In a randomized double-blinded clinical trial of patients with ST segment elevation myocardial infarction (STEMI), goflikicept, an interleukin-1 blocker, significantly reduced systemic inflammation, measured as the area under the curve (AUC) for high-sensitivity C reactive protein at 14 days. We report secondary analyses of biomarkers at 28 days, and cardiac function and clinical end points at 1 year. Patients received a single administration of goflikicept 80 mg (n = 34), goflikicept 160 mg (n = 34), or placebo (n = 34). Both doses of goflikicept significantly reduced the AUC for high-sensitivity C reactive protein at 28 days compared with placebo, without statistically significant differences between the doses. There were no statistically significant differences between groups in the AUC for natriuretic peptides at 28 days. There were no significant differences between placebo, goflikicept 80 mg, and 160 mg groups in deaths (2.9%, 2.9%, and 0%), hospitalization for cardiovascular reasons (9.1%, 5.9%, and 0%), new-onset or progression of heart failure (9.1%, 5.9%, and 5.9%), and new or increased use of loop diuretics (24.2%, 14.7%, and 17.6%), nor in the number of patients with treatment emergent adverse events, with no treatment-related serious adverse events in any group. In conclusion, in patients with STEMI, interleukin-1 blockade with goflikicept 80 mg or 160 mg was well tolerated and associated with significant reduction of systemic inflammation. Further adequately powered studies are warranted to determine whether the reduction in systemic inflammation with goflikicept translates into a clinical benefit in patients with STEMI.

The treatment of inflammatory diseases can be achieved by inhibiting relevant cytokine pathways including the interleukin-1 (IL-1) family. RPH-104 (Goflikicept) is a newly developed heterodimeric fusion protein to block IL-1. Preclinical studies were conducted to evaluate the efficacy and safety of RPH-104 using both in vitro and in vivo studies including investigations in relevant species. A surface plasmon resonance-based approach was used to determine the affinity of RPH-104 to IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra). In vitro efficacy was demonstrated in a cell-based model system. Its ability to interact with Fcɣ receptors, and therefore estimate influence on PK/PD, was also assessed. RPH-104 was well tolerated in single-dose and 4-week repeat-dose toxicity studies in Macaca fascilularis (cynomolgus monkeys). Single dose toxicity study included the assessment of the toxicity and pharmacokinetics of RPH-104 following a single subcutaneous and intravenous (bolus) administration. Repeated-dose toxicity and toxicokinetics studies were performed following subcutaneous administrations for 28 days. There were no clinical signs of local or systemic toxicity during in vivo studies. The results of nonclinical studies facilitated the successful advancement of RPH-104 into the clinical trials (recurrent pericarditis, familial Mediterranean fever).

Background/Objectives: Olokizumab (OKZ) is a humanized monoclonal antibody targeting interleukin-6 (IL-6). OKZ demonstrated efficacy in subjects with active rheumatoid arthritis (RA) in randomized controlled trials versus adalimumab (ADLM) and placebo over 24 weeks, with sustained efficacy confirmed through 106 weeks in an open-label single-arm extension study (OLE). This analysis aimed to predict 1-year efficacy of OKZ 64 mg administered every two weeks (q2w) and every four weeks (q4w) compared with ADLM and placebo through virtual clinical trial simulations based on population pharmacokinetic/pharmacodynamic (PK/PD) models. Methods: Nonlinear mixed-effects models were developed using pooled data from phase III studies. Turnover models with a maximum inhibition I_max-type relationship between OKZ concentrations and clinical scores were applied. Simulated clinical trials were performed to estimate 52-week response rates, defined as proportions of patients achieving low disease activity (DAS28-CRP ≤ 3.2) and remission (CDAI ≤ 2.8). The reliability of the simulated extrapolations was validated against published data. Results: Log-transformed C-reactive protein (CRP) baseline levels and region were identified as significant covariates, influencing the dynamics of RA activity scores. OKZ and ADLM showed comparable predicted efficacy profiles, with overlapping 95% prediction intervals, and both were superior to placebo. Model predictions showed strong agreement with published long-term data for ADLM and placebo and closely reproduced the actual 1-year response profiles from the OKZ OLE. Conclusions: The developed PK/PD models showed good agreement with observed long-term efficacy outcomes for OKZ, ADLM, and placebo in MTX-IR RA patients. Both OKZ dosing regimens sustained low disease activity and remission rates comparable with those for ADLM over 52 weeks, supporting their use as effective treatment options.

Background/Objectives: This study aimed to evaluate the pharmacokinetics (PK), effectiveness, and safety of the direct interleukin-6 (IL-6) inhibitor olokizumab (OKZ) in adolescent patients with active polyarticular juvenile idiopathic arthritis (pJIA) who had an inadequate response or intolerance to methotrexate (MTX). Methods: We analyzed results from an open-label, single-arm trial of OKZ therapy at a dose of 64 mg every 4 weeks for 24 weeks. We evaluated pharmacokinetic (PK) parameters, clinical effectiveness, serum C-reactive protein (CRP) dynamics, and adverse events (AEs). Results: Sixteen patients were included in the study, of whom 13 (81.2%) received OKZ through Week 24. The PK profile was consistent with observations in adults with rheumatoid arthritis (RA). By Week 16, 12 (80%) patients achieved an ACRpedi30 response, 11 (73.3%) achieved an ACRpedi50 response, and 2 (13.3%) reached inactive disease status. This response was sustained through Week 24, and no disease flares were observed. A trend toward a better response was noted among patients with baseline CRP > 10 mg/L, higher baseline IL-6, and those naïve to biologic DMARDs. Twelve patients (75.0%) experienced twenty-three mild or moderate AEs. Infections were the most frequent AEs (in 6 patients, 37.5%). No serious AEs or deaths occurred. Conclusions: OKZ treatment reduced pJIA disease activity and was well tolerated. The safety profile was consistent with that of other IL-6 inhibitors, and the PK profile matched that seen in adult RA patients.