Evaluation of Efficacy and Safety of Subcutaneous Navepegritide in Adolescents with Achondroplasia: A Phase 2b Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-514208-15-00
Protocol: ASND0045
Sponsor: Ascendis Pharma Growth Disorders A/S

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Diseases & Conditions

Osteochondrodysplasia

Objectives

The primary objective of this study is to evaluate the **efficacy** of navepegritide on growth in adolescents aged 12 to less than 18 years with **achondroplasia**. Achondroplasia is a genetic disorder characterized by disproportionate short stature, and assessing the impact of navepegritide on growth is clinically significant as it may offer a therapeutic option to improve height outcomes in affected individuals.

Secondary objectives include evaluating the efficacy of navepegritide on growth, further supporting the primary aim by providing additional insights into the treatment's potential benefits.

Participants

The clinical trial focuses on evaluating the efficacy of **navepegritide** on growth in children and adolescents diagnosed with **achondroplasia**. The study population includes both male and female participants aged between 12 and less than 18 years at the time of randomization. Participants are required to have a clinical diagnosis of achondroplasia with documented genetic confirmation. The trial involves a vulnerable population, as it includes minors who require consent from their parent(s) or legal guardian(s). Participants must have at least one historical standing height measurement available from medical records, collected between 6 to 15 months prior to screening. The sponsor has not provided information regarding the total number of participants in the trial. The selection criteria ensure that participants are capable of adhering to the protocol, including the administration of weekly subcutaneous injections of the investigational medicinal product by their parent(s) or legal guardian(s). The trial does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of a subcutaneous solution for injection, TransCon CNP, in adolescents with **achondroplasia**. This is a Phase 2b, multicenter, double-blind, randomized, placebo-controlled trial. Participants will be randomly assigned to receive either the investigational medicinal product (IMP) or a placebo, with both groups receiving weekly injections for a duration of 52 weeks. The primary endpoint is the assessment of annualized growth velocity (AGV) at Week 52, while secondary endpoints include changes from baseline in height Z-score at the same time point.

The trial will commence with a screening visit to confirm eligibility, which includes criteria such as age between 12 and <18 years, a clinical diagnosis of achondroplasia with genetic confirmation, and the ability of the participant's parent(s) or legal guardian(s) to administer the weekly injections. Following successful screening, participants will be randomized and begin the treatment phase. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. These visits will include physical examinations, laboratory tests, and assessments of growth parameters.

The expected length of participant involvement is approximately 52 weeks, with the trial estimated to conclude by January 2027. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial is not categorized as low intervention, and it is conducted under the oversight of an institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC) to ensure ethical standards are maintained throughout the study.

Treatment

The clinical trial involves the administration of **TransCon CNP**, an experimental medication designed for the treatment of achondroplasia. **TransCon CNP** is a **solution for injection** containing **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 medication is administered subcutaneously once weekly, with a maximum daily dose of 14.3 µg/kg. The treatment period extends up to 52 weeks. The administration of **TransCon CNP** is facilitated using devices such as the STERiJECT Hypodermic Needle, BD 1ml Syringe Luer Lok Tip, and Needle, Sterican 21Gx1’’, 0.80X25mm, all of which have CE marks.

The study also includes a **placebo** group to serve as a comparator for evaluating the efficacy and safety of **TransCon CNP**. The **placebo** is designed to mimic the experimental treatment in appearance and administration but does not contain the active substance. The **placebo** is administered following the same schedule and route as the experimental medication, ensuring blinding and maintaining the integrity of the trial's double-blind design. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of the investigational medicinal product, **navepegritide**, will be assessed in a Phase 2b, multicenter, double-blind, randomized, placebo-controlled trial. The primary endpoint for evaluating efficacy is the Annualized Growth Velocity (AGV) at Week 52. Additionally, a secondary endpoint includes the change from baseline in height Z-score at Week 52. These endpoints are designed to measure the impact of **navepegritide** on growth in adolescents with achondroplasia.

Measurements will be collected at specified timepoints, with the primary and secondary endpoints being assessed at the conclusion of the 52-week treatment period. The trial will utilize validated methods for measuring growth parameters, ensuring the reliability and accuracy of the data collected. The use of standardized tools and instruments for height measurement will be integral to the assessment process. The data collected will be analyzed to determine the efficacy of **navepegritide** in promoting growth compared to placebo, providing insights into its potential therapeutic benefits for adolescents with achondroplasia.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written, signed informed consent and/or assent of the participant, participant parent(s) or legal guardian(s) of the participant, and as required by the institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC). For participants who are below the age of consent, a written assent will be obtained in accordance with applicable requirements as required by IRB/HREC/IEC. Upon reaching the legal age of consent, depending on applicable requirements, these participants will be asked to give their own written consent.
Male or female, between 12 (inclusive) and <18 years of age at the time of randomization
Clinical diagnosis of ACH with documented genetic confirmation available. Documentation of historic test results are acceptable for proof of diagnosis.
Parent(s)/legal guardian(s) willing and able to administer weekly SC injections of IMP and to follow the protocol.
At least one historical standing height measurement available from medical records. The measurement must have been collected between 6 months to 15 months prior to the time of screening.

