TransCon CNP Infant Data: Foramen Magnum Signal Compelling, But Open-Label Design Caps Evidentiary Weight

Ascendis' TransCon CNP Shows Positive Infant Data in Achondroplasia

Ascendis Pharma A/S announced Week 52 data from the open-label sentinel cohort of the reACHin Trial, evaluating once-weekly TransCon CNP (navepegritide) in infants aged 0 to <2 years with achondroplasia. The data showed that treatment led to stabilization or improvement in foramen magnum stenosis, a critical skull bone narrowing, with all children showing stable or improved Achondroplasia Foramen Magnum Score (AFMS) and a mean sagittal diameter change of +3.15 mm. Additionally, linear growth benefits were observed, including a mean change of +0.42 in ACH-specific supine length Z-score and a mean annualized growth velocity (AGV) of 9.9 cm/year. TransCon CNP was generally well tolerated, with no injection site reactions or serious adverse events related to treatment, supporting its potential as an early intervention.

• Treatment with TransCon CNP demonstrated significant benefits in cranio-cervical junction health. All children in the sentinel cohort showed stable or improved Achondroplasia Foramen Magnum Score (AFMS) between baseline and Week 52. The mean change from baseline in the sagittal diameter of the foramen magnum was +3.15 mm, and notably, no decompression surgeries were required during the 52-week treatment period, indicating a potential to mitigate severe neurological complications.
• The trial data highlighted positive effects on linear growth in infants. Treatment with TransCon CNP resulted in a mean change from baseline in ACH-specific supine length Z-score of +0.42 and a mean annualized growth velocity (AGV) of 9.9 cm/year at Week 52. These growth improvements suggest that early intervention with TransCon CNP can address growth limitations in this vulnerable pediatric population.
• TransCon CNP exhibited a favorable safety and tolerability profile, consistent with previous trials. Over the 52-week treatment period, there were no reports of injection site reactions, deaths, fractures, bone-related safety events, or symptomatic hypotension. Furthermore, no adverse events were assessed by investigators as related to treatment, and none led to treatment disruption, discontinuation, or trial withdrawal, underscoring its potential for long-term use.
• In addition to the new infant data, TransCon CNP, marketed as YUVIWEL®, received U.S. FDA approval in February 2026 for pediatric patients aged 2 years and older with achondroplasia and open epiphyses. Ascendis Pharma's Marketing Authorisation Application for YUVIWEL is currently under review by the European Medicines Agency, with a regulatory decision anticipated in the fourth quarter of 2026, expanding its global market potential.

TransCon CNP Shows Early Promise in Infant Achondroplasia

Several recent clinical studies have advanced the therapeutic landscape for achondroplasia, evaluating agents across distinct mechanistic classes — from CNP analogues to FGFR-targeted inhibitors. The trials summarized below span phase 2 and phase 3 designs and report on both growth and non-growth endpoints.

• PROPEL 2 (NCT04265651) — Infigratinib: This phase 2, open-label, dose-finding study evaluated oral infigratinib, an FGFR1-3 selective tyrosine kinase inhibitor, in 72 children aged 3–11 years across five sequential dose cohorts (0.016 to 0.25 mg/kg/day). All participants experienced at least one adverse event, most mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5 (0.25 mg/kg), the mean change from baseline in annualized height velocity at 18 months was 2.50 cm/year (95% CI, 1.22 to 3.79; P = 0.001), the mean change in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population, and the mean change in upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06).

• APPROACH (NCT05598320) — Navepegritide: This pivotal phase 2b, randomized, double-blind, placebo-controlled trial enrolled 84 children aged 2–11 years, randomized 2:1 to navepegritide 100 μg/kg/wk subcutaneously or placebo. The trial met its primary endpoint, with a least-squares mean treatment difference in annualized growth velocity at week 52 of 1.49 cm/y (95% CI, 1.05 to 1.93; P < .001). Secondary skeletal outcomes showed improvements in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), and fibula to tibia length ratio (-0.016 [-0.024 to -0.008]). Achondroplasia Child Experience Measures-Physical Functioning improved by -11.1 [-21.5 to -0.80] in children younger than 5 years. No serious adverse events were treatment-related, no deaths occurred, injection site reaction rates were low, and no symptomatic hypotension or fractures were observed.

• Phase 3 Open-Label Extension — Vosoritide: In an ongoing phase 3 extension study, 119 participants received vosoritide 15 μg/kg daily. Mean differences in annualized growth velocity between treated and untreated children across each integer age (6–16 years) were 1.84 (SD 0.38) cm/year in boys and 1.44 (SD 0.63) cm/year in girls. Three-year comparisons demonstrated an additional height gain of 5.75 cm (95% CI: 4.93, 6.57) with vosoritide versus untreated controls. A significant improvement in upper-to-lower body segment ratio at 3 years was observed for participants assessed below age 11 (females) and 12 (males) versus population-level, age-matched, untreated controls (p = 0.0087). Vosoritide had a favorable safety profile with continuous treatment for up to 6 years (464.05 person years of exposure), with no long-term harms or deaths observed.

