Navepegritide: an investigational growth therapy for achondroplasia

What is navepegritide?

Navepegritide is an investigational protein-based substance developed as a treatment for achondroplasia. It is a prodrug derived from C-type natriuretic peptide (CNP), meaning it is an inactive form that becomes active in the body.7 The substance appears in the product records under several names, including TransCon CNP, TransCon CNP 3.9 mg CNP-38/vial, navepegritide 2.8 mg CNP(89-126), and navepegritide 1.3 mg CNP(89-126).1 It has no marketing authorisation in the product records, meaning it is still an investigational substance.1 Navepegritide has received orphan designation in six product records, which reflects its intended use in a rare disease.1 The product is supplied by Ascendis Pharma Growth Disorders A/S.1 The trade name Yuviwel has been used for navepegritide in some medical references.6

How does navepegritide work?

Achondroplasia is caused by an activating mutation in the fibroblast growth factor receptor 3 (FGFR3), which leads to destructive signalling that slows bone growth. Navepegritide, as a CNP-derived prodrug, interferes with this destructive FGFR3 signalling.7 The prodrug is designed to provide continuous exposure to the parent molecule through gradual degradation of a linker after weekly injection.7 CNP opposes the effects of the overactive FGFR3 pathway, which normally limits the growth of cartilage cells (chondrocytes) at the growth plates of bones.7 By blocking this inhibitory signal, navepegritide aims to allow more normal bone growth in children with achondroplasia.7

Which conditions is it studied for?

• Achondroplasia in children and adolescents — a genetic condition that causes short stature due to impaired bone growth. Three of the four trials focus on this population.142
• Achondroplasia in infants — one trial specifically studies infants with achondroplasia to assess safety and growth effects in this younger age group.2
• Children with achondroplasia in combination with lonapegsomatropin — one trial studies navepegritide together with another growth-related medicine, lonapegsomatropin (a prodrug of somatropin), in children with achondroplasia.3

How is navepegritide given?

Navepegritide is given as a solution for injection under the skin (subcutaneous injection).1 The product records list the pharmaceutical form as solution for injection, and the route of administration is subcutaneous injection.1 The paediatric investigation plan also describes a powder and solvent for solution for injection, intended for subcutaneous use.5 In the clinical trials, navepegritide is administered once weekly.17 The trials use several dose strengths, including 0.6 mg, 1.3 mg, 2.8 mg, and 5.5 mg CNP(89-126), as well as TransCon CNP 3.9 mg CNP-38/vial.1

What do the clinical trials show?

Four Phase 2 clinical trials of navepegritide are listed in the EU Clinical Trials Information System, all authorised and all interventional.1–[4]The trials range in size from 18 to 208 participants. The largest trial, AttaCH, is a long-term open-label extension trial with 208 children and adolescents, measuring safety, tolerability, and growth over time.1 The smallest trial, COACH, has 18 children and studies navepegritide in combination with lonapegsomatropin.3 Another trial includes 86 infants and compares navepegritide with placebo.2 A fourth trial with 20 adolescents compares navepegritide with placebo, focusing on annualised growth velocity at week 52.4

The trials measure growth in several ways. Annualised growth velocity (AGV), which is how fast a child grows in centimetres per year, is the main measure in two trials.43 Height Z-scores, which compare a child's height to the average for their age and sex, are measured in the AttaCH and infant trials.12 Safety is also a key measure: all four trials record treatment-emergent adverse events (TEAEs), which are any unwanted medical events that occur during treatment.1–[4]The infant trial additionally records serious adverse events, TEAEs leading to discontinuation, and deaths.2

Interim results from a related Phase 2 trial presented at a medical conference reported that in 21 children with achondroplasia aged 2–11 years who received navepegritide together with lonapegsomatropin, annualised growth velocity increased from 4.92 to 9.14 cm per year in children who had not previously received treatment, and from 5.14 to 8.25 cm per year in children who had previously received navepegritide.7 A prior Phase 2 trial of navepegritide alone showed that it outperformed placebo, with better annualised growth velocity at week 52.7

What side effects are known?

The available sources do not provide a detailed list of side effects for navepegritide. The clinical trials are designed to collect information on treatment-emergent adverse events, serious adverse events, and events leading to discontinuation, but specific side effect data are not reported in the registry records.12 The supplementary sources reviewed do not contain a specific side effect profile for navepegritide.