Translation Strategy for the Qualification of Drug-induced Vascular Injury Biomarkers

Abstract

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.

Scientific and Regulatory Policy Committee Points-to-consider Paper*

“…Similar vascular lesions are found in laboratory animals and humans (Bendjama et al 2014). Changes specifically in the endothelium include degeneration, apoptosis/necrosis, hypertrophy, and hyperplasia.…”

“…It is well recognized that with few exceptions, like dopamine, small molecule drugs that result in preclinical DIVI have not been shown to cause vascular injury in humans and have long records of safe clinical administration (Bendjama et al 2014;Joseph 2000). Sporadic clinical cases of drug-induced vasculitis cannot always be differentiated from spontaneous idiopathic vasculitides (Radic, Martinovic Kaliterna, and Radic 2012).…”

Human Vascular Microphysiological System for in vitro Drug Screening

“…Evaluating drug-induced vasodilation in a human model would be a significant development in the progress toward finding human biomarkers for DIVI. DIVI typically manifests in animal studies through changes in vascular tone, leading to endothelial dysfunction and inflammation 52 . Endothelial dysfunction has been detected in patients who have undergone treatment with cytotoxic drugs for chemotherapy 53 .…”

Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat

“…In humans, a multivariate analysis was used by Safer and Faster Evidence-based Translation to identify a panel of circulating biomarkers that separates healthy volunteers, patients with acute vasculitis, and patients in remission (Bendjama et al 2014;Bendjama et al 2013). The original panel was comprised of 24 circulating proteins (Supplemental Table S1).…”

“…Despite different inciting causes and outcomes, vasculitides share multiple common features, including activation and damage to endothelial cells (ECs) and inflammation. Thus, the Vascular Injury Working Group (VIWG) of the Predictive Safety Testing Consortium of the Critical Path Institute (PSTC) is assessing candidate biomarkers of DIVI in research animals (Mikaelian et al 2014), while the ''Safer and Faster Evidence-based Translation'' program of the innovative medicine initiative is doing the same in humans (Bendjama et al 2014;Bendjama et al 2013).…”