Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia

Timothy C R Prickett,Jonathan R S Day,Ravi Savarirayan,Eric A Espiner,Ming Liang Chan,Melita Irving,Elena Fisheleva,George S Jeha,John A Phillips,Kevin Larimore,Carlos Bacino

doi:10.1038/s41598-021-03593-1

Abstract

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

Highlights

Evidence from genetic disorders of C-type natriuretic peptide (CNP) signalling suggests that plasma concentrations of CNP are subject to feedback regulation
NTproCNP standard deviation score (SDS) was lower in Cohort 1, and age was lower in Cohort 4
The possibility that CNP production may be subject to negative feedback regulation is an important issue that needs study in light of the peptide’s increasing use in growth disorders in children

Summary

Introduction

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and related to skeletal growth. The normal reciprocal a ntagonism[10] between FGFR3 pathway activity (inhibitory to endochondral bone growth) and CNP signalling (stimulating bone growth) is overridden by a gain of function mutation in FGR311, reducing intracellular CNP activity, and is associated with modest elevations in concentrations of CNP products in p lasma[6] These findings suggest that CNP production is subject to feedback regulation. Our hypotheses were that: (1) daily dosing of Vosoritide—depending on dose and duration—inhibits endogenous CNP secretion during phases of increasing growth velocity (indirect feedback) and (2) endogenous CNP will be unaffected by Vosoritide administered 4 h previously (direct feedback)

Methods

Results

Conclusion