Dataset Information

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

ABSTRACT:

Aims

The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (triggering receptor expressed on myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. This first-in-man, randomized, double-blind, ascending dose, placebo-controlled Phase I study evaluated the safety, tolerability and pharmacokinetics of nangibotide.

Methods

Twenty-seven healthy subjects (aged 18-45 years) were randomized into eight groups. Nangibotide was administered as a single continuous intravenous infusion. The first two groups received a single i.v. dose of 1 and 10 mg, respectively, over 15 min. Subsequent groups were randomized in a product : placebo ratio of 3:1 at doses ranging from 0.03 to 6 mg kg^-1 h^-1 over 7 h 45 min, preceded by a 15-minute loading dose of up to 5 mg kg^-1 .

Results

Nangibotide was safe and well tolerated up to the highest dose tested. There were only few adverse events and they were mild in severity and considered unrelated to treatment. Nangibotide displayed dose-proportional PK properties, with a clearance of 6.6 l kg^-1 h^-1 for a subject of 70 kg and a 3 min effective half-life, which are compatible with extensive enzymatic metabolism in blood. Central and peripheral volumes of distribution were 16.7 l and 15.9 l respectively, indicating limited distribution of the drug mainly in blood and interstitial fluid. No circulating anti-drug antibodies were detectable up to 28 days after administration.

Conclusions

The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development.

SUBMITTER: Cuvier V

PROVIDER: S-EPMC6138490 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

Cuvier Valerie V Lorch Ulrike U Witte Stephan S Olivier Aurelie A Gibot Sebastien S Delor Isabelle I Garaud Jean-Jacques JJ Derive Marc M Salcedo-Magguilli Margarita M

British journal of clinical pharmacology 20180720 10

<h4>Aims</h4>The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (triggering receptor expressed on myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. This first-in-man, randomized, double-blind, ascending dose, placebo-controlled Phase I study evaluated the safety, tolerability and pharmacokinetics of nangibotide.<h4>Methods</h4>Twenty-seven healthy subjects (aged 18-45 years) were randomi ...[more]

PMID: 29885068

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Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),

Dataset Information

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

Aims

Methods

Results

Conclusions

Publications

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

Similar Datasets

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