POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS
Authors: D. Jayne, J. Steffgen, J. Romero-Diaz, H. Amano, K. Noppakun, H. M. Gomez, R. Recto, V. Belsack, N. Fagan, S. Padula, I. Revollo, J. Wu, S. Visvanathan, R. Furie
Journal: Annals of the Rheumatic Diseases (2021)

Background: In patients with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. Objectives: To assess the efficacy and safety over 52 weeks of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in patients with active proliferative LN (ClinicalTrials.gov number: NCT02770170 ). Methods: Overall, 121 patients with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 weeks, followed by dosing every 2 weeks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (&lt;3 vs ≥3). The primary efficacy endpoint was complete renal response (CRR), defined as 24 h proteinuria &lt;0.5 g/day and stable eGFR at Week 52. Results: The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Week 52 compared with placebo. However, CRR at Week 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Week 4. Time to CRR was shorter in the 180 mg group (17.3 weeks) vs placebo (20.4 weeks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Weeks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five patients treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion: The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Weeks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively. Table 1. Efficacy endpoints at Week 52 Placebo (n=40) BI 655064 120 mg (n=21) 180 mg (n=20) 240 mg (n=40) Observed CRR, n 20 8 9 18 Adjusted* CRR, % 48.3 38.3 45 44.6 Observed cCRR, n 13 5 9 16 Adjusted* cCRR, % 29.1 22.5 44.3 38.2 Mean change from baseline in SLEDAI Total score −6.5 −6.1 −9.7 −8.2 Non-renal score −1.4 −3.0 −2.8 −3.1 Renal score −5.1 −3.7 −6.8 −5.0 Clinical score −5.7 −3.9 −7.9 −6.5 CRR based on 24 h proteinuria; cCRR based on UP/UC (spot urine) at Weeks 46 and 52. *Logistic regression model including treatment and the covariates race and proteinuria at screening. Disclosure of Interests: David Jayne Consultant of: DRJ has received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline Research &amp; Development Ltd, Novartis, and Roche, Juergen Steffgen Employee of: JS is employed by Boehringer Ingelheim., Juanita Romero-Diaz Consultant of: JRD has received research consulting fees from Boehringer Ingelheim, Hirofumi Amano Grant/research support from: HA has received research grants from Boehringer Ingelheim, Kajohnsak Noppakun Consultant of: KN has received honoraria from Boehringer Ingelheim, Novartis, Roche, Jansen, AstraZeneca, Otsuka Pharmaceuticals, Astellas Pharma, Abbott, Sanofi and Novo Nordisk, Grant/research support from: KN has received research grants from Boehringer Ingelheim, GlaxoSmithKline Research &amp; Development Ltd, Visterra Inc., Kalbe Genexine Biologics, Aurinia Pharmaceuticals Inc., and Omeros Corporation., Harold Michael Gomez Speakers bureau: HMG has received speaker’s fees for Pfizer, MSD, Unilab, Astellas Pharma, AstraZeneca, GlaxoSmithKline Research &amp; Development Ltd, and Aurinia Pharmaceuticals Inc., Rhona Recto: None declared, Valérie Belsack Employee of: Boehringer Ingelheim, Nora Fagan Employee of: Boehringer Ingelheim, Steven Padula Employee of: Boehringer Ingelheim, Ivette Revollo Employee of: Boehringer Ingelheim, Jing Wu Employee of: Boehringer Ingelheim, Sudha Visvanathan Employee of: Boehringer Ingelheim, Richard Furie Consultant of: RF has received research consulting fees, Grant/research support from: RF has received clinical trial support