Highlight
– Once-weekly navepegritide produced a statistically significant increase in annualized growth velocity versus placebo at 52 weeks (LS mean difference 1.49 cm/year; 95% CI, 1.05–1.93; P < .001) in children with genetically confirmed achondroplasia.
– Treatment was associated with measurable improvements in limb alignment (tibial-femoral angle, mechanical axis deviation, fibula:tibia length ratio) and age-appropriate physical functioning scores.
– The 52-week safety profile was favorable: no treatment-related serious adverse events, no deaths, low injection-site reaction rates, and no symptomatic hypotension or fractures reported.
Background: clinical context and unmet need
Achondroplasia is the most common skeletal dysplasia leading to disproportionate short stature. It is caused by recurrent gain-of-function variants in FGFR3, which limit endochondral bone growth and also contribute to multisystem morbidity including spinal stenosis, foramen magnum constriction, obstructive and central sleep-disordered breathing, disproportionate limb-to-trunk proportions, orthopedic deformities, and condition-specific impacts on mobility and health-related quality of life. Historically management has been supportive and multidisciplinary, with orthopedic and neurosurgical interventions for specific complications, physiotherapy, and attention to respiratory and neurodevelopmental complications.
Therapeutic approaches that target the molecular pathway of achondroplasia have been a major focus of recent research. C-type natriuretic peptide (CNP) signaling antagonizes FGFR3-driven inhibition of chondrocyte proliferation and differentiation; pharmacologic CNP analogs and prodrugs are therefore logical disease-modifying therapies. Navepegritide is an investigational once-weekly prodrug of CNP designed to provide sustained exposure with less frequent dosing than daily agents.
Study design: APPROACH trial overview
APPROACH was a phase 2b, randomized, double-blind, placebo-controlled, multinational trial (ClinicalTrials.gov NCT05598320) that enrolled children aged 2 to 11 years with genetically confirmed achondroplasia. Between March and August 2023, 84 participants were randomized 2:1 to receive navepegritide 100 μg/kg once weekly by subcutaneous injection (n = 57) or placebo (n = 27). Important exclusion criteria included radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or other medical conditions known to affect growth. Participants had documented pre-randomization growth measures and were treatment-naive to growth-promoting agents. Randomization was stratified by age and sex. Participants received blinded treatment for 52 weeks; an open-label extension is ongoing.
The primary endpoint was annualized growth velocity at week 52. Secondary and exploratory outcomes included radiographically assessed skeletal measures (tibial-femoral angle, mechanical axis deviation, fibula-to-tibia length ratio) and health-related quality of life measured with the Achondroplasia Child Experience Measures (ACEM), including a physical functioning domain. Safety assessments included adverse events, clinical labs, bone age, blood pressure monitoring, and immunogenicity testing.
Key findings: efficacy
The trial met its primary endpoint. At 52 weeks, navepegritide produced a least-squares mean treatment difference versus placebo in annualized growth velocity of 1.49 cm/year (95% CI, 1.05 to 1.93; P < .001). All randomized participants (n = 84) were included in efficacy and safety analyses; two participants randomized to navepegritide discontinued treatment before week 52 (at weeks 26 and 34).
Beyond linear growth, the study reported statistically significant and clinically relevant improvements in objective skeletal measures: tibial-femoral angle improved by a least-squares mean treatment difference of −1.81° (95% CI, −3.16 to −0.47), mechanical axis deviation improved by −2.78 mm (95% CI, −4.71 to −0.86), and fibula-to-tibia length ratio changed by −0.016 (95% CI, −0.024 to −0.008). These changes suggest favorable effects on limb alignment and proportionality over 1 year of treatment.
On patient- and caregiver-reported outcomes, the Achondroplasia Child Experience Measures—Physical Functioning domain demonstrated improvement in the subgroup of children younger than 5 years with a least-squares mean treatment difference of −11.1 (95% CI, −21.5 to −0.80), indicating better physical functioning. The ACEM is a disease-specific instrument that captures condition-related physical limitations relevant to achondroplasia; interpretation of domain scores should be made in the context of instrument scaling and clinically meaningful change thresholds.
Safety and tolerability
Short-term safety through 52 weeks was acceptable. There were no treatment-related serious adverse events and no deaths. Injection-site reactions were infrequent. Importantly for a natriuretic-peptide mechanism, no symptomatic hypotension was observed in the treated cohort. No fractures attributable to therapy were reported. The trial included monitoring for immunogenicity and bone age progression; detailed immunologic and bone-age data were collected though full long-term implications remain to be established in the open-label extension.
