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Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel Psyk Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers

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Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel Psyk Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Clin Drug Investig (2017) 37:195–205 DOI 10.1007/s40261-016-0476-x ORIGINAL RESEARCH ARTICLE Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers 1 1 1 1 1 Srini Ramanathan • Julie A. Di Paolo • Feng Jin • Lixin Shao • Shringi Sharma • 1 1 Michelle Robeson • Brian P. Kearney Published online: 26 October 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract concentrations (corresponding pSYK inhibition of[70 and Background and Objectives Entospletinib is a selective, [50%). reversible, adenosine triphosphate-competitive small- Conclusion The overall safety, pharmacokinetics, and molecule spleen tyrosine kinase (SYK) inhibitor that pharmacodynamics profiles of entospletinib support further blocks B cell receptor-mediated signaling and proliferation clinical evaluation. in B lymphocytes. This study evaluated the safety, phar- macokinetics, and pharmacodynamics of entospletinib in a double-blind, single/multiple ascending dose study in Key Points healthy volunteers. Methods In sequential cohorts, 120 subjects received Entospletinib is a selective oral inhibitor of spleen entospletinib (25–1200 mg; fasted) as single or twice-daily tyrosine kinase (SYK) that has been linked to the oral doses for 7 days. Along with pharmacokinetics, the pathogenesis of a variety of B cell malignancies, study assessed functional inhibition of ex vivo anti-im- including chronic lymphocytic leukemia and various munoglobulin E-stimulated CD63 expression on basophils subtypes of non-Hodgkin’s lymphoma. and pervanadate-evoked phosphorylated SYK (pSYK) Y525. Safety and tolerability were assessed throughout the When administered in single or multiple oral doses study. in healthy adults, entospletinib monotherapy is Results Entospletinib was generally well-tolerated over a generally well-tolerated. 48-fold dose range. Adverse events (AEs) were generally Entospletinib displays a median plasma half-life of mild to moderate, with no AE-driven study drug discon- 9–15 h; exposures plateau at C600 mg twice-daily tinuations noted. Entospletinib displayed a median plasma doses, which provides [50% coverage at trough half-life of 9–15 h; entospletinib exposures reached a pla- concentrations (based on CD63/phosphorylated SYK teau at C600 mg twice daily (likely due to solubility-lim- biomarker assessment). ited absorption) and provided [90% CD63 inhibition at peak concentrations and [60% inhibition at trough Electronic supplementary material The online version of this 1 Introduction article (doi:10.1007/s40261-016-0476-x) contains supplementary material, which is available to authorized users. Spleen tyrosine kinase (SYK) is a non-receptor, cytoplas- & Shringi Sharma mic protein tyrosine kinase that is predominantly expressed [email protected] in cells of hematopoietic lineage. It is an important medi- 1 Gilead Sciences, Inc., 333 Lakeside Drive, ator of immunoreceptor signaling in macrophages, neu- Foster City, CA 94404, USA trophils, mast cells, and B cells. 196 S. Ramanathan et al. In B lymphocytes, antigen-mediated stimulation of the aspartate aminotransferase elevations. Overall, entosple- B cell receptor (BCR) results in the recruitment and tinib demonstrated clinical activity in subjects with phosphorylation of various kinases, including SYK. Phos- relapsed or refractory CLL with acceptable toxicity [7]. phorylation of SYK (pSYK) leads to the activation and This paper reports the results of the first-in-human (FIH) amplification of downstream receptor signaling and likely study conducted to evaluate the safety, tolerability, phar- plays a role in chemokine signaling and cellular responses macokinetics, and pharmacodynamics of entospletinib in such as proliferation, survival, differentiation, and apop- healthy volunteers following single- and multiple-dose oral tosis [1, 2]. administration. The data from this study provided the basis Uncontrolled BCR signaling via SYK has been impli- for subsequent testing of the safety and efficacy of cated in the pathogenesis of several common B cell entospletinib in cancer patients. malignancies, including chronic lymphocytic leukemia Further, this paper describes entospletinib pharmacoki- (CLL), diffuse large B cell lymphoma (DLBCL), follic- netics following multiple-dose administration (doses of ular lymphoma (FL), mantle cell lymphoma (MCL), 100–1200 mg twice daily) under fed conditions across marginal zone lymphoma, and B-lineage acute lym- additional healthy volunteer studies. phoblastic leukemia. Given the vital role of SYK in BCR signaling, inhibitors