Once-Weekly TransCon CNP (Navepegritide) in Children With Achondroplasia (ACcomplisH): A Phase 2, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial

Authors

Ravi Savarirayan
Daniel G Hoernschemeyer
Merete Ljungberg
Yuri A Zarate
Carlos A Bacino
Michael B Bober
Janet M Legare
Wolfgang Högler
Teresa Quattrin
M Jennifer Abuzzahab
Paul L Hofman
Klane K White
Nina S Ma
Dirk Schnabel
Sérgio B Sousa
Meng Mao
Alden Smith
Mukta Chakraborty
Adebola Giwa
Bent Winding
Birgitte Volck
Aimee D Shu
Ciara McDonnell

Publication Date

11-1-2023

Journal

eClinicalMedicine

DOI

10.1016/j.eclinm.2023.102258

PMID

37823031

PMCID

PMC10562841

PubMedCentral® Posted Date

10-2-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Achondroplasia, C-type natriuretic peptide, Growth, TransCon CNP, Paediatric

Abstract

BACKGROUND: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.

METHODS: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).

FINDINGS: Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.

INTERPRETATION: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.

FUNDING: Ascendis Pharma, A/S.

Comments

Associated Data