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Specific Therapy for Leukemias
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
Various therapeutic strategies are now being developed for attempting to block the proliferative stimulus associated with the JAK2 and related mutations. Currently there are about 10 drugs, such as INCB018424, XL019, TG101348, ITF2357, and CEP-701, which have been specifically developed to inhibit JAK2.in clinical studies (Table 8.1). The largest clinical experience so far appears to be with INCB018424. The drug leads to significant reduction in splenomegaly and improvement in constitutional symptoms in patients with MF.
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
Ruxolitinib for the treatment of graft-versus-host disease
Published in Expert Review of Clinical Immunology, 2020
Haris Ali, Amandeep Salhotra, Badri Modi, Ryotaro Nakamura
Similarly, during the second phase of GVHD, accumulating evidence supports that JAK1/2 is required for T cell activation following interaction with APCs [29]. Pretreatment of mouse CD4+ or CD8+ T cells with ruxolitinib reduced proliferation responses after exposure to activated APCs or CD3/CD28 beads [33]. Ruxolitinib treatment of APC and T cell co-cultures was also associated with reduced production of IFNγ, IL-17A, and IL-2. In a separate study, Betts et al., demonstrated that addition of the JAK2 inhibitor TG101348 to co-cultures of DCs and T cells inhibited T cell proliferation and increased the Treg: T effector cell ratio [34].
Fedratinib, the first selective JAK2 inhibitor approved for treatment of myelofibrosis – an option beyond ruxolitinib
Published in Expert Review of Hematology, 2022
Fedratinib was first developed as a small molecular inhibitor of JAK2 soon after the JAK2 V617F mutation was discovered in 2005. This molecule was subsequently optimized to generate low-nanomolar activity against JAK2 (50% inhibitory concentration = 3 nM) and was found to be selective for JAK2 relative to other JAK members, for example JAK1, JAK3, and TYK2 [23]. The molecule (initially known as TG101348/SAR302503) was found to be safe and efficacious in preclinical mouse models [23,24]. Following this promising data clinical development proceeded (summary in Table 1) with a phase 1 clinical trial opening in 2008 with eight dose cohorts that demonstrated the agent had significant and durable impact on spleen and MF symptom responses [23]. A reduction in JAK2 V617F allele burden, good tolerability, and a maximum tolerated dose (MTD) of 680 mg/day with dose limiting toxicity of asymptomatic and reversible increase in serum amylase levels was identified [25]. These findings led to phase 3 clinical trials including the pivotal phase 3 trial in JAK2 inhibitor treatment-naïve MF patients in 2011 (known as JAKARTA) [22] and a phase 2 clinical trial in patients with MF resistant or intolerant to Ruxolitinib in 2012 (known as JAKARTA-2) [17] (Table 1). However, clinical development of this agent faced a major setback in 2013 with a ‘clinical hold’ put by the US FDA due to the development of neurological symptoms similar to Wernicke’s Encephalopathy (WE) in 8 of 608 patients (1.3%) who were exposed to this drug. The clinical hold on the drug was eventually lifted in 2017. In August 2019, the FDA granted approval of Fedratinib for the treatment of adults with intermediate-2 or high-risk MF with a ‘black box warning’ on the risk of serious and fatal encephalopathy, including WE [15,26].