Pharmacokinetics/Pharmacodynamics
A Randomized, Placebo‐Controlled Study of the Pharmacokinetics, Pharmacodynamics, and Tolerability of the Oral JAK2 Inhibitor Fedratinib (SAR302503) in Healthy Volunteers
The Journal of Clinical Pharmacology 54(4) 415–421 © 2013, The American College of Clinical Pharmacology DOI: 10.1002/jcph.218
Meng Zhang, MD, PhD1, Christine R. Xu, PhD1, Elias Shamiyeh, MS1, Feng Liu, PhD2, Jian Y. Yin, MD1, Lisa L. von Moltke, MD3, and William B. Smith, MD4
Abstract Fedratinib (SAR302503/TG101348) is a Janus kinase 2 (JAK2)‐selective inhibitor in clinical development for the treatment of myelofibrosis. In this randomized, placebo‐controlled, Phase 1 study, the pharmacokinetics, pharmacodynamics and tolerability of ascending single doses of fedratinib (10– 680 mg) were assessed in healthy male subjects. Fedratinib was rapidly absorbed, with peak plasma concentration observed approximately 3 hours after dosing. The mean terminal half‐life of fedratinib was approximately 67 hours, which was unaffected by dose. Fedratinib exposure increased in a greater than dose‐proportional manner. Suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation, indicative of JAK2 inhibition, was observed at 3 hours post‐dose for subjects in the 300, 500, and 680 mg groups, with the level of suppression increasing with dose. The relationship between fedratinib exposure and suppression of STAT3 phosphorylation was described using an inhibitory effect sigmoid Emax model, with an EC50 of 1,210 ng/mL in healthy subjects. The most common adverse events were mild gastrointestinal toxicities.
Keywords fedratinib, SAR302503, myelofibrosis, pharmacokinetics, healthy subjects
Myelofibrosis is a BCR‐ABL1‐negative chronic myeloproliferative neoplasm (MPN), resulting from transformation of hematopoietic stem/progenitor cells.1 Myelofibrosis, which can occur de novo (primary myelofibrosis) or develop from polycythemia vera or essential thrombocythemia, is characterized by clonal myeloproliferation, dysregulated hematopoiesis, and abnormal expression of cytokines/chemokines.2 The clinical sequelae are anemia, splenomegaly resulting from extramedullary hematopoiesis,2 and debilitating constitutional symptoms.3 Primary myelofibrosis of intermediate‐2 or high‐risk has a median survival of under 4 years, with common causes of death including leukemic transformation, thrombosis, and bleeding.4 The Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway controls a number of basic cell functions, including differentiation, survival, and proliferation.5 Of the JAK family of kinases, JAK2 plays the most important role in the regulation of hematopoiesis, as it is primarily responsible for the mediation of signaling for cytokines such as erythropoietin, thrombopoietin, and granulocyte colony‐stimulating factor.6 Constitutive activation of the JAK‐STAT pathway, most frequently as a result of the V617F activating mutation in the JAK2 protein, is common in patients with
myelofibrosis, and has been implicated in the disease phenotype.7,8 Indeed, hyperactivity of JAK2 may mediate the abnormal cytokine signaling observed in patients with myelofibrosis.9 Ruxolitinib, a JAK1/JAK2 inhibitor approved by the Food and Drug Administration (FDA) for the treatment of myelofibrosis, has demonstrated clinically meaningful reductions in splenomegaly and symptom burden as well as modulation of the level of a number of cytokines.10,11 Fedratinib (SAR302503/TG101348) is an orally administered, JAK2‐selective inhibitor under clinical development for the treatment of myelofibrosis. In
1
Sanofi Clinical and Exploratory Pharmacology, Bridgewater, NJ, USA Sanofi Oncology, Cambridge, MA, USA 3 Sanofi Clinical and Exploratory Pharmacology, Cambridge, MA, USA 4 Volunteer Research Group, University of Tennessee Medical Center, Knoxville, TN, USA 2
Submitted for publication 30 September 2013; accepted 23 October 2013. Corresponding Author: Meng Zhang, Sanofi U.S., Inc., Clinical & Exploratory Pharmacology, P. O. Box 55C‐315A, 55 Corporate Drive, Bridgewater, NJ 08807, USA Email: [email protected]
416 preclinical studies, fedratinib inhibited proliferation of cells carrying JAK2 mutations (e.g., V617F), and reduced extramedullary hematopoiesis and JAK2V617F disease burden in a dose‐dependent manner in a murine MPN model.12,13 In Phase 1/2 clinical trials, fedratinib treatment resulted in durable improvements in splenomegaly and myelofibrosis‐related constitutional symptoms in patients with myelofibrosis, with a consistent and manageable tolerability profile.14,15 This study was conducted as part of the clinical development program of fedratinib, and had the specific aim of characterizing the pharmacokinetic (PK), pharmacodynamic (PD), and safety profile of ascending single doses of fedratinib in healthy subjects (study number: TDU12620).
