Navepegritide in children with achondroplasia

Achondroplasia is the most common skeletal dysplasia presenting with a disproportionate short stature. Achondroplasia is a condition caused by heterozygous mutations in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. FGFR3 is a negative regulator of chondrocyte proliferation and differentiation in the growth plate. Mutations in FGFR3 causing achondroplasia result in (hyper-) activation of the FGFR-3 receptor and, consequently, increased intracellular signalling, which leads to a reduction of chondrocyte assembling in the growth plates impairing growth. Nearly all patients with achondroplasia present with the mutation at the same position (1138 G>A or 1138 G>C) in FGFR3. Other mutations in FGFR3 can lead to other skeletal diseases like hypochondroplasia (1). Further research elucidated the intracellular pathways and how FGFR3 is regulated, and which role other genes and proteins play in the context of chondrocyte activity. One of these substances is the C-natriuretic peptide (CNP) counteracting the hyperactivity of FGFR-3 receptor and downstream signalling. In achondroplasia FGFR3 is increased due to the gain of function mutation. CNP binds to the “natriuretic peptide receptor B” inhibiting the intracellular pathway. Therefore, an analog of CNP theoretically prevents the hyperactivity of the FGFR-3 and thereby leads to an increase of chondrocyte proliferation resulting in an increase of annualized growth velocity.

The leading phenotypical characteristic is a disproportionate short stature with short arms and legs, a macrocephaly, midface hypoplasia and often combined with a hypermobility of joints (1). Previously, before growth supporting treatments became available, the mean final height of persons with achondroplasia was 130 cm for males and 125 cm for females (2,3).

Diagnosis can be suspected based on the typical phenotype already during pregnancy by ultrasound. Postnatally, the skeletal features are prominent and radiological findings can support the diagnosis. Genetical testing can confirm the diagnosis pre- or postnatally and can differentiate from other skeletal dysplasia which can also present with disproportionate short stature like hypochondroplasia or osteogenesis imperfecta (4,5).

During the first two years of life patients might be affected by severe complications like foramen magnum stenosis and sleep apnea which can lead to sudden death of infants which might require neurosurgical intervention. The incidence of surgical need varies widely between 5–35% of patients (6,7). During childhood ear, nose, and throat (ENT) problems like otitis media and hyperplastic tonsils are more in the focus of medical care. Additionally, orthopedic problems like deformities of the legs and spinal problems (lumbar hyperlordosis or thoracal hyperkyphosis) need medical monitoring and treatment. In young adults orthopedic problems like joint pain, deformities of lower legs and lumbar spinal stenosis are the aspects with the highest burden of disease (8). Regardless of these problems most patients achieve an independent life with good education and report a good quality of life. However, short stature, chronic pain, deformities of legs and spine complications could decrease patients independency also in adulthood (9). Even if no direct effect of FGFR3 alterations on mental function is elucidated, some studies suggest a slightly impaired mental and intellectual function within the lower normal range in children with achondroplasia, even if the numbers assessed are quite small (10-12).

In 2021 a recombinant analog of the CNP “vosoritide” was approved by the United States Federal Drug Administration (FDA) and the European Medical Agency (EMA) to increase annualized growth velocity in growing children with genetically confirmed achondroplasia (13). By now the treatment is approved from birth on by FDA and from the age of 4 months by EMA. Vosoritide is a CNP analog which needs to be injected subcutaneously daily. In the clinical trials a mean increase of annual growth velocity of 1.57 cm has been shown (13). This effect has been confirmed by numerous real-world reports in the last few years (14-16). In addition to the effect on annualized growth velocity which was proven in a placebo controlled trial, some reports mentioned additional effects of vosoritide on leg deformities, spine or quality of life (17,18).

The treatment of children with achondroplasia requires a multidisciplinary approach. Drug treatment to increase height is only one part of the overall treatment concept for these patients. Regular physiotherapy support motor development and can increase muscle function and endurance. Body coordination is especially crucial to avoid falls based on the disproportionality and the macrocephaly, which impairs balance. Recurrent orthopedic consultations are recommended for assessment of long bone deformities and functionality. During the first two years of life neurosurgical monitoring of forum magnum stenosis and ENT monitoring of sleep apnea are mandatory to allow a regular development of the children. Psychological support for the parents and the affected individuals should also be an undisputable part of the overall treatment approach. Psychological effects need to be carefully assessed specially if new treatments become available, which include some burden of treatment like frequent injections (19,20).

Beside vosoritide further drugs are currently investigated in children with achondroplasia. There are ongoing trials assessing the efficacy and safety of long acting CNP analogues like navepegritide and BMN 333 in different age groups. In addition, FGFR antibodies are evaluated as a treatment approach (21,22). Oral infigratinib is an oral FGFR1–3 antibody while dabogratinib is a selective FGFR3 antibody. Preliminary results have shown a beneficial safety profile and increased mean annualized growth velocity by 1.5–2.0 cm/year. The described drugs differ in the route of administration (subcutaneous versus oral) and frequency (daily versus weekly). First reports about a combination of CNP analogue and recombinant growth hormone revealed a favorable outcome in the short term.

