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A Closer Look at Pacritinib: a JAK2/FLT3 Inhibitor for The

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A Closer Look at Pacritinib: a JAK2/FLT3 Inhibitor for The Drug Evaluation A closer look at pacritinib: a JAK2/ FLT3 inhibitor for the treatment of myelofibrosis 1. Background † Leslie Padrnos & Ruben A Mesa 2. JAK2 targeted therapy † Mayo Clinic Cancer Center, Division of Hematology and Medical Oncology, Mayo Clinic, 3. Pacritinib Scottsdale, AZ, USA 4. Other JAK inhibitors Introduction: Myelofibrosis (MF) is a chronic myeloid neoplasm that bears a 5. Conclusion significant symptom burden, impacts on quality of life and carries a risk of 6. Expert opinion transformation to acute leukemia. Advances in MF therapy by inhibition of Janus kinase type 2 (JAK2) receptor have shown clinical improvements in spleen size and symptom burden, but are often limited by hematological side effects. Areas covered: Treatment for patients with MF who are not suitable candidates for allogeneic stem cell transplant is limited and, historically, palliative in intent. The approval of ruxolitinib, a JAK2 inhibitor, has enabled clinical improvement in these individuals. In this paper, treatments for MF are briefly reviewed, including historically palliative therapies and the clinical data leading to ruxolitinib approval. This JAK2 therapy is limited by cytope- nias, either due to the disease process or a medication side effect. Finally, the preclinical and clinical data of pacritinib use in MF and other hematologic conditions are evaluated. Expert opinion: Ruxolitinib use in patients with MF who are deemed to be inappropriate transplant candidates can be limited by cytopenias, particularly thrombocytopenia. This demonstrates an unmet therapeutic need in patients with MF. Pacritinib, SB1518, a dual JAK2 and FMS-like tyrosine kinase 3 inhib- itor has been suggested to provide clinical benefit to patients with MF without producing adverse hematologic events that restrict ruxolitinib utility. If ongoing phase 3 trials of pacritinib are positive, based on efficacy to improve splenomegaly and constitutional symptoms with a tolerable adverse event profile, pacritinib may provide a much needed oral therapeutic option for patients with MF. Keywords: hematologic malignancy, Janus kinase type 2 inhibitors, myelofibrosis, myeloproliferative neoplasm, pacritinib, SB1518 Expert Opinion on Orphan Drugs (2014) 2(7):725-733 1. Background 1.1 Myelofibrosis: diagnosis and risk Myeloproliferative neoplasms (MPNs) are a class of bone marrow diseases that result in excessive cell lineage production. Myelofibrosis (MF) is included in the spectrum of Philadelphia chromosome negative MPNs, and it is characterized by dysfunctional and extramedullary hematopoiesis leading to cytopenias and spleno- megaly. MF can develop de novo, termed primary MF or following a diagnosis of either PV or ET, termed post-PV-MF and post-ET-MF, respectively. As knowledge regarding MF has grown, identification of risk factors including age > 65, hemoglo- bin level < 10 g/dl, white blood cell count greater than 25 Â 109/l, circulating blasts greater than 1%, and presence of constitutional symptoms has allowed for classifi- cation as low, intermediate 1 and intermediate 2 and high-risk disease with median 10.1517/21678707.2014.927761 © 2014 Informa UK, Ltd. e-ISSN 2167-8707 725 All rights reserved: reproduction in whole or in part not permitted L. Padrnos & R. A. Mesa Box 1. Drug summary. Drug Name Pacritinib, SB1518 Phase Two Phase III Studies ongoing Impact of pacritinib 400 mg oral daily therapy verses physician selected best available therapy on splenomegaly and symptom burden in intermediate and high-risk myelofibrosis patients Impact of pacritinib 400 mg oral daily versus pacritinib 200 mg oral twice a day versus physician-selected best available therapy on splenomegaly and symptom burden in intermediate and high-risk myelofibrosis patients with platelet count < 100,000/µl Indication Refractory myelofibrosis Mechanism of action Inhibition of transcription factor activation via inhibition of JAK2 tyrosine kinase Route of administration Oral Chemical structure N O O O HN N N Pivotal trial(s) Phase II trials in refractory myelofibrosis Demonstrated clinical benefit regarding splenomegaly and systemic symptoms and infrequent hematological adverse events Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com). survival between categories of 135, 95, 48 and 27 months, leukocytosis, thrombocytosis, erythrocytosis, bone pain and respectively [1]. This International Prognostic Scoring System constitutional symptoms. provides prognostic stratification of patients for healthcare Hydroxyurea has been shown to improve splenomegaly, decision making regarding treatment recommendations [1]. anemia, bone pain, constitutional symptoms and pruritus in 40% of patients with MPNs in a small retrospective study of 40 individuals with benefit noted for 13 months [4]. 