#5413 FRONTIER-1: A PHASE 2B STUDY OF IL-33 BLOCKADE IN DIABETIC KIDNEY DISEASE
Authors: Marin Elena Liarte , Musial Barbara , Seth Asha , Slidel Timothy , Conway James , Baker David , Hansen Pernille Laerkegaard , Challis Benjamin , Bhat Maria , Bartesaghi Stefano , Pecoits-Filho Roberto , Tu Xiao , Selvarajah Viknesh , Woollard Kevin , Heerspink Hiddo Lambers , Hofherr Alexis 
Published: June 2023

Abstract

Background and Aims
Several biomarkers of inflammation have been correlated with poor renal outcomes and mortality in DKD. However, an effective, well-tolerated treatment of progressive renal disease driven by inflammation has remained elusive. Inhibition of IL-33 may provide a novel opportunity to address this unmet medical need in high-risk patients. Here, we: 1) show that tozorakimab, a high-affinity IL-33-neutralizing mAb, promotes glomerular health in inflammation; 2) describe the clinical study to test tozorakimab in patients with DKD; 3) present participant baseline characteristics; and 4) evaluate inflammation-associated biomarker in FRONTIER-1 and four external validation cohorts.

Method
FRONTIER-1 (NCT04170543) is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2DM with an eGFR of 25-75 mL/min/1.73 m2 and a UACR in the range of 100-3,000 mg/g. All participants are expected to receive an ACEi/ARB for &gt; 6 weeks before the treatment period. Approximately 565 patients from multiple countries will be randomized to four dose levels of tozorakimab, or volume-matched placebo dosed subcutaneously every 28 days over a 24-week treatment period. All participants will receive 10 mg dapagliflozin Day 85-168. The primary objective of the study is to evaluate the effect of tozorakimab on albuminuria. Secondary objectives are to assess the safety and tolerability of tozorakimab with and without SGLT2i, evaluate the effect of tozorakimab in combination with ACEi or ARB with and without SGLT2i on albuminuria, and describe the PK and immunogenicity of tozorakimab. Key exploratory objective is to assess baseline and treatment-response for urine and/or circulating biomarkers of inflammation, including hsCRP, IL-33/sIL1RL1, CCL2, and TNFR-1/2. Biomarker response was, furthermore, evaluated in pre-clinical models of DKD, and respective distributions and risk were assessed in four independent DKD cohorts (N &gt; 200).

Results
Transcriptomic profiling of kidney biopsies from patients with DKD indicated a significant glomerular up-regulation of IL-33. Inhibition of IL-33 signalling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model of DKD. This was associated with improved glomerular endothelial health as indicated by decreased cellular inflammation and reduced release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFR-1, and CCL2. Hence, FRONTIER-1 was started in 2019. So far, all trial groups are well-balanced and in line with our expectations for this patient population (N = 574). At baseline, &gt; 95% were receiving ACEi/ARBs and approximately 25% were receiving SGLT2i. The mean eGFR was 47.8 ml/min/1,73 m2 (+/- 14.7) and mean UACR was 765 mg/g (+/- 775). The inflammatory state of participants at baseline was assessed in circulation and urine by hsCRP, TNFR-1 and CCL2 (N &gt; 146). Comparison to independent reference cohorts (N &gt; 200) confirmed elevated risk in DKD patients with high urinary TNFR-1 and CCL2 and showed that 6-week treatment of dapagliflozin did not alter these biomarkers significantly.

Conclusion
Taken together, inhibition of IL-33 may be beneficial in patients with DKD on standard of care, who have elevated biomarkers of inflammation such as TNFR-1 and/or CCL2. This hypothesis is currently being tested in the FRONTIER-1 phase 2b clinical study. To identify the patients most likely to benefit from immunomodulatory treatment with tozorakimab, the study will conduct a retrospective analysis of albuminuria and inflammatory biomarkers. The primary analysis of the study is planned for the second half of 2023.