Date: Sunday, November 8, 2020
Session Title: Osteoarthritis I: Clinical Trials (1482–1486)
Session Type: Abstract Session
Session Time: 4:00PM-4:50PM
LNA043 is a modified human angiopoietin-like 3 (ANGPTL3) protein identified in a phenotypic screen for inducers of chondrogenesis and cartilage repair. The primary objective of this trial (NCT02491281) was to assess safety and tolerability of single intraarticular doses of LNA043 into the knee of patients with knee osteoarthritis (OA).
A first-in-human, randomized, single-center, placebo-controlled, double-blind, single ascending dose trial was conducted in patients aged 50–75 years with knee OA scheduled for total knee replacement (TKR). Patients were randomized 3:1 (LNA043 to placebo) in each of 7 cohorts consisting of 4 patients each. The 5 increasing intraarticular dose levels ranging 0.2–40 mg (0.2 mg, 2 mg, 10 mg, 20 mg, 40 mg) administered 7 days before TKR. Two additional 20 mg dose levels were also administered 2 hours or 21 days before TKR. Key safety parameters included adverse events (AEs), injection-site reactions and detection of anti-drug antibodies against LNA043. Knee tissues were obtained during the TKR procedure to assess local exposure to LNA043 through immunohistochemical (IHC) staining, and cartilage biopsies were harvested from worn and unworn areas of the knee to perform RNA-Seq analysis.
Results: 30 patients were randomized to LNA043 (n=21) or placebo (n=7), 2 withdrew consent prior to treatment. Pertinent demographic information included: a mean age of 63 years, 68% female (n=19), and 96% Caucasian (n=27) participants. A total of 19 (14 on LNA043 and 5 on placebo) patients experienced at least one AE. The overall incidence of AEs for LNA043 was 66.7% (14/21). The overall incidence of AEs for placebo was 71.4% (5/7). One case of dry mouth/dysgeusia was reported in the 40 mg cohort, which resolved spontaneously and was considered mild. Ten non-study drug-related, serious AEs were reported in five patients (LNA043, n=3; placebo, n=2). Anti-LNA043 antibodies were not detected in the patients. After intraarticular injection, LNA043 was dose-dependently distributed from the joint to systemic circulation with Cmax typically reached between 2 to 6 hours after the intraarticular injection. IHC demonstrated that LNA043 penetrated the articular cartilage shortly after injection (2 hours), with more pronounced penetration into the damaged areas (Figure 1A). LNA043 was not detectable in the articular cartilage or synovial-fluid 7 days post intraarticular injection. RNA-Seq analysis demonstrated modulation of several genes involved in cartilage homeostasis and repair, suggesting a broad effect by LNA043 up to 21 days post-injection (Figure 1B). These effects were both dose-dependent and mostly present in the worn cartilage tissue.
Conclusion: In this study, LNA043 displayed a favorable safety profile without any clinically significant drug-related safety signals or immunogenicity. In addition, LNA043 penetrated transiently into the articular cartilage; was quickly cleared locally and systemically; and elicited a chondroanabolic response as shown by modulating several pathways in chondrocytes involved in OA and cartilage repair at the RNA level. Further studies of LNA043 for treatment of knee OA are now in progress.
To cite this abstract in AMA style:Scotti C, Gimbel J, Laurent D, Madar A, Peters T, Zhang Y, Polus F, Beste M, Vostiar I, Choudhury S, Gerwin N, Goldhahn J, Schieker M, Roubenoff R. LNA043, a Novel Cartilage Regenerative Treatment for Osteoarthritis: Results from a First-In-Human Trial in Patients with Knee Osteoarthritis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/lna043-a-novel-cartilage-regenerative-treatment-for-osteoarthritis-results-from-a-first-in-human-trial-in-patients-with-knee-osteoarthritis/. Accessed March 27, 2023.
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