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Through activation of LANCL2, NIM\u20101324 modulates CD4+ T cells to bias signaling and cellular metabolism toward increased immunoregulatory function while providing similar support to phagocytes. In primary human immune cells, NIM\u20101324 reduces type I interferon and inflammatory cytokine (IL\u20106, IL\u20108) production. Oral NIM\u20101324 was assessed for safety, tolerability and PK in normal healthy volunteers in a randomized, double\u2010blind, placebo\u2010controlled trial. Subjects (<jats:italic>n<\/jats:italic>\u2009=\u200957) were randomized into five single ascending dose (SAD) cohorts (250, 500, 750, 1000, 1500\u2009mg, p.o.) and three multiple ascending dose (MAD) cohorts (250, 750, 1500\u2009mg QD for 7\u2009days, p.o.). NIM\u20101324 did not increase total AE rates in individual cohorts or pooled active groups in SAD or MAD with no SAEs in the study. Oral NIM\u20101324 dosing does not result in any clinically significant findings by biochemistry, coagulation, ECG, hematology, or urinalysis when compared to placebo. Plasma exposure, as measured by area under the curve from 0 to 24\u2009h (AUC<jats:sub>0\u201024<\/jats:sub>), scaled dose proportionally over 250\u20131000\u2009mg. At 250\u2009mg, NIM\u20101324 successfully engaged the target with an upregulation of Lancl2 and key transcriptional biomarkers in whole blood. In conclusion, NIM\u20101324 treatment is well\u2010tolerated up to daily oral doses of at least 1500\u2009mg (nominal), a\u2009\u2265\u2009six\u2010fold margin over the anticipated therapeutic dose, and 1000\u2009mg (maximum observed exposure), at least a four\u2010fold margin over the anticipated therapeutic dose with no dose limiting toxicities.<\/jats:p>","DOI":"10.1111\/cts.70129","type":"journal-article","created":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T07:39:34Z","timestamp":1736581174000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Safety, Tolerability, and Pharmacokinetics of <scp>NIM<\/scp>\u20101324 an Oral <scp>LANCL2<\/scp> Agonist in a Randomized, Double\u2010Blind, Placebo\u2010Controlled Phase I Clinical Trial"],"prefix":"10.1111","volume":"18","author":[{"given":"Andrew","family":"Leber","sequence":"first","affiliation":[{"name":"NIMML Institute  Blacksburg Virginia 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