DUBLIN – 4Teen4 Pharmaceuticals GmbH raised €6.9 million (US$7.7 million) in a series A round to take procizumab, a first-in-class inhibitor of circulating dipeptidyl-peptidase 3 (cDPP3), into clinical trials for patients with cardiogenic shock. A phase I trial in 24 healthy volunteers is due to get underway early next year. A phase II trial in 200 to 300 patients could follow in late 2020, assuming that the phase I readout is positive.

Hennigsdorf, Germany-based 4Teen4 was previously known as Sphingotec Therapeutics but has changed its name, at the behest of its new investors, to differentiate it from its partner, Sphingotec GmbH, also of Hennigsdorf, which has in-licensed diagnostic rights to cDPP3. The new moniker is derived from the Enzyme Commission number for DPP3, EC

Andreas Bergmann, CEO, 4Teen4

The enzyme was originally identified in the 1960s, 4Teen4 CEO Andreas Bergmann told BioWorld, but its clinical significance has been underappreciated until recent times. Scientists from 4Teen4 and academic collaborators recently published a clinical observation study in Finland, involving 174 patients with cardiogenic shock, an acute and often fatal loss of cardiac function that can follow a severe heart attack or other events or conditions, such as septic shock, burn, trauma, surgery and severe malaria.

They established that elevated cDPP3 levels were associated with a higher risk of death in the short-term (standardized hazard ratio 1.4 (1.1–1.8)), whereas a rapid decrease of cDPP3 within 24 hours was associated with a favorable outcome. The same study also reported that injecting cDPP3 into mice caused depression of cardiac and renal function and that those effects were alleviated by the administration of procizumab. The data were published online in the European Journal of Heart Failure on Aug. 31, 2019, in a paper, titled “Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics.” A second study, in 57 patients in France, published on the same day and in the same journal reported similar findings.

The enzyme – which is distinct from the long-established diabetes drug target DPP4 – catalyzes the breakdown of angiotensin II, a peptide hormone that increases blood pressure through vasoconstriction, and leu-enkephalin and met-enkephalin, which are involved in controlling pain and respiratory functions. It mainly exists as a cytosolic enzyme, but as 4Teen4 aims to target the circulating enzyme only, it opted for an antibody-based drug development program. “We wanted to have a very targeted blocking of DPP3,” Bergmann said. “We want to have it in plasma only – not in the cells and not in the brain.” Drug therapy will be very much an acute affair – cDPP3 has a half-life of just 20 minutes, he said.

The upcoming phase I study will be conducted at the University of Nijmegen, in the Netherlands. As well as providing safety and tolerability data, it also should provide preliminary signs of biological activity. Although healthy people have low circulating levels of DPP3, Bergmann said, administration of procizumab should result in an increase in patients’ blood pressure and cardiac output. The phase II study will be conducted across 30 centers in Europe and should take about two years to complete, Bergmann said.

In patients, 4Teen4 will only administer procizumab to those with elevated cDPP3. Those constitute more than 50% of the patient population, who have what is termed refractory or “vasopressor-resistant” cardiogenic shock. Administration of vasopressor therapy to those patients, Bergmann said, will kill them, whereas it is the standard therapy for patients whose cardiogenic shock arises from endothelial dysfunction. The company will employ Sphingotec’s point-of-care diagnostic, IB10 Sphingotest DPP3, which recently gained European approval, to distinguish between the two patient groups. The phase II study will be powered to assess the drug’s effect on mortality, which will constitute the primary endpoint. Additional secondary endpoints will assess the antibody’s effects on the function of multiple organs.

The present round was led by Brandenburg Kapital GmbH, a subsidiary of the ILB Investitionsbank des Landes Brandenburg, with additional participation from undisclosed private and angel investors. The company will seek another €20 million to fund the phase II study, Bergmann said.

Bergmann has two antibodies in his life, as he is also chief scientific officer of Hennigsdorf-based Adrenomed AG, which is running a phase II trial of adrecizumab, an antibody that sequesters within the lumen of blood vessels the vasodilatory peptide hormone adrenomedullin. A readout is expected in February.

Adrecizumab is aimed at patients with high levels of adrenomedullin, which is associated with endothelial dysfunction. Procizumab also has potential in septic shock, but in a different category of patients, whose condition is also linked to high cDDP3. “We are eating the elephant, slice by slice,” Bergmann said.

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