Recently Savarirayan et al. published the results of the APPROACH trial [A Clinical Trial to Evaluate Efficacy and Safety of TransCon CNP Compared With Placebo in Children With Achondroplasia (ApproaCH)] (23). This was a trial in children with achondroplasia who were treated with once weekly administered navepegritide. Navepegritide is a prodrug of CNP which is connected to a linker and a carrier. During a period of one week CNP is released continuously inhibiting the negative effect of FGFR3 hyperactivity. Linker and carrier will be resorbed and excreted via the kidneys completely. This technology with linker and carrier has been used by the company previously in other drugs like parathyroid hormone and growth hormone and has proven to cause no side effects.

In the APPROACH trial 84 children with achondroplasia with a mean age of 5.5 years and a mean height of −5.01 standard deviation (SD) compared with Centers for Disease Control (CDC) growth curves, were randomized to either receive navepegritide weekly or placebo. This phase 2b study was powered to assess changes of annualized growth velocity (AGV) during a 52-week treatment. The trial was approved by all required ethical boards and authorities, and was conducted in the US, Europe and Australia.

Primary endpoint was the increase of AGV. The mean increase was 1.49 cm per year compared to the placebo group. Comparing the height with disease specific reference ranges and CDC references the children treated with navepegritide increased their z-score by 0.28 SD/0.3 SD respectively, compared with the placebo group. Subgroup analysis showed a more pronounced effect in children older 5 years of age with a mean increase of 1.78 cm/year compared to only 1.02 cm/year in children younger 5 years. As secondary outcomes disproportionality was assessed and showed a mild improvement caused by an increased growth of the legs compared to the upper body. Additionally, the deformity of the lower legs with the disease specific overgrowth of the fibula seems to respond to the treatment. The tibial-femoral angle improved by 1.88 degree in the whole study population and in children with more severe deformations at baseline the improvement was nearly 4 degrees during 52 weeks of treatment. Safety was quite good with no discontinuations due to side effects and with no symptomatic hypotension and only mild injection site reactions.

In summary this trial showed an increase of AGV comparable to the effect of vosoritide with a reasonable safety profile and the benefit of a once weekly injection. Comparing the results with the initial study of vosoritide (13) there are some differences. The cohort treated with navepegritide was considerably younger than those treated with vosoritide (5.4 years compared 8.35 years). This is relevant because the response to navepegritide seems to be more pronounced in older children. This APPROACH trial is the first placebo controlled trial presenting data on deformities and proportionality in a large cohort. Recently White et al. published data combining patients from two clinical trials [CANOPY ACH-2I (111-206) and CANOPY ACH-3 (111-301)] demonstrating also a positive effect of vosoritide on genu varum (18).

In none of these studies psychological effects of treatment or burden of treatment were assessed. One might assume that the reduced frequency of injections using navepegritide will be less stressful for the families compared to daily injections. This has previously been shown in children with a growth hormone deficiency, switching from daily growth hormone treatment to weekly injections (24). Alternative routes of administration like oral preparations would be even more appropriate in a pediatric setting, but need to be developed and investigated in the future (25).

Another area of research will be the combination or the sequential use of different growth promoting drugs mentioned above. Recently data of a 52-week pilot study using a combination of navepegritide and recombinant human growth hormone have been presented. This combination showed a huge mean increase of AGV of 3.9 cm. Currently it is not known how long this increased growth will remain or if there will be a weaning of the effect after some time. In addition, it needs to be observed carefully whether a high increase of AGV, which is higher than AGV in healthy children, might cause orthopedic or safety problems like slipped capital femoral epiphysis or skeletal pain.

It needs to be stated that with all these treatments aiming to increase of AGV only the short stature of children with achondroplasia will be targeted. This is a major step in the treatment of achondroplasia but it is not a cure. Affected people will still end up with a short final height and other phenotypic signs will also remain visible. Symptoms which are not directly influenced by height like sleep apnea, foramen magnum stenosis and spine deformities will require a multidisciplinary team, even if more therapies targeting the final height will become available. Therefore health-related quality of life remains an ongoing topic of discussion and investigation. All information are required to allow the families a careful and shared decision-making which treatment with which benefits and which burdens they want to choose for their child.

Overall, the availability of different drugs like vosoritide and navepegritide for children with achondroplasia is a valuable milestone on the way to a safe, convenient and effective treatment for persons with achondroplasia. Having a choice of different drugs will allow physicians and families to choose the most suitable treatment for the individual child with achondroplasia.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0366/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0366/coif). O.S. received honoraria and travel support for presentations at conferences and for participating in Advisory Boards from Ascendis Pharma and Biomarin. H.H.K. received honoraria and travel support for presentations at conferences and for participating in Advisory Boards from Ascendis Pharma, Biomarin and Merck. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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