Dataset Information

Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

ABSTRACT: AIMS:This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079. METHODS:A randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure. RESULTS:TAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg?kg-1 , respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38-expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg?kg-1 TAK-079, maximum observed serum concentration (Cmax ) was 100.4 (%CV: 52) ng?mL-1 , time to Cmax was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg?kg-1 TAK-079, Cmax was 23.0 (%CV: 67) ng?mL-1 with time to Cmax of 24 (range 7.98-96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15-60% and had not returned to baseline levels within 78 days after administration at ?0.3 mg?kg-1 s.c. Reductions in NK cells at 0.6 mg?kg-1 s.c. were approximately 2-3 times more durable than at 0.06 mg?kg-1 i.v. CONCLUSIONS:TAK-079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.

SUBMITTER: Fedyk ER

PROVIDER: S-EPMC7319013 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

Fedyk Eric R ER Zhao Lin L Koch Annelize A Smithson Glennda G Estevam Jose J Chen Grace G Lahu Gezim G Roepcke Stefan S Lin Jianchang J Mclean Lachy L

British journal of clinical pharmacology 20200222 7

<h4>Aims</h4>This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079.<h4>Methods</h4>A randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure.<h4>Results</h4>TAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, ...[more]

PMID: 32045493

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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

Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

Publications

Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

Similar Datasets

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