Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial
ABSTRACT NIM‐1324 is an oral investigational new drug for autoimmune disease that targets the Lanthionine Synthetase C‐like 2 (LANCL2) pathway. Through activation of LANCL2, NIM‐1324 modulates CD4+ T cells to bias signaling and cellular metabolism toward increased immunoregulatory function while pro...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Science |
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| Online Access: | https://doi.org/10.1111/cts.70129 |
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| author | Andrew Leber Raquel Hontecillas Nuria Tubau‐Juni Josep Bassaganya‐Riera |
| author_facet | Andrew Leber Raquel Hontecillas Nuria Tubau‐Juni Josep Bassaganya‐Riera |
| author_sort | Andrew Leber |
| collection | DOAJ |
| description | ABSTRACT NIM‐1324 is an oral investigational new drug for autoimmune disease that targets the Lanthionine Synthetase C‐like 2 (LANCL2) pathway. Through activation of LANCL2, NIM‐1324 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‐1324 reduces type I interferon and inflammatory cytokine (IL‐6, IL‐8) production. Oral NIM‐1324 was assessed for safety, tolerability and PK in normal healthy volunteers in a randomized, double‐blind, placebo‐controlled trial. Subjects (n = 57) were randomized into five single ascending dose (SAD) cohorts (250, 500, 750, 1000, 1500 mg, p.o.) and three multiple ascending dose (MAD) cohorts (250, 750, 1500 mg QD for 7 days, p.o.). NIM‐1324 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‐1324 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 h (AUC0‐24), scaled dose proportionally over 250–1000 mg. At 250 mg, NIM‐1324 successfully engaged the target with an upregulation of Lancl2 and key transcriptional biomarkers in whole blood. In conclusion, NIM‐1324 treatment is well‐tolerated up to daily oral doses of at least 1500 mg (nominal), a ≥ six‐fold margin over the anticipated therapeutic dose, and 1000 mg (maximum observed exposure), at least a four‐fold margin over the anticipated therapeutic dose with no dose limiting toxicities. |
| format | Article |
| id | doaj-art-5e3785bd3ac843868348e8fd9641fc72 |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj-art-5e3785bd3ac843868348e8fd9641fc722025-01-24T08:17:46ZengWileyClinical and Translational Science1752-80541752-80622025-01-01181n/an/a10.1111/cts.70129Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical TrialAndrew Leber0Raquel Hontecillas1Nuria Tubau‐Juni2Josep Bassaganya‐Riera3NIMML Institute Blacksburg Virginia USANIMML Institute Blacksburg Virginia USANIMML Institute Blacksburg Virginia USANIMML Institute Blacksburg Virginia USAABSTRACT NIM‐1324 is an oral investigational new drug for autoimmune disease that targets the Lanthionine Synthetase C‐like 2 (LANCL2) pathway. Through activation of LANCL2, NIM‐1324 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‐1324 reduces type I interferon and inflammatory cytokine (IL‐6, IL‐8) production. Oral NIM‐1324 was assessed for safety, tolerability and PK in normal healthy volunteers in a randomized, double‐blind, placebo‐controlled trial. Subjects (n = 57) were randomized into five single ascending dose (SAD) cohorts (250, 500, 750, 1000, 1500 mg, p.o.) and three multiple ascending dose (MAD) cohorts (250, 750, 1500 mg QD for 7 days, p.o.). NIM‐1324 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‐1324 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 h (AUC0‐24), scaled dose proportionally over 250–1000 mg. At 250 mg, NIM‐1324 successfully engaged the target with an upregulation of Lancl2 and key transcriptional biomarkers in whole blood. In conclusion, NIM‐1324 treatment is well‐tolerated up to daily oral doses of at least 1500 mg (nominal), a ≥ six‐fold margin over the anticipated therapeutic dose, and 1000 mg (maximum observed exposure), at least a four‐fold margin over the anticipated therapeutic dose with no dose limiting toxicities.https://doi.org/10.1111/cts.70129LANCL2NIM‐1324phase 1 clinical trialsafetysystemic lupus erythematosus |
| spellingShingle | Andrew Leber Raquel Hontecillas Nuria Tubau‐Juni Josep Bassaganya‐Riera Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial Clinical and Translational Science LANCL2 NIM‐1324 phase 1 clinical trial safety systemic lupus erythematosus |
| title | Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial |
| title_full | Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial |
| title_fullStr | Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial |
| title_full_unstemmed | Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial |
| title_short | Safety, Tolerability, and Pharmacokinetics of NIM‐1324 an Oral LANCL2 Agonist in a Randomized, Double‐Blind, Placebo‐Controlled Phase I Clinical Trial |
| title_sort | safety tolerability and pharmacokinetics of nim 1324 an oral lancl2 agonist in a randomized double blind placebo controlled phase i clinical trial |
| topic | LANCL2 NIM‐1324 phase 1 clinical trial safety systemic lupus erythematosus |
| url | https://doi.org/10.1111/cts.70129 |
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