SEATTLE — A combination of a prodrug derived from C-type natriuretic peptide (CNP) called navepegritide (TransCon CNP) and a prodrug of somatropin, called lonapegsomatropin (Skytrofa), augmented the growth of children with achondroplasia, according to interim results from a new phase 2 clinical trial.

Both prodrugs are designed to be injected weekly and provide continuous exposure to the parent molecule through gradual degradation of a linker. CNP interferes with the destructive signaling of fibroblast growth factor receptor 3 (FGFR3) that occurs as a result of an activating mutation in achondroplasia, whereas somatotropin promotes the formation and proliferation of chondrocytes.

Navepegritide outperformed placebo in a prior phase 2 trial of children with achondroplasia, demonstrating better annualized growth velocity (AGV) at week 52.

The rationale behind testing the two drugs in combination is that “if you know that growth hormone can recruit stem cells to form chondrocytes, the growth hormone and [insulin-like growth factor-1, IGF1] will promote an increase in number of chondrocytes, and this leads on to IGF1 promoting chondrocyte growth and differentiation. But in achondroplasia, [our idea is] that if this [process of chondrocyte growth and differentiation] is blocked through an FGFR3-induced inhibition, then wouldn’t giving CNP together with growth hormone unlock the potential for augmented growth?” said Ciara McDonnell, MD, a consultant in endocrinology at Children’s Health Ireland, Dublin, Ireland, during a presentation of the study at American Society for Bone and Mineral Research (ASBMR) 2025 Annual Meeting.

The researchers conducted a phase 2 trial of 21 children with achondroplasia aged 2-11 years who received weekly doses of the combination. The participants were either treatment naive (n = 12; eight were male; mean age, 4.7 years) or were recruited from trials of navepegritide (n = 9; six were male; mean age, 7.9 years). At baseline, mean achondroplasia-specific height Z-scores were 0.46 in the treatment-naive group and 1.28 in the navepegritide group. At week 26, AGV increased from 4.92 to 9.14 cm/y in treatment-naive participants (P = .0063) and from 5.14 to 8.25 cm/y in the navepegritide group (P = .0006). The achondroplasia-specific height Z-score increased from 0.46 to 0.99 in the treatment naive group (P = .0009) and from 1.28 to 1.72 in the navepegritide group (P = .0002). Body proportionality improved with decreased upper to lower body segment ratio compared with baseline. The AGV in both groups was higher than the 97th percentile of AGV in children of average stature.

Treatment-emergent adverse events occurred in 71.4% of participants but none led to discontinuation. The most common were injection site erythema and nasopharyngitis.

The researchers intend to present the 52-week outcome results in early 2026.

In an earlier session highlighting research presented at ASBMR 2025, Benjamin Leder, MD, said the results are “potentially revolutionary, in my opinion.” He is a professor of medicine at Harvard Medical School, Boston.

During the Q&A period after the presentation, an audience member called the results impressive, especially for the older children in the previously treated group. He asked if any of the participants had experienced intracranial hypertension, which can occur independent of treatment in this population. “That’s a really important comment. It’s one of the things that needs to be looked out for, especially when you’re seeing such an increase in growth velocity, but I’m pleased to report there have been no cases of this to date, and no one has suggested that they had headaches or symptomatology,” McDonnell responded.

Session co-moderator Anna Spagnoli, MD, speculated whether there was some resistance in the navepegritide group, and if the effect was only due to lonapegsomatropin. “If that is the case, as a clinician, would you decide to do the treatments together, to do them sequentially, or to start with the growth hormone? These are clearly very important questions,” said Spagnoli, who is a professor of orthopedic surgery and pediatrics at Rush University Medical Center, Chicago.

McDonnell acknowledged the concern and noted that the trial was a proof of concept that combination therapy gives better results than monotherapy. “What dose, what duration, what timing — [all of that] still needs to be elucidated. And to that end, we are moving forward to look at the phase 3 study to answer some of those questions,” she said.

This study was funded by Ascendis Pharma. McDonnell reported consulting for Ascendis Pharma and BioMarin. Leder reported receiving research funding from Amgen and consulting for Radius Pharma. Spagnoli did not declare any disclosures.

Jim Kling is a writer based in Bellingham, Washington.