 January 2011-31 October 2020). Patients were stratified by post-ruxolitinib treatment (fedratinib vs non-fedratinib). Results: Characteristics were comparable between fedratinib (n=70) and non-fedratinib (n=159) groups (median age: 71.0 vs 70.0 years; females: 55.7 vs 50.3%; median follow-up: 7.0 vs 6.0 months). Median overall survival (not reached vs 17 months) and 12 month survival (71.6 vs 53.5%) were improved with fedratinib versus the non-fedratinib therapies. Conclusion: In MF patients who received frontline ruxolitinib, survival was improved with subsequent fedratinib versus non-fedratinib care.

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes.

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

Systematic transcriptome profiling of pyroptosis related signature for predicting prognosis and immune landscape in lower grade glioma.

BACKGROUND: Pyroptosis is a programmed cell death mediated by the gasdermin superfamily, accompanied by inflammatory and immune responses. Exogenously activated pyroptosis is still not well characterized in the tumor microenvironment. Furthermore, whether pyroptosis-related genes (PRGs) in lower-grade glioma (LGG) may be used as a biomarker remains unknown. METHODS: The RNA-Sequencing and clinical data of LGG patients were downloaded from publicly available databases. Bioinformatics approaches were used to analyze the relationship between PRGs and LGG patients' prognosis, clinicopathological features, and immune status. The NMF algorithm was used to differentiate phenotypes, the LASSO regression model was used to construct prognostic signature, and GSEA was used to analyze biological functions and pathways. The expression of the signature genes was verified using qRT-PCR. In addition, the L1000FWD and CMap tools were utilized to screen potential therapeutic drugs or small molecule compounds and validate their effects in glioma cell lines using CCK-8 and colony formation assays. RESULTS: Based on PRGs, we defined two phenotypes with different prognoses. Stepwise regression analysis was carried out to identify the 3 signature genes to construct a pyroptosis-related signature. After that, samples from the training and test cohorts were incorporated into the signature and divided by the median RiskScore value (namely, Risk-H and Risk-L). The signature shows excellent predictive LGG prognostic power in the training and validation cohorts. The prognostic signature accurately stratifies patients according to prognostic differences and has predictive value for immune cell infiltration and immune checkpoint expression. Finally, the inhibitory effect of the small molecule inhibitor fedratinib on the viability and proliferation of various glioma cells was verified using cell biology-related experiments. CONCLUSION: This study developed and validated a novel pyroptosis-related signature, which may assist instruct clinicians to predict the prognosis and immunological status of LGG patients more precisely. Fedratinib was found to be a small molecule inhibitor that significantly inhibits glioma cell viability and proliferation, which provides a new therapeutic strategy for gliomas.

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design.

Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.

Imetelstat is a new type of treatment being studied in patients with myelofibrosis (MF). Encouraging clinical benefits were seen in a phase II clinical trial of imetelstat in higher risk MF. This article discusses the ongoing phase III trial, called IMpactMF. IMpactMF is comparing imetelstat to best available therapy (BAT) in MF patients not responding to a specific type of treatment, a JAK inhibitor. Imetelstat is an intravenous infusion, given every 21 days. This study will determine if patients who receive imetelstat live longer than patients who are given BAT. It will also collect information on additional outcomes, including safety. Trial Registration Number: NCT04576156 (ClinicalTrials.gov).

JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells.

P-glycoprotein (P-gp) overexpression is one of the major mechanisms of multidrug resistance (MDR). Previously, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. In this study, we assessed the cytotoxic effects of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC). However, fedratinib-induced cytotoxicity was little effect on VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were used to further investigate fedratinib's mechanism of action in VIC-treated KBV20C cells. We found that fedratinib reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC-fedratinib-co-treated cells resulted from the upregulation of p21 and the DNA damaging marker pH2AX. Compared with dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells showed two-fold higher P-gp-inhibitory activity, indicating that VIC-fedratinib sensitization is dependent on the activity of fedratinib. Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC-fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC-CEP-33779 or VIC-NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR.

Fedratinib-induced orbital inflammation.

