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Published in: Rheumatology and Therapy 3/2024

Open Access 25-04-2024 | Pharmacokinetics | Original Research

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers

Authors: Lyrialle W. Han, Samira Jamalian, Joy C. Hsu, X. Rebecca Sheng, Xiaoyun Yang, Xiaoying Yang, Sharareh Monemi, Sharmeen Hassan, Rajbharan Yadav, Katie Tuckwell, Rebecca Kunder, Lin Pan, Sara Glickstein

Published in: Rheumatology and Therapy | Issue 3/2024

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Abstract

Introduction

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs).

Methods

This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations.

Results

The study enrolled 49 HVs, with a median age of 39 (range 18–73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration–time curve from time 0 to infinity (AUC0–inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition.

Conclusion

RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy.

Trial Registration

ISRCTN13175485.
Appendix
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Metadata
Title
A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers
Authors
Lyrialle W. Han
Samira Jamalian
Joy C. Hsu
X. Rebecca Sheng
Xiaoyun Yang
Xiaoying Yang
Sharareh Monemi
Sharmeen Hassan
Rajbharan Yadav
Katie Tuckwell
Rebecca Kunder
Lin Pan
Sara Glickstein
Publication date
25-04-2024
Publisher
Springer Healthcare
Published in
Rheumatology and Therapy / Issue 3/2024
Print ISSN: 2198-6576
Electronic ISSN: 2198-6584
DOI
https://doi.org/10.1007/s40744-024-00670-5

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