Efficacy, pharmacokinetics and safety of iscalimab (CFZ533) in patients with proliferative lupus nephritis: a randomised, double-blind, placebo-controlled, phase II study

Abstract

Background: Iscalimab (CFZ533) is a novel, anti-CD40 monoclonal antibody. This study evaluated the efficacy, pharmacokinetics and safety of iscalimab versus placebo as add-on to standard-of-care (SoC) therapy in patients with biopsy-proven active proliferative lupus nephritis (LN).

Methods: This was a phase II, randomised, double-blind, placebo-controlled, multicentre study including patients with a diagnosis of systemic lupus erythematosus with active LN. Patients were randomly assigned (2:1) to receive either intravenous iscalimab (10 mg/kg) or placebo for 24 weeks on top of SoC for LN. The primary efficacy endpoint was the ratio from baseline in urinary protein-to-creatinine ratio (UPCR) at week 24. Safety assessments included adverse events (AEs) and serious AEs (SAEs) during treatment and follow-up up to 49 weeks.

Findings: Of the 57 patients (iscalimab, n=39; placebo, n=18) randomised, 31 (54.4%) completed the study. The primary efficacy endpoint was met: at week 24, the relative improvement from baseline in proteinuria (UPCR) was 63.1% and 36.3% in the iscalimab and placebo arms, respectively. UPCR to baseline at week 24 showed a statistically significant reduction of 42.1% in the iscalimab versus placebo arm. Most AEs were of mild to moderate severity in both treatment arms. Overall, seven SAEs were reported in six patients (15.4%) in the iscalimab arm versus four in three patients (16.7%) in the placebo arm.

Interpretation: Iscalimab showed a significant improvement in proteinuria (UPCR) in patients with active LN. Iscalimab was generally well tolerated with the exception of a few severe infections and one case of macrophage-activation syndrome in immunosuppressed and comorbid patients.

Trial registration number: NCT03610516.

Keywords: Autoimmune Diseases; Biological Therapy; Glucocorticoids; Lupus Erythematosus, Systemic; Lupus Nephritis.

Figure 1. Study design. *Iscalimab or placebo 10 mg/kg intravenous on days 1, 15, 29, 57, 85, 113 and 141. **For steroid tapering regimen, refer to online supplemental Table 1 included in the appendix. EOS, end of study; R, randomisation.

Figure 2. Patient disposition. AE, adverse event.

Figure 3. Estimated geometric mean UPCR and UPCR relative reduction (iscalimab improvement from baseline vs placebo improvement from baseline) over time UPCR estimated using first morning void sample, if available, at visit or otherwise using the clinic spot sample. Error bar indicates 80% CI. UPCR, urine protein-to-creatinine ratio.

Figure 4. Percentage of patients with complete and partial renal response at week 24 complete renal remission is defined as UPCR≤0.2 mg/mg as well as eGFR≤25% of baseline and normal urine sediment. Complete response is defined as UPCR ≤0.2 mg/mg and >50% reduction in UPCR versus baseline. Partial response is defined as 2.0>UPCR >0.2 mg/mg and >50% reduction in UPCR versus baseline. eGFR, estimated glomerular filtration rate; UPCR, urine protein-to-creatinine ratio.