A 69-year-old man with myelofibrosis presented with a two-day history of left periorbital swelling, blurred vision, and non-radiating dull orbital pain. On examination, there was restricted left-sided extraocular motility with conjunctival injection, chemosis, and periorbital edema. Magnetic resonance imaging demonstrated left-sided pre- and post-septal fat stranding concerning for orbital cellulitis. Two weeks before symptom onset, the patient began fedratinib therapy for myelofibrosis but discontinued this medication upon hospital admission. After restarting fedratinib, he presented with similar right-sided ophthalmic signs. A review of his medication history revealed a temporal relationship between symptom onset and fedratinib use. After medication discontinuation, his symptoms improved rapidly.

Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.

Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-ß1 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with multiple causes, characterized by excessive myofibrocyte aggregation and extracellular matrix deposition. Related studies have shown that transforming growth factor-ß1 (TGF-ß1) is a key cytokine causing fibrosis, promoting abnormal epithelial-mesenchymal communication and fibroblast-to-myofibroblast transition. Fedratinib (Fed) is a marketed drug for the treatment of primary and secondary myelofibrosis, targeting selective JAK2 tyrosine kinase inhibitors. However, its role in pulmonary fibrosis remains unclear. In this study, we investigated the potential effects and mechanisms of Fed on pulmonary fibrosis in vitro and in vivo. In vitro studies have shown that Fed attenuates TGF-ß1- and IL-6-induced myofibroblast activation and inflammatory response by regulating the JAK2/STAT3 signaling pathway. In vivo studies have shown that Fed can reduce bleomycin-induced inflammation and collagen deposition and improve lung function. In conclusion, Fed inhibited inflammation and fibrosis processes induced by TGF-ß1 and IL-6 by targeting the JAK2 receptor.

JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells.

Several signalling pathways, including the JAK/STAT signalling pathway, have been identified to regulate the differentiation of human bone marrow skeletal (mesenchymal) stem cells (hBMSCs) into bone-forming osteoblasts. Members of the JAK family mediate the intracellular signalling of various of cytokines and growth factors, leading to the regulation of cell proliferation and differentiation into bone-forming osteoblastic cells. Inhibition of JAK2 leads to decoupling of its downstream mediator, STAT3, and the subsequent inhibition of JAK/STAT signalling. However, the crucial role of JAK2 in hBMSCs biology has not been studied in detail. A JAK2 inhibitor, Fedratinib, was identified during a chemical biology screen of a small molecule library for effects on the osteoblastic differentiation of hMSC-TERT cells. Alkaline phosphatase activity and staining assays were conducted as indicators of osteoblastic differentiation, while Alizarin red staining was used as an indicator of in vitro mineralised matrix formation. Changes in gene expression were assessed using quantitative real-time polymerase chain reaction. Fedratinib exerted significant inhibitory effects on the osteoblastic differentiation of hMSC-TERT cells, as demonstrated by reduced ALP activity, in vitro mineralised matrix formation and downregulation of osteoblast-related gene expression, including ALP, ON, OC, RUNX2, OPN, and COL1A1. To identify the underlying molecular mechanisms, we examined the effects of Fedratinib on a molecular signature of several target genes known to affect hMSC-TERT differentiation into osteoblasts. Fedratinib inhibited the expression of LIF, SOCS3, RRAD, NOTCH3, TNF, COMP, THBS2, and IL6, which are associated with various signalling pathways, including TGFß signalling, insulin signalling, focal adhesion, Notch Signalling, IL-6 signalling, endochondral ossification, TNF-α, and cytokines and inflammatory response. We identified a JAK2 inhibitor (Fedratinib) as a powerful inhibitor of the osteoblastic differentiation of hMSC-TERT cells, which may be useful as a therapeutic option for treating conditions associated with ectopic bone formation or osteosclerotic metastases.

[Perspectives on a new therapeutic approach for myeloproliferative neoplasms].

After the discovery of driver mutations for myeloproliferative neoplasms (MPN), treatment approach for the disease has achieved tremendous progress. Ruxolitinib, a JAK inhibitor, is now widely used for both patients with myelofibrosis and polycythemia vera in several countries, including Japan. Fedratinib, another JAK inhibitor, has been recently approved in the United States. One of the biggest limitations of treatment with JAK inhibitors is the relatively small proportion of patients who achieve a complete molecular response. Furthermore, most of the patients with myelofibrosis had to discontinue the treatment due to drug-related adverse events or disease progression. Therefore, MPN treatment is still at an early and challenging stage, thereby highlighting the urgent need for establishment of a new and more effective therapeutic strategy. One of the promising candidates for MPN treatment is the use of interferons. Modern forms of interferons demonstrate not only a good hematological response but also a deep molecular response, eradicating abnormal MPN clones harboring driver mutations. A number of new agents targeting molecules outside of the JAK-STAT pathway, PI3kinase, NF-kB, or Bcl-2 family of anti-apoptotic proteins are also being considered and tested in clinical studies as single-agent therapies or in combination with JAK inhibitors.

