LBA0011 SAFETY AND IMMUNOGENICITY OF AN ACTIVE ANTI-IL-6 IMMUNOTHERAPY IN A PHASE 1 CLINICAL TRIAL IN KNEE OSTEOARTHRITIS PATIENTS
Authors: F. Rannou, C. Nguyen, C. Daste, Q. Kirren, M. M. Lefevre Colau, O. Launay, L. Desallais, E. Dolimier, R. Azoulai, J. P. Salles, J. F. Zagury
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Interleukin-6 (IL-6) is a major inflammatory cytokine involved in pain and potentially in osteoarthritis disease progression. PPV-06 is an IL-6-derived peptide coupled with a carrier protein, CRM197. The goal of the PPV-06 active immunotherapy is to induce the production of anti-IL-6 antibodies to buffer its biological activity. The PPV-06 conjugate has been shown to be safe in preclinical studies. We report here the results of a phase 1 clinical trial (First-in-human). <h3>Objectives:</h3> To assess the safety, tolerability and immune response of PPV-06 vaccine in participants with inflammatory KOA. <h3>Methods:</h3> This study (NCT04447898) was a randomized, double-blind, placebo-controlled, phase 1 in adults (aged ≥ 40 years) with a diagnosis of KOA, with moderate-to-severe pain and signs of knee effusion, KL grade ≥ 2, with BMI of 18-32 kg/m<sup>2</sup>, who had not undergone knee surgery prior to baseline visit. Patients were randomized in a 3:1 ratio in either: <b>a</b>) Cohort 1: Low dose (10 μg per injection) in SC administration=9 PPV-06 and 3 placebo; or <b>b</b>) Cohort 2: High dose (50 μg per injection) in SC administration=9 PPV-06 and 3 placebo. Each patient received 3 injections of PPV-06/placebo at Day 1, at W4 and W16 and were followed during 6 months after the last injection. The primary endpoint was the proportion of patients with Dose-Limiting Toxicities (DLTs) defined as Grade ≥3 Treatment-Emergent Adverse Events (TEAEs) of special interest (anaphylactic shock, allergy, and occurrence of infection) during the study. The secondary endpoints were the occurrence of AEs and SAEs, the quantification of inflammatory markers (IL-6, hsCRP and CRPM levels in blood), the quantitative analysis of the B-cell immune response and the existence of a cellular immune response. Additional endpoints were the quantification of exploratory markers of OA (C1M, C2M, C3M, ARGS, PRO-C2 in serum, CTX-II level in urine), changes in the Knee Injury and OA Outcome Score (KOOS), and pain scale on Numeric Rating Scale (NRS) assessed at baseline and EoS. <h3>Results:</h3> Overall, 24 patients were randomized in the study. No patient experienced a DLT during the study. AEs induced by PPV-06 administration were mostly transient and of mild to moderate severity. The reported events were the ones usually known for vaccines: injection site induration, injection site pain, myalgia, back pain, headache and pruritus. All AEs were TEAEs, except for 1 event in the PPV-06 high dose group that was already ongoing at Baseline (dysphonia). In the PPV-06 low dose group, one patient reported an AE leading to study discontinuation (Grade 2 induration at injection site). Neither serious TEAEs nor SAEs leading to study discontinuation were reported. Anti-IL-6 antibody levels and anti-IL-6 neutralizing antibodies were detected in both treated groups, but not in the placebo group. Transient increases of IL-6 levels with no matching increase of hsCRP were observed in the PPV-06 treated groups, reflecting the presence of immune complexes and their capacity to reduce inflammation. No T-cell responses were observed against the IL-6 peptide of the PPV-06 conjugate, nor against the full human IL-6 protein, indicating the absence of autoreactive T cells post-vaccination. Serum biomarkers for OA showed a downward trend in C2M and C3M levels, in the PPV-06 groups compared to placebo. A non-statistically significant trend towards improvement of all KOOS scores was observed in the PPV-06 groups compared to the placebo, more prominently for QoL and Symptoms. NRS pain score remained unchanged throughout the study. <h3>Conclusion:</h3> The PPV-06 active immunotherapy administered to patients with inflammatory KOA at two dose levels (10 µg and 50 µg) demonstrated a favorable safety profile and the evidence of immunogenicity in both PPV-06 treated groups. This outcome represents a significant milestone in the development of the PPV-06 active immunotherapy for the treatment of patients with inflammatory KOA. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Funding of this study was provided by Peptinov SAS, France. We are grateful to the patients for their participation and contribution to this study. <h3>Disclosure of Interests:</h3> François Rannou: None declared, Christelle Nguyen: None declared, Camille Daste: None declared, Quentin Kirren: None declared, Marie-Martine Lefevre Colau: None declared, Odile Launay: None declared, Lucille Desallais Lucille Desallais is an employee of Peptinov, Edita Dolimier Edita Dolimier is an employee of Peptinov, René Azoulai René Azoulai is an employee of Peptinov, Jean-Pierre Salles Jean-Pierre Salles is an employee of Peptinov, Jean-François Zagury Jean-François is a founder of Peptinov.