ObjectiveA phase 2 trial tested different doses of the anti-CD40 monoclonal antibody BI 655064 as an add-on therapy to the standard of care in patients with class III or IV lupus nephritis (LN) with active disease. A post hoc analysis showed a potential benefit of the higher tested doses (180 and 240 mg) versus a low dose (120 mg) or placebo. We investigated whether the treatment effect of BI 655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well-known role in LN pathogenesis.MethodsOne hundred one renal biopsies of patients with LN enrolled in the BI 655064 trial were scored centrally. The estimated glomerular filtration rate (eGFR), spot urine protein/urine creatinine ratio (UP/UC), and complete renal response (CRR) were evaluated over 52 weeks. Patients were divided according to a "better" or "worse" performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders were used to assess the association between different treatment doses and outcomes according to the presence or absence of monocytes.ResultsA higher BI 655064 dose (180 or 240 mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsy samples (odds ratio [OR] 3.66 [95% confidence interval (CI) 1.09-12.3], P = 0.04; OR 4.58 [95% CI 1.24-16.9], P = 0.02). A trend toward improved eGFR was also observed in these patients (at 52 weeks, P = 0.08).ConclusionIn LN kidney biopsy samples with glomerular monocytes, high-dose BI 655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsy samples without glomerular monocytes. Histologic features may guide the choice of treatment for individual patients with LN.

Objective: Safe, effective therapies are urgently needed for patients with systemic sclerosis. However, clinical trial recruitment is challenging given the limited number of people with systemic sclerosis and further restrictions imposed by eligibility criteria. Innovative approaches are needed to accelerate development of new therapies. This article describes the rationale and trial design for CONQUEST (NCT06195072), a novel platform clinical trial sponsored by the Scleroderma Research Foundation, a not-for-profit organization. Methods: CONQUEST is a multicentre, double-blind, randomized, placebo-controlled, Phase 2b platform trial evaluating the efficacy, safety and pharmacodynamics of multiple investigational products to treat early active systemic sclerosis with interstitial lung disease versus placebo. The primary objective is to evaluate change from baseline to Week 52 in forced vital capacity (mL). Secondary objectives include evaluating changes from baseline to Week 52 in high-resolution computed-tomography-assessed lung involvement and dyspnoea, and overall treatment response (measured using the revised composite response index in diffuse systemic sclerosis score in participants with diffuse cutaneous systemic sclerosis). Results: Patients will be enrolled across more than 150 centres in over 25 countries. Recruitment started on 15 April 2024. Conclusion: As the first platform clinical trial in the rheumatology field, CONQUEST aims to meaningfully accelerate the development of new therapies for early active systemic sclerosis. Depending on regimen-specific results, trial data could be used to plan and design a Phase 3 trial or may be used alone or together with another registrational trial to establish substantial evidence of effectiveness and safety. The first molecules to be studied, amlitelimab and nerandomilast, both have a strong scientific rationale to modify underlying disease processes in systemic sclerosis. ClinicalTrials.gov: Platform Clinical Study for Conquering Scleroderma (CONQUEST); NCT06195072; https://www.clinicaltrials.gov/study/NCT06195072

To characterize its dose‐response relationship, BI 655064 (an anti‐CD40 monoclonal antibody) was tested as an add‐on to mycophenolate and glucocorticoids in patients with active lupus nephritis (LN).