Management of myelofibrosis after ruxolitinib failure.

Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update.

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is currently the subject of many drug discovery programs in the pharmaceutical industry. The US FDA approved four small molecule protein kinase antagonists in 2019; these include entrectinib, erdafitinib, pexidartinib, and fedratinib. Entrectinib binds to TRKA/B/C and ROS1 and is prescribed for the treatment of solid tumors with NTRK fusion proteins and for ROS1-postive non-small cell lung cancers. Erdafitinib inhibits fibroblast growth factor receptors 1-4 and is used in the treatment of urothelial bladder cancers. Pexidartinib is a CSF1R antagonist that is prescribed for the treatment of tenosynovial giant cell tumors. Fedratinib blocks JAK2 and is used in the treatment of myelofibrosis. Overall, the US FDA has approved 52 small molecule protein kinase inhibitors, nearly all of which are orally effective with the exceptions of temsirolimus (which is given intravenously) and netarsudil (an eye drop). Of the 52 approved drugs, eleven inhibit protein-serine/threonine protein kinases, two are directed against dual specificity protein kinases, eleven target non-receptor protein-tyrosine kinases, and 28 block receptor protein-tyrosine kinases. The data indicate that 46 of these drugs are used in the treatment of neoplastic diseases (eight against non-solid tumors such as leukemias and 41 against solid tumors including breast and lung cancers; some drugs are used against both tumor types). Eight drugs are employed in the treatment of non-malignancies: fedratinib, myelofibrosis; ruxolitinib, myelofibrosis and polycythemia vera; fostamatinib, chronic immune thrombocytopenia; baricitinib, rheumatoid arthritis; sirolimus, renal graft vs. host disease; nintedanib, idiopathic pulmonary fibrosis; netarsudil, glaucoma; and tofacitinib, rheumatoid arthritis, Crohn disease, and ulcerative colitis. Moreover, sirolimus and ibrutinib are used for the treatment of both neoplastic and non-neoplastic diseases. Entrectinib and larotrectinib are tissue-agnostic anti-cancer small molecule protein kinase inhibitors. These drugs are prescribed for the treatment of any solid cancer harboring NTRK1/2/3 fusion proteins regardless of the organ, tissue, anatomical location, or histology type. Of the 52 approved drugs, seventeen are used in the treatment of more than one disease. Imatinib, for example, is approved for the treatment of eight disparate disorders. The most common drug targets of the approved pharmaceuticals include BCR-Abl, B-Raf, vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and ALK. Most of the approved small molecule protein kinase antagonists (49) bind to the protein kinase domain and six of them bind covalently. In contrast, everolimus, temsirolimus, and sirolimus are larger molecules (MW ≈ 1000) that bind to FK506 binding protein-12 (FKBP-12) to generate a complex that inhibits the mammalian target of rapamycin (mTOR) protein kinase complex. This review presents the physicochemical properties of all of the FDA-approved small molecule protein kinase inhibitors. Twenty-two of the 52 drugs have molecular weights greater than 500, exceeding a Lipinski rule of five criterion. Excluding the macrolides (everolimus, sirolimus, temsirolimus), the average molecular weight of the approved drugs is 480 with a range of 306 (ruxolitinib) to 615 (trametinib). More than half of the antagonists (29) have lipophilic efficiency values of less than five while the recommended optima range from 5 to 10. One of the troublesome problems with both targeted and cytotoxic drugs in the treatment of malignant diseases is the near universal development of resistance to every therapeutic modality.

Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice.

OBJECTIVE: Increased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis. METHODS: A selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)-fed wild-type (WT) or Apoe-/- mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe-/- mice were assessed. RESULTS: TG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe-/- mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe-/- mice which was substantially reduced by TG101348. CONCLUSIONS: Selective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe-/- mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.

Management of Myelofibrosis: from Diagnosis to New Target Therapies.

OPINION STATEMENT: Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation.