Nangibotide

A synthetic 12-amino-acid TREM-1 inhibitor peptide derived from TREM-like transcript-1, infused intravenously in septic shock and COVID-19 trials, that did not meet its phase 2b primary endpoint and passed to Genfit in 2026 for a planned liver-failure trial.

Also referenced as: LR12, LR-12, Motrem, nangibotide trifluoroacetate

Also appears in: Cardiovascular

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What is Nangibotide?

Nangibotide (development names LR12 and MOTREM) is a synthetic 12-amino-acid peptide (Leu-Gln-Glu-Glu-Asp-Ala-Gly-Glu-Tyr-Gly-Cys-Met, C-terminally amidated) that inhibits TREM-1, the triggering receptor expressed on myeloid cells-1, an amplifier of the innate immune response carried on neutrophils, monocytes, and macrophages. Its sequence is taken from the extracellular domain of TREM-like transcript-1 (TLT-1), a platelet receptor in the same family whose soluble form damps leukocyte activation during sepsis; the peptide is made by chemical synthesis rather than isolated from any biological source, and laboratory reagent lots are usually supplied as the trifluoroacetate salt. Nangibotide is the International Nonproprietary Name; MOTREM was the project name the originator, Inotrem (Paris), used in early trial registrations, and LR12 is the laboratory name that still appears on reagent listings and in the EMA’s PRIME list.

It was developed as an intravenous immunomodulator for septic shock, where no targeted therapy is approved, and was tested in critically ill COVID-19 during the pandemic. In summer 2026 the asset moved to Genfit, which announced on September 14, 2026 that it would take nangibotide into a phase 2a trial in acute-on-chronic liver failure. It is a clinical-stage drug candidate that appears only in reagent catalogs for in vitro use, if at all, and is not a research-market product.

How it works

• A decoy for the TREM-1 ligand. TREM-1 amplifies toll-like-receptor signaling once engaged, and nangibotide does not bind the receptor itself. The TLT-1-derived peptides (the 17-residue LR17 and the shorter LR12) compete with the TREM-1 ligand, so TREM-1 is not engaged and the downstream burst of cytokine release and NF-κB activation is dampened without abolishing pathogen clearance; early or late LR17 treatment improved survival in septic mice, and TLT-1-deficient mice were highly susceptible to polymicrobial infection (Derive et al., Journal of Immunology, 2012;188(11):5585–5592).
• Hemodynamic protection in large-animal sepsis. In minipigs with fecal peritonitis, LR12 attenuated hypotension, myocardial dysfunction, lactic acidosis, coagulation abnormalities, and multiple organ failure, with better mean arterial pressure and cardiac index despite lower norepinephrine requirements (Derive et al., Shock, 2013;39(2):176–182). In cynomolgus monkeys given intravenous endotoxin, LR12-treated animals stayed normotensive while placebo animals lost 25–40% of their blood pressure, and leukopenia and cytokine production were attenuated (Derive et al., Anesthesiology, 2014;120(4):935–942).
• Vascular and cardiac inflammation beyond sepsis. Genetic and pharmacological TREM-1 inhibition with LR12 limited the development of experimental atherosclerosis in mice (Joffre et al., Journal of the American College of Cardiology, 2016;68(25):2776–2793), and TREM-1 blockade limited inflammatory injury and adverse remodeling after experimental myocardial infarction (Boufenzer et al., Circulation Research, 2015;116(11):1772–1782). These findings are the basis for the cardiovascular interest in the compound but have not been tested in humans.
• Very short half-life, so continuous infusion. In healthy volunteers, nangibotide showed dose-proportional pharmacokinetics with a clearance of 6.6 L/kg/h and an effective half-life of 3 minutes, consistent with extensive enzymatic metabolism in blood, and a distribution limited mainly to blood and interstitial fluid; no anti-drug antibodies were detected through day 28 (Cuvier et al., British Journal of Clinical Pharmacology, 2018;84(10):2270–2279). All patient trials have therefore used a continuous intravenous infusion for days rather than discrete doses.

