Nangibotide for Septic Shock
Nangibotide is not recommended for routine use in septic shock, as the phase 2b ASTONISH trial failed to meet its primary endpoint of improving organ dysfunction scores at the predefined biomarker threshold. 1
Current Evidence Status
The most recent and highest quality evidence comes from the 2023 ASTONISH trial published in The Lancet Respiratory Medicine, which evaluated nangibotide in 355 patients with septic shock across 42 ICUs in seven countries. 1
Primary Outcome Results
In patients with high sTREM-1 (≥400 pg/mL): No significant improvement in SOFA score from baseline to day 5 was observed
In the overall population: Similarly negative results with no statistically significant benefit 1
Post-Hoc Exploratory Findings
The trial identified a potential signal at higher sTREM-1 cutoff concentrations (≥532 pg/mL), where high-dose nangibotide showed clinically relevant SOFA score improvement of two points or more. 1 However, this was an exploratory post-hoc analysis, not the predefined primary endpoint, and requires prospective validation before clinical application.
Safety Profile
Nangibotide demonstrated acceptable safety across all doses tested:
- Treatment-emergent adverse events were similar between groups (96% placebo, 96% low-dose, 95% high-dose) 1
- Serious adverse events occurred in 24-26% across all groups 1
- Phase 1 studies showed dose-proportional pharmacokinetics with rapid clearance (3-minute half-life) and no anti-drug antibodies 2
Mechanism and Rationale
Nangibotide targets the TREM-1 (triggering receptor expressed on myeloid cells-1) pathway, which is activated during septic shock and associated with worse outcomes. 3 Preclinical models showed that TREM-1 inhibition tempered host-pathogen interactions, restored vascular function, and improved survival. 4 However, these promising preclinical results did not translate to clinical benefit at the predefined biomarker threshold.
Current Standard of Care
The Surviving Sepsis Campaign guidelines do not include TREM-1 inhibitors or nangibotide in their recommendations for septic shock management. 5 Standard therapy remains:
- Immediate antimicrobial therapy: Broad-spectrum IV antibiotics within one hour of recognition 6, 7
- Fluid resuscitation: 30 mL/kg IV crystalloid within first 3 hours 6
- Vasopressor support: Norepinephrine as first-line agent targeting MAP ≥65 mmHg 6
- Source control: Surgical or procedural intervention when indicated 7
Clinical Implications
Do not use nangibotide outside of clinical trials. The drug failed to demonstrate efficacy at its predefined primary endpoint and remains investigational. 1 While exploratory analyses suggest potential benefit at higher sTREM-1 concentrations, this hypothesis requires prospective validation in future trials before any clinical recommendation can be made.
Common Pitfall to Avoid
Do not confuse the exploratory post-hoc findings (benefit at sTREM-1 ≥532 pg/mL) with established efficacy. 1 Post-hoc subgroup analyses are hypothesis-generating only and cannot substitute for prospectively defined endpoints in clinical decision-making.