OR36-05 Safety and Tolerability of Navepegritide Treatment in Children With Achondroplasia: 52-Week Results From the Pivotal ApproaCH Trial
Bibliographic record
Abstract
Abstract Disclosure: C. McDonnell: Ascendis Pharma, BioMarin, Pfizer, Inc. H. Hove: Ascendis Pharma, Pfizer, Inc.. J.M. Legare: None. P.M. Campeau: Ascendis Pharma, BioMarin, Ipsen, Pfizer, Inc., Takeda. P.L. Hofman: Eli Lilly & Company, Novo Nordisk. D.G. Hoernschemeyer: BioMarin, Orthopediatrics, Zimvie. J.M. de Bergua Domingo: None. M.J. Abuzzahab: Ascendis Pharma, Endo, Inhale, Lumos, Medtronic, Novo Nordisk, Pfizer, Inc., Rhythm, Soleno. M. Mao: Ascendis Pharma. I. Ballance: Ascendis Pharma. L.C. Freiberg: Ascendis Pharma. L.W. Dalby: Ascendis Pharma. A.D. Shu: Ascendis Pharma. C.A. Bacino: Ascendis Pharma, BioMarin, Ionis Pharmaceuticals Inc., Roche. R. Savarirayan: Ascendis Pharma, BioMarin, BridgeBio. Background: Safety and tolerability are key considerations in assessing the value of emerging therapies that aim to address clinical manifestations and potentially life-threatening complications of achondroplasia (ACH). Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered SC 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) characteristic of ACH. We report safety and tolerability data from ApproaCH, a pivotal, randomized, double-blind, placebo-controlled trial in which children with ACH were treated with navepegritide or placebo for 52 weeks. Based on the reported experience with an available daily CNP analogue, symptomatic hypotension and injection site reactions (ISRs) were defined as adverse events of special interest in the ApproaCH trial. 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. Safety and tolerability were assessed via treatment-emergent adverse events (TEAEs), laboratory values, vital signs, physical and skeletal examination, electrocardiogram, Tanner staging, bone age, and bone-related safety events. Results: Navepegritide demonstrated AGV superiority over placebo with an LS mean AGV of 5.89 cm/year vs. 4.41 cm/year in the placebo group (LS mean difference 1.49 cm/year, p<0.0001). Navepegritide was well tolerated, with ∼99% of reported AEs being mild (Grade 1) or moderate (Grade 2). No AEs led to trial withdrawal or treatment discontinuation. Incidence of treatment-related AEs was similar between groups (21.1% with navepegritide vs 25.9% with placebo). There was a low incidence of ISRs in both groups (19.3% or 0.41 events per person year of exposure to navepegritide vs 14.8% or 0.15 with placebo). All ISRs were mild (Grade 1). AEs of asymptomatic hypotension were documented in two participants in each the navepegritide group (3.5%) and the placebo group (7.4%); none were considered treatment-related. Conclusion: In the pivotal ApproaCH trial, navepegritide significantly improved linear growth in children with ACH while maintaining a safety profile comparable to placebo. The treatment was well-tolerated and most TEAEs were mild or moderate. Weekly administration of navepegritide was associated with a low incidence of ISRs and no evidence of treatment-related hypotensive effects. These results suggest that the design of once-weekly navepegritide as a prodrug with a low CNP Cmax contributes to a favorable safety and tolerability profile, and may address limitations of existing ACH therapies and support improved treatment adherence. Presentation: Monday, July 14, 2025
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".