Two participants discontinued navepegritide prior to 52 weeks; the reported reasons for discontinuation were captured in trial data but did not change the overall safety signal. The relatively small sample size and limited duration (52 weeks) constrain the ability to detect rare adverse events and long-term safety signals, which mandates continued follow-up.
Expert commentary: interpretation, biological plausibility, and limitations
The observed increase in growth velocity is biologically plausible given the mechanism of action: CNP signaling opposes FGFR3-mediated inhibition of endochondral ossification, thereby promoting chondrocyte proliferation and long bone growth. The findings that navepegritide also improved measures of limb alignment and physical functioning are notable because they reflect anatomic and functional domains that drive morbidity (orthopedic deformity, mobility limitations) and healthcare use (orthopedic procedures). Improvements in tibial-femoral angle and mechanical axis deviation over 1 year, while modest numerically, could be clinically meaningful if sustained over several years during rapid growth phases.
Key limitations to consider include the 52-week blinded treatment window, which limits conclusions about long-term increases in final adult height, sustained improvements in function, and potential modification of lifetime complication rates (foramen magnum stenosis, spinal stenosis, obstructive sleep apnea, need for orthopedic surgeries). The trial excluded children with certain severe comorbidities (e.g., severe untreated sleep apnea) and those with closed growth plates, which affects generalizability to all children with achondroplasia. The sample size (n = 84) is appropriate for a phase 2b study but not powered to detect rare adverse events.
Comparisons with other disease-modifying agents in achondroplasia must be made cautiously. Daily CNP analogs and other targeted approaches have been evaluated in prior trials; navepegritide’s once-weekly formulation aims to offer a favorable dosing schedule that may improve adherence, but head-to-head efficacy comparisons and long-term outcome data are needed.
Clinical implications and practical considerations
For clinicians caring for children with achondroplasia, the APPROACH data provide evidence that pharmacologic modulation of the CNP pathway with once-weekly navepegritide can accelerate growth and produce early improvements in skeletal alignment and physical function with an acceptable short-term safety profile. Important practical considerations include:
- Baseline assessment: genetic confirmation, growth documentation, baseline limb alignment radiographs where clinically indicated, bone age, blood pressure, and screening for sleep-disordered breathing and foramen magnum stenosis as per standard care pathways.
- Monitoring during therapy: at minimum, periodic growth and height velocity assessments, blood pressure monitoring, assessment for injection-site reactions, and interval orthopedic and neurologic evaluations. Immunogenicity and bone-age monitoring were incorporated into the trial and should be part of clinical surveillance.
- Multidisciplinary care: pharmacologic therapy should be integrated into comprehensive care involving genetics, endocrinology, orthopedics, neurosurgery, pulmonology/sleep medicine, physiotherapy, and psychosocial support.
- Shared decision-making: families should be counseled about the expected magnitude of growth gain over 1 year, the uncertainty about long-term effects on final height and complication rates, the safety profile observed to date, and the need for ongoing monitoring and possible eventual transition to other care strategies.
Conclusion
The phase 2b APPROACH trial demonstrates that once-weekly navepegritide significantly increases annualized growth velocity at 52 weeks in children with achondroplasia and produces promising improvements in limb alignment and physical functioning, with a favorable short-term safety profile. These data support further evaluation in longer-term follow-up to determine effects on final adult height, durability of skeletal and functional benefits, and rare or delayed adverse events. If confirmed in extended follow-up and larger cohorts, navepegritide has the potential to become an important component of disease-modifying care for children with achondroplasia.
Funding and trial registration
The trial is reported in: Savarirayan R, McDonnell C, Bacino CA, et al. Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial. JAMA Pediatr. 2025 Nov 17:e254771. doi: 10.1001/jamapediatrics.2025.4771. ClinicalTrials.gov Identifier: NCT05598320.
References
1. Savarirayan R, McDonnell C, Bacino CA, et al. Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial. JAMA Pediatr. 2025 Nov 17:e254771. doi: 10.1001/jamapediatrics.2025.4771. PMID: 41247754; PMCID: PMC12624480.
2. ClinicalTrials.gov. NCT05598320. APPROACH: A Randomized, Double-Blind, Placebo-Controlled Trial of Navepegritide in Children With Achondroplasia. https://clinicaltrials.gov/ct2/show/NCT05598320 (accessed 2025).
Thumbnail image prompt (for visual generation)
A hopeful clinical vignette: a pediatrician measuring a young child’s height on a stadiometer in a bright outpatient clinic while the child’s parent watches; next to them a transparent overlay shows a stylized long bone and a peptide ribbon labeled ‘CNP’ with subtle molecular schematic, conveying targeted therapy. Diverse family; warm, professional colors; focus on child and clinician interaction; high realism, medium shot.
