DUBLIN – Adrenomed AG has reported encouraging, albeit limited, data for its antibody adrecizumab in eight COVID-19 patients in Germany with life-threatening acute respiratory distress syndrome (ARDS).
The drug was made available on a named-patient basis to critically ill patients undergoing mechanical ventilation. Prior to receiving the antibody, the patients had a median Sequential Organ Failure Assessment (SOFA) score of 12.5 – the 24-point scale assesses respiratory, CNS, cardiovascular, liver and kidney functions, as well as blood coagulation – and a median score of 39 on the 163-point Simplified Acute Physiology Score II (SAPS-II), which is based on multiple parameters. All of them had severe underlying conditions – five had both type 2 diabetes and hypertension, and five developed renal failure with a need for renal replacement therapy following the onset of shock.
Shortly after undergoing ventilation, each patient received either a single low dose (4mg/kg; n=2) or a single high dose (8mg/kg; n=6) of the drug. One of the low-dose patients died four days after receiving the antibody from a pulmonary embolism. At follow-up, which ranged from 13 to 29 days, three of the surviving patients had been transferred from ICU to a regular ward, and the other four were still alive although still on ventilation.
Five patients exhibited SOFA score reductions within 12 days – three of them had reductions of over 50% compared with their baseline scores. “We also saw a good response to our treatment with respect to oxygenation. It improved within hours, which was astonishing,” Jens Zimmermann, chief medical officer at Hennigsdorf-based Adrenomed told BioWorld. The data were reported Aug. 11 in Biomolecules.
The main limitation, as the study authors noted, is that the study had no control group so the actual contribution of adrecizumab to the patients’ status is not clear. A full-scale phase II trial would have been difficult to conduct in Germany, Zimmermann said, as patient numbers were falling when the study was undertaken. “We came to the conclusion it would be hard to get a reasonable number of patients for such a trial in that time frame,” he said. In addition, Adrenomed had a limited amount of clinical trial material available at the time.
The company has no concrete plans for a controlled phase II trial, but such a study is under consideration. It would aim to treat patients at an earlier stage in the disease course, which would open the possibility of employing avoidance of the need for mechanical ventilation as an endpoint. If case numbers start to rise dramatically – a second wave appears to be breaking in several European countries at present – such a trial would become a more realistic prospect.
The rationale for testing the drug in COVID-19 is solid. Adrecizumab, which earlier this year hit the primary endpoint in a phase II trial in septic shock, binds the peptide hormone adrenomedullin and sequesters it within the lumen of the vasculature, where it helps to preserve endothelial barrier function and reduce capillary leakage, a key aspect of the pathology of shock. The hormone has a Janus-like profile, however, as it exerts harmful vasodilatory effects in the extravascular space, where elevated levels can lead to a fall in blood pressure.
ARDS is one of the main contributors to morbidity and mortality in COVID-19. Adrenomed made the drug available to two existing clinical collaborators of Adrenomed who had prior experience of the drug, Mahir Karakas, of the German Center for Cardiovascular Research and the University Heart & Vascular Center Hamburg, and Stefan Kluge, of the University Medical Center Hamburg-Eppendorf.
In its septic shock trial, Adrenomed followed a biomarker-guided patient selection strategy, treating only those patients with plasma-elevated levels of adrenomedullin – greater than 70 pg per ml – which is indicative of endothelial dysfunction. In COVID-19, the treating physicians followed a similar but less stringent patient selection strategy, opting for a lower concentration threshold (greater than 60 pg/ml) than in the septic shock trial. They also allowed patients with a 25% increase in adrenomedullin levels to receive the drug.
The company has yet to report the full dataset from the phase II trial in septic shock. A presentation at the International Symposium on Intensive Care and Emergency Medicine was originally scheduled for March, but the meeting will now go ahead, in virtual form, in September. A paper is also in preparation for journal publication.
Recruitment onto additional studies of adrecizumab in cardiogenic shock and in acute heart failure has been hampered by the COVID-19 outbreak. Company execs said each will complete enrollment by the year end, with data to follow next year. It is currently seeking additional private equity investment, CEO Jens Schneider-Mergener told BioWorld. Talks with potential partners are also ongoing.
“We are already talking to a number of companies, and who knows what will happen,” he said.