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.

BackgroundBlocking the CD40-CD40L pathway may be a new emergent treatment for patients with RA. BI 655064 is a humanized, purely antagonistic anti-CD40 monoclonal antibody. In healthy volunteers, BI 655064 was well tolerated in doses up to 240 mg q1w s.c. for 4 weeks. Doses ≥120 mg resulted in persistent >90% CD40 receptor occupancy and >90% inhibition of CD40L-induced CD54 upregulation.ObjectivesBI 655064 was investigated in RA patients with prior inadequate response (IR) to a stable dose of MTX at ≥15 mg.MethodsIn this double-blind, randomized trial, RA patients (n=67) were treated with either 120 mg BI 655064 or placebo q1w (2:1, respectively) for 12 weeks as add-on to MTX. Patients were stratified based on region (Eastern Europe vs. Western Europe/New Zealand). Inclusion criteria were ≥6 swollen and ≥6 tender joints, CRP ≥8 mg/L or ESR ≥28 mm/1h. The primary efficacy endpoint was ACR20 response at week 12.ResultsBaseline variables of the 2 groups were comparable except mean baseline CRP, which was substantially lower in patients treated with BI 655064 (9.8 mg/L) vs. placebo (23.6 mg/L). Treatment was prematurely discontinued by 4 patients (9.1%) in the BI 655064 group and 4 (17.4%) in the placebo group. Adverse events (AE) were reported in 65.9% of BI 655064-treated patients vs. 78.3% of placebo-treated patients. Two SAEs were reported in each group, neither was considered drug-related. The most frequently reported AEs were nasopharyngitis (BI 655064: 13.6%, placebo: 21.7%) and headache (BI 655064: 6.8%, placebo: 13.0%). There were no relevant changes in safety-related laboratory parameters. Efficacy results of all patients (FAS), including a subgroup of patients with CRP > median (7.5 mg/L; upper limit of normal: 6.0 mg/L), are listed in the table.Table 1BI 655064 (N=44)Placebo (N=22*)ACR20 response %68.245.5ACR50 response %36.418.2Mean change† in DAS28-CRP @wk12−1.65−1.42Subgroup with CRP > medianBI 655064 (N=17)Placebo (N=16)Mean change† in DAS28-CRP @wk12−1.83−1.38CRP change from baseline, mean (SE)−10.45 (3.54)−3.90 (3.65)*1 patient excluded from efficacy analysis due to early use of i.v. steroids. †Adjusted for region, anti-TNF history and baseline CRP.All 6 patients who had previously received anti-TNF therapy were in the BI 655064 group; 4 achieved an ACR20 and 2 achieved an ACR50 response. There was a median decrease in ESR and total rheumatoid factor in the BI 655064-treated group by 16 mm/h and 81.5 IU/mL, respectively, compared with a decrease of 9 mm/h and 0.2 IU/mL in the placebo group.ConclusionsIn this relatively small proof-of-clinical-concept trial, treatment of MTX IR RA patients with BI 655064 did not indicate a relevant safety concern and showed moderate efficacy, which might have been impacted by the relatively high placebo response rate and the imbalance in baseline CRP.Disclosure of InterestS. Daniluk: None declared, R. Ptaszynski: None declared, U. Mueller-Ladner Consultant for: Boehringer Ingelheim, A. Petrikova: None declared, H. Kellner: None declared, E. Dokoupilova: None declared,...

BackgroundThe CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis (RA). Blocking this pathway may be a promising new treatment for RA-patients. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody, free of agonistic activity and without antibody-dependent cellular- or complement-dependent cytotoxicity. BI 655064 binds human CD40 on B cells in whole blood with an EC90 of 6.85±0.74 nM.ObjectivesBI 655064 was investigated in healthy volunteers to assess safety, tolerability, PK and PD after single and multiple dosing.MethodsIn a single-blinded randomized, placebo-controlled trial in healthy subjects, BI 655064 was administered to 72 male subjects in increasing single doses of 0.2-120 mg i.v. and 40-120 mg s.c. A double-blinded multiple rising dose study was conducted in 40 male and female subjects at doses of 80-240 mg q1w s.c. for 4 weeks. Blood samples were analyzed for PK, CD40-receptor occupancy (RO) and inhibition of CD40L-induced CD54-upregulation throughout the entire trial duration.ResultsAll doses of BI 655064 were well tolerated in both studies. There was no-drug related serious adverse event (AE) or significant AE reported. Reported AEs were mainly of mild intensity and did not show a dose-relationship. There was no significant difference in the total number of subjects with AE [BI 655064: 47/86 (54%) vs. placebo: 16/26 (61%)] or category of reported AEs between subjects treated with BI 655064 or placebo (combined data from both studies). The most frequently reported AEs were headache (BI 655064 23% vs. placebo 19%) and upper respiratory tract infection (BI 655064 13% vs placebo 12%) in both studies (combined data). There was no evidence of thromboembolism or bleeding, no hypersensitivity reaction, no cytokine release and no relevant change in safety laboratory tests including coagulation parameters. BI 655064 plasma exposure increased in a supra-proportional manner indicating target mediated drug clearance with a terminal half-life ranging between 6 and 13 days. At single i.v. doses of 20 mg and higher, there was >90% RO and >90% inhibition of CD40L-induced CD54 upregulation for 24 hours after dosing. Single doses of 120 mg i.v. or s.c resulted in >90% RO and >90% inhibition of CD54 upregulation for at least one week. After multiple dosing, persistent >90% RO and >90% inhibition of CD40L-induced CD54 upregulation was maintained for the entire treatment period and for 3 weeks after the last dose for all doses of 120 mg q1w and above.ConclusionsEarly trials with BI 655064 show a favorable clinical safety profile and high potential to block the CD40-CD40L pathway supporting clinical trials with BI 655064 in RA-patients.Disclosure of InterestC. Schwabe Employee of: Auckland Clinical Studies, F. Wagner Employee of: Charité Research Institute, I. Filler Employee of: Charité Research Institute, M. Albulescu Employee of: Boehringer-Ingelheim, P. Rose Employee of: Boehringer-Ingelheim, B. Emerson Employee of: Boehringer-Ingelheim, T. Doan Employee of: Boe...

La poussée matinale de la pression artérielle et les facteurs associés chez les patients ayant une hypertension primaireIntroduction. Les patients souffrant d'hypertension artérielle ont un taux plus élevé d'augmentation de la pression artérielle matinale (poussée matinale, PM) que les patients non hypertendus. La PM augmente le risque d'accident vasculaire cérébral, d'infarctus du myocarde, de mort subite d'origine cardiaque, de rigidité artérielle, d'hypertrophie ventriculaire gauche, d'athérosclérose carotidienne et d'inflammation vasculaire. La prévalence et les prédicteurs de PM peuvent varier considérablement entre les régions géographiques. L'objectif de l'étude était de déterminer l'incidence de la PM et des facteurs associés chez les patients souffrant d'hypertension primaire. Matériel et méthodes. Une étude descriptive transversale a été menée chez des patients âgés de 35 ans et plus, diagnostiqués avec une hypertension artérielle primaire, et hospitalisés dans le service de cardiologie