Navepegritide's bone-alignment effects hold through 2 years

New radiographic data from the pivotal ApproaCH trial show that children with achondroplasia treated with once-weekly navepegritide (YUVIWEL; Ascendis Pharma) experienced continued improvement in lower extremity alignment through 2 years of treatment, with the largest gains observed in children who had preexisting leg bowing (genu varum) at baseline.¹

The findings were presented at the 12th International Conference on Children's Bone Health, held in Montreal, Canada, and add a musculoskeletal alignment data set to navepegritide's previously reported effects on linear growth.

"These results show that continuous exposure to active C-type natriuretic peptide provided by once-weekly TransCon CNP positively affected skeletal growth and lower limb alignment in children with achondroplasia, with the potential to address serious complications of skeletal dysplasia that contribute to chronic pain, altered mobility, and need for surgical intervention," said Leanne M. Ward, MD, FRCPC, a professor of pediatrics at the University of Ottawa and the Children's Hospital of Eastern Ontario, who presented the data.¹ "These outcomes reinforce previously reported data showing TransCon CNP's ability to support healthy and proportional growth, further highlighting its potential to advance pharmacological treatment for achondroplasia."

Trial design and Week 104 radiographic findings

ApproaCH was a randomized, double-blind, placebo-controlled trial enrolling 84 children with achondroplasia aged 2 to 11 years, who received once-weekly navepegritide (100 µg/kg) or placebo for 52 weeks, followed by an open-label extension in which all participants received active treatment through Week 104.¹ Radiographic assessment of tibial-femoral angle (TFA)—a standard measure of lower extremity alignment, with higher values indicating greater genu varum—was performed at baseline, Week 52, and Week 104.

Among children treated with navepegritide throughout the double-blind period, mean TFA decreased from 9.1° at baseline to 7.7° at Week 52 and 6.9° at Week 104, a mean absolute change of −2.2° over 2 years.¹ In the subgroup with baseline TFA of 5° or greater—reflecting children with clinically apparent genu varum at enrollment—mean TFA decreased from 13.4° at baseline to 9.6° at Week 104, a change of −3.8°. Children originally randomly assigned to placebo, who began active treatment at Week 52, showed a similar pattern after starting navepegritide: Mean TFA in the high-baseline-TFA subgroup decreased from 18.7° at Week 52 to 14.9° at Week 104.¹

Fibula-to-tibia length ratio remained stable throughout the open-label extension, indicating that lower leg growth remained proportional during treatment.¹ Through up to 2 years of exposure, navepegritide was reported to be generally well tolerated, with a low rate of mild injection-site reactions, no episodes of symptomatic hypotension, and no acceleration of bone age. Most adverse events were mild to moderate, and none led to treatment discontinuation.¹

Clinical context: Why lower-limb alignment matters

Achondroplasia is the most common skeletal dysplasia, caused by a gain-of-function variant in the fibroblast growth factor receptor 3 (FGFR3) gene, with an estimated birth prevalence of approximately 1 in 25,000 to 30,000 live births.² Genu varum is a frequent orthopedic complication, arising from asymmetric growth plate activity at the knee and contributing to gait abnormalities, joint pain, and, in more severe cases, the need for corrective osteotomy. Beyond the skeleton, FGFR3 is expressed broadly throughout the body, and children with achondroplasia face elevated risk for spinal stenosis, sleep-disordered breathing, recurrent otitis media, and hydrocephalus across childhood.¹

Until recently, management of achondroplasia-related orthopedic complications relied primarily on surveillance and surgical correction when bowing became severe enough to affect function. The emergence of disease-modifying pharmacotherapy targeting the FGFR3 pathway has shifted the treatment conversation toward whether early intervention can reduce the downstream need for these procedures, though that question remains incompletely answered by current trial data.

Navepegritide background and approval history

Navepegritide is a prodrug of C-type natriuretic peptide (CNP) designed for once-weekly subcutaneous administration, providing more continuous CNP receptor activation than a daily-injection approach. CNP binds natriuretic peptide receptor-B and antagonizes the overactive FGFR3 signaling that suppresses chondrocyte proliferation in the growth plate, the mechanistic basis for its growth-promoting effect in achondroplasia.³

The FDA approved navepegritide under the trade name YUVIWEL on February 27, 2026, under the agency's Accelerated Approval Program, based on improvement in annualized growth velocity (AGV) as the primary end point across 3 randomized, placebo-controlled trials and supporting open-label extension data, for children aged 2 years and older with achondroplasia and open epiphyses.³ Continued approval for the AGV-based indication may depend on verification of clinical benefit in confirmatory trials, consistent with standard accelerated-approval requirements. Navepegritide became the first approved achondroplasia therapy providing continuous, rather than peak-and-trough, CNP receptor exposure across the weekly dosing interval, distinguishing it mechanistically from daily-injection vosoritide (Voxzogo; BioMarin), which has been approved for the same growth indication since 2021.⁴

References

1. Ascendis Pharma A/S. Children with achondroplasia treated with TransCon CNP showed continued improvements in lower extremity alignment at Week 104 of the pivotal ApproaCH trial. Press release. June 30, 2026. Accessed June 30, 2026. https://investors.ascendispharma.com/news-releases/news-release-details/children-achondroplasia-treated-transcon-cnp-showed-continued

2. Foreman PK, van Kessel F, van Hoorn R, van den Bosch J, Shediac R, Landis S. Birth prevalence of achondroplasia: a systematic literature review and meta-analysis. Am J Med Genet A. 2020;182(10):2297-2316. doi:10.1002/ajmg.a.61787

3. Ascendis Pharma A/S. FDA approves once-weekly YUVIWEL (navepegritide) for children with achondroplasia aged 2 years and older. Press release. February 27, 2026. Accessed June 2026. https://investors.ascendispharma.com/news-releases/news-release-details/fda-approves-once-weekly-yuviwelr-navepegritide-children

4. Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet. 2020;396(10252):684-692. doi:10.1016/S0140-6736(20)31541-5

5. Ryabets-Lienhard A. Navepegritide (Yuviwel) for children with achondroplasia: new drugs and therapeutics. Pediatric Endocrine Society. Updated 2026. Accessed June 2026. https://pedsendo.org/new-meds-and-tech/navepegritide-yuviwel-for-children-with-achondroplasia-new-drugs-and-therapeutics/