Background:LNA043 is a modified, recombinant version of the human angiopoietin-like 3 (ANGPTL3) protein acting directly on cartilage-resident cells to transmit its cartilage anabolic effect. A first-in-human study previously demonstrated the favourable safety profile and the modulation of several pathways involved in cartilage homeostasis and osteoarthritis (OA)1. A previous proof-of-mechanism imaging study used high field (7 Tesla) magnetic resonance imaging (MRI) to show formation of hyaline-like tissue after a single injection of 20 mg LNA043 (unpublished data).Objectives:To evaluate non-invasively the chondro-regenerative capacity of multiple intra-articular (i.a.) injections of LNA043 in patients with articular cartilage lesions in the knee (NCT03275064).Methods:This was a randomised, double-blind, placebo (PBO)-controlled, proof-of-concept study in patients with a partial thickness cartilage lesion. In total, 58 patients (43 [20 mg LNA043]; 15 [PBO]), stratified by lesion type (condylar or patellar) were treated with 4 weekly i.a. injections. The primary endpoint was T2 relaxation time measurement as a marker of collagen fiber network, and cartilage lesion-volume was a secondary endpoint, both using 3-Tesla MRI. Assessments were performed at baseline, weeks (wks) 8, 16, 28 and 52 (the latter in 23/58 patients). While lesion-volume for the secondary endpoint was determined from manually segmented images, the cartilage volume of 21 sub-regions spanning the entire knee was also measured from 3D isotropic MR images employing an automated segmentation prototype software (MR Chondral Health 2.1 [MRCH], Siemens Healthcare)2. An exploratory analysis evaluated the treatment effect for the additive volume of the 3 subregions in the weight-bearing area of the medial femur.Results:No change in T2 relaxation time was detected between treatment and PBO groups. Manual segmentation showed continuous filling of the cartilage lesions up to wk 28 in LNA043-treated patients with femoral lesions (p=0.08, vs PBO) while no effect was detected for patients with patellar lesions. Given the limitations of measuring small, irregularly shaped lesions with manual image-analysis, the MRCH approach was used (Figure 1). In the medial femoral weight-bearing region, refilling was detected over time (Δ=123 mm3 at wk 28, N= 37, p= 0.05). No overgrowth was detected in the lateral femoral condyles without cartilage damage. The overall safety profile was favourable; only mild/moderate local reactions were reported, including a higher incidence of joint swelling (9.3% vs 0%) and arthralgia (11.6% vs 6.7%) for LNA043 vs PBO resolving spontaneously or with paracetamol/NSAIDs. No anti-drug antibodies were detected.Conclusion:Treatment with 4 weekly i.a. injections of 20 mg LNA043 resulted in regeneration of damaged cartilage in patients with femoral articular cartilage lesions. Automated measurement of cartilage volume in the femoral index region was able to detect a relevant treatment effect and was found to be more sensitive than the manual segmentation method. No sign of cartilage overgrowth was observed in healthy femoral regions. A Phase 2b study in patients with mild to moderate knee OA is in preparation.References:[1]Scotti et al. ACR Convergence 2020; Abstract #1483[2]Juras et al. Cartilage 2020; Sep 29:1-12Disclosure of Interests:Siegfried Trattnig: None declared, Celeste Scotti Shareholder of: Novartis, Employee of: Novartis, Didier Laurent Shareholder of: Novartis, Employee of: Novartis, Vladimir Juras: None declared, Scott Hacker Grant/research support from: Novartis, Brian Cole: None declared, Libor Pasa: None declared, Roman Lehovec: None declared, Pavol Szomolanyi: None declared, Esther Raithel Employee of: Siemens Healthcare GmbH, Franziska Saxer Shareholder of: Novartis, Employee of: Novartis, Jens Praestgaard Shareholder of: Novartis, Employee of: Novartis, Fabiola La Gamba Shareholder of: Novartis, Employee of: Novartis, José L. Jiménez Employee of: Novartis, David Sanchez Ramos Shareholder of: Novartis, Employee of: Novartis, Ronenn Roubenoff Shareholder of: Novartis, Employee of: Novartis, Matthias Schieker Shareholder of: Novartis, Employee of: Novartis
Comparison of proteoglycans extracted from high and low weight-bearing human articular cartilage, with particular reference to sialic acid content.