AttaCH: A Phase 2, Multicenter, Long-Term, Open Label Extension Trial Evaluating Safety, Tolerability, and Efficacy of Subcutaneous Doses of TransCon CNP Administered Once Weekly in Children and Adolescents with Achondroplasia

The primary objective of this study is to evaluate the **safety** and **tolerability** of long-term use of TransCon CNP in children and adolescents with **achondroplasia**. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in a pediatric population, which is crucial for managing a chronic condition like achondroplasia.

Secondary objectives include:

• To evaluate the sustained efficacy of long-term treatment with navepegritide on growth, which is important for assessing the long-term benefits of the treatment in promoting normal growth patterns.
• To evaluate the safety and tolerability of long-term treatment with navepegritide, further supporting the primary objective by providing additional safety data.
• To evaluate the pharmacokinetic properties of navepegritide, which will help in understanding the drug's absorption, distribution, metabolism, and excretion, essential for optimizing dosing regimens.
• To assess the potential immunogenic response to navepegritide, which is critical for identifying any adverse immune reactions that could affect treatment safety and efficacy.

The clinical trial involves a total of **96 participants** diagnosed with **achondroplasia in children and adolescents**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on their completion of a prior clinical trial with TransCon CNP and their eligibility determined by safety evaluations from the previous study. The trial population is considered vulnerable, given the age and specific medical condition of the participants. Lifestyle considerations such as diet, physical activity, or habits are not specified. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is designed as a **Phase 2**, multicenter, long-term, open-label extension study to evaluate the safety, tolerability, and efficacy of subcutaneous doses of TransCon CNP administered once weekly in children and adolescents with **achondroplasia**. The trial will involve participants who have previously completed a clinical trial with TransCon CNP. The primary objective is to assess the long-term safety and tolerability of TransCon CNP, as well as its sustained efficacy on growth. The trial will monitor the incidence of treatment-emergent adverse events and changes in height Z-scores as primary endpoints. Secondary endpoints include annualized growth velocity, near-final adult height, and various safety assessments such as laboratory results, vital signs, and imaging assessments of bone age.

The trial is expected to last until March 2039, with participant involvement potentially extending up to 156 weeks. Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on prior safety evaluations. Follow-up visits will be scheduled regularly to monitor the participants' response to treatment and to conduct safety assessments. The end-of-study visit will conclude the trial, where final evaluations will be performed. Participants may be withdrawn from the study early if they experience significant adverse events or if they do not comply with the study protocol.

Inclusion criteria require written informed consent from the parent(s) or legal guardian(s), and assent from participants below the age of consent. Participants must have completed a previous clinical trial with TransCon CNP and be willing to adhere to the protocol, including the administration of weekly subcutaneous injections. The study will utilize devices such as the BD 1ml Syringe Luer Lok Tip and the STERiJECT Hypodermic Needle, both of which have CE marks. The trial is not classified as low intervention and is categorized under Phase 4, with a focus on ensuring the confidentiality of commercially sensitive information.

The clinical trial involves the administration of **TransCon CNP**, a **solution for injection** designed for the treatment of achondroplasia. The active substance in TransCon CNP is a **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 pharmaceutical form is a solution for injection, and it is administered via **subcutaneous injection**. The dosing regimen involves a maximum daily dose of 14.3 µg/kg, with the treatment period extending up to 156 weeks. The administration is facilitated using devices such as the BD 1ml Syringe Luer Lok Tip and the STERiJECT Hypodermic Needle, both of which have CE marks, ensuring compliance with European safety standards.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety, tolerability, and efficacy of TransCon CNP in a long-term, open-label extension study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the sustained efficacy of TransCon CNP on growth in children and adolescents with achondroplasia, with a particular emphasis on long-term safety and tolerability.

Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the incidence of treatment emergent adverse events (TEAEs) and **Height Z-scores**, both measured through trial completion. Secondary endpoints encompass annualized growth velocity (AGV) in centimeters per year, near final adult height, and various safety assessments. These safety assessments will include laboratory results of safety blood parameters, vital signs such as blood pressure, heart rate, and body temperature, abnormal physical examination findings, 12-lead electrocardiogram (ECG), Tanner stage, and imaging assessments of bone age and bone-related safety events. Additionally, plasma concentrations of Total CNP, Free CNP, and mPEG will be measured through treatment completion, along with the detection and analysis of anti-drug antibodies (ADAs).

The efficacy parameters will be collected and analyzed throughout the trial duration, with specific time frames extending through trial completion. The tools and instruments involved in these assessments include laboratory tests for blood parameters, ECG for cardiac monitoring, and imaging techniques for bone assessments. The trial aims to evaluate the sustained efficacy of TransCon CNP on growth in children and adolescents with achondroplasia, with a focus on long-term safety and tolerability. The trial is designed as a Phase 2, multicenter, long-term, open-label extension study, with the estimated end date set for March 1, 2039.