A case-study of model-informed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II

Abstract

Here, we show model-informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first-in-human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de-risk a phase IIb study. The focus of the case-study is on the cross-functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.

FIGURE 1

Overview of MIDD strategy (a), early clinical program (b), and the core clinical MIDD team composition (c). FDA, US Food and Drug Administration; LDL‐C, low‐density lipoprotein cholesterol; MAD, multiple ascending dose; MIDD, model‐informed drug development; PCSK9, proprotein convertase subtilisin/kexin type 9; Ph2, phase II; PMX, pharmacometrics; SAD, single ascending dose.

FIGURE 2

Quantitative relationship between PCSK9 and LDL‐C. Mean digitized evolocumab and inclisiran data (gray circles) at steady‐state levels. The size of the gray circles is proportional to the sample size. Colored points represent nadir observations in the SAD study. Lines represent mean steady‐state PCSK9~LDL‐C relationship by inclisiran (red) K‐PD model and evolocumab (black) PK‐PD model; corresponding shaded areas represent 90% prediction intervals. Model simulations and observed data from evolocumab and inclisiran are at steady‐state. The observed AZD8233 data are nadir observations from a single dose. K‐PD, kinetic‐pharmacodynamic; mAb, monoclonal antibody; PK‐PD, pharmacokinetic‐pharmacodynamic; SAD, single ascending dose; siRNA, small interfering ribonucleic acid.

FIGURE 3

Continuous dose prediction based live data stream from the SAD in healthy volunteers. Left panel indicates date of data delivery. Middle panel shows the PCSK9 change from baseline at each delivery by dose. Right panel indicates the dose prediction at time of data delivery. The light blue line indicates dose prediction based on NHP data. The dark blue line and gray lines indicate the dose prediction based on the PCSK9 data from the SAD study. The gray lines indicate the 90% confidence interval. NHP, non‐human primate; SAD, single ascending dose.

FIGURE 4

Justification of phase II study sample size (top row) and dose selection (bottom row). Probability to select the correct dose by sample size (a), posterior probability of observing an LDL‐C reduction >69% in future studies with various sample size (b), PCSK9 dose–response curve (c), probability of technical success to reach 90% PCSK9 inhibition in 50% of subjects (orange), and 90% of subjects (green) by dose (d). CI, confidence interval; MAD, multiple ascending dose; SAD, single ascending dose.