Effects of navepegritide on growth in children with achondroplasia: 52-week results from the approach clinical trial

Hanne Hove; Ciara McDonnell; Carlos Bacino; Philippe Campeau; Paul Hofman; Janet Legare; Daniel Hoernschemeyer; Bergua Domingo Josep de; Jennifer Abuzzahab; Bart Degreve; Laerke Freiberg; Meng Mao; Allison Komirenko; Aimee Shu; Ravi Savarirayan

doi:10.1530/endoabs.110.OC14.6

OC14.6

Prev Next

Section Contents Cite

Endocrine Abstracts (2025) 110 OC14.6 | DOI: 10.1530/endoabs.110.OC14.6

ECEESPE2025 Oral Communications Oral Communications 14: Growth Axis and Syndromes (6 abstracts)

Effects of navepegritide on growth in children with achondroplasia: 52-week results from the approach clinical trial

Hanne Hove ¹ , Ciara McDonnell ² , Carlos Bacino ³ , Philippe Campeau ⁴ , Paul Hofman ⁵ , Janet Legare ⁶ , Daniel Hoernschemeyer ⁷ , Josep de Bergua Domingo ⁸ , Jennifer Abuzzahab ⁹ , Bart Degreve ¹⁰ , Lærke Freiberg ¹⁰ , Meng Mao ¹¹ , Allison Komirenko ¹¹ , Aimee Shu ¹¹ & Ravi Savarirayan ^12,13,14

Author affiliations

¹Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; ²Children’s Health Ireland at Temple Street, Dublin, Ireland; University of Dublin, Trinity College, Dublin, Ireland; ³Baylor College of Medicine, Houston, TX, United States; ⁴CHU Sainte-Justine Research Center, Montreal, Canada; ⁵The Liggins Institute, University of Auckland, Auckland, New Zealand; ⁶University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; ⁷University of Missouri Children’s Hospital, Columbia, MO, United States; ⁸Unidad de Cirugía Artroscópica, Vithas Vitoria Hospital, Vitoria-Gasteiz, Spain; ⁹Children’s Minnesota, Minneapolis, MN, United States; ¹⁰Ascendis Pharma A/S, Hellerup, Denmark; ¹¹Ascendis Pharma Inc., Palo Alto, CA, United States; ¹²Murdoch Children’s Research Institute, Parkville, Australia; ¹³Royal Children’s Hospital, Parkville, Australia; ¹⁴University of Melbourne, Parkville, Australia

JOINT185

Background: Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered subcutaneously once weekly and designed to provide a low C_max through sustained release of active CNP. Continuous exposure to the released CNP stimulates natriuretic peptide receptor B (NPR-B) to counteract the constitutively active fibroblast growth factor receptor 3 (FGFR3) in achondroplasia (ACH). ApproaCH is a pivotal, randomized, double-blind, placebo-controlled trial evaluating navepegritide in children with ACH.

Methods: Children with ACH (n=84, aged 2-11 years) were stratified by age and sex and randomized 2:1 to receive navepegritide (100 µg/ kg/week) or placebo for 52 weeks. The primary endpoint was annualized growth velocity (AGV) at week 52. Secondary endpoints included ACH-specific height Z-scores. Safety and tolerability were evaluated through treatment-emergent adverse events (TEAEs), including injection site reactions (ISRs), and changes in bone age.

Results: The trial met its primary endpoint, demonstrating superiority of navepegritide over placebo in AGV at week 52. Children treated with navepegritide achieved a least square (LS) mean AGV of 5.89 cm/year compared with 4.41 cm/year in children who received placebo (LS mean treatment difference 1.49 cm/year, P<0.0001). Change from baseline in ACH-specific height Z-score at 52 weeks was also significantly greater in the navepegritide group than the placebo group (LS mean treatment difference 0.28, P<0.0001). In subgroup analyses of children aged ≥5 years (n=53), participants treated with navepegritide had a higher AGV at Week 52 (LS mean treatment difference 1.78 cm/year, P<0.0001) and a greater change from baseline in ACH-specific height-Z-score (LS mean treatment difference 0.31, P<0.0001) than those who received placebo. Most TEAEs were mild or moderate, with a low event rate of ISRs (all mild) across groups (0.41 events per person year of exposure with navepegritide vs. 0.15 with placebo). The incidence of treatment-related AEs was similar between the navepegritide (21.1%) and placebo (25.9%) groups. The mean bone age to chronological age ratio remained relatively unchanged from baseline (change of 0 in the navepegritide group and -0.01 in the placebo group).

Conclusion: Navepegritide demonstrated superiority over placebo in AGV at week 52 of the ApproaCH trial. Statistically significant improvements in ACH-specific height Z-scores in children treated with navepegritide compared with placebo were also observed. These findings suggest that the design of navepegritide – to provide continuous exposure to active CNP – improves growth in children with ACH while maintaining a safety and tolerability profile comparable to placebo.