SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study
▪ Background Hepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as con...
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Veröffentlicht in: | Blood 2021-11, Vol.138 (Supplement 1), p.2009-2009 |
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Sprache: | eng |
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Background
Hepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers.
Objectives
The primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated.
Methods
Each subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo.
Results
Three cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed.
Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively.
Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57.
The mean (±SD) per |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2021-147852 |