Improvements in Lower Extremity Alignment are Associated with Physical Functioning in Children with Achondroplasia Treated with Navepegritide: 52-Week Results from the ApproaCH Trial

Melita Irving; Leanne Ward; Daniel Hoernschemeyer; Janet Legare; Hanne Hove; Carlos Bacino; Philippe Campeau; Paul Hofman; de Bergua Domingo Josep Maria; M.Jennifer Abuzzahab; Kevin Smit; Sasha Carsen; Andrew Tice; Stefan Jackowski; Maya Scharke; Meng Mao; Freiberg Laerke Clement; Michael Makara; Michael Ominsky; Aimee Shu; Ravi Savarirayan; Ciara McDonnell

doi:10.1530/endoabs.117.OC3.5

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Endocrine Abstracts (2026) 117 OC3.5 | DOI: 10.1530/endoabs.117.OC3.5

SFEBES2026 Oral Communications Bone and Reproductive Endocrinology (6 abstracts)

Improvements in Lower Extremity Alignment are Associated with Physical Functioning in Children with Achondroplasia Treated with Navepegritide: 52-Week Results from the ApproaCH Trial

Melita Irving ¹ , Leanne Ward ² , Daniel Hoernschemeyer ³ , Janet Legare ⁴ , Hanne Hove ⁵ , Carlos Bacino ⁶ , Philippe Campeau ⁷ , Paul Hofman ⁸ , Josep Maria de Bergua Domingo ⁹ , M.Jennifer Abuzzahab ¹⁰ , Kevin Smit ^11,12 , Sasha Carsen ^12,13 , Andrew Tice ^12,13 , Stefan Jackowski ¹⁴ , Maya Scharke ¹⁴ , Meng Mao ¹⁵ , Lærke Clement Freiberg ¹⁶ , Michael Makara ¹⁵ , Michael Ominsky ¹⁵ , Aimee Shu ¹⁵ , Ravi Savarirayan ^17,18,19 & Ciara McDonnell ^20,21

Author affiliations

¹Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom; ²Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada; ³University of Missouri Children’s Hospital, Columbia, USA; ⁴University of Wisconsin School of Medicine and Public Health, Wisconsin, USA; ⁵Copenhagen University Hospital, Copenhagen, Denmark; ⁶Baylor College of Medicine, Texas, USA; ⁷CHU Sainte-Justine Research Center, Montreal, Canada; ⁸The Liggins Institute, University of Auckland, Auckland, New Zealand; ⁹Unidad de Cirugía Artroscópica, Vithas Vitoria Hospital, Vitoria- Gasteiz, Spain; ¹⁰Children’s Minnesota, Minneapolis, USA; ¹¹Department of Surgery, Division of Pediatric Orthopedics, Children’s Hospital of Eastern Ontario, Ottawa, Canada; ¹²University of Ottawa, Ottawa, Canada; ¹³Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada; ¹⁴The Ottawa Pediatric Bone Health Research Group, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada; ¹⁵Ascendis Pharma Inc., Palo Alto, USA; ¹⁶Ascendis Pharma A/S, Hellerup, Denmark; ¹⁷Murdoch Children’s Research Institute, Parkville, Australia; ¹⁸Royal Children’s Hospital, Parkville, Australia; ¹⁹University of Melbourne, Parkville, Australia; ²⁰Children’s Health Ireland at Temple Street, Dublin, Ireland; ²¹University of Dublin, Trinity College, Dublin, Ireland

Genu varum is common in children with achondroplasia, and can lead to pain, impaired mobility, and a negative impact on health-related quality of life. In this post-hoc analysis from the pivotal ApproaCH trial we report the effects of navepegritide, a prodrug of C-type natriuretic peptide (CNP), on genu varum and its association with Achondroplasia Child Experience Measure-Physical Functioning (ACEM-PF), an achondroplasia-specific clinical outcome assessment. ApproaCH randomized 84 children (aged 2-11 years) 2:1 to receive once-weekly navepegritide (100 µg/kg/week) or placebo. Radiographs were collected at baseline and Week 52, with key features of skeletal dysplasia assessed by blinded central readers. Data are reported as least square (LS) mean differences versus placebo calculated by ANCOVA, and Pearson correlation coefficients (r). The primary endpoint—annualized growth velocity at Week 52—was greater in navepegritide-treated children versus placebo (LS mean difference 1.49 cm/year, P < 0.0001). Compared with placebo at Week 52, navepegritide significantly reduced tibial-femoral angle (TFA) (difference -1.81 degrees, P = 0.0094), significantly improved fibula-to-tibia ratio (difference -0.016, P = 0.0001), and improved ACEM-PF scores (difference -4.6, P = 0.252). Compared with the overall population, children with prominent genu varum at baseline (TFA ≥5 degrees) treated with navepegritide had greater improvements versus placebo in TFA (difference -3.99 degrees, P = 0.0073) and ACEM-PF (difference -8.2, P = 0.048). Changes in ACEM-PF were associated with improvements in TFA in children with more severe genu varum at baseline (r = 0.31; P = 0.062); the correlation was stronger in this subgroup aged <8 years (r = 0.39; P = 0.035). Navepegritide demonstrated superiority over placebo in AGV, and reduced TFA at Week 52 in the ApproaCH trial. Associations between improvements in genu varum and ACEM-PF support that changes in lower extremity alignment with once-weekly navepegritide positively impact physical functioning, and suggest that navepegritide may offer benefits beyond promoting linear growth that translate into meaningful improvements in children living with achondroplasia.