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Jump to Key Points At its October meeting, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a positive recommendation for the marketing authorization of Yuviwel (navepegritide, Ascendis Pharma Growth Disorders A/S) for treating achondroplasia in children.
If approved by the European Commission, Yuviwel will be indicated for the treatment of achondroplasia in children aged 2 years and older whose epiphyses are not closed, with diagnosis confirmed by appropriate genetic testing.
Disease Background and Treatment Landscape
Achondroplasia is caused by a pathogenic variant in the fibroblast growth factor receptor 3 (FGFR3 ) gene. At the time of orphan designation in 2020, it affected roughly 0.6 in 10,000 people in the EU, or about 30,000 people. Once regarded mainly as a skeletal dysplasia, it is increasingly recognized as a multisystem condition. The FGFR3 variant is widely expressed and can affect muscle, neurologic function, and cardiorespiratory health, in addition to causing disproportionate short stature.
Skeletal complications include spinal kyphosis, lordosis, and stenosis, which can lead to nerve compression and pain. In the lower limbs, fibular overgrowth relative to the shorter tibia often produces progressive bowing. This increases mechanical strain on the joints and can reduce physical functioning and health-related quality of life.
- CHMP positive for Yuviwel (navepegritide) in achondroplasia, age ≥2 years; open epiphyses; genetic confirmation required.
- Weekly SC CNP prodrug; TransCon sustained release counteracts FGFR3 signaling.
- APPROACH trial: 84 children; growth velocity 5.89 vs 4.41 cm/yr; +1.49 cm/yr, P<.001.
- Improved lower-limb alignment: tibial-femoral angle, mechanical axis deviation, fibula:tibia ratio.
- Safety similar to placebo; common AEs: fever, nasopharyngitis, otitis media, URTI, vomiting, headache.
A Weekly CNP Prodrug
Yuviwel contains navepegritide, a prodrug of C-type natriuretic peptide (CNP). Its CNP moiety is identical to amino acids 89-126 of endogenous CNP. Using the TransCon technology platform, the peptide is transiently linked to an inert carrier. After subcutaneous injection, the linker autocleaves at physiologic pH and temperature, providing sustained release of active CNP.
Active CNP binds to natriuretic peptide receptor B (NPR-B), generating cyclic GMP to counteract overactive FGFR3 signaling, promote chondrocyte proliferation, and stimulate endochondral bone growth without high peak plasma concentrations.
Growth and Skeletal Alignment Improve
The recommendation was based on the APPROACH study, a pivotal phase 2b randomized, double-blind, placebo-controlled trial that enrolled 84 children aged 2 to 11 years with genetically confirmed achondroplasia who had not previously received growth-promoting therapy.
Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous navepegritide 100 μg/kg (n = 57) or placebo (n = 27) for 52 weeks.
The primary endpoint was annualized growth velocity at week 52. Children receiving navepegritide achieved a least-squares mean growth velocity of 5.89 cm/year, compared with 4.41 cm/year in the placebo group. The treatment difference was 1.49 cm/year (95% CI, 1.05-1.93; P < .001), with the benefit evident by week 12 and maintained throughout the treatment period.
Navepegritide also improved several measures of skeletal alignment compared with placebo. The least-squares mean treatment differences at week 52 were:
- Tibial-femoral angle: −1.81° (95% CI, −3.16 to −0.47).
- Mechanical axis deviation: −2.78 mm (95% CI, −4.71 to −0.86).
- Fibula-to-tibia length ratio: −0.016 (95% CI, −0.024 to −0.008).
These findings suggest that treatment may help reduce lower-limb malalignment and disproportionate fibular growth. Improvements in tibial-femoral angle were more pronounced among children with greater leg bowing at baseline.
The researchers also observed improvements in physical functioning, measured using the Achondroplasia Child Experience Measures–Physical Functioning scale, among children younger than 5 years. The treatment difference was −11.1 points (95% CI, −21.5 to −0.8).
Safety Profile and Dosing
Navepegritide exhibited a safety and tolerability profile similar to placebo. The most common adverse events reported include injection site reactions and hypertrichosis.
The most frequently reported adverse events with navepegritide were fever (35.1%), nasopharyngitis (31.6%), otitis media (24.6%), upper respiratory tract infection (19.3%), vomiting (19.3%), and headache (17.5%).
Yuviwel will be supplied as 1.3 mg, 2.8 mg, and 5.5 mg powder and solvent for solution for injection, and it should be prescribed and monitored by physicians experienced in diagnosing and managing children with achondroplasia.
