10.3.8 - Regeneration of Hyaline Cartilage at the Biopsy Site of ACI Patients with a Single Injection of LNA043, an ANGPTL3 Mimetic
- S. Nehrer (Krems, AT)
- S. Nehrer (Krems, AT)
- D. Laurent (Basel, CH)
- C. Scotti (Basel, CH)
- M. Schreiner (Vienna, AT)
- M. Neubauer (Krems, AT)
- T. Muellner (Krems, AT)
- O. Zaric (Vienna, AT)
- V. Juras (Vienna, AT)
- P. Szomolanyi (Vienna, AT)
- J. Goldhahn (ETH Zurich, CH)
- J. Praestgaard (East Hanover, US)
- N. Gerwin (Basel, CH)
- R. Roubenoff (Basel, CH)
- M. Schieker (Basel, CH)
- S. Trattnig (Wien, AT)
Abstract
Purpose
LNA043 is a modified human angiopoietin-like-3 (ANGPTL3) protein with chondro-anabolic properties. A first-in-human trial showed a favorable safety profile and modulation of pathways involved in osteoarthritis. The primary objective of this trial (NCT 03334812) was to assess the efficacy of a single intra-articular (i.a.) injection of LNA043 in regenerating hyaline cartilage at the donor site in patients undergoing autologous chondrocyte implantation (ACI).
Methods and Materials
This randomized, placebo-controlled, double-blind, proof-of-mechanism study included 14 subjects who received an i.a. LNA043 injection (randomization 2:1) at the end of the cartilage-harvesting procedure. Cartilage regeneration in the full-thickness defect at the ACI donor and index lesion was assessed via lesion-volume changes and glycosaminoglycan content (GAG) at Day 3 (baseline), Weeks 4 (primary endpoint), 12 and 28, using 7T magnetic resonance imaging (MRI), and histology of biopsies (second surgery, Week 4).
Results
LNA043 treatment resulted in a 65±8% refilling (vs placebo: 38±11%, p=0.04) of the donor site after 4 weeks (Figure 1), and increased to 86±11% at Week 28 (vs placebo: 63±14%, p=0.12). The index lesion showed partial repair at Week 4 (change from baseline-volume of the defect-encompassing sub-region: LNA043: +128±97mm3 vs placebo: +16±30mm3, p=0.03). Sodium-MRI demonstrated increased GAG-content of the regenerated donor site (sodium signal-increase of 26±5%, 16±6% and 38±7% for LNA043 vs. -2±12% (p=0.12), 13±10% (p=0.51) and 8±21% (p=0.15) for placebo at Weeks 4, 12 and 28) (Figure 2). Histology and immunohistochemistry confirmed the presence of hyaline cartilage. LNA043 was rapidly distributed into the circulation, no drug-related adverse events (AEs) or serious AEs were reported. No binding anti-LNA043 antibodies were detected.
Conclusion
A single i.a. injection of LNA043 at 20 mg promoted refilling of the donor site in patients undergoing ACI. The newly formed tissue showed hyaline-like quality, LNA043 displayed a favorable safety profile without significant drug related safety signals or immunogenicity.