of SYK activity are an attractive therapeutic option for hematopoietic B cell lymphomas 2 Methods and other non-Hodgkin’s lymphoma histologies, where SYK inhibition would prevent BCR-mediated signaling 2.1 Ethics and therefore prevent the uncontrolled growth of lym- phoma cells [3, 4]. All study protocols were reviewed and approved by the A number of molecules targeting the SYK pathway for local institutional review boards (all studies were con- allergic, autoimmune, and neoplastic disorders are cur- ducted at Algorithme Pharma, Inc., Laval, QC, Canada). rently in various stages of development. These include The studies were conducted in accordance with recognized adenosine triphosphate (ATP)-binding site inhibitors (fos- international scientific and ethical standards, including but tamatinib, CG14979, and P505-15), P-site inhibitors (C- not limited to the International Conference on Harmo- 61), antisense oligonucleotides, and small-interfering nization guideline for Good Clinical Practice and the RNAs [5]. original principles embodied in the Declaration of Helsinki. Clinical investigation of fostamatinib, the prodrug of These standards are consistent with the requirements of the SYK inhibitor R406, in B cell malignancies demonstrated US Code of Federal Regulations Title 21, Part 312 responses in CLL/small lymphocyte leukemia (overall (21CFR312) and the European Community Directive response rate [ORR] 55%), DLBCL (ORR 22%), MCL 2001/20/EC. Written informed consent was obtained from (ORR 11%), and FL (ORR 10%) following doses of 200 or all participants. 250 mg twice daily. Reported toxicities included diarrhea, nausea, hypertension, cytopenias, and fatigue, which lim- 2.2 Study Design ited dosing and have been partially attributed to off-target effects, including the inhibition of multiple kinases in The FIH study was a phase I, randomized, double-blind, addition to SYK [6]. placebo-controlled, single and multiple dose-escalation Entospletinib (GS-9973) is a highly selective and oral study, involving an oral tablet formulation of the mono- SYK inhibitor and is currently undergoing clinical evalu- mesylate salt of entospletinib. Subjects received either ation for autoimmune and oncology indications. single or multiple doses of entospletinib (or placebo) under Entospletinib is an ATP-competitive inhibitor of SYK that fasted conditions (Table 1). The study cohorts were disrupts kinase activity with a half-maximal inhibitory enrolled in a staggered fashion; single-dose cohorts were concentration (IC50) of 7.6 nmol/L. A phase II study escalated after review of the safety/pharmacokinetic data, involving entospletinib 800 mg twice-daily oral adminis- allowing at least 1 week between cohorts, and multiple- tration in subjects with relapsed or refractory CLL dose cohorts were initiated/escalated after review of safety/ (n = 41) showed a progression-free survival (PFS) rate of pharmacokinetics from the single-dose cohorts (up to 70.1% (at 24 weeks), median PFS of 13.8 months, and an 200 mg) (Electronic Supplementary Material Fig. S1). ORR of 61.0%. The most common treatment-emergent Additionally, open-label, multiple-cohort, multiple-dose serious adverse events (AEs) included dyspnea, pneumo- studies were conducted that evaluated the pharmacokinet- nia, febrile neutropenia, dehydration, and pyrexia. Com- ics of entospletinib under fed conditions, i.e., co-adminis- mon Grade 3/4 laboratory abnormalities included tration with a standard meal of *400–500 calories with neutropenia and reversible alanine aminotransferase/ *10–13 g of fat (Table 1). PKs and PDs of Entospletinib 197 Table 1 Study design and baseline characteristics of phase I clinical studies included in the analyses Clinical characteristic FIH study (fasted) Fed studies Dose Single (day 1):a 25, 75, Multiple (day 1 to day 7, twice daily):b Multiple (day 1 to day 6, twice daily):c 200, 600, 1200 mg 25, 75, 200, 600, 900, 1200 mg 100, 200, 600, 900, 1200 mg Multiple (day 1 to day 7, once daily): 900 mg Population Healthy subjects Healthy subjects Healthy subjects Subjects (n)507064 Body weight [median (range); kg] 73 (52–94) 74 (46–101) 70 (52–96) Age [median (range); years] 36 (19–45) 32 (18–45) 33 (18–57) Sex [n (%); male] 28 (56) 60 (86) 34 (56) Race [n (%); white] 41 (82) 62 (89) 54 (84) FIH first-in-human a Pharmacokinetic sampling times were conducted at 0, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 18, 24, 28, 36, and 48 h post-dose. Pharma- codynamic sampling times were conducted at 0, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 18, 24, 28, and 48 h post-dose b Pharmacokinetic sampling times for day 1 were conducted at 0, 2, 4, 6, and 12 h post-dose. Pharmacodynamic sampling times for day 1 were conducted at 0, 2, 4, 6, and 12 h post-dose. Pharmacokinetic
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