Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context
Summary: 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 achond...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537023004352 |
| _version_ | 1827631680527007744 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ravi Savarirayan |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-09T14:25:26Z |
| format | Article |
| id | doaj.art-07498b64dfd0403e9988b282f640b406 |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-03-09T14:25:26Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-07498b64dfd0403e9988b282f640b4062023-11-28T07:26:43ZengElsevierEClinicalMedicine2589-53702023-11-0165102258Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in contextRavi Savarirayan0Daniel G. Hoernschemeyer1Merete Ljungberg2Yuri A. Zarate3Carlos A. Bacino4Michael B. Bober5Janet M. Legare6Wolfgang Högler7Teresa Quattrin8M. Jennifer Abuzzahab9Paul L. Hofman10Klane K. White11Nina S. Ma12Dirk Schnabel13Sérgio B. Sousa14Meng Mao15Alden Smith16Mukta Chakraborty17Adebola Giwa18Bent Winding19Birgitte Volck20Aimee D. Shu21Ciara McDonnell22Murdoch Children's Research Institute, Parkville, Australia; Royal Children's Hospital, Parkville, Australia; University of Melbourne, Parkville, Australia; Corresponding author. Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, VIC, 3052, Australia.University of Missouri Children's Hospital, Columbia, MO, USACopenhagen University Hospital Rigshospitalet, Copenhagen, DenmarkUniversity of Arkansas for Medical Sciences, Little Rock, AR, USA; University of Kentucky, Lexington, KY, USABaylor College of Medicine, Houston, TX, USANemours Children's Hospital, Wilmington, DE, USAUniversity of Wisconsin School of Medicine and Public Health, Madison, WI, USAJohannes Kepler University Linz, Linz, AustriaUniversity at Buffalo, Buffalo, NY, USAChildren's Minnesota, Minneapolis, MN, USAThe Liggins Institute, University of Auckland, Auckland, New ZealandChildren's Hospital Colorado, Aurora, CO, USAChildren's Hospital Colorado, Aurora, CO, USACenter for Chronically Sick Children, Charité – University Medicine Berlin, Berlin, GermanyHospital Pediátrico de Coimbra, Coimbra, PortugalAscendis Pharma Inc., Palo Alto, CA, USAAscendis Pharma Inc., Palo Alto, CA, USAAscendis Pharma Inc., Palo Alto, CA, USAAscendis Pharma Inc., Palo Alto, CA, USAAscendis Pharma A/S, Hellerup, DenmarkAscendis Pharma A/S, Hellerup, DenmarkAscendis Pharma Inc., Palo Alto, CA, USAChildren's Health Ireland at Temple Street, Dublin, Ireland; University of Dublin, Trinity College, Dublin, IrelandSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589537023004352AchondroplasiaC-type natriuretic peptideGrowthTransCon CNPPaediatric |
| spellingShingle | 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 Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context EClinicalMedicine Achondroplasia C-type natriuretic peptide Growth TransCon CNP Paediatric |
| title | Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context |
| title_full | Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context |
| title_fullStr | Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context |
| title_full_unstemmed | Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context |
| title_short | Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trialResearch in context |
| title_sort | once weekly transcon cnp navepegritide in children with achondroplasia accomplish a phase 2 multicentre randomised double blind placebo controlled dose escalation trialresearch in context |
| topic | Achondroplasia C-type natriuretic peptide Growth TransCon CNP Paediatric |
| url | http://www.sciencedirect.com/science/article/pii/S2589537023004352 |
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