Designing the reACHin Trial for Infants with Achondroplasia

Several pivotal trials have evaluated vosoritide and navepegritide in children with achondroplasia across a range of age groups, employing varied designs and endpoints to characterize both growth efficacy and safety. The studies span phase 2 randomized controlled trials, open-label trials, and real-world cohort analyses, collectively informing the clinical profile of these agents.

• Vosoritide Phase 2 Trial in Infants and Young Children (aged 3–59 months): This multinational, randomized, double-blind, placebo-controlled, phase 2 trial was conducted across 16 hospitals in Australia, Japan, the UK, and the USA. Participants were enrolled into three sequential cohorts by age at screening: 24–59 months (cohort 1), 6–23 months (cohort 2), and 0–5 months (cohort 3). Vosoritide was administered via daily subcutaneous injection at 30.0 μg/kg for infants aged 0–23 months and 15.0 μg/kg for children aged 24–59 months, or placebo, for 52 weeks. The two co-primary outcomes were safety and tolerability (assessed in all participants receiving at least one study dose) and change in height Z-score at 52 weeks from baseline (analyzed in all randomly assigned participants). The least-squares mean difference for change from baseline in height Z-score between the vosoritide and placebo groups was 0.25 (95% CI -0.02 to 0.53). Adverse events occurred in all 75 (100%) participants, with the most common being transient injection-site reactions and injection-site erythema.

• APPROACH Trial — Navepegritide (NCT05598320): This pivotal phase 2b, randomized, double-blind, placebo-controlled trial enrolled 84 participants aged 2 to 11 years with genetically confirmed achondroplasia at 10 hospitals across Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US. Participants were randomized 2:1 to receive navepegritide 100 μg/kg/wk or placebo via once-weekly subcutaneous injection, stratified by age and sex, with blinded treatment through 52 weeks followed by an open-label extension. The primary endpoint was annualized growth velocity at week 52. Secondary measures included radiographically assessed skeletal outcomes and health-related quality of life evaluated using Achondroplasia Child Experience Measures. The trial met its primary endpoint, with a least-squares mean treatment difference of 1.49 cm/y (95% CI, 1.05 to 1.93; P < .001) in annualized growth velocity versus placebo. Improvements were also observed in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years).

• Vosoritide Phase 2 Trial in Hypochondroplasia (NCT04219007): A single-arm, phase 2, open-label trial conducted at a single centre in the USA enrolled 26 children with hypochondroplasia. The design included a 6-month observation period to establish baseline annualized growth velocity, followed by a 12-month intervention period with vosoritide 15 μg/kg/day via daily subcutaneous injection. Co-primary endpoints were the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height SDS after 12 months of treatment. Annualized growth velocity increased by 2.26 SD and height SDS increased by 0.36 SD during the treatment period versus the observation period, with a 1.81 cm/year increase in absolute annualized growth velocity.

• Phase 2 Basket Trial — Vosoritide in RASopathies, ACAN and NPR2 Deficiency: This prospective phase 2 basket trial enrolled 30 pre-pubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height <-2.25 SD at an academic medical center. The design comprised a 6-month observation period followed by 12-month treatment with vosoritide 15 micrograms/kg/day subcutaneously. Co-primary outcomes included incidence of adverse events, change in annualized growth velocity, and height standard deviation scores. The AGV increased from 4.53±1.61 cm/yr to 8.09±1.58 cm/yr with treatment (p<0.0001), corresponding to a 4.0 SD (95% CI 3.08–4.91) increase in age and sex-adjusted AGV Z-score (p<0.0001), with a height increase of 0.65 SD (95% CI 0.53–0.77) in the treatment versus observation period (p<0.0001).

• Real-World Cohort Study — Portugal (Single Center): This retrospective cohort study evaluated 27 children aged 2–14 years with genetically confirmed achondroplasia treated with vosoritide under an early access program at a single Portuguese center for at least 6 months between January 2022 and June 2024. Key anthropometric endpoints included height SDS and annualized growth velocity (AGV). Among the 15 children completing at least 24 months of treatment, mean variation in height SDS increased from baseline by +0.95 SD (P ≤ 0.0001) referenced to an untreated achondroplasia-specific population and +0.56 SD (P ≤ 0.0001) relative to children of average stature; mean AGV from baseline was 5.87 cm/year (95% CI 5.14–6.60), a significant increase of +1.62 cm/year (P ≤ 0.0001). Safety and tolerability endpoints included adverse drug reactions and treatment adherence.

