China
Africa
Explore chapters and articles related to this topic
Myeloproliferative and Related Neoplasms
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
At present, in addition to IFNα being tested as a monotherapy and in combination, many drugs including the next-generation JAK inhibitors are in clinical trials, principally for the treatment of patients with PMF and MF. The clinical development of next-generation JAK2 inhibitors has been difficult with many studies being discontinued due to the emergence of serious neurotoxicity, in particular Wernicke’s encephalopathy. Fedratinib’s development in MF was discontinued in 2013, and is now being re-evaluated. It was previously shown to be superior to placebo for control of splenomegaly and symptoms in patients with MF in the Jakarta I study, in addition to be active in the second-line setting for patients with MF who had previously been on ruxolitinib in the Jakarta II study. Another JAK2 inhibitor, pacritinib, previously shown to be active in the PERSIST-1 and PERSIST-2 studies, is undergoing further development with refinement of optimal dosage. And the recent phase 3 study results show pacritinib 200 mg twice daily to be significantly better than the best available therapy, including ruxolitinib, for reducing splenomegaly and clinical symptoms in patients with MF and thrombocytopenia, for both previously untreated and those who had received prior ruxolitinib. Momelotinib, a JAK2 inhibitor, was tested in the SIMPLIFY-1 study in late 2017, but the trial failed to meet its primary endpoint. In addition to JAK inhibition and interferons, many other investigational agents, either alone or in combination with ruxolitinib, are being tested. These include hedgehog, aurora kinase, SMAC, HDAC and MDM2 inhibitors, in addition to the JAK2-allosteric inhibitors, such as LS104 and ON044580, which have a greater specificity for JAK2V617F and are inhibitory in a non-ATP competitive manner.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
At present, in addition to IFNα being tested as a monotherapy and in combination, many drugs including the next-generation JAK inhibitors are in clinical trials, principally for the treatment of patients with MF.115 The clinical development of next-generation JAK2 inhibitors has been difficult, with many studies discontinued due to the emergence of serious toxicity (e.g. Wernicke’s encephalopathy). Fedratinib’s development in MF was discontinued in 2013, then re-evaluated in 2017, and licensed in 2019.113 Another JAK2 inhibitor, pacritinib, previously shown to be active in the PERSIST-1 and PERSIST-2 studies, is undergoing further development with refinement of optimal dosage. Recently, the Phase III study results show pacritinib 200 mg twice daily to be significantly better than the best available therapy, including ruxolitinib, for reducing splenomegaly and clinical symptoms in patients with MF and thrombocytopenia, both previously untreated patients and those who had received prior ruxolitinib. Momelotinib, a JAK2 inhibitor, was tested in the SIMPLIFY-1 and -2 studies in 2017, in first- and second-line settings, respectively, but trials failed to meet their primary endpoint. In addition to JAK inhibition and interferons, many other investigational agents, either alone or in combination with ruxolitinib, are being tested. These include hedgehog, aurora kinase, SMAC, HDAC, and MDM2 inhibitors, in addition to the JAK2-allosteric inhibitors, such as LS104 and ON044580, which have a greater specificity for JAK2V617F and are inhibitory in a non-ATP competitive manner. A novel agent, tagraxofusp, which targets CD123 and plasmacytoid dendritic cells, observed in MF patients, is currently being tested in a Phase II study.
Pacritinib for the treatment of patients with myelofibrosis and thrombocytopenia
Published in Expert Review of Hematology, 2022
Orally administered pacritinib is readily absorbed regardless of food intake, has a mean terminal elimination half-life of 27.7 hours, and is predominantly metabolized by the CYP3A4 isozyme and biliary excretion [27,84]. Pacritinib achieves maximum plasma concentration at approximately four to five hours post dose and has an apparent volume of distribution of 229 L with 98.8% plasma protein binding [27]. Pacritinib is a time-dependent inhibitor of CYP1A2 and CYP3A4 isozymes and a reversible inhibitor of CYP3A4 and CYP2C19 isozymes based on in vitro metabolism data [27]. Moreover, with multiple dose administration, pacritinib is an inducer of CYP1A2 and CYP3A4 isozymes [27]. It also inhibits BCRP, OCT1, OCT2, and P-glycoprotein transporters [27]. In patients with moderate and severe hepatic impairment, pacritinib exposure is decreased by 36% and 45%, respectively, compared with healthy volunteers [27].
Beyond JAK-2: potential targets for myeloproliferative neoplasm therapy
Published in Expert Review of Hematology, 2018
Patrick M. Harrington, Claire N. Harrison
Pacritinib is a selective JAK2 inhibitor which also inhibits FLT-3 signaling and is thought to be minimally myelosuppressive. Phase I and II trials showed a significant spleen response with minimal hematological toxicity. The PERSIST-1 study went on to compare pacritinib with BAT in the treatment of 327 JAK-I naïve patients with PMF, including patients with a baseline platelet count of <50 × 109/l [18]. At week 24, the primary end point of a reduction in spleen volume of >35% was reached in 19% of the pacritinib group, compared with 5% in the BAT group, which did not include ruxolitinib as an alternative therapy. Of note, subgroup analysis showed substantial benefits in the patients with significant cytopenias on entry, with 25% of transfusion-dependent patients achieving transfusion independence in the pacritinib group.
Improving symptom burden and quality of life in patients with myelofibrosis: current strategies and future directions
Published in Expert Review of Hematology, 2021
Several other JAK inhibitors are in development for niche populations. Pacritinib, a dual JAK2/FLT3 inhibitor, may meet a specific need for patients with thrombocytopenia. In the PERSIST-1 and −2 studies, pacritinib demonstrated superiority over BAT (which included ruxolitinib in PERSIST-2) in terms of spleen and symptom responses. However, concerns over cardiovascular toxicity and bleeding events led to a clinical hold on development of pacritinib, which has since been lifted [36,37]. Momelotinib, a JAK1/2 inhibitor, was compared to ruxolitinib in the frontline setting in the SIMPLIFY-1 trial, and compared to BAT (which was primarily ruxolitinib continuation) in the second line or later setting in SIMPLIFY-2. As frontline treatment, there were no significant differences between momelotinib and ruxolitinib in terms of symptom or spleen responses, though anemia parameters were improved with momelotinib [38]. Similarly in those previously treated with ruxolitinib, momelotinib provided no significant benefit compared to BAT in terms of SVR, although there was a suggestion of symptom benefit seen [39]. Peripheral neuropathy may be a limiting toxicity with momelotinib, and was reported in 8.4%-11% of patients treated on the SIMPLIFY-1 and −2 protocols, respectively. While most cases were low-grade and did not require treatment discontinuation, there has been 1 case of grade 3 neuropathy reported [38] Additional phase 3 studies of both pacritinib and momelotinib are underway in more selective patient populations: pacritinib versus physician’s choice is being studied for those who are JAK inhibitor naïve with platelet counts <50,000/µL (NCT03165734); and momelotinib versus danazol is being studied for those with prior JAK inhibitor exposure who are symptomatic and anemic (NCT04173494).