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Treatment with a novel monoclonal antibody against circulating dipeptidyl peptidase 3 (cDPP3) led to complete reversal of cardiogenic shock in three compassionate use cases in Germany, according to a new research letter.

The cases mark the first time the intervention has been used to treat cardiogenic shock in humans. Only one of the patients survived, however.

“The findings are highly promising and represent a significant step forward in causally addressing cardiogenic shock, a condition with limited treatment options and high mortality,” Mahir Karakas, MD, of the University Medical Center Hamburg-Eppendorf, Hamburg, Germany, told Medscape Medical News. He is the chief technology officer of 4TEEN4 Pharmaceuticals GmbH, the pharmaceutical company developing the monoclonal antibody called procizumab.

‘Out-of-the-Box’ Approach

The mortality rate of cardiogenic shock exceeds 50%, and current interventions treat only symptoms rather than addressing the root cause, said Alexandre Mebazaa, MD, PhD, of the Université Paris Cité in Paris, France, and a coauthor on the letter. Recent research has revealed a strong link between elevated cDPP3 and higher mortality rates in patients with cardiogenic shock.

Procizumab targets DPP3, an enzyme released during cell death that breaks down angiotensin II and disrupts the renin-angiotensin-aldosterone system. By blocking this enzyme’s activity, procizumab “is intended to rapidly stabilize hemodynamics and therefore cardiovascular and renal function,” Mebazaa and his colleagues wrote.

“With these three cases, we [were] really thinking outside of the box, saying, ‘There is a protein that is toxic inside the blood: let’s inactivate it and see what we can do,’” Mebazaa told Medscape Medical News.

The research letter, published online on July 10 in the European Journal of Heart Failure, documented the treatment of three patients in critical condition with signs of multiorgan failure due to refractory septic shock. Patient 1 (age 64 years) and patient 3 (age 80 years) were women; patient 2 (age 84 years) was a man.

All conventional therapies had been tried in these patients “with no further options for escalation of conventional therapy in the presence of a high chance of immediate mortality,” the authors wrote.

All three patients had elevated DPP3 activity, acute kidney injury, and needed renal replacement therapy. Patients 1 and 2 were intubated and received mechanical ventilation.

Procizumab was administered at a 10 mg/kg dose over 2 hours, and patients were followed for 48 hours. Efficacy was assessed by shock reversal, defined as a norepinephrine dose of 0.2 µg/kg/min or less, or a reduction by at least half of the initial dose.

A decline in DPP3 activity over 2 days was accompanied by a marked reduction in norepinephrine dose and lactate concentrations. All three patients demonstrated improved arterial oxygen partial pressure/fractional inspired oxygen ratios, a measure to assess hypoxemia, compared with baseline.

Early, but ‘Impressive’ Findings

“These very early findings support the potential of this specific anti-DPP3 antibody, procizumab, which has previously been shown in animal studies in septic and cardiogenic shock,” said Holger Thiele, MD, director of the Heart Center Leipzig at the University of Leipzig, in Leipzig, Germany, who was not involved with the case study.

Both Thiele and the authors acknowledged the uncontrolled design and small sample size preclude any firm conclusions around the potential efficacy of the treatment.

“This is far too early to draw conclusions [about whether] all these effects are related to procizumab, although the drop in [interleukin 6] IL-6 and the improvement in renal function are impressive,” Thiele said. “However, like always with promising devices or drugs, initial results are often too good to be true. We have to wait for the phase 2, and more importantly, the phase 3 trials to see if this drug in cardiogenic shock or septic shock is able to reduce the mortality.”

Two of the patients who received the treatment died less than 2 weeks later: one from recurrent shock likely due to papillary muscle rupture from untreated myocardial infarction (MI), and another from refractory shock due to exacerbation of right heart failure. Patient 2 recovered organ function and was transferred to rehab at 8 weeks despite a new MI at week 4, the researchers reported.

“That two of the three patients had refractory shock again is the typical nature of these severely ill patients,” Thiele said. “This probably will also be one of the challenges to show a possible benefit of this drug in the subsequent phase 2 and phase 3 trials.”

Ongoing Trial

Mebazaa is now leading a phase 1b trial to evaluate the safety and tolerability of procizumab as well as the ideal dose for a phase 2 trial. The study, PROCARD 1b, aims to enroll 130 patients with cardiogenic shock due to acute coronary syndrome or sepsis with elevated DPP3.

“It is most likely that specific cutoffs for DPP3 are required,” Thiele said; while too low of a concentration will probably show no benefit, “too high with too many organ dysfunctions may also result in neutral results. Therefore, a well-designed trial for phases 2 and 3 is of paramount importance.”

4TEEN4 Pharmaceuticals GmbH (Hennigsdorf, Brandenburg, Germany) provided procizumab and technical support for this case series. Mebazaa reported having research contracts with 4TEEN4 Pharmaceuticals GmbH, Roche, SphingoTec, Abbott Diagnostics, and Windtree; consultancy fees from Roche, Corteria, Adrenomed, and Fire-1; and lecture honoraria from Merck, Novartis, Roche, and Bayer. He is a coinventor on patents related to dyspnea treatments and on a patent owned by S-Form Pharma. Karakas was supported by the Else Kröner-Fresenius-Stiftung (W3 Else Kröner Clinician Scientist Professorships). He reported receiving grants and nonfinancial support from Adrenomed AG and CSL Vifor and consulting fees or honoraria from Adrenomed AG, CSL Vifor, Daiichi Sankyo, SphingoTec, Pharmacosmos, and 4TEEN4 Pharmaceuticals GmbH. Thiele disclosed having no relevant financial relationships.