Phase 2 Multicenter Double-Blind Randomized Placebo-Controlled Trial of TransCon CNP in Infants with Achondroplasia Evaluating Safety, Tolerability, and Efficacy

The primary objective of this study is to evaluate the **safety** and **tolerability** of TransCon CNP in infants with **achondroplasia**. This is clinically relevant as it aims to ensure that the treatment is safe for use in this vulnerable population, addressing potential adverse effects and overall patient well-being. Additionally, the study seeks to assess the effect of TransCon CNP on growth, which is crucial for understanding its potential benefits in promoting normal growth patterns in children affected by this condition.

Secondary objectives include evaluating the effect of TransCon CNP on various growth and developmental parameters:

• Annualized growth velocity (AGV)
• Long-term growth
• Developmental milestones
• Morphology and growth of bones and spine
• Foramen magnum morphology and growth
• Treatment impact on non-linear growth manifestations and complications in children with achondroplasia

The clinical trial involves a total of **37 participants** diagnosed with **achondroplasia** in children and adolescents. The study population includes both male and female subjects, specifically targeting those younger than 2 years of age at the time of randomization. Participants were selected based on a clinical diagnosis of achondroplasia with genetic confirmation, and they are required to comply with daily Vitamin D supplementation if necessary. The trial population is considered vulnerable, and the selection process ensured that participants were not eligible for treatment with vosoritide due to various reasons, including its unavailability or the inability of parents or caregivers to cover related expenses. The general health status of participants was assessed through medical history, physical examination, and various clinical tests during the screening period. Lifestyle considerations such as the ability of parents or caregivers to administer weekly subcutaneous injections of the trial treatment were also taken into account.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety, tolerability, and efficacy of TransCon CNP in infants with **achondroplasia**. The trial will involve subcutaneous administration of TransCon CNP once weekly for a duration of 52 weeks, followed by an open-label extension period. The primary objective is to assess the incidence of treatment-emergent adverse events (TEAEs) and changes in length/height Z-score over the 52-week period. Secondary endpoints include annualized growth velocity and various changes in physical and developmental parameters over 52 and 104 weeks.

Participants will be involved in the study for a total of 156 weeks, with the initial 52 weeks being the core study period. The trial will commence with a screening visit to confirm eligibility based on inclusion criteria such as age, clinical diagnosis, and genetic confirmation of achondroplasia. Following successful screening, participants will be randomized to receive either TransCon CNP or placebo. Study visits will occur regularly to monitor safety, efficacy, and compliance, with assessments including physical examinations, laboratory tests, and imaging studies. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all collected data.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for the participant's safety. The trial is expected to start recruitment in May 2024 and conclude by December 2026. The study is not classified as low intervention, and it is conducted under the auspices of Ascendis Pharma Growth Disorder A/S, with the investigational product being a synthetically manufactured peptide. The trial will utilize devices such as BD 1ml Syringe Luer Lok Tip and Sterican needles, all of which have CE marks, to ensure the safe administration of the investigational product.

The clinical trial involves the administration of **TransCon CNP**, a **solution for injection** designed for subcutaneous use. The active substance in TransCon CNP is **C-type natriuretic peptide** conjugated to a multi-arm polyethylene glycol carrier molecule through a cleavable linker. This formulation is synthetically manufactured and classified as a protein of other origin. The product is administered once weekly at a dosage of 14.3 µg/kg, with a maximum treatment period of 156 weeks. The administration is facilitated using devices such as the BD 1ml Syringe Luer Lok Tip, Sterican 21Gx1’’ Needle, and STERiJECT Hypodermic Needle, all of which have CE marks. The trial aims to evaluate the safety, tolerability, and efficacy of TransCon CNP in infants with achondroplasia.

The study also includes a **placebo** group, where participants receive a placebo for TransCon CNP. The placebo is designed to match the experimental treatment in appearance and administration method, ensuring the double-blind nature of the trial. The placebo is administered subcutaneously with the same frequency and using the same devices as the active treatment. This allows for a controlled comparison to assess the true effects of TransCon CNP on growth and safety in the target population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent adverse events (TEAEs) over 52 weeks, including Grade ≥ 3 TEAEs, serious adverse events (SAEs), TEAEs leading to discontinuation, deaths due to TEAEs, and all deaths. Additionally, the change from baseline to 52 weeks in length/height Z-score will be evaluated.

Secondary endpoints will further assess efficacy by measuring the annualized growth velocity (AGV) in centimeters per year at 52 weeks and 104 weeks, and the change from baseline to 104 weeks in length/height Z-score. Other secondary measures include changes from baseline to 52 weeks and 104 weeks in the Bayley Scales, motor and language scales (4th edition), and evaluations of long bones and angles in lower limbs through X-ray. MRI evaluations of the spine and foramen magnum will also be conducted, assessing parameters such as spine interpedicular distance, spinal cord volume, and the **Achondroplasia Foramen Magnum Score (AFMS)**. The incidence of complications and manifestations of achondroplasia, including breathing-related sleep disorders, otitis media, hearing loss, musculoskeletal pain, and deformities, will be recorded.