No abstract

No abstract

The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development.

IntroductionSeptic shock is the subgroup of patients with sepsis, which presents as vasopressor dependence, an elevated blood lactate concentration and is associated with a mortality of at least 30%. Expression of the triggering receptor expressed on myeloid cells 1 (TREM-1) pathway, measured using a serum biomarker of pathway activation (soluble TREM-1, sTREM-1) has been associated with outcome in septic shock. Preclinical and early phase patient data suggest that therapeutic modulation of this pathway may improve survival.Methods and analysisEfficacy, Safety and Tolerability of Nangibotide in Patients with Septic Shock is a phase IIb randomised controlled trial that will take place in up to 50 centres in seven countries and recruit 450 patients with septic shock to receive either placebo or one of two doses of nangibotide, a novel regulator of the TREM-1 pathway. The primary outcome will be the impact of nangibotide therapy on the change in Sequential Organ Failure Assessment score from a baseline determined before initiation of study drug therapy. This will be assessed first in the patients with an elevated sTREM-1 level and then in the study population as a whole. In addition to safety, secondary outcomes of the study will include efficacy of nangibotide in relation to sTREM-1 levels in terms of organ function, mortality and long-term morbidity. This study will also facilitate the development of a novel platform for the measurement of sTREM-1 at the point of care.Ethics and disseminationThe study has been approved by the responsible ethics committees/institutional review boards in all study countries: Belgium: Universitair Ziekenhuis Antwerpen, France: CPP Ile de France II, Denmark: Region Hovedstaden, Spain: ethics committee from Valld’Hebron Hospital, Barcelona, Finland: Tukija, Ireland: St. James’ Hospital (SJH) / Tallaght University Hospital (TUH) Joint Research Ethics Committee, USA: Lifespan, ProvidenceTrial registration numbersEudraCT Number: 2018-004827-36 and NCT04055909.

Background:One of main new avenue of exploration in critical care medicine is the development of personalized medicine approaches to better determine which therapy provides the optimal risk/benefit ratio for subgroups of septic shock patients presenting with similar clinical syndromes. This paper describes the early clinical development of a personalized medicine approach for a novel therapeutic agent targeting the TREM-1 pathway, nangibotide, in the treatment of septic shock.Methods:Soluble TREM-1 (sTREM-1) is a mechanism-based candidate biomarker with the potential to select patients at high risk of death and who may respond best to an anti-TREM-1 strategy. Validation of a potential cut-off value and choice of surrogate endpoint for phase 2b clinical trial are built on data from a retrospective cohort study of 293 septic shock patients and data from a multicentre prospective phase 2a study of 49 septic shock patients treated either by placebo or nangibotide. Logistic regression modelling is combined with receiver operator characteristic analysis to validate the prognostic potential of sTREM-1. In addition, the potential predictive cut-off is defined by modelling the ability of different values to detect treatment effect.Results:sTREM-1 at baseline in the AdrenOSS-1 cohort is strongly associated with 28day mortality with a standardized odds ratio for mortality of 2.86 (95%CI 1.91-4.27, p<0.0001) and an optimum value for predicting mortality of 408pg/ml with an area under the receiver operator characteristic curve of 0.694. Based on the performance of different cut-off values as predictors of treatment response to nangibotide in the Phase IIa MOT-C-201 trial, a preliminary tentative value of 400pg/ml was selected. In patients with the high sTREM-1 group the mean change of SOFA from baseline to 48 hours is +1.5 points in the AdrenOSS-1 cohort. Conclusions: This study improves our understanding of the behaviour of sTREM-1 as a potential mechanism-based biomarker with the potential to offer both prognostic and predictive enrichment in clinical trials of nangibotide. These data inform the design of the ongoing ASTONISH phase 2b study which intends to validate the proposed cut-off value as a predictive biomarker in septic shock.Trial Registration: AdrenOSS-1 study: clinicaltrials.gov: NCT02393781, MOT-C-201: clinicaltrials.gov: NCT03158948