TREM-1 inhibitor · septic shock
An experimental peptide that dampens an inflammation amplifier called TREM-1. It is being developed by Inotrem as an intravenous treatment for septic shock, where the body's response to infection spirals out of control and blood pressure collapses. It is also known by its research code, LR12, and as Motrem.
TREM-1 (triggering receptor expressed on myeloid cells-1) sits on neutrophils and monocytes and amplifies the inflammatory signals these cells send after their toll-like receptors detect bacteria. In sepsis, this amplification can feed the cytokine surge, blood-vessel dysfunction and organ damage of septic shock. Nangibotide is a peptide that inhibits TREM-1 signaling, with the aim of tempering this amplification. Because TREM-1 activity varies widely between patients, trials measure soluble TREM-1 (sTREM-1) in the blood to find those whose pathway is most switched on. The peptide is broken down by enzymes in blood within minutes, so it is given as a continuous intravenous infusion in intensive care.
In monkeys given bacterial endotoxin, LR12 kept blood pressure normal and blunted cytokine release and white-cell drops5. In healthy volunteers, single infusions were well tolerated at all doses studied, with an effective half-life of about three minutes1. A phase 2a trial in 49 septic shock patients found no excess adverse events and a non-significant trend toward better organ-failure scores, larger in people with high sTREM-12. The phase 2b ASTONISH trial (355 patients) missed its primary endpoint, change in organ-failure score by day 5; exploratory analyses suggested benefit with the higher dose in patients with the highest sTREM-1 levels3.
In COVID-19 patients on respiratory support, the ESSENTIAL trial stopped early for slow recruitment; it reported better clinical status and lower 28-day mortality with nangibotide, but in only 219 analyzed patients4.
Not approved by the FDA, and we found no approval by any other regulator. It has been studied in phase 2 trials in septic shock and COVID-19.
In phase 1, adverse events were few, mild and judged unrelated to the drug, and no anti-drug antibodies appeared1. In the septic shock trials, treatment-emergent and serious adverse events occurred at similar rates with nangibotide and placebo, with nearly all critically ill patients having some event2,3. The COVID-19 trial also reported similar adverse-event rates between groups4. All human data so far come from hospital infusions lasting hours to days.
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