China
Africa
Explore chapters and articles related to this topic
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ruxolitinib (JakaviTM in the EU, JakafiTM in the US), developed by Novartis after licensing from Incyte, was the first JAK inhibitor to be approved (2011), and this was for the treatment of myelofibrosis. Other JAK/STAT inhibitors have since been developed, but these are mostly for inflammatory diseases. For example, tofacitinib (XeljanzisTM) is used to treat moderate to severe active psoriatic arthritis or rheumatoid arthritis in adults who have failed on methotrexate or related medications. Tofacitinib is sometimes given in combination with methotrexate or other arthritis medicines to treat psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis. Other analogues include filgotinib (GLPG0634), which is currently under development by Gilead/Galapagos. The pharmaceutical company Eli Lilly has developed baricitinib (OlumiantTM), which selectively and reversibly inhibits JAK1 and JAK2 and is used to treat rheumatoid arthritis in patients who have had an inadequate response to other anti-rheumatic agents. Finally, AbbVie has developed upadacitinib (RinvoqTM), which, like filgotinib, is a selective and reversible inhibitor of JAK1 and is used mainly for rheumatoid arthritis. However, it has received a black box warning for its potential toxicities. Other examples of agents of this type include oclacitinib (ApoquelTM), used for the control of pruritus associated with allergic dermatitis; peficitinib (SmyrafTM), which mainly inhibits JAK3 and is used for treatment of rheumatoid arthritis; and fedratinib (InrebicTM), a JAK2 inhibitor used for the treatment of primary or secondary myelofibrosis.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Currently, the only licensed therapies for patients with MF who have disease associated symptoms or have intermediate- or high-risk disease are the JAK inhibitors ruxolitinib and fedratinib.111–113 Ruxolitinib was approved almost a decade ago on the basis of efficacy for improving splenomegaly and MF-associated symptoms and also probably improvement in survival; ruxolitinib is being tested in the peritransplant period as a bridging strategy for allo-SCT. Though this concept appears attractive, the drug’s precise impact on clinical outcome following SCT is not known, nor is the drug’s long-term efficacy and safety. Fedratinib was approved in 2019 by the FDA for intermediate-2 and high-risk MF patients. In this regard, the current unmet medical need includes the optimal management of asymptomatic low-risk patients, those with thrombocytopenia with platelets (defined as <50 × 109/L), and those with an associated monocytosis, which is associated with an inferior survival. For patients with higher-risk disease, it is reasonable to consider an allograft, which can accord long-term remission and may also limit clonal evolution.114 Unfortunately, a significant proportion of candidate patients are considered ineligible, largely due to poor general condition, advanced age, or significant comorbidity. For all patients with intermediate-2 or high-risk MF, ruxolitinib should be offered in the first instance, or eligibility for a suitable clinical trial should be considered. For intermediate-1 disease, ruxolitinib should be considered for those patients who are symptomatic and require therapy; for low-risk MF patients, the drug should only be offered in the context of one of the ongoing trials. For patients who have cytopenias, in particular anemia, it is reasonable to consider erythropoietin and red blood cell transfusions. It has also been noted that patients who have low platelet counts at the beginning or end of ruxolitinib therapy, or clonal evolution while on therapy, often tend to have a poor prognosis. Figure 28.11 depicts the current ELN treatment guidelines for patients with MF.
Fedratinib, the first selective JAK2 inhibitor approved for treatment of myelofibrosis – an option beyond ruxolitinib
Published in Expert Review of Hematology, 2022
Fedratinib is rapidly absorbed following single oral dose with peak plasma concentration achieved 2 to 4 hours following the administration of Fedratinib 400 mg once daily. The pharmacokinetic (PK) studies show a first-order absorption incorporating a lag time and first-order elimination [15,32,33]. Plasma Fedratinib levels reached steady state within 15 days of once-daily dosing [30]. Fedratinib is metabolized by cytochrome P450 enzymes [15] (CYP3A4, CYP2C19) and, hence, dose reductions, even in some cases, avoiding co-administration of cytochrome P450 inhibitors may be necessary [34]. Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4 [35]. Gastric acid suppression by co-administration of pantoprazole did not affect Fedratinib pharmacokinetics significantly [36]. Fedratinib is mainly excreted in feces [37], and the half-life was found to be 41 hours [15]. PK is not significantly affected by age (between 20 and 95 years), sex, race (White and Asian), body weight (between 40 and 135 kg), mild to moderate liver dysfunction, or mild renal dysfunction [15]. However, moderate (creatinine clearance 30–59 mL/min) or severe (creatinine clearance 15–29 mL/min) renal impairment increases Fedratinib exposure significantly, mandating a dose reduction for severe renal impairment [15,38].
Therapeutic options for COVID-19: a quick review
Published in Journal of Chemotherapy, 2020
Muhammad Sani Ismaila, Faruku Bande, Aminu Ishaka, Aminatu Abubakar Sani, Karla Georges
Fedratinib (SAR302503, TG101348) is an antiviral JAK2 inhibitor drug that was tested in vitro and approved by FDA for myeloproliferative neoplasms. The drug got its first approval in August 2019 at the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis.77 It was tested on TH17 cell cytokine production.44 Fedratinib is specific for JAK2 but did not affect JAK1, JAK3, and TYK2. They found out that Fedratinib treatment decreased the expression of IL-17 by murine TH17 cells. Fedratinib has been reported to have an effect in vitro on SARS-COVID though the regulation of JAK-STAT Signaling Pathway in cytokine release storm (CRS). In severe coronavirus disease 2019 (COVID-19), an increase in the level of cytokine release is observed, leading to increased interleukin (IL)-6, IL-2, IL-7, and IL-10 and severe inflammation.78 Although this drug showed a promising effect in SARS-COVID management. However, caution should be observed due to reported side effects in a clinical trial conducted to assess its safety in patients with myelofibrosis where treatment with fedratinib 500-mg caused anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. Wernicke encephalopathy was diagnosed using magnetic resonance imaging in 3 cases and suspected clinically in one case.79
Novel treatments to tackle myelofibrosis
Published in Expert Review of Hematology, 2018
Eran Zimran, Alla Keyzner, Camelia Iancu-Rubin, Ronald Hoffman, Marina Kremyanskaya
WE is a neurological disorder linked to thiamine deficiency. In a cohort of 92 MPN patients from the UK, there was no evidence of thiamine deficiency as determined by peripheral blood levels, regardless of disease entity, treatment or spleen size, supporting the concept that development of WE in patients treated with fedratinib is drug-related [49]. In a study conducted by Incyte Corporation, fedratinib was shown to inhibit the human thiamine transporter (hTHTR2) in human cell-lines (while other JAK inhibitors did not), providing a molecular basis for the development of WE upon fedratinib treatment, due to its structural similarity to thiamine [50]. Conversely, in a non-industry funded study, fedratinib did not lead to experimental WE or to thiamine deficiency in an in vivo model, and did not inhibit thiamine uptake by human astrocytes in vitro. Rats treated with fedratinib exhibited mild weight loss and occasional cases of diarrhea that were attributed to GI irritation. The authors suggested that gastrointestinal adverse effects of fedratinib including nausea and diarrhea may have indirectly contributed to WE in several patients [51]. Additional analyses are needed to elucidate the risk of WE with fedratinib treatment, with the hope that close surveillance of gastrointestinal toxicities and dietary intake may overcome the above concerns and enable further development of this drug with apparent potential clinical benefit.