ECEESPE2025 Oral Communications Oral Communications 7: Bone and Mineral Metabolism (9 abstracts)
Effects of navepegritide on bone morphometry in children with achondroplasia: 52-week results from the approach clinical trial
Leanne Ward 1,2 , Daniel Hoernschemeyer 3 , Janet Legare 4 , Hanne Hove 5 , Carlos Bacino 6 , Philippe Campeau 7 , Paul Hofman 8 , Josep de Bergua Domingo 9 , Jennifer Abuzzahab 10 , Stefan Jackowski 2 , Kevin Smit 2 , Andrew Tice 2 , Sasha Carsen 2 , Meng Mao 11 , Lærke Freiberg 12 , Michael Makara 11 , Michael Ominsky 11 , Aimee Shu 11 , Ravi Savarirayan 13,14,15 & Ciara McDonnell 16
1University of Ottawa, Ottawa, ON, Canada; 2Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; 3University of Missouri Children’s Hospital, Columbia, MO, United States; 4University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; 5Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; 6Baylor College of Medicine, Houston, TX, United States; 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, MN, United States; 11Ascendis Pharma Inc., Palo Alto, CA, United States; 12Ascendis Pharma A/S, Hellerup, Denmark; 13Murdoch Children’s Research Institute, Parkville, Australia; 14Royal Children’s Hospital, Parkville, Australia; 15University of Melbourne, Parkville, Australia; 16Children’s Health Ireland at Temple Street, Dublin, Ireland; University of Dublin, Trinity College, Dublin, Ireland
JOINT1778
Background: In children with achondroplasia (ACH), morphometric changes in the spine and lower extremities are associated with a range of orthopaedic and neurological complications. Increased rates of thoracolumbar kyphosis, lumbar lordosis, stenosis of the spinal canal, and genu varum may lead to pain, altered mobility, and the need for orthopaedic surgery. Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered by subcutaneous injection once weekly and designed to provide a low Cmax 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 ACH. We report radiographic findings from ApproaCH, a pivotal randomized, double-blind, placebo-controlled trial evaluating navepegritide in children with ACH.
Methods: Participants (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. The primary endpoint was annualized growth velocity (AGV) at week 52. Bone morphometry parameters were exploratory endpoints assessed by blinded central readers using spine and lower extremity radiographs, with data expressed as changes from baseline at week 52.
Results: Navepegritide demonstrated superiority over placebo in AGV at Week 52, with a least square (LS) mean AGV of 5.89 cm/year in children treated with navepegritide vs. 4.41 cm/year with placebo (LS mean treatment difference 1.49 cm/year [P<0.0001]). Safety and tolerability were comparable between treatment groups. Spinal canal dimensions were numerically improved with navepegritide compared to placebo across L1-L5, with a significant increase from baseline observed for interpedicular distance at L1 (LS mean difference of 0.618 mm, P=0.0222). No statistically significant changes were observed in thoracolumbar kyphosis or lumbar lordosis. Compared to placebo, navepegritide significantly reduced tibia femoral angle (LS mean difference of -1.814 degrees, P=0.0094) and mechanical axis deviation in the lower limbs (LS mean difference of -2.781 mm, P=0.0063). These changes corresponded to a normalization in fibular overgrowth, considered the key cause of leg bowing, as reflected in the reduced fibula-to-tibia ratio (LS mean difference of -0.016, P=0.0001).
Conclusion: In the ApproaCH trial, weekly administration of navepegritide demonstrated superiority over placebo in AGV and improved aspects of bone morphometry in children with ACH. These findings highlight that the design of navepegritide, which provides continuous exposure to active CNP, may deliver benefits that go beyond promoting linear growth – actively targeting and addressing critical aspects of skeletal dysplasia in ACH, which are key contributors to health-related complications.
Volume 110
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Endocrine Abstracts
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