Dirk van Lier

Shock is a clinical expression of acute circulatory failure, signifying an insufficient supply of oxygen to the cells. Shock affects one-third of intensive care unit patients.1 Typically, shock dia...

The cytosolic protease dipeptidyl peptidase 3 (DPP3) is released into the circulation upon profound cellular stress. In the bloodstream, circulating DPP3 (cDPP3) rapidly degrades several important mediators of vascular tone. The cDPP3-antagonizing antibody Procizumab (PCZ) improved outcome in animal models of shock. This study aimed to establish the safety and tolerability of PCZ across relevant animal species. In the first study, mice received vehicle (n = 72), 37.5 (n = 114), 75 (n = 114), or 150 (n = 126) mg/kg of PCZ intravenously on days 1, 2, 13, and 14. In the second study, cynomolgus monkeys received vehicle (n = 10), 40 (n = 6), 120 (n = 6), or 350 (n = 10) mg/kg of PCZ intravenously on days 1, 2, 13 and 14. Toxicokinetic analyses demonstrated instant and dose-dependent peak concentrations. PCZ was eliminated relatively fast compared to other monoclonal antibodies and administration resulted in an instant reduction of cDPP3 enzyme activity, confirming the intended pharmacodynamic mechanism-of-action. Apart from fully reversible, non-dose-dependent increases of enzymes aspartate aminotransferase, alanine aminotransferase, and creatinine kinase in monkeys, and decreased rarefaction of the cytoplasm of hepatocytes in treated mice compared to the control group, toxicologic analyses showed no test item-related effects. In both studies, no mortality, moribund condition or any other adverse histopathological findings were attributed to PCZ therapy. These findings demonstrate that intravenous, repeated administration of high doses of PCZ was well tolerated in mice and cynomolgus monkeys. Results of this study were followed by a Phase 1 safety assessment of PCZ in humans, with single-administration clinical doses of 3, 6, and 12 mg/kg (NCT06331884).

Dipeptidyl peptidase 3 (DPP3), an aminopeptidase that degrades several key cardiovascular mediators, may induce and exacerbate hemodynamic instability during cardiogenic shock. Procizumab (PCZ) is a first-in-class humanized monoclonal antibody that inhibits DPP3 activity. In preclinical shock models, PCZ increased angiotensin metabolite levels, improved cardiovascular function, and increased survival. Here, results are presented for a first-in-human Phase 1 trial (NCT06331884) that evaluated the safety, tolerability, and pharmacokinetics and pharmacodynamics of PCZ. Twenty-four healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled Phase 1 trial. Participants (n = 6 per group) received placebo or one of three doses of PCZ (3 mg/kg, 6 mg/kg, and 12 mg/kg). Participants were monitored clinically for 24 h after drug administration, as well as at 6 follow-up visits performed during a 28-d period. Adverse events associated with PCZ were predominantly mild, and no serious adverse events were reported. Local tolerability, vital signs, laboratory assessments, and electrocardiograms did not reveal any safety concerns. PCZ exhibited a terminal elimination half-life of 24, 34, and 53 h in the low, intermediate, and high-dose groups, respectively. A volume of distribution of roughly 9.8-10.2 liters indicates that the drug predominantly remains within the circulation. Results of this trial are currently being followed up in the PROCARD Phase 1b/2a (NCT06832722) study, which is evaluating safety and determining the optimal dose of PCZ in cardiogenic shock patients.

Introduction: Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and “circulating DPP3” (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80).Methods: A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI).Results: cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56–0.82, p=0.023), 0.77 (0.64–0.90, p<0.001) and 0.81 (0.65–0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI, with AUROCs of 0.64 (0.51–0.77, p=0.048), 0.75 (0.64–0.86, p<0.001) and 0.83 (0.74–0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day mortality (hazard ratio 11.8; 95% CI 2.5–55.3, p<0.001).Conclusions: cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM-related pathways may improve outcome of COVID-19.

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) are cornerstone treatments in several cardiovascular disease entities [1]. The RAAS is a central regulator of blood pressure, consisting of two counterregulatory pathways, commonly described as classical and non-classical, respectively [1]. The main effect of classical RAAS activation is the generation of angiotensin II by angiotensin converting enzyme (ACE) [1]. In contrast, non-classical RAAS activation results in cleavage of angiotensin II by angiotensin converting enzyme-2 (ACE2) to form angiotensin 1–7, which directly counteracts the effects of classical RAAS activation [1].

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM‐enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3‐blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted.

Aims: Adrenomedullin (ADM) is an important regulator of endothelial barrier function and vascular tone, and may represent a novel treatment target in sepsis. The non‐neutralizing ADM antibody adrecizumab has shown promising results in preclinical sepsis models. In the present study, we investigated the safety, tolerability and pharmacokinetics (PK)/pharmacodynamics of adrecizumab in a first‐in‐man study and in a second study during experimental human endotoxaemia.Methods: Forty‐eight healthy male volunteers were enrolled in two randomized, double‐blind, placebo‐controlled phase I studies. In both studies, subjects received placebo or one of three doses of adrecizumab (n = 6 per group). In the second study, a bolus of 1 ng kg^–1 endotoxin was followed by infusion of 1 ng kg^–1 h^–1 endotoxin for 3 h to induce systemic inflammation, and the study medication infusion started 1 h after endotoxin bolus administration.Results: Adrecizumab showed an excellent safety profile in both studies. PK analyses showed proportional increases in the maximum plasma concentration of adrecizumab with increasing doses, a small volume of distribution, a low clearance rate and a terminal half‐life of ~14 days. adrecizumab elicited a pronounced increase in plasma ADM levels, whereas levels of mid‐regional pro‐adrenomedullin remained unchanged, indicating that de novo synthesis of ADM was not influenced. In the second study, no effects of adrecizumab on cytokine clearance were observed, whereas endotoxin‐induced flu‐like symptoms resolved more rapidly.Conclusions: Administration of adrecizumab is safe and well tolerated in humans, both in the absence and presence of systemic inflammation. These findings pave the way for further investigation of adrecizumab in sepsis patients.