Research status

Nangibotide has completed one phase 1 and three phase 2 trials, did not meet the primary endpoint of its only phase 2b, and has no approval anywhere. A phase 3 trial was designed and agreed with the FDA but never registered or started, and the program changed hands in 2026.

Phase 1 (NCT03463044). A randomized, double-blind, ascending-dose study in 27 healthy men at a London phase 1 unit, started in April 2016 under the name MOTREM (LR12), found the peptide safe and well tolerated up to the highest dose tested, with few, mild, unrelated adverse events; the registry entry has posted results (Cuvier et al., British Journal of Clinical Pharmacology, 2018;84(10):2270–2279).

Phase 2a (NCT03158948). A multicenter, randomized, double-blind, two-stage study in Belgium, France, the Netherlands, and Spain that enrolled 50 and randomized 49 adults in septic shock to one of three continuous infusion rates or placebo, begun within 24 hours of shock onset and continued for up to five days (July 2017 to June 2018). The primary safety outcomes showed no difference in treatment-emergent adverse events between groups, no drug withdrawals for adverse events, and no anti-drug antibodies. Pharmacodynamic markers did not change significantly. The exploratory signal was a numerically larger fall in SOFA score from baseline to day 5 in pooled nangibotide groups versus placebo (least-squares mean change −0.7 overall and −1.5 in patients with high baseline plasma sTREM-1), neither significant, which set up the biomarker-enrichment hypothesis (François et al., Intensive Care Medicine, 2020;46(7):1425–1437).

ASTONISH, phase 2b (NCT04055909, EudraCT 2018-004827-36). A double-blind, randomized, placebo-controlled trial across 42 ICUs in seven countries (Belgium, Denmark, Finland, France, Ireland, Spain, and the United States) that screened 402 and analyzed 355 adults with non-COVID septic shock between November 14, 2019 and April 11, 2022, randomized 1:1:1 to a low-dose infusion, a high-dose infusion, or placebo (116 placebo, 118 low dose, 121 high dose). The primary outcome was the difference in SOFA score change from baseline to day 5, assessed first in the predefined high sTREM-1 population (≥400 pg/mL, 71% of patients) and then overall. It was not met: in the high sTREM-1 population the difference versus placebo was 0.21 (95% CI −1.45 to 1.87, p = 0.80) for low dose and 1.39 (−0.28 to 3.06, p = 0.104) for high dose; overall it was 0.20 (p = 0.76) and 1.06 (p = 0.108). Day-28 mortality in the high sTREM-1 population was 31% on placebo, 39% on low dose, and 28% on high dose (25%, 32%, and 25% overall). Treatment-emergent and serious adverse events were similar across arms. A post hoc analysis found that high-dose nangibotide produced a clinically relevant SOFA improvement of two points or more over placebo only in patients with baseline sTREM-1 at or above 532 pg/mL, a higher cutoff than the one prespecified (François et al., Lancet Respiratory Medicine, 2023;11(10):894–904). An accompanying commentary from NIH Clinical Center intensivists framed this as a precision-medicine hypothesis still to be confirmed (Neupane and Kadri, Lancet Respiratory Medicine, 2023;11(10):855–857). The registry entry still lists the trial as active, not recruiting, with no results posted.

ESSENTIAL, COVID-19 (NCT04429334, EudraCT 2020-001504-42). A double-blind, randomized, placebo-controlled trial of nangibotide against placebo in adults within 48 hours of starting invasive or non-invasive respiratory support for COVID-19 ARDS, run in France and Belgium from September 2020 to April 2022 with a recruitment pause from January to August 2021. Expanded in July 2021 into a phase 2/3 program planned for up to 730 patients, it was stopped after 220 had been recruited because enrollment of critically ill COVID-19 patients collapsed. In the 219 patients analyzed, improvement on a seven-point ordinal clinical scale at day 28 occurred in 64.7% on nangibotide versus 52.0% on placebo (odds ratio 1.79, 95% CI 1.02–3.14, p = 0.043); in the high sTREM-1 half the figures were 48.1% versus 32.7% (odds ratio 2.17, 0.96–4.90, p = 0.063). Day-28 mortality was 16.0% versus 28.0%, an adjusted absolute reduction of 12.1% (1.18–23.05), and 22.2% versus 41.8% in the 109 high sTREM-1 patients (19.9%, 2.78–36.98). Adverse event rates were similar (François et al., eClinicalMedicine, 2023;60:102013). The trial is positive on its primary endpoint but underpowered relative to its design, and the mortality finding is a secondary endpoint in a trial that stopped early.

