Navepegritide NDA submitted to treat children with achondroplasiaLatest revision | Image Credit: © Araki Illustrations - © Araki Illustrations - stock.adobe.com.

On March 31, 2025, Ascendis Pharma A/S announced it has submitted a new drug application (NDA) to the FDA for navepegritide (TransCon CNP) to treat children with achondroplasia.¹

In a press release from Ascendis, the company stated navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP). Administered once weekly, navepegritide is designed to treat achondroplasia patients by providing continuous exposure of active CNP to receptors on tissues throughout the body, including growth plates and skeletal muscle.

Clinical data

Submission to the federal agency is based on data from 3 randomized, double-blind, placebo-controlled trials, as well as up to 3 years of open-label extension data, including from the ApproaCH Trial.

The trial featured 84 children with achondroplasia aged 2 to 11 years, randomized to receive navepegritide or placebo. Superior annualized growth velocity (AGV) was observed for navepegritide compared to placebo, and it delivered statistically significant improvements in other growth parameters such as height Z-score and change from baseline AGV.²

Topline data from the ApproaCH Trial included the following, according to Ascendis²:

Primary endpoint

For the primary endpoint of AGV at Week 52, children treated with navepegritide (n = 57) demonstrated a least squares (LS) mean AGV of 5.89 cm/year compared to 4.41 cm/year in the placebo arm (n = 27), a LS mean difference of 1.49 cm/year (P < 0.0001).

Sub-group analyses showed that children aged 2 to <5 years treated with navepegritide (n = 21) demonstrated a LS mean AGV at Week 52 of 6.07 cm/year compared to 5.06 cm/year in the placebo arm (n = 10), an LS mean difference of 1.02 cm/year (P = 0.0084). Children aged 5-11 years treated with navepegritide (n = 36) demonstrated a LS mean AGV at Week 52 of 5.79 cm/year compared to 4.02 cm/year in the placebo arm (n = 17), a LS mean difference of 1.78 cm/year (P < 0.0001).

AGV change from baseline

Children aged 2 to <5 years treated with navepegritide (n = 19) demonstrated a change from baseline AGV at Week 52 of 1.57 cm/year compared to 0.43 cm/year in the placebo arm (n = 10), a LS mean difference of 1.15 cm/year (P = 0.0047). Children aged 5-11 years treated with navepegritide (n = 35) demonstrated a change from baseline AGV at Week 52 of 2.29 cm/year compared to 0.52 cm/year in the placebo arm (n = 17), a LS mean difference of 1.78 cm/year (P < 0.0001).

Secondary endpoints

For the secondary endpoint of change in ACH Height Z-score, children treated with navepegritide (n = 57) demonstrated a LS mean change from baseline ACH Height Z-score of 0.30 compared to 0.01 in the placebo arm (n = 27), an LS mean difference of 0.28 (P < 0.0001). For the secondary endpoint of change in CDC Height Z-score, children treated with navepegritide (n = 55) demonstrated a LS mean change from baseline CDC Height Z-score of 0.15 compared to -0.15 in the placebo arm (n = 27), a LS mean difference of 0.30 (P = 0.0003).

Commentary

“We are pleased to share clinical data with the FDA demonstrating that, in addition to increased growth velocity, treatment with [navepegritide] was associated with reduced health-related burden, stronger muscle function, and straightening of abnormal leg bowing for the majority of treated children,” said Aimee Shu, MD, executive vice president and chief medical officer at Ascendis Pharma, in a statement.¹

“In addition to once-weekly administration, these outcomes and a safety and tolerability profile comparable to placebo support [navepegritide's] potential to be recognized as a best-in-class treatment for achondroplasia," said Shu.

The rare genetic condition arises from a systemic fibroblast growth factor receptor 3 (FGFR3) variant that leads to an imbalance in the effects of the FGFR3 and CNP signaling pathways, estimated to affect more than 250,000 people worldwide, according to the announcement from Ascendis.

The FGFR3 variant in achondroplasia is expressed in tissues throughout the body. This can result in muscular, neurological, and cardiorespiratory complications as well as skeletal dysplasia.

Spinal deformities, upper airway obstructions, impaired muscle strength and stamina, hearing deficits and chronic ear infections, chronic pain, sleep-disordered breathing, hip problems, leg bowing, and enlarged brain ventricles can be complications throughout infancy and childhood.

Ascendis plans to submit a marketing authorization application to the European Medicines Agency in the third quarter of 2025.

References:

1. Ascendis Submits U.S. NDA for TransCon CNP (Navepegritide) for the Treatment of Children with Achondroplasia. Ascendis Pharma A/S. Press release. March 31, 2025. Accessed March 31, 2025. https://investors.ascendispharma.com/news-releases/news-release-details/ascendis-submits-us-nda-transcon-cnp-navepegritide-treatment

2. Pivotal ApproaCH Trial of TransCon CNP (Navepegritide) Achieved Primary Objective, Demonstrated AGV Superior to Placebo. Ascendis Pharma A/S. Press release. September 16, 2024. Accessed March 31, 2025. https://investors.ascendispharma.com/news-releases/news-release-details/pivotal-approach-trial-transcontm-cnp-navepegritide-achieved