#2547 Humoral response to COVID vaccine and infection is intact during sibeprenlimab treatment of IgAN: data from the ENVISION trial

Abstract Background and Aims In the Phase 2 placebo-controlled ENVISION trial, the APRIL (A Proliferation Inducing Ligand) inhibitor sibeprenlimab significantly decreased proteinuria and stabilized estimated glomerular filtration rate decline in patients with immunoglobulin A nephropathy (IgAN) 1. A substudy was conducted to evaluate the humoral response to SARS-CoV-2 mRNA vaccination and infection. Here, we report the unblinded analysis of COVID outcomes in the overall and substudy populations of ENVISION. Method Patients enrolled in ENVISION (NCT04287985) received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo and were followed for 16 months after the first dose of study drug. Recognized COVID infection (reported as an adverse event AE) and vaccination data were recorded for all patients. For patients in the substudy, serum antibody responses to SARS-CoV-2 spike and nucleocapsid proteins were measured monthly using a validated Meso Scale Discovery V-PLEX SARS-CoV-2 Panel 24 multiplex assay. Vaccine responses among those who received a primary two-dose mRNA COVID vaccine series, with no recent or concurrent COVID infection, were evaluated. Peak post-vaccine serum SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin G (IgG) titers were reported in World Health Organization binding antibody units (BAU)/mL. Slopes of RBD IgG decline curves were used to generate estimates of time above a protective threshold of 300 BAU/mL. Welch's two-sample t-test was applied to log-transformed peak RBD titers for significance testing. COVID infection–induced antibody responses and severity of COVID symptoms were also assessed. In substudy patients, retrospective serologic diagnosis of COVID infection was established when simultaneous elevation of nucleocapsid and spike antibody titers, unexplained by vaccine history, was observed. Results Among 155 patients who received sibeprenlimab (n = 117) or placebo (n = 38), 56 (36.1%) had COVID infection reported as an AE during the study (Table 1). Overall, proportionally fewer sibeprenlimab recipients (33.3%) had a reported COVID AE compared with placebo recipients (44.7%). Two patients (one each in the sibeprenlimab and placebo groups) were hospitalized with serious COVID AEs in accordance with local management protocols; none were admitted to intensive care or mechanically ventilated and there were no COVID-related deaths. The majority of COVID AEs were of mild severity, regardless of treatment/dosing arm. In the serology substudy (n = 74), symptomatic COVID (reported as an AE) occurred in 47.3% of all patients. With the addition of serologic diagnoses (in the absence of AEs), the overall rate of COVID infection increased to 68.9%. Asymptomatic COVID was identified in 1 of 15 (6.7%) placebo recipients versus 15 of 36 (41.7%) sibeprenlimab recipients, raising the possibility that patients treated with sibeprenlimab may have had attenuated symptom presentation compared with patients who received placebo. COVID seroconversion rates were 100% and peak RBD IgG antibody titers following primary mRNA vaccination exceeded the protective threshold of 300 BAU/mL in all patients (Fig. 1a), with higher geometric mean peak titers in placebo (4670 BAU/mL) compared with sibeprenlimab (1700 BAU/mL) recipients (p = 0.005). The rate of decline of peak RBD IgG titers after mRNA vaccination (in patients with ≥1 dose without confounding subsequent vaccination or infection) was similar between groups (Fig. 1b), with modeled time above the 300 BAU/mL threshold of 192 and 174 days in the sibeprenlimab and placebo groups, respectively. Conclusion COVID-specific antibody responses to vaccination or infection were preserved in patients with IgAN treated with sibeprenlimab. The possibility that COVID symptom presentation may have been modulated by sibeprenlimab warrants further investigation.