Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies

Abstract

4853 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions. PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and contribute to the development and maintenance of inflammatory and autoimmune diseases and hematologic malignancies. IPI-145 is a potent inhibitor of PI3K- δ,γ isoforms (Ki = 23 pM and 243 pM, respectively) in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The pharmacokinetics (PK) and pharmacodynamics (PD) of IPI-145 were evaluated in a Phase 1 clinical study in healthy subjects and are being characterized in patients with advanced hematologic malignancies. Methods: In a healthy subject study, IPI-145 was administered orally as a single dose and as multiple doses once daily (QD) or twice daily (BID) for 14 days. In a Phase 1 oncology study, IPI-145 was administered orally starting at a dose of 8 mg BID. PK and PD markers were evaluated after the first dose and at steady state. PD activity (PI3K inhibition) in whole blood was evaluated using a basophil activation assay which measured reduction in CD63 expression on the surface of basophils following ex vivo stimulation. Results: IPI-145 was well tolerated in healthy subjects at single doses up to 30 mg (highest dose tested) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of IPI-145 is characterized by rapid absorption (peak plasma concentrations reached within 0.5–1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). Minimal accumulation was observed after multiple dose administration (accumulation ratio 1.65–1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged IPI-145 in urine was <2% of the administered dose, indicating minimal renal elimination of parent drug. CD63 expression on the surface of activated CCR3+ basophils was reduced in a dose-dependent manner at all single and multiple dose levels, with a maximum reduction at 1 hour post dose, corresponding to the time of maximum IPI-145 plasma concentrations. Inhibition of basophil activation mirrored the IPI-145 concentration-time profile, with CD63 expression returning to baseline levels as plasma concentrations declined. Administration of 5 mg BID maintained PI3K-δ inhibition (EC50 = 48 ng/mL) throughout the 12 hour dosing interval. Concomitant administration of a high-fat, high-calorie meal decreased Cmax approximately 10%, shifted median Tmaxfrom 1 to 3 hours, and increased overall exposure (AUC) approximately 8–9%. These data suggest IPI-145 may be administered without regard to meals. Emerging data from a Phase 1, dose escalation study in subjects with hematologic malignancies demonstrate rapid drug absorption and dose-proportional PK. As in healthy subjects, maximum inhibition of basophil activation was observed 1 hour post dose. Prior to dose administration at the beginning of Cycle 2 (i.e. after 28 days of BID dosing), CD63 expression was reduced 45% or more relative to the start of treatment. Mean steady-state trough concentrations were maintained above levels sufficient for PI3K-δ inhibition following doses ≥15 mg BID. Early signs of clinical response have been observed. Conclusions: Across both Phase 1 studies, IPI-145 drug absorption was rapid and exposure was proportional to dose. CD63 expression on the surface of activated basophils was reduced in the presence of IPI-145 in both healthy and oncology subjects, an observation consistent with PI3K-δ inhibition. An exposure-response relationship was evident, suggesting a concentration-dependent pharmacological response to IPI-145. Preliminary PK/PD data from the oncology study demonstrate inhibition of PI3K-δ activity and suggest higher doses may increasingly suppress PI3K-γ activity. Dose escalation and PK/PD monitoring are ongoing. Collectively, the data available support the clinical development of IPI-145 as a potential therapeutic in hematologic malignancies and inflammatory diseases. Disclosures: Dunbar: Infinity Pharmaceuticals, Inc.: Employment. Nevejans:Infinity Pharmaceuticals, Inc.: Employment. McKee:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Zhao:ApoCell: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Patel:Infinity Pharmaceuticals, Inc.: Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc.: Research Funding; Gilead: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Research Funding.

Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

“…The pharmacokinetics, safety and efficacy of IPI-145 have been studied in early phase clinical trials that included healthy subjects as well as patients with advanced hematologic malignancies [ 138 , 139 ]. The compound was well tolerated at doses up to 25 mg BID, exhibited excellent target inhibition (CD63 expression), and showed initial clinical activity in patients with iNHL, MCL, and CLL [ 139 ].…”

Theoretical studies on beta and delta isoform-specific binding mechanisms of phosphoinositide 3-kinase inhibitors

“…9 Extensive efforts have been made to discover and develop inhibitors that target the PI3K pathway. Fortunately, a variety of class I PI3K inhibitors have been developed and some of them have even been pushed into preclinical or clinical studies, [10][11][12] such as the pan-PI3K inhibitors, including GDC-0941 (phase I/II clinical trials), 13 NVP-BKM120 (phase I/II clinical trials), 14 PX-866 (phase I/II clinical trials), 15 and XL-147 (phase I/II clinical trials), 16 and the isoform-specific inhibitors, including INK1117 (phase I clinical trials) 17 and PIK-75 (preclinical) 18 that target p110a, TGX-221 (preclinical) 19 that targets p110b, IC87114 (preclinical) 20 and AMG-319 (phase I clinical trials) 21 that target p110d, and IPI-145 (phase I/II clinical trials) 22 that targets p110g. Most of these small molecule inhibitors bind to the ATP-binding site of the catalytic domain of PI3K.…”