Date Published: January 3, 2020
Publisher: Springer International Publishing
Author(s): Jason H. Williams, Chandrasekhar Udata, Bishu J. Ganguly, Samantha L. Bucktrout, Tenshang Joh, Megan Shannon, Gilbert Y. Wong, Matteo Levisetti, Pamela D. Garzone, Xu Meng.
IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.
Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell–mediated destruction of the insulin-secreting beta cells, resulting in insulin deficiency and hyperglycemia . The standard-of-care treatment is daily insulin injections in an effort to normalize blood glucose levels throughout the day and ultimately to prevent long-term diabetic complications including diabetic retinopathy, nephropathy, and neuropathy. Despite the improvements in management of diabetes, there are no approved therapies which modulate the course of disease, and a large proportion of subjects with T1D fail to achieve optimal glycemic control.
A mechanism-based model was proposed which integrates the PK and target engagement biomarker profiles into a single mathematical framework, described by a set of algebraic and ordinary differential equations. The estimated rate of absorption and peripheral volume of distribution were consistent with previous estimates for therapeutic mAbs . The estimate of the central volume of distribution (1.1 L) was lower relative to published values for mAbs (2.4 to 5.5 L) which may have been due to the lack of PK data in T1D subjects following IV administration as well as rapid binding of PF-06342674 to IL-7Rα in the central compartment. Clearance of free mAb (CLA = 1 L/day) was more rapid than the value reported for mAbs which ranged from 0.2 to 0.5 L/day . Estimation of the dissociation constant for drug-target binding (KD), which relied on rich PK/PD sampling schemes and measurements of drug concentration, total soluble receptor, and cellular receptor using independent bioanalytical approaches, indicated that PF-06342674 binds with high affinity to cellular (KD2 = 0.450 nM) and soluble IL-7 receptor targets (KD1 = 0.779 nM).
The proposed modeling framework adequately characterized the PK, target engagement biomarkers, and immunomodulatory activity of PF-06342674, a humanized mAb against IL-7Rα in subjects with T1D. PF-06342674 binds with high affinity to cellular (KD2 = 0.450 nM) and soluble IL-7 receptor targets (KD1 = 0.779 nM), with elimination of PF-06342674 via the cellular IL-7 receptor-mediated pathway the most likely source of nonlinear PK. Inter-individual variability in PK and RO was mainly attributed to variation in the absorption rate, central volume, and clearance of the free antibody. The DR relationship characterizing the effects of PF-06342674 on the Treg:TEM T cell ratio provides evidence that IL-7Rα blockade may shift the balance from autoimmunity towards immune tolerance. The Treg:TEM T cell ratio increased with higher doses up to approximately 3 mg/kg q2w, after which further increasing the dose resulted in a decline in the Treg:TEM T cell ratio due to an increasing inhibitory effect of PF-06342674 on Treg numbers. Notably, the maximal effective dose with respect to Treg:TEM T cell ratio coincides with the dose level that results in near maximal IL-7 RO. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of integrating PK and multiple biomarkers using insightful mechanistic modeling approaches to gain quantitative understanding of the PK/PD relationships and support dose selection of a drug candidate in the early phases of development.