1.2 Traditional MPN treatment options Although 40% noted clinical improvement, 45% of patients 1.2.1 Stem cell transplantation experienced hematological toxicities, including worsening Historically, treatment options for MF have been limited. anemia or pancytopenia. Hydroxyurea provides modest bene- The only curative treatment in MF is allogeneic hematological fit of hyperproliferative symptoms, with the frequent side stem cell transplant (HSCT), but it carries significant mortal- effect of anemia often requiring concomitant therapy. ity and morbidity and may not be appropriate for patients IFN-a use in MF has demonstrated mild benefit but is with advanced age or multiple comorbidities [2]. It is reserved well tolerated with few significant side effects. Its clinical for patients with intermediate or high-risk disease who are effect in patients with MF vary from clinical responses of deemed suitable for a trial of transplantation. Reduced inten- 20% in 1 study of 118 patients [5] and 16 of 18 patients in sity conditioning stem cell transplantation (SCT) is currently another study [6], and 1 of 11 patients in another study [7]. being evaluated as a viable option for patients with intermedi- Alkylating agents have also been used to treat splenomegaly ate and high-risk disease unlikely to tolerate the traditional in MF. Reduction of spleen size in MF by alkylating agents, conditioning regimen due to concern for significant mortality such as melphalan and busulfan, is countered by the and morbidity [3]. The risk versus benefit analysis must be fact that these agents are associated with increased risk of individualized for each patient and particular disease. Prior transformation to acute myeloid leukemia (AML) [8]. to 2011, no pharmacotherapy was approved by the FDA to Surgical intervention for splenomegaly can be considered treat MF, with the available therapies focused on palliation but due to the risk of mortality and morbidity, candidates of symptoms. require thorough evaluation [9]. Long-term improvement fol- lowing splenectomy includes improved symptomatic spleno- 1.2.2 Hyperproliferative symptoms megaly (48%), anemia (50%), portal hypertension (40%) To address the hyperproliferative symptoms of MPNs, and severe thrombocytopenia (30%). The complication rate cytoreductive agents are used to address hepatosplenomegaly, of 27% includes bleeding, thrombosis and infection. The 726 Expert Opinion on Orphan Drugs (2014) 2(7) Pacritinib mortality rate is 6.7% [10]. Similarly, radiotherapy is used in this substitution leads to persistent autophosphorylation and MF to address extramedullary hematopoiesis and splenomeg- activation of JAK2 and its downstream transcription factors aly. In one study of 23 patients, who received a median course enabling cell proliferation independent of, or hyperresponsive of 277 cGy in 8 fractions, 94% experienced a decreased spleen to, cytokine signaling [22]. This mutation has been identified size whereas 44% experienced cytopenias [11]. in nearly 95% of cases of PV and nearly half of patients with either ET or PMF [23]. 1.2.3 Hypoproliferative symptoms Another segment of MF therapies target the hypoproliferative 2.2 Ruxolitinib symptoms of cytopenias that impact quality of life and prog- Ruxolitinib is an oral JAK1 and JAK2 inhibitor [24]. Phase I nosis. These hypoproliferative symptoms include fatigue and II trials, reported in 2010, demonstrated improved con- attributed to anemia, treatment limiting hemoglobin levels stitutional symptoms and exercise tolerance and decreased and the frequent need for transfusions. cytokine (IL-6 and TNF-a) levels, in JAK2V617F-positive Efficacy of thalidomide, often in combination with predni- and -negative patients, indicating the benefit of this JAK2 sone and occasionally in concert with other immunomodulators inhibitor is irrespective of mutation status [25]. The Phase III (such as cyclophosphamide or etanercept), was investigated in a trials of ruxolitinib, the COMFORT I and COMFORT II 50-person study in patients with MF. The study revealed a randomized controlled trials, focused on response of response rate (RR) of 28% based on the International Working splenomegaly, constitutional symptoms and blood product Group for Myelofibrosis Research and Treatment (IWG- transfusions. The COMFORT I trial of patients from the MRT) Criteria. Major adverse events were grade 3 -- 4 neurop- USA, Canada and Australia compared ruxolitinib with pla- athy in 6%, and grade 3 -- 4 cytopenias seen in 20% of cebo with a primary end point of reduction in spleen size by patients [12]. Similarly, a Phase II trial in 42 patients with
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