作者: Dugel, Pravin ; Sivaprasad, Sobha ; Brucker, Alexander ; Jin, Xidong ; Berger, Brian ; Patel, Sunil ; Barranco, Jose Juan Escobar ; Figueira, João ; Silva, Rufino ; Habib, Maged ; Calvo, Pilar ; Bailey, Claire ; Hu, Allen ; Jhaveri, Chirag ; Boyer, David S. ; Ghanchi, Faruque ; Dong Nguyen, Quan ; Erke, Maja Gran ; Bandello, Francesco ; Kunimoto, Derek ; Donate Lopez, Juan ; Talks, James ; Giani, Andrea ; Pagliarini, Sergio ; Varano, Monica ; Menon, Geeta ; Maturi, Raj ; Sen, Harsha ; Rosen, Richard ; Androudi, Sofia ; Ehrlich, Michael S. ; Fawzi, Amani ; Weger, Martin ; Cunningham, Matthew ; Hahn, Paul ; Antoszyk, Andrew ; Manjunatha, Nonavinakere ; Ehlers, Justis P. ; Brown, David

AbstractObjectiveTo evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR).MethodsROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks.ResultsSeventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group.ConclusionsBI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.

2006-09-01·Arthritis & Rheumatism

Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo

Article

作者: Kati Elima ; Gennady G. Yegutkin ; Craig Stolen ; Marko Salmi ; Nathalie Mercier ; David J. Smith ; Sakari Alaranta ; Marjo Pihlavisto ; Olli Pentikäinen ; Ulla Pentikäinen ; Fumiko Marttila-Ichihara ; Ferenc Fülöp ; Sirpa Jalkanen ; Riku Kiviranta

AbstractObjectiveLeukocyte traffic from the blood to the joints is crucial in the pathogenesis of arthritis. A bifunctional endothelial cell–surface glycoprotein, AOC3 (amine oxidase, copper‐containing 3; also known as vascular adhesion protein 1), has both adhesive and enzymatic properties. We undertook this study to determine the contribution of AOC3 and its oxidase activity to leukocyte trafficking into inflamed joints in vivo.MethodsWe used gene‐modified animals, molecular modeling, an AOC3 enzyme inhibitor, oxidase assays, and arthritis models (adjuvant‐induced arthritis [AIA] in rats and anti–type II collagen antibody–induced arthritis in mice) to dissect the importance of AOC3 in vivo.ResultsThe AOC3 inhibitor fitted well with a covalent binding mode into the active site of the AOC3 crystal structure. It selectively blocked the oxidase activity of AOC3 in enzyme assays. Intraperitoneal and oral administration of the AOC3 inhibitor significantly ameliorated rat AIA. In anti–type II collagen antibody–induced arthritis in mice, the AOC3 inhibitor also improved the outcome of the joint inflammation. The acute semicarbazide‐sensitive amine oxidase blockade by the inhibitor had even more pronounced effects than genetic deletion of AOC3. Enzymatic analyses showed that the inhibitor also blocked 2 other structurally very closely related AOCs, but not any of more than 100 other enzymes tested.ConclusionThese are the first data to demonstrate that the enzymatic activity of the atypical endothelial adhesion molecule AOC3, and possibly that of other closely related ecto‐oxidases, is crucial for leukocyte exit from the vessels in inflamed joints in vivo.

100 项与 AoC3 inhibitor (Faron Pharmaceuticals) 相关的药物交易

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