Methods Study Subjects Subjects were healthy (certified by a comprehensive clinical assessment) men aged 18–45 years. Eligible subjects had laboratory parameters within the normal (not considered clinically significant) range, and normal systolic and diastolic blood pressure, heart rate, and 12‐ lead electrocardiogram (ECG). Key exclusion criteria included: hepatitis B or C, or HIV infection; history or presence of drug or alcohol abuse; consumption of citrus fruits or their juices 5 days before inclusion; vaccination 28 days before inclusion; any medication taken 14 days prior to inclusion. Study Design This was a randomized, double‐blind, placebo‐controlled, sequential, ascending single‐dose study. Subjects were recruited at a single center (Volunteer Research Group, Knoxville, TN) and were randomly allocated, using a randomized list generated by the study sponsor, to receive a single oral dose of placebo or fedratinib 10, 30, 80, 150, 300, 500, or 680 mg. Subjects were fasted for at least 10 hours before, and 4 hours after, fedratinib administration. Subject visits were scheduled as follows: screening (Days 28 to 2), drug administration (Days 1–5), end‐of‐ study (Days 8–10), and post‐study (Days 24–30). Dose escalation was stopped if any of the following occurred in one or more subject: more than one adverse event (AE) of severe intensity at the same dose level; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 upper limit of normal (ULN); serum amylase or lipase >3 ULN; absolute neutrophil count
A Randomized, Placebo‐Controlled Study of the Pharmacokinetics, Pharmacodynamics, and Tolerability of the Oral JAK2 Inhibitor Fedratinib (SAR302503) in Healthy Volunteers
The Journal of Clinical Pharmacology 54(4) 415–421 © 2013, The American College of Clinical Pharmacology DOI: 10.1002/jcph.218
Meng Zhang, MD, PhD1, Christine R. Xu, PhD1, Elias Shamiyeh, MS1, Feng Liu, PhD2, Jian Y. Yin, MD1, Lisa L. von Moltke, MD3, and William B. Smith, MD4
Abstract Fedratinib (SAR302503/TG101348) is a Janus kinase 2 (JAK2)‐selective inhibitor in clinical development for the treatment of myelofibrosis. In this randomized, placebo‐controlled, Phase 1 study, the pharmacokinetics, pharmacodynamics and tolerability of ascending single doses of fedratinib (10– 680 mg) were assessed in healthy male subjects. Fedratinib was rapidly absorbed, with peak plasma concentration observed approximately 3 hours after dosing. The mean terminal half‐life of fedratinib was approximately 67 hours, which was unaffected by dose. Fedratinib exposure increased in a greater than dose‐proportional manner. Suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation, indicative of JAK2 inhibition, was observed at 3 hours post‐dose for subjects in the 300, 500, and 680 mg groups, with the level of suppression increasing with dose. The relationship between fedratinib exposure and suppression of STAT3 phosphorylation was described using an inhibitory effect sigmoid Emax model, with an EC50 of 1,210 ng/mL in healthy subjects. The most common adverse events were mild gastrointestinal toxicities.
