A FIRST-IN-HUMAN PHASE 1/2A CLINICAL STUDY OF ICM-203 AAV GENE THERAPY: PROMISING SIGNALS AS A DMOAD CANDIDATE

INTRODUCTION

ICM-203, a recombinant AAV vector designed to express a truncated form of human Nkx3.2, a transcription factor which plays an important role in both chondrocyte and synoviocyte activity, is in clinical development as a potential DMOAD.

OBJECTIVE

An unblinded interim analysis of the low dose cohort of the first-in-human phase 1/2a study of ICM-203 was conducted to assess the safety, immunogenicity, and biological activity of ICM-203.

METHODS

In the low dose cohort of this phase 1/2a, double-blind, placebo-controlled, dose escalation study (NCT04875754), 8 subjects with Kellgren-Lawrence grade 3 osteoarthritis (OA) of the knee were randomized to receive a single intra-articular injection of ICM-203 or placebo in a 3:1 ratio. The primary safety endpoint was safety and tolerability of ICM-203 through assessment of treatment-emergent adverse events (TEAEs). Immunogenicity endpoints included measuring serum neutralizing antibody (NAb) titers and T-cell responses to ICM-203’s AAV capsid. As efficacy endpoints, changes in knee pain and function were assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale and KOOS activities of daily living (ADL) subscale, respectively; these KOOS scores were converted to calculate Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Imaging endpoints included Magnetic Resonance Imaging (MRI) Osteoarthritis Knee Scores (MOAKS) focusing on bone marrow lesions (BML), synovitis, articular cartilage damage, and osteophytes.

RESULTS

Of 11 screened subjects, 8 qualified and received a single intra-articular injection of ICM-203 (N=6) or placebo (N=2); all subjects completed 52 weeks of follow-up. Subject age ranged from 56 to 73 years; body mass index (BMI) ranged from 24.6 to 38.6 kg/m2. No significant concerns about safety or tolerability arose. The most common treatment-related TEAE was mild to moderate arthralgia, which occurred in 3 of 6 ICM-203 subjects and 1 of 2 placebo subjects. At baseline, 3 ICM-203 subjects had positive NAb responses to AAV capsid; no subjects had significant T-cell responses. All 6 ICM-203 subjects developed both a humoral and cellular response against AAV capsid, whereas neither placebo subject did. ICM-203 subjects with negative NAb at baseline (N=3) demonstrated greater improvement over placebo subjects (N=2) in KOOS pain, KOOS ADL, WOMAC, as well as in imaging endpoints, including MOAKS BML and synovitis. For articular cartilage and osteophytes, no significant changes were observed in any subject between baseline and week 52.

CONCLUSION

Intra-articular injections of ICM-203 were safe and well tolerated. ICM-203 appeared to show greater therapeutic activity over placebo in subjects with negative NAb at baseline. Current findings indicate ICM-203 may demonstrate potential as a disease-modifying osteoarthritis drug (DMOAD), between reducing osteoarthritis symptoms, ameliorating structural joint damage, and alleviating synovial inflammation. Investigation of higher doses of ICM-203 is in progress.