Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

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.
Competing Interests: RS reports participation on advisory boards with Ascendis and BioMarin and consulting role for BridgeBio. AGH reports research funding from, speaker's bureau support for, and grants from Zimvie; patents and stock options with, consulting for, and travel support from Orthopediatrics; and honoraria from BioMarin. ML reports consulting role with and travel support from Ascendis. CAB reports research funding from Ascendis, BioMarin, Ionis, NIH, and Roche; board member for the American Board of Medical Genetics and Genomics; author for 8 chapters in Genetics in UpToDate. MBB reports research funding from Ascendis, BioMarin, QED, and Therachon/Pfizer; consulting fees from Tyra; honoraria from Novo Nordisk; participation on a data and safety monitoring board (DSMB) for BioMarin, QED, and Therachon/Pfizer; and leadership for SDMC. JML reports research funding and honoraria from BioMarin and travel support from Ascendis. WH reports research funding and consulting fees from Ascendis and consulting fees from BioMarin. TQ reports research funding from Ascendis, Janssen, Merck, NIH, and Provention Bio; consulting fees from Janssen and Provention Bio; honoraria from Merck and MH Life Sciences; expert testimony payment from Janssen; and travel support from Provention Bio. MJA reports research funding from Ascendis, Lumos, MannKind, Medtronic, Novo Nordisk, Rhythm, and Soleno; participation on a DSMB for Ascendis, Broad Group, Rhythm, and Pfizer; and leadership with Raymond A Wood Foundation. KKW reports honoraria from BioMarin; patents with UpToDate; and research funding from Ascendis, BioMarin, Pfizer, and Ultragenyx. NSM reports research funding from and consulting role for Ascendis. DS reports honoraria from Hexal/Sandoz, Kyowa Kirin, Novo Nordisk, and Pfizer; travel support from Ascendis and Novo Nordisk; participation on a DSMB for Ascendis, BioMarin, Hexal/Sandoz, Kyowa Kirin, and Novo Nordisk; and leadership with German Society for Pediatric Endocrinology and Diabetes. SBS reports honoraria from and advisory role for Ascendis and BioMarin; honoraria from Kiowa Kirin; and travel support from BioMarin. MM, AS, MC, AG, BW, BV, and ADS report employment and stock options with Ascendis. CM reports research funding and travel support from Ascendis; consulting role with BioMarin; travel support from Pfizer; leadership with International Society of Children's Bone Health. YAZ and PLH have no conflicts to disclose.
(© 2023 The Author(s).)