The latest on navepegritide for children with achondroplasia, with Carlos Bacino, MD

A randomized clinical trial published November 17, 2025, in JAMA Pediatrics evaluated the efficacy and safety of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, in children with achondroplasia.1 The findings add to growing evidence supporting targeted pharmacologic approaches for achondroplasia, which is now recognized as a multisystem condition affecting skeletal development, physical function, and quality of life.

The phase 2b APPROACH trial enrolled 84 children aged 2 to 11 years across seven countries in a randomized, double-blind, placebo-controlled design. Participants were assigned 2:1 to receive weekly subcutaneous navepegritide 100 μg/kg or placebo. All randomized participants were included in the efficacy and safety analyses.

The study met its primary endpoint at week 52, demonstrating a statistically significant improvement in annualized growth velocity (AGV). The least-squares mean treatment difference was 1.49 cm/year. Investigators reported that “children treated with navepegritide achieved an LS mean AGV of 5.89 vs 4.41 cm/y for those treated with placebo.” The treatment effect emerged by week 12 and was sustained through week 52, with the greatest gains observed among children aged 8 years and older.

Secondary outcomes showed improvements in height z scores. At week 52, the least-squares mean difference in achondroplasia-specific height z score between treatment groups was 0.28. Investigators noted that observed mean values for both achondroplasia-specific and CDC-based height z scores increased from baseline in the navepegritide group, while CDC-based height scores declined in the placebo group.

Exploratory radiographic measures suggested improvements in skeletal alignment. At week 52, treatment was associated with reductions in tibial-femoral angle (−1.81°), mechanical axis deviation (−2.78 mm), and fibula-to-tibia length ratio (−0.016). Investigators reported that improvements in lower limb alignment were observed with navepegritide compared with placebo.

Health-related quality-of-life outcomes favored navepegritide across all Achondroplasia Child Experience Measures subscales. The largest improvement occurred in physical functioning among children younger than 5 years, with a least-squares mean difference of −11.1. The SF-10 Physical Summary Score did not differ between treatment groups at week 52.

The safety profile was similar between navepegritide and placebo. Most adverse events were mild or moderate, with no treatment-related serious adverse events or deaths reported. No symptomatic hypotension or fractures occurred, and transient anti-CNP antibodies did not affect safety or efficacy.

Q&A: Clinical insights on navepegritide in achondroplasia

Below, Carlos A. Bacino, MD, Baylor College of Medicine, Houston, Texas, discusses the clinical implications of the APPROACH trial data and the evolving treatment landscape for children with achondroplasia.

Contemporary Pediatrics:
1What is your reaction to the new FDA PDUFA date for potential approval of navepegritide to treat children with achondroplasia, being moved to February 28, 2026?

Carlos Bacino, MD:
As you may have seen, the FDA let Ascendis know it would take more time to complete their review of their application for TransCon CNP. Regardless of timing, to me having navepegritide FDA approved would mean a great addition to the current treatments in achondroplasia. We went from solely conservative treatments a few years ago, just addressing medical complications, to treatments that allow us to promote harmonic growth and improvement of known associated complications. In addition, a clear advantage of navepegritide is its weekly dosage.

Contemporary Pediatrics:
Related to the recent data published in JAMA Pediatrics, navepegritide significantly improved annualized growth velocity compared with placebo. How should providers interpret the clinical relevance of a 1.49 cm/year treatment difference for children with achondroplasia?

Bacino:
The increase in the annualized growth velocity (AGV) of 1.49 cm per year in a group of children with achondroplasia compared to a placebo group was recently reported in the peer-reviewed study you mentioned for a group of patients receiving navepegritide between the ages of 2 to 11 years. This represents additional growth above their expected yearly growth rate for their disease.

It should also be noted that achondroplasia children who are less than 5 years of age grew at a lesser rate; in fact, treated patients 5 years of age and older experienced a higher AGV of 1.78 cm per year. These results indicate a healthy growth profile for those treated patients. This treatment, therefore, can potentially add several inches to their growth during years of active growth development and before the closure of their growth plates, if treatment is started in the early years.

Contemporary Pediatrics:
The study reported in JAMA Pediatrics also described improvements in skeletal alignment and functional measures. Which of these secondary outcomes may have the most meaningful long-term implications for mobility, orthopedic complications, or overall quality of life?

Bacino:
The JAMA Pediatrics publication highlighted some interesting findings that were part of exploratory endpoints. One of them was the measurement of the tibial femoral angle as well as mechanical axial deviation, both proxy measurements of limb malalignment. Patients treated with navepegritide showed improvements in knee bowing and limb malalignment, often encountered in patients with achondroplasia, which can ultimately prevent future orthopedic interventions. In addition, improvements were reported in health-related quality of life parameters.

Contemporary Pediatrics:
Safety and tolerability are key when considering long-term therapy for young children. What should providers know about the adverse event profile observed in this trial, including injection-site reactions, cardiovascular considerations, and general tolerability?

Bacino:
Injection-site reactions were reported but were rather infrequent in this trial; in fact, they were observed in 11 cases of subjects treated with navepegritide, which is equivalent to a 0.41% rate of injection-site reactions. With regards to hypotension, this was a concern given the known effects of natriuretic peptides in humans. In this trial, no episodes of clinical hypotension have been documented, so it has not been clinically significant. Only 4 cases of asymptomatic hypotension were reported.

Contemporary Pediatrics:
As navepegritide moves closer to potential clinical use, how can frontline providers—including general pediatricians and specialists—help identify appropriate candidates, monitor response, and counsel families about expected benefits and limitations?

Bacino:
It is very important that primary care providers become aware of the availability of these treatments so they can refer their patients to specialists such as clinical geneticists or pediatric endocrinologists for further assessment and treatment. This is important as these drugs can clearly make a difference in AGV, height velocity, health-related quality of life, as well as improvements of limb misalignment.

References:

1. Ravi Savarirayan, McDonnell C, Bacino CA, et al. Once-Weekly Navepegritide in Children With Achondroplasia. JAMA Pediatrics. Published online November 17, 2025. doi:https://doi.org/10.1001/jamapediatrics.2025.4771
2. Ebert M. Navepegritide demonstrates growth velocity, skeletal alignment in children with achondroplasia. Contemporary Pediatrics. Published November 29, 2025. Accessed December 19, 2025. https://www.contemporarypediatrics.com/view/navepegritide-demonstrates-growth-velocity-skeletal-alignment-in-children-with-achondroplasia