Addressing Critical Unmet Needs in Infant Achondroplasia

Recent literature highlights several critical gaps in achondroplasia management, spanning both the timing of therapeutic intervention and the breadth of populations who may benefit from targeted treatment. The evidence underscores that current standard-of-care approaches leave meaningful clinical needs unaddressed across distinct patient subgroups.

• Infants and neonates requiring immediate postnatal treatment: A mouse model study aligned with human clinical timelines demonstrated that premature fusion of skull base synchondroses occurs immediately after birth, leading to defective cranial development and foramen magnum stenosis. Early postnatal treatment (from day 1) with the FGFR3 inhibitor infigratinib produced significant restoration of this phenotype, whereas late postnatal treatment (from day 4, equivalent to approximately 5 months in humans) provided "weak to no rescue" of cranial defects. Current therapy beginning at 2 years of age does not address cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. The study described this as a "paradigm-shifting argument for the development of prenatal therapy for achondroplasia."

• Children with severe complications and real-world access gaps: A retrospective cohort study from Portugal included children with severe achondroplasia-associated complications treated under an early access program, a population not always represented in pivotal trials. After 24 months of vosoritide treatment, mean variation in height SDS increased from baseline by +0.95 SD (P ≤ 0.0001) referenced to an untreated achondroplasia-specific population, and +0.56 SD (P ≤ 0.0001) relative to children of average stature, with no serious adverse drug reactions reported.

• Children with neurosurgical complications requiring standardized care: A systematic review of 287 pediatric achondroplasia patients identified high rates of complications and reoperations following neurosurgical intervention for cervicomedullary compression, spinal stenosis, and hydrocephalus — with complication rates of 21% and 17% for cervicomedullary and spinal stenosis procedures, respectively, and an average of 1.5 shunt revisions per shunted hydrocephalus patient. The authors noted "a lack of clinical guidelines and reliable estimates of the benefits and risks of these interventions" and called for further studies with follow-up into adulthood.

• Families and endocrinologists lacking specialized center access: Clinical guidance published in 2025 identified an urgent need to support pediatric endocrinologists who encounter infants and children with achondroplasia outside of specialized skeletal dysplasia centers. The paper explicitly noted that not all treated children exhibit a response in linear growth, and that treatment does not negate the necessity of actively surveilling for potential complications that are part of the natural history of achondroplasia.

• Broader FGFR3-related skeletal dysplasia populations beyond achondroplasia: A phase 2 trial in 24 children with hypochondroplasia — another FGFR3 activating variant disorder with no approved medications — demonstrated that vosoritide increased annualized growth velocity by 2.26 SD and height SDS by 0.36 SD during the treatment period versus the observation period, with no treatment-related serious adverse events. Separately, research into SLC26A2-related chondrodysplasia in mouse models suggested that inhibition of FGFR3 signaling pathway overactivation via NVP-BGJ398 "could be a route for the treatment of SLC26A2-associated skeletal disorders."

TransCon CNP: A New Frontier in Infant Achondroplasia Care

Achondroplasia, often perceived primarily as a condition of short stature, is in fact a complex multisystemic disorder with potentially life-threatening complications. Among the most critical is foramen magnum stenosis (FMS), a narrowing at the base of the skull that can compress the brainstem and spinal cord, leading to severe neurological issues, sleep apnea, and even sudden death, particularly in infants. Historically, management for FMS has often involved invasive surgical decompression.

The recent Week 52 data for TransCon CNP (navepegritide) in infants aged 0 to <2 years represents a significant step forward in addressing this urgent unmet need. The findings indicate that treatment not only led to improvements in linear growth, with a mean annualized growth velocity of 9.9 cm/year, but crucially, also demonstrated stabilization or improvement in foramen magnum stenosis. All children in the sentinel cohort showed stable or improved Achondroplasia Foramen Magnum Score (AFMS), alongside a mean sagittal diameter change of +3.15 mm. This suggests a direct impact on cranial bone development, a benefit that could be independent of systemic growth effects, as research with other C-type natriuretic peptide (CNP) analogs has also hinted at.

This early intervention strategy holds immense promise. By targeting FMS in the most vulnerable age group, TransCon CNP could potentially alter the disease trajectory, reducing the need for surgical interventions and mitigating long-term neurological sequelae. However, as with any emerging therapy, important considerations remain. The open-label nature and limited size of this initial infant cohort mean that the long-term durability of these benefits and the generalizability across a broader patient population will need further validation in larger, controlled studies. While the safety profile appears favorable, with no serious treatment-related adverse events reported, continued monitoring for rare or delayed effects is essential. The ability to definitively compare TransCon CNP's impact on FMS against the natural history of the condition or other therapies will also require more extensive comparative data. Nevertheless, these results position TransCon CNP as a potentially transformative therapy, offering a proactive medical approach to a critical complication in infant achondroplasia.