Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The plasma pharmacokinetics (PK) of second generation antisense oligonucleotides (ASOs) are fairly well understood with well conserved pharmacokinetic properties across species, moderate clearance and extensive volume of distribution. WHAT THIS STUDY ADDS • The tissue distribution and exposure and the pharmacodynamic (PD) or target inhibition following ASO administration are not yet well understood leading to still fairly empiric early clinical development strategies. This paper illustrates how preclinical PK and PD data were used to predict more accurately the ASO tissue exposure in humans and to support the early clinical development strategy. AIMS To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans. METHODS An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non‐linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles. RESULTS Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g−1 were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g−1 (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central Vd, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h−1, peripheral Vds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h−1 (5.6, 33.4) and mean terminal half‐life, 32.7 days (range 22–52 days). CONCLUSION The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.

Tumor Survivin Is Downregulated by the Antisense Oligonucleotide LY2181308: A Proof-of-Concept, First-in-Human Dose Study

“…The transition from part A to part B was planned on the basis of either development of toxicity or evidence from PK that the predicted biological effective dose (BED) had been reached. The recommended dose for phase 2 studies was determined from both DLT and the reduction in survivin expression in tumor tissue at the anticipated BED as defined by the preclinical PK/PD model of Callies et al (10). At the recommended phase 2 dose, 2 companion studies were conducted at the Universities of Oxford (study 1, endobronchial tumor sampling) and Manchester (study 2, […”

“…Compared with phosphorothioate or first-generation ASOs, second-generation ASOs are more stable, have an improved pharmacokinetic (PK) profile, increased potency, and reduced toxicity (9). Using aggregate data from preclinical pharmacology and toxicology, an integrated PK/PD (pharmacodynamic) model was developed to predict a biologically effective dose range for clinical evaluation (10). On the basis of this, a firstin-human dose (FHD) study was designed to evaluate the biodistribution profile of LY2181308 by measuring the following tumor-specific PD changes: tumor tissue penetration of LY2181308, downregulation of tumor survivin at the mRNA, and protein levels and restoration of tumor apoptosis at a dose and schedule that was safe in humans.…”

Clinical aspects for survivin: a crucial molecule for targeting drug-resistant cancers

“…An added advantage in the use of gataparsen is its high drug retention capacity in the host which goes up to 21 days. The distribution of this drug in animal tissues is rapid and the levels of drug elimination are low-to-moderate [86]. Analysis of plasma samples collected from patients showed that the primary sites of uptake of gataparsen were the renal and hepatic tissues and the elimination time of the drug was close to 31 h with a half-life of 12 h [87].…”

Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML)

“…Thereafter, PK assessment samples were taken every fourth week starting on Visit 3, Day 57 (prior to LY2181308 infusion) and at the follow up visit 21 days after patients had taken their last dose of study drug. Mean population plasma LY2181308 PK parameters (clearance, exposure, volume of distribution, half-lives) and subject variability were computed using non-linear mixed effect modeling [15] (implemented in NONMEM®, ICON corporation, Ellicott City, MD, version VI).VI In addition, LY2181308 PK parameters (maximum concentration [Cmax], area under the curve [AUC], and clearance [Cl]) were determined by standard non-compartmental methods of analysis using WinNonlin ® Professional Edition version 5.2 (Pharsight Corporation, Mountain View, CA).…”