Keywords fedratinib, SAR302503, myelofibrosis, pharmacokinetics, healthy subjects
Myelofibrosis is a BCR‐ABL1‐negative chronic myeloproliferative neoplasm (MPN), resulting from transformation of hematopoietic stem/progenitor cells.1 Myelofibrosis, which can occur de novo (primary myelofibrosis) or develop from polycythemia vera or essential thrombocythemia, is characterized by clonal myeloproliferation, dysregulated hematopoiesis, and abnormal expression of cytokines/chemokines.2 The clinical sequelae are anemia, splenomegaly resulting from extramedullary hematopoiesis,2 and debilitating constitutional symptoms.3 Primary myelofibrosis of intermediate‐2 or high‐risk has a median survival of under 4 years, with common causes of death including leukemic transformation, thrombosis, and bleeding.4 The Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway controls a number of basic cell functions, including differentiation, survival, and proliferation.5 Of the JAK family of kinases, JAK2 plays the most important role in the regulation of hematopoiesis, as it is primarily responsible for the mediation of signaling for cytokines such as erythropoietin, thrombopoietin, and granulocyte colony‐stimulating factor.6 Constitutive activation of the JAK‐STAT pathway, most frequently as a result of the V617F activating mutation in the JAK2 protein, is common in patients with
myelofibrosis, and has been implicated in the disease phenotype.7,8 Indeed, hyperactivity of JAK2 may mediate the abnormal cytokine signaling observed in patients with myelofibrosis.9 Ruxolitinib, a JAK1/JAK2 inhibitor approved by the Food and Drug Administration (FDA) for the treatment of myelofibrosis, has demonstrated clinically meaningful reductions in splenomegaly and symptom burden as well as modulation of the level of a number of cytokines.10,11 Fedratinib (SAR302503/TG101348) is an orally administered, JAK2‐selective inhibitor under clinical development for the treatment of myelofibrosis. In
1
Sanofi Clinical and Exploratory Pharmacology, Bridgewater, NJ, USA Sanofi Oncology, Cambridge, MA, USA 3 Sanofi Clinical and Exploratory Pharmacology, Cambridge, MA, USA 4 Volunteer Research Group, University of Tennessee Medical Center, Knoxville, TN, USA 2
Submitted for publication 30 September 2013; accepted 23 October 2013. Corresponding Author: Meng Zhang, Sanofi U.S., Inc., Clinical & Exploratory Pharmacology, P. O. Box 55C‐315A, 55 Corporate Drive, Bridgewater, NJ 08807, USA Email: [email protected]
416 preclinical studies, fedratinib inhibited proliferation of cells carrying JAK2 mutations (e.g., V617F), and reduced extramedullary hematopoiesis and JAK2V617F disease burden in a dose‐dependent manner in a murine MPN model.12,13 In Phase 1/2 clinical trials, fedratinib treatment resulted in durable improvements in splenomegaly and myelofibrosis‐related constitutional symptoms in patients with myelofibrosis, with a consistent and manageable tolerability profile.14,15 This study was conducted as part of the clinical development program of fedratinib, and had the specific aim of characterizing the pharmacokinetic (PK), pharmacodynamic (PD), and safety profile of ascending single doses of fedratinib in healthy subjects (study number: TDU12620).
Methods Study Subjects Subjects were healthy (certified by a comprehensive clinical assessment) men aged 18–45 years. Eligible subjects had laboratory parameters within the normal (not considered clinically significant) range, and normal systolic and diastolic blood pressure, heart rate, and 12‐ lead electrocardiogram (ECG). Key exclusion criteria included: hepatitis B or C, or HIV infection; history or presence of drug or alcohol abuse; consumption of citrus fruits or their juices 5 days before inclusion; vaccination 28 days before inclusion; any medication taken 14 days prior to inclusion. Study Design This was a randomized, double‐blind, placebo‐controlled, sequential, ascending single‐dose study. Subjects were recruited at a single center (Volunteer Research Group, Knoxville, TN) and were randomly allocated, using a randomized list generated by the study sponsor, to receive a single oral dose of placebo or fedratinib 10, 30, 80, 150, 300, 500, or 680 mg. Subjects were fasted for at least 10 hours before, and 4 hours after, fedratinib administration. Subject visits were scheduled as follows: screening (Days 28 to 2), drug administration (Days 1–5), end‐of‐ study (Days 8–10), and post‐study (Days 24–30). Dose escalation was stopped if any of the following occurred in one or more subject: more than one adverse event (AE) of severe intensity at the same dose level; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 upper limit of normal (ULN); serum amylase or lipase >3 ULN; absolute neutrophil count
