The Hennigsdorf, Germany-based company is keeping the efficacy data under wraps for now, however. It did report a trend suggesting that adrecizumab provided a benefit on all-cause mortality vs. placebo. Those in the latter group had a mortality rate of 28% after 28 days of follow-up, which is on a par with current best clinical care standards. It has not disclosed the equivalent number for either of the study’s two drug treatment groups. “We saw a clear trend – a reduction in mortality at 14 days, 28 days and also 90 days,” Adrenomed CEO Jens Schneider-Mergener told BioWorld.
Data analysis is ongoing, and more data will come in the coming months – or even weeks. The International Symposium on Intensive Care and Emergency Medicine (ISICEM) meeting in Brussels in late March is one possibility, Adrenomed’s chief business officer, Frauke Hein, told BioWorld.
But comments from the lead clinical investigators on the AdrenOSS-2 trial, which Adrenomed included in a news release, suggest that the drug does work. “For the first time, we have seen a positive effect on early death in septic shock,” stated Pierre-François Laterre, who heads the medical-surgical intensive care unit at Saint Luc University Hospital at the Université Catholique de Louvain in Brussels. “Undoubtedly, AdrenOSS-2 exhibited benefits on survival in septic shock patients, suggesting great potential for endothelial modulation on septic shock outcomes,” stated Alexandre Mebazaa, who chairs the department of anesthesiology and critical care at Hôpital Lariboisière, which is affiliated with Université de Paris.
The study recruited 301 patients with early septic shock and elevated levels of the peptide hormone adrenomedullin, the target of adrecizumab. They were randomized in a 1-to-1-to-2 ratio to receive a single infusion of low-dose (2 mg/kg) adrecizumab, high-dose (4 mg/kg) adrecizumab, or placebo. All participants received standard of care.
The primary endpoint included several measures of safety and tolerability over a 90-day observation period, including mortality due to adrecizumab, interruption of infusion of adrecizumab due to drug intolerability, new treatment-emergent adverse events due to adrecizumab, and changes in the frequency and severity of treatment-emergent adverse events. The study also included several secondary efficacy endpoints, including mortality rate, sepsis support index (which measures the number of days requiring organ support and death within 14 days), organ dysfunction and length of ICU stay. It has previously passed an interim analysis, which assessed the drug’s performance on the SSI endpoint in half of the recruited patients.
Adrecizumab works by sequestering adrenomedullin within the vasculature, where it helps to maintain endothelial barrier function during sepsis. High levels of the hormone, however, can lead to a build-up in the interstitium, outside of the blood vessels, where it has potent vasodilatory effects and contributes to the septic shock pathology. The antibody does not neutralize the hormone, but localizes its effect within the blood vessel, while also reducing levels in the interstitium.
A predecessor study, AdrenOSS-1, published in Critical Care on Dec. 18, 2018, confirmed that baseline levels of active adrenomedullin above 70 picograms per milliliter of blood (pg/ml) were associated with organ dysfunction and higher mortality. That threshold level was employed as an inclusion criterion in the present trial – only those above that level were recruited onto the study. They constitute a large fraction of the patient population. “It’s 70% of shock patients,” Hein said. For those with sepsis only, “the percentage is a little bit lower.” As well as completing the data analysis, the company will start to consult with regulators on the next steps required for the program. It will also seek additional venture capital, Schneider-Mergener said. It is also considering how to broaden its range. “Obviously the drug could have great potential in preventing shock,” he said.
It also has additional data disclosures on the way, from two investigator-initiated studies. One study, in cardiogenic shock, is recruiting 150 participants and is scheduled to enroll the last patient in July. The second, in acute heart failure, is recruiting 40 patients. Both trials are expected to read out in H2 2020.