Therapy

Shock

Shock is an acute life-threatening condition with a mortality rate of over 50%.^2,3 This medical emergency occurs when the circulatory system cannot deliver enough oxygen to meet the body’s metabolic needs. Shock can be divided into 4 subtypes based on cause:

1. Cardiogenic shock (CS), which is caused by a primary heart dysfunction, i.e. myocardial infarction,
2. Hypovolemic shock, when circulation issues are caused by a drop of fluid volume, i.e. following blood loss,
3. Obstructive shock, caused by mechanical blockages in the circulatory system, i.e. pulmonary embolism, and
4. Distributive shock, when pathological maldistribution of the effective circulating intravascular volume secondary to systemic vasodilation and increased microvascular permeability lead to reduction in systemic vascular resistance (SVR) and failure of tissue perfusion, i.e. septic shock.

While the cause varies, shock in all of its forms can lead to organ failure and drastically increase the risk of mortality.

Cardiogenic shock

Cardiogenic shock is the second-most common cause of circulatory failure. Underlying cardiac conditions may induce cardiogenic shock, with acute myocardial infarction accounting for approximately 30% while other acute and chronic heart disease accounts for the remaining 70%.^7,2,8 Despite the severity of the condition, treatment options remain limited, and very few have shown an effect on reducing mortality.⁹

Current management relies largely on clinical experience rather than evidence-based guidelines. Best care is usually provided in specialized cardiogenic shock centers and may involve revascularization strategies, treatment with inotropes and vasopressors, implantation of mechanical circulatory support and intensive care interventions for organs such as lungs and kidneys. While these therapies can temporarily stabilize patients, they primarily address symptoms rather than the underlying pathophysiological cause of shock which explains their limited impact on survival.

For more than two decades, no new drug therapies have been approved in this field. Best care measures, such as prolonged vasopressor use or mechanical circulatory support, often carry the risks that further contribute to poor outcomes. As a result, shock continues to represent an acute, high-mortality cardiovascular emergency with a pressing need for pathophysiology-based treatments.

Novel pathway: cDPP3

cDPP3 is a prognostic marker, a major cause of circulatory failure and, ultimately, death. The pathological cDPP3 pathway has been validated across several shock types, including shock due to cardiac failure, burns, major surgery and septic myocardiopathy.

In cardiogenic and septic shock, ~50% of patients have elevated cDPP3 levels and this elevation is associated with poor outcomes including multiple organ failure and increased short-term mortality.^{10,11,12,13,14,15} Injection of DPP3 in healthy animals causes cardiac depression, modulates systemic and renal hemodynamics and leads to alteration of the renin-angiotensin-aldosterone-system (RAAS), validating cDPP3 as a causal factor and a promising drug target.^10,16

In a healthy state, DPP3 is an intracellular aminopeptidase that regulates oxidative stress. Once released into the bloodstream, circulating DPP3 (cDPP3) degrades angiotensin peptides resulting in RAAS dysregulation. Loss of RAAS control can ultimately spiral into shock, multiple organ failure, and death.

Drug candidate: invobenitug (procizumab)

We have developed invobenitug (procizumab), a humanized monoclonal antibody that binds and inhibits cDPP3 activity, to subsequently restore control over RAAS, normalize cardiovascular function, reverse organ dysfunction and by that increase survival. Invobenitug (procizumab) has demonstrated non-clinical efficacy and safety in four independent efficacy models.^10,17,18

We have also completed a Phase 1 trial in healthy volunteers establishing a favorable safety and tolerability profile. Invobenitug (procizumab) was also safe and well-tolerated in three shock patients in the context of named-patient program.¹⁹ These results further confirmed the translation of non-clinical to clinical safety and efficacy findings, including in vivo cDPP3 activity inhibition leading to improvement of organ function (heart, kidney, and lung), reduced inflammation, and shock reversal.

Our ongoing Phase 1b/2a trial is designed to establish the dosing regimen in cardiogenic shock patients with elevated cDPP3 levels, which will be rapidly advanced into a Phase 2/3 study in cardiogenic shock patients in Europe and in the USA.

We secured commercial drug supply with a manufacturer that has production capabilities in Europe, Japan, and the USA, and with upscaling potential to meet future commercial supply requirements.