Clinical stage biotech company Inotrem has announced results from its phase IIb ASTONISH clinical trial in septic shock patients.
The results were revealed at the International Sepsis Forum in Barcelona, Spain.
ASTONISH was designed to show the efficacy of nangibotide in septic shock with a precision medicine approach aiming to identify patients who benefit the most from the treatment. The global study enrolled 361 patients in 41 clinical sites in six European countries and the U.S.
Nangibotide is Inotrem’s lead compound. It is a synthetic peptide and first-in-class TREM-1 inhibitor. Nangibotide blocks the TREM-1-mediated immune dysregulations in sterile or infectious acute inflammatory syndromes. It restores a balanced inflammatory response and improves outcomes, particularly in patients with high levels of TREM-1 pathway activation.
The study succeeded in demonstrating a therapeutic benefit of nangibotide in patients with high levels of the TREM-1 pathway activation marker, soluble TREM-1 (sTREM-1).
ASTONISH studied as a primary endpoint the improvement in SOFA score, a well-established morbidity score evaluating patient clinical evolution and organ function. The change of this score at five days after initiation of treatment in the nangibotide-treated arms was compared to the placebo arm in all patients and in patients with a high level of sTREM-1.
Importantly, and as part of the prespecified analysis for defining the optimal sTREM-1 cut-off, the benefit of nangibotide high dose treatment versus placebo was clinically and statistically significant at higher concentrations of sTREM-1, representing about 50% of the study population.
Consistent with prior preclinical, observational and phase IIa trial data in this setting, ASTONISH confirmed that excessive TREM-1 activity is associated with severe immune dysregulation, organ dysfunction and ultimately death.
ASTONISH demonstrates that TREM-1 modulation with nangibotide improves respiratory, cardiovascular and renal function. The study also provided evidence that nangibotide meaningfully impacts other relevant clinical parameters, displaying a trend towards improvement in all-cause mortality at day 28 and the proportion of patients alive and free of organ support at day 28.
Jean-Jacques Garaud, senior VP head of scientific and medical affairs at Inotrem, said: “The ASTONISH trial was designed as a phase III enabling trial; it generated positive and important insights about nangibotide’s therapeutic activity and our precision medicine approach in septic shock. We are enthusiastic about this study and Inotrem’s capacity to bring a first in class product in an area with a major unmet medical need.”
“These results represent a major advancement for patients suffering from septic shock. They provide compelling evidence that Inotrem’s innovative solution targeting the TREM-1 pathway has the potential to become the first causal treatment for this severe and often fatal indication,” said Sven Zimmermann, CEO of Inotrem.
“Based on these data, we intend to advance nangibotide towards registration studies in septic shock. We look forward to discussing next steps with regulatory authorities.”
Professor Bruno François, Limoges University Hospital and coordinating investigator, added: “We observed that the TREM-1 pathway was activated in severe infections leading to septic shock. Nangibotide is the first TREM-1 inhibitor and ASTONISH confirms its potential as a new therapeutic option for the septic shock patient population. We are looking forward to bringing definitive evidence, in a phase III clinical study that nangibotide can reduce mortality in these critically ill patients.”
Septic shock is the ultimate complication of sepsis and currently constitutes a high unmet medical need. The incidence of septic shock is rising, and mortality remains elevated. It is the 10th leading cause of death in developed countries and the main cause of death in intensive care units.
There is currently no specific therapy approved for this indication besides antibiotics and symptomatic treatment. Inotrem’s solution has the potential to become the first mechanism-based treatment for septic shock.