Abstract Background and Aims Lupus nephritis (LN) is the most serious complication of systemic lupus erythematosus with a high risk of end-stage kidney disease and a high need of better treatment. A recent randomized, double-blind, placebo-controlled, phase II trial tested doses of 120, 180 and 240 mg of the anti-CD40 monoclonal antibody BI 655064 as add-on to standard of care (MMF + glucocorticoids), in patients with active LN (proteinuria > 1 g/day) for 52 weeks. Although the trial did not demonstrate a dose-response relationship for the primary endpoint determined by complete renal response, a potential efficacy benefit of BI 655064 180 mg and 240 mg was found in a post-hoc analysis. We investigated whether a treatment effect was related to findings in the pre-treatment renal biopsy. Method Biopsies from 101 patients with LN class III or IV, confirmed in a central review conducted according to a previously established protocol, were included. Protein/creatinine ratio (UPCR, based on spot urine) and eGFR were determined at every visit. For each, the last available UPCR and the last available eGFR values, linear regressions (based on the respective baselines) of all patients irrespective of therapy were calculated, and subjects were classified according to their individual performance, “Better” or “Worse” than the average. The modified activity and chronicity indices as well as all biopsy parameters, which are not already contained in the indices, were compared for differences between the “Better” and “Worse”. Parameters with p< 0.1 in the univariate analyses were entered into a multivariate logistic regression model, and a routine model selection procedure (with p< 0.2) was used to identify parameters predictive for clinical outcome. As monocytes express CD40, which is the target of BI 655064, a further question was whether high dose treatment with BI 655064 (180/240 mg) was beneficial when monocytes were present in the biopsy, using a model which adjusted for all predictors identified in the multivariate model. Results The results of the univariate and the multivariate analysis of biopsy parameters are shown in Table 1. Improvement in UPCR was better if the modified chronicity index was low. In addition, LN class IV subjects had a marginally better prognosis than class III. The effect of high-dose treatment with BI 655064 was better when monocytes were present. eGFR outcome was better if the modified chronicity index was low and, conversely, the modified activity index was high. Further, the presence of synechia/adhesions was a negative predictor for positive outcome. There was no indication for an effect of high-dose treatment with 655064 on eGFR when monocytes were present. Conclusion This post-hoc analysis of the BI 655064 trial used a novel approach which investigated whether specific histological lesions in renal biopsies were related to treatment outcome. Although the number of patients was limited, our results suggest that treatment with higher dose anti-CD40 may improve the reduction of proteinuria when monocytes are present in the biopsy. This indicates that specific information from renal biopsies could ultimately improve the choice of treatment for individual LN patients.

AIMS:To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS:BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS:All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION:BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.

Objective To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). Methods In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. Results At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40–CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. Conclusion Although blockade of the CD40–CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study. Trial registration number NCT01751776

BI 655064 is a humanized antagonistic anti-cluster of differentiation (CD) 40 monoclonal antibody that selectively blocks the CD40-CD40L interaction. The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. The safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated once-weekly BI 655064 subcutaneous dosing over 4 weeks were evaluated in a multiple-dose study in healthy subjects. Subjects (N = 40) were randomized 4:1 to four sequential BI 655064 dose groups (80, 120, 180, 240 mg) or to placebo. Safety and tolerability, plasma exposure, CD40 receptor occupancy, and CD40L-induced CD54 upregulation were assessed over 64 and 78 days for the 80- to 180-mg and 240-mg dose groups, respectively. BI 655064 exposure increased in a supraproportional manner, due to target-mediated drug clearance, for doses between 80 mg and 120 mg, but was near proportional for doses greater than 120 mg. Terminal half-life ranged between 6 and 8 days. Dose-dependent accumulation of BI 655064 supports the use of a loading dose in future clinical studies. Following 4 weeks of dosing, >90% CD40 receptor occupancy and inhibition of CD54 upregulation were observed at all dose levels, lasting for 17 days after the last dose. BI 655064 was generally well tolerated. There were no serious adverse events and the frequency and intensity of adverse events were similar for BI 655064 and placebo; no dose relationship or relevant signs of an acute immune reaction were observed. These findings support further investigation of BI 655064 as a potential treatment for autoimmune diseases.

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

Background & Aims: BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro.Methods: In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n = 27 treatment-nave [TN]; n = 30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay.Results: HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log(10), TE 4.2 log(10)) and 800 mg (TN 5.4 log(10), TE 4.5 log(10)). Rapid virological response (RVR; HCV RNA < 15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound > 1log(10) from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg.Conclusions: BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background BILB 1941 is a potent and specific non-nucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro. Methods In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0–2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10–450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan® assays. Results VL decreased by ≥1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued. Conclusions BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.