Toward precision medicine

Cardiogenic shock

Cardiogenic shock (CS) is an acute life-threatening condition accounting for more than 100,000 deaths per year in the U.S. & Europe alone. CS is a tremendous cost burden for society with an average cost per patient of US$ 150 to 190k in the U.S.⁸

CS is a syndrome of life-threatening peripheral hypoperfusion and organ dysfunction due to cardiac dysfunction^3,9,10. Several underlying cardiac conditions may induce CS, with acute myocardial infarction accounting for approximately 30% of CS while other acute and chronic heart disease accounts for the remaining 70%^11–13. CS is accompanied by relevant morbidity and mortality rates of up to 50%^14,15. Limited CS management strategies are available, and even fewer lead to mortality reduction¹⁶.

CS management is largely based on experience rather than evidence-based recommendations as few adequately designed randomized clinical trials to guide treatment exist^17,18. Best management of CS is usually accomplished in tertiary cardiogenic shock centres and encompasses revascularization strategies, treatment with inotropes and vasopressors, implantation of mechanical circulatory support and intensive care support for other organs (mostly lungs and kidneys). All these therapies address symptoms of CS and not the underlying pathophysiological cause with limited effect on mortality.

In summary, over two decades, there have been no new drug therapies approved in this field. CS poor prognosis is partly driven by exposure to standard of care, such as prolonged vasopressor use, and requirement of mechanical circulatory support. CS represents an acute cardiovascular condition with a high socio-economic burden and a lack of adequate treatment options.

Novel pathway: cDPP3

cDPP3 is a prognostic marker and a major cause of circulatory failure and, ultimately, death. The harmful cDPP3 pathway has been validated in more than 100,000 patients in 90 clinical studies across 350 clinical sites in 17 countries in conditions such as shock due to cardiac failure, burns, major surgery and septic myocardiopathy.

In shock, ~50% of patients have elevated cDPP3 levels and this elevation is associated with poor outcomes such as multiple organ failure and increased short-term mortality^5,19–23.

As proof-of-concept, injection of DPP3 in healthy animals causes cardiac depression, modulates systemic and renal hemodynamics and leads to RAAS alteration, validating cDPP3 a causal factor and a promising drug target^5,6.

In health, DPP3 is an intracellular aminopeptidase regulating oxidative stress. Once released into the bloodstream, cDPP3 (circulating DPP3) degrades angiotensin peptides resulting in dysregulation of the Renin-Angiotensin-Aldosterone-System (RAAS). Loss of RAAS control ultimately spirals into organ failure, shock, and death.

Drug candidate: Procizumab (PCZ)

PCZ is a humanized monoclonal antibody that binds and inhibits cDPP3 and, hence, restores control over RAAS, normalizes cardiovascular function, reverses organ dysfunction, and increases survival. Non-clinical efficacy and safety of PCZ were demonstrated in three independent efficacy models^4,5,7.

Fully IND-enabled compound with Phase 1 trial in healthy volunteers completed with no safety findings and a favorable safety and tolerability profile.

Three PCZ-treated patients in the context of named-patient use have shown that PCZ is safe and well-tolerated. These results further confirmed translation of non-clinical to clinical safety and efficacy findings, such as in vivo cDPP3 activity inhibition leading to improvement of organ function (heart, kidney, and lung), reduced inflammation, and shock reversal.

Phase 1b/2a to establish dosing regimen in cardiogenic shock patients with elevated cDPP3 is planned to start in Q1 2025 followed by a pivotal Phase 2/3 clinical proof-of-concept study in cardiogenic shock patients.

Commercial drug supply is assured with a PCZ manufacturer with production capabilities in Europe, Japan, and U.S. and with upscaling potential to meet future commercial supply requirements.