Safety, Pharmacokinetics and Pharmacodynamics of the Anti-Hepcidin Spiegelmer Lexaptepid Pegol in Healthy Subjects

Br J Pharmacol. 2016 May;173(10):1580-8. doi: 10.1111/bph.13433. Epub 2016 Apr 8.

Abstract

Background and purpose: Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l-oligoribonucleotide, binds and inactivates hepcidin.

Experimental approach: We conducted a placebo-controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg(-1) .

Key results: After treatment with lexaptepid, serum iron concentration and transferrin increased dose-dependently. Iron increased from approximately 20 μmol·L(-1) at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg(-1) lexaptepid. The pharmacokinetics showed dose-proportional increases in peak plasma concentrations and moderately over-proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti-drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg(-1) and with local injection site reactions after s.c. but not after i.v. administration.

Conclusions and implications: Lexaptepid pegol inhibited hepcidin and dose-dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Monitoring
  • Female
  • Healthy Volunteers
  • Hepcidins / antagonists & inhibitors*
  • Humans
  • Iron / blood
  • Male
  • Oligoribonucleotides / administration & dosage
  • Oligoribonucleotides / adverse effects*
  • Oligoribonucleotides / pharmacokinetics*
  • Structure-Activity Relationship
  • Transferrin / analysis

Substances

  • Hepcidins
  • Oligoribonucleotides
  • Transferrin
  • NOX-H94
  • Iron