Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial

Zeeuw, Dick de; Renfurm, Ronny W.; Bakris, George L.; Rossing, Peter; Perkovic, Vlado; Hou, Fan Fan; Nangaku, Masaomi; Sharma, Kumar; Heerspink, Hiddo J L; García-Hernández, Alberto; Larsson, Tobias E.

doi:10.1016/s2213-8587(18)30289-4

Cited by 35 publications

(36 citation statements)

References 23 publications

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“…VAP-1 plasma levels are elevated in diabetic patients, being associated to eGFR decline and albuminuria [88,89], and may be related with cardiovascular and cancer mortality risk of these patients [89,90]. A recent phase II clinical trial in diabetic and CKD patients showed that the administration of the oral VAP-1 inhibitor ASP8232 in combination with RAS blockade, delayed progression of renal damage [91].…”

Section: Cell Adhesion Moleculesmentioning

confidence: 99%

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Rayego‐Mateos

Morgado‐Pascual

Opazo-Ríos

et al. 2020

IJMS

187

127

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Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

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Section: Cell Adhesion Moleculesmentioning

confidence: 99%

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Rayego‐Mateos

Morgado‐Pascual

Opazo-Ríos

et al. 2020

IJMS

187

127

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“…Astellas' ASP8232 VAP-1 inhibitor was tested in placebo-controlled phase II trials for diabetic macular edema and diabetic nephropathy [44,45]. In macular edema, this inhibitor was not effective, although it efficiently inhibited VAP-1 enzymatic activity in plasma.…”

Section: Clinical Trialsmentioning

confidence: 99%

Human Copper-Containing Amine Oxidases in Drug Design and Development

et al. 2020

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Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches.

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“…The dependent variables for the PK-PD analysis were the log-transformed total ASP8232 and sVAP-1 plasma concentrations, as well as VAP-1 plasma activity, which were predicted by the model according to the following individual prediction (IPRED) Eqs. (10)(11)(12).…”

Section: Asp8232 Pk-pd Tmdd Model Developmentmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model

Snelder¹,

Hoefman²,

García-Hernández

et al. 2020

J Pharmacokinet Pharmacodyn

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ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.

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Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial

Cited by 35 publications

References 23 publications

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Human Copper-Containing Amine Oxidases in Drug Design and Development

Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model

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