2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T4a9,Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P < .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed.31:Tdf0,Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life. To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia. Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n = 2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment. Navepegritide (100 μg/kg/wk) or placebo administered by once-weekly subcutaneous injection. The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity. Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P < .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed. In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth. ClinicalTrials.gov Identifier: NCT05598320.32:T143f, Importance Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life. Objective To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia. Design, Setting, and Participants Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n = 2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment. Interventions Navepegritide (100 μg/kg/wk) or placebo administered by once-weekly subcutaneous injection. Main Outcomes and Measures The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity. Results Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P &lt; .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (−1.81° [−3.16 to −0.47]), mechanical axis deviation (−2.78 mm [−4.71 to −0.86]), fibula to tibia length ratio (−0.016 [−0.024 to −0.008]), and Achondroplasia Child Experience Measures–Physical Functioning (−11.1 [−21.5 to −0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed. Conclusions In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth. Trial Registration ClinicalTrials.gov Identifier: NCT05598320 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Achondroplasia: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Achondroplasia (condition). Clinician-written summaries and actionable practice insights. 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The upper-to-lower body segment ratio did not change significantly (–0.02; 96% CI, –0.06 to 0.01). Serious adverse events occurred in 5% of the infigratinib group vs. 3% of placebo; none were deemed treatment-related.","limitations":"- Trial duration was only 52 weeks; long-term safety and effects on final adult height are unknown.\n- The upper-to-lower body segment ratio (a key body proportion endpoint) did not show a significant benefit.\n- No serious adverse events were attributed to treatment by investigators, but the open-label follow-up data are not yet available.","practice_takeaway":"Once-daily oral infigratinib produces a clinically meaningful boost in growth velocity in children with achondroplasia over one year, with a safety profile similar to placebo. Clinicians should note that body proportion improvement was not demonstrated in this timeframe, and longer-term data are needed before making conclusions about skeletal outcomes."}},{"doi":"10.1001/jamapediatrics.2025.4771","pmid":"41247754","title":"Once-Weekly Navepegritide in Children With Achondroplasia","journal_title":"JAMA Pediatrics","journal_issn":"2168-6203","published_at":"2025-11-17T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12624480/","source_score":59,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-01-10","doi":"10.1001/jamapediatrics.2025.4771","days":"14","issn":"2168-6203","rank":"9","field":"Clinical Medicine","score":"59","category":"Pediatrics","categories":["Pediatrics"],"_categories":["Pediatrics"]},"pubmed":{"doi":"10.1001/jamapediatrics.2025.4771","title":"Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial.","journal":"JAMA pediatrics","methods":"","results":"$30","abstract":"$31","keywords":[],"pubmed_id":"41247754","conclusions":"","publication_date":"2025-11-17T00:00:00"},"crossref":{"DOI":"10.1001/jamapediatrics.2025.4771","URL":"https://doi.org/10.1001/jamapediatrics.2025.4771","ISSN":["2168-6203"],"link":[{"URL":"https://jamanetwork.com/journals/jamapediatrics/articlepdf/2841492/jamapediatrics_savarirayan_2025_oi_250064_1767894261.89192.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"18","type":"journal-article","issue":"1","score":1,"title":["Once-Weekly Navepegritide in Children With Achondroplasia"],"author":[{"given":"Ravi","family":"Savarirayan","sequence":"first","affiliation":[{"name":"Skeletal Biology, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia"},{"name":"Royal Children’s Hospital, Parkville, Melbourne, Australia"},{"name":"Department of Pediatrics, University of Melbourne, Parkville, Melbourne, Australia"}]},{"given":"Ciara","family":"McDonnell","sequence":"additional","affiliation":[{"name":"Paediatric Endocrinology and Diabetes, Children’s Health Ireland at Temple Street, Dublin, Ireland"},{"name":"Paediatric Endocrinology, University of Dublin, Trinity College, Dublin, Ireland"}]},{"given":"Carlos A.","family":"Bacino","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas"}]},{"given":"Daniel G.","family":"Hoernschemeyer","sequence":"additional","affiliation":[{"name":"Pediatric Intensive Care Unit, University of Missouri Children’s Hospital, Columbia"}]},{"given":"Janet M.","family":"Legare","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison"}]},{"given":"M. Jennifer","family":"Abuzzahab","sequence":"additional","affiliation":[{"name":"McNeely Pediatric Diabetes Center and Endocrine Clinic, Children’s Minnesota, Minneapolis"}]},{"given":"Paul L.","family":"Hofman","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, The Liggins Institute, University of Auckland, Auckland, New Zealand"}]},{"given":"Philippe M.","family":"Campeau","sequence":"additional","affiliation":[{"name":"Department de Pediatrie, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Quebec, Canada"}]},{"given":"Josep Maria","family":"de Bergua Domingo","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Unidad de Cirugía Artroscópica, Vithas Vitoria Hospital, Vitoria-Gasteiz, Spain"}]},{"given":"Leanne M.","family":"Ward","sequence":"additional","affiliation":[{"name":"Pediatric Bone Health, University of Ottawa, Ottawa, Ontario, Canada"},{"name":"Paediatric Orthopaedic Surgery, Children’s Hospital of 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Natriuretic Peptide Analog","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"sample_size","value":"n=84","value_numeric":84},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"warning","value":"Adverse event rates are summarized qualitatively; detailed incidence by group is not provided in the provided text.","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"warning","value":"Only the treatment difference for growth velocity is provided here; absolute growth rates by arm are not shown in the excerpt.","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2025.4771","tag_type":"warning","value":"The open-label extension is ongoing, so long-term efficacy and safety are not available from this report.","value_numeric":null}],"summaries":{"what_studied":"A phase 2b randomized, double-blind, placebo-controlled trial tested once-weekly subcutaneous navepegritide 100 μg/kg vs placebo for 52 weeks in 84 treatment-naive children aged 2–11 years with genetically confirmed achondroplasia.","key_result":"At 52 weeks, navepegritide increased annualized growth velocity vs placebo by a least-squares mean difference of 1.49 cm/y (95% CI, 1.05 to 1.93; P<.001); secondary improvements included tibial-femoral angle (-1.81°), mechanical axis deviation (-2.78 mm), fibula:tibia length ratio (-0.016), and ACEM-Physical Functioning in children <5 years (-11.1). No treatment-related serious adverse events or deaths occurred; injection site reaction rates were low, with no symptomatic hypotension or fractures observed.","limitations":"Phase 2b sample (n=84) with a 52-week duration; exclusion of patients with factors like severe untreated sleep apnea or planned bone surgery may limit generalizability; the open-label extension is ongoing.","practice_takeaway":"In children 2–11 years with achondroplasia, once-weekly navepegritide increased growth velocity by 1.49 cm/y over 52 weeks and improved skeletal alignment measures with few safety signals; longer-term outcomes and durability should be confirmed before changing practice."}}],"initialOffset":2,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Achondroplasia"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Achondroplasia"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Achondroplasia"}}}]]

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