The enrichment strategy and the phase 3 that did not start. On January 8, 2024, Inotrem announced the outcome of its end-of-phase 2 meeting with the FDA: a single biomarker-guided phase 3 registration trial, ACCURATE, enrolling about 1,300 adults in septic shock with high blood sTREM-1 (about half of all septic shock patients) at roughly 100 sites in the Americas, Europe, and Japan, with a primary analysis population of 900 and a primary endpoint of the proportion alive and free of organ support at day 29, using a Roche Elecsys sTREM-1 assay intended as a companion diagnostic. A 2025 letter by the ASTONISH steering committee and Derek Angus set out the mechanism-based prognostic enrichment rationale (François et al., Intensive Care Medicine, 2025;51(5):965–967), and Inotrem’s July 23, 2025 release said the strategy had been agreed with the FDA, EMA, and Japan’s PMDA, reporting a SOFA difference of −2.5 points (p = 0.007) and a 22.2% increase in shock reversal (p = 0.006) in the sTREM-1-selected ASTONISH population. ACCURATE was never posted to ClinicalTrials.gov or any other public registry, and no first patient was announced.

Change of ownership. Genfit (Lille) announced on September 14, 2026 that it had acquired nangibotide in summer 2026 and planned a phase 2a proof-of-concept trial in acute-on-chronic liver failure, relying on a safety database of more than 400 subjects across the four prior trials and on the existing manufacturing and regulatory packages. No ACLF trial had been registered as of November 2026, Genfit has said nothing about continuing the septic shock program, and nangibotide has never been given to a patient with liver failure. Separately, Inotrem registered an observational ex vivo study of anti-TREM-1 treatment in intestinal biopsies from people with inflammatory bowel disease (NCT06580418, Italy), and the EMA granted nangibotide orphan designation for sickle cell disease on November 21, 2025 (EU/3/25/3147), an indication with no registered clinical trial.

Common dosage forms

• Investigational solution for intravenous infusion. Supplied in vials to clinical-trial sites only; it has never been available outside a trial.
• Reagent-grade peptide. Lyophilized nangibotide, usually as the trifluoroacetate salt, from laboratory suppliers for in vitro and animal research.
• No approved presentation. No approved pharmaceutical presentation exists in any country.

Key considerations

• Regulatory status. The Investigational status reflects an active clinical program under a new owner with no marketing application anywhere. Genfit has announced a planned phase 2a trial in acute-on-chronic liver failure, the septic shock phase 3 agreed with the FDA in January 2024 was never registered or started, and the compound holds FDA Fast Track and EMA PRIME designations for septic shock plus a 2025 EU orphan designation for sickle cell disease.
• Subgroup-dependent efficacy. The only adequately sized septic shock trial did not meet its prespecified primary endpoint, and the benefit reported since comes from a higher sTREM-1 cutoff chosen after the data were seen. The COVID-19 trial that met its primary endpoint was a fraction of its planned size, and the planned liver-failure trial starts from post hoc signals in other diseases.
• Short safety record. Across about 400 critically ill patients, adverse event rates matched placebo and no anti-drug antibodies were seen, although day-28 mortality on the low dose in ASTONISH was numerically higher than placebo. There are no long-term, pediatric, or outpatient safety data, because the drug has only ever been infused for a few days in an ICU.
• Naming. LR12 is the laboratory name for the 12-residue peptide, LR17 the longer parent fragment never developed clinically, MOTREM Inotrem’s early program name, and ACCURATE a trial name rather than a product. Soluble TREM-1 (sTREM-1) is the companion biomarker measured in blood, not the drug.