TY - JOUR
T1 - Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH)
T2 - a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial
AU - Savarirayan, Ravi
AU - Hoernschemeyer, Daniel G.
AU - Ljungberg, Merete
AU - Zarate, Yuri A.
AU - Bacino, Carlos A.
AU - Bober, Michael B.
AU - Legare, Janet M.
AU - Högler, Wolfgang
AU - Quattrin, Teresa
AU - Abuzzahab, M. Jennifer
AU - Hofman, Paul L.
AU - White, Klane K.
AU - Ma, Nina S.
AU - Schnabel, Dirk
AU - Sousa, Sérgio B.
AU - Mao, Meng
AU - Smith, Alden
AU - Chakraborty, Mukta
AU - Giwa, Adebola
AU - Winding, Bent
AU - Volck, Birgitte
AU - Shu, Aimee D.
AU - McDonnell, Ciara
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - Achondroplasia
KW - C-type natriuretic peptide
KW - Growth
KW - Paediatric
KW - TransCon CNP
UR - https://www.scopus.com/pages/publications/85173146336
U2 - 10.1016/j.eclinm.2023.102258
DO - 10.1016/j.eclinm.2023.102258
M3 - Article
AN - SCOPUS:85173146336
SN - 2589-5370
VL - 65
JO - eClinicalMedicine
JF - eClinicalMedicine
M1 - 102258
ER -