A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9

Abstract

Purpose: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.

Methods: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.

Results: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.

Conclusions: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.

Trial registration: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

Keywords: Active immunotherapy; First-in-human study; Hypercholesterolemia; In vivo antibody development; LDLc reduction; PCSK9.

Conflict of interest statement

All authors have completed and submitted the “ICMJE Form for Disclosure of Potential Conflicts of Interest.” Conflicts of interests have been declared by the following authors: PL, CL, GS AK and GG are or were employees of AFFiRiS AG at the time of the study. RM, CS, and RMM receive honoraria from AFFiRiS AG. RMS is an employee and shareholder of The Medicines Company and Novartis AG, after completion of the study. GL received research funding from AFFiRiS AG. The Medical University of Vienna received financial support for conducting the study. No direct honoraria were obtained by MZ, MB, RRS, EBS, HL, ZO, and BW.

© 2021. The Author(s).

Figures

Fig. 1

Study design

Fig. 2

Titers against immunizing peptides AT04 and AT06, and the PCSK9 target epitope over time

Fig. 3

Impact of the active treatments on LDL cholesterol (post hoc analysis)

Fig. 4

Waterfall plot for the individual LDLc change upon exposure to AFFITOPE® AT04A at week 70 and week 90