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Exclusion Criteria

Participation (signed informed consent) in any interventional clinical trial within 3 months prior to Screening unless no doses of IMP was given.
Decreased growth velocity (AGV < 1.5 cm/year based on measurement over a period of at least 6 months) or radiological evidence of growth plate closure.
Known or suspected hypersensitivity to the IMP or related products (trehalose, tris[hydroxymethyl]aminomethane, succinate, and mPEG).
Have a growth disorder or medical condition other than ACH that results in short stature, or abnormal growth such as SADDAN, hypochondroplasia, growth hormone deficiency, Turner syndrome, pseudo-ACH, inflammatory bowel disease, celiac disease, hypothyroidism, hyperthyroidism, or diabetes mellitus.
Severe mutation in the FGFR3 gene, e.g. two variants on the same allele or severe ACH with developmental delay and acanthosis nigricans , are not eligible for trial participation.
Have received any dose of prescription medications and/or IMP (placebo treatment only is allowed, if documented) or surgical intervention intended to affect stature, growth, or body proportionality at any time.
Requires, or anticipated to require, chronic (> 4 weeks) or repeated treatment (more than twice/year and >3 weeks/year) with systemic corticosteroids during participation in the trial. Chronic use of high dose inhaled corticosteroids is not allowed.
Known history of presence of injury or disease of the growth plate(s), other than ACH, that affects growth potential of long bones.
Known history of any bone-related surgery affecting growth potential of long bones, such as: • Orthopedic reconstructive surgery for bone lengthening (e.g., procedures for leg bowing such as 8-plate are not exclusionary). • Ventriculoperitoneal (VP) shunt and laminectomy with full recovery are allowed with minimum of 6 months of bone healing. • Bone fracture within 6 months prior to screening (within 2 months for fracture of digits and buckle fractures).
Clinically significant findings at Screening, such as: • Expected to require surgical intervention during participation in the trial that may significantly affect trial parameters (confounding of safety events) or would prevent the participant from performing trial procedures. Common surgeries, such as insertion of grommets, adenoidectomy, tonsillectomy, or myringotomy tube placement, are permitted. • Severe untreated sleep apnea or newly initiated sleep apnea treatment (e.g., Continuous Positive Airway Pressure [CPAP] in the previous 2 months prior to Screening. MS disease, such as Salter-Harris fractures or clinical and/or radiographic evidence of severe hip pathology • Otherwise, are considered by the Investigator to be unfit to receive trial treatment or undergo trial related procedures.
Have a clinically significant finding or arrhythmia as determined by the investigator in consultation with the medical monitor that indicates abnormal cardiac function or conduction that includes, but is not exclusive to: • Repaired or unrepaired coarctation. • Moderate or greater complexity congenital heart disease including tetralogy of Fallot, Atrioventricular septal defects, truncus arteriosus, total anomalous pulmonary venous return, double outlet right ventricle, or single ventricle heart disease.
QT corrected using Fridericia’s correction (QTcF) ≥ 450 msec at Screening
Known history or presence of condition that impacts hemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
Known history or presence of the following: • Chronic anemia (iron deficiency anemia that is resolved or adequately treated in the Investigator’s opinion is allowed). • Chronic renal insufficiency defined as estimated glomerular filtration rate (eGFR) according to the revised bedside Schwartz equation < 60 mL/min/1.73 m2 for >3 months. • Chronic or recurrent illness that can affect hydration or volume status, including conditions associated with decreased nutritional intake or increased volume loss.
Known history or presence of malignant disease
Participant with serum 25-hydroxy-vitamin D (25OHD) levels of <30 nmol/L (<12 ng/mL) at Screening Visit will be excluded. Participants with 25OHD levels between 30-50 nmol/L (12-20 ng/mL) can be randomized provided treatment with Vitamin D supplementation is initiated according to local standards
Any disease or condition that, in the opinion of the Investigator, may make the participant unlikely to fully complete the trial, may confound interpretation of trial results, or may present undue risk from receiving trial treatment. This could include family situations, complications or manifestations, or medications that might impact safety or be considered confounding.
Sexually active male and female participants and female partners of male participants of childbearing potential not using a highly effective form of contraceptive for the entire trial period and for 90 days after last dose of trial treatment.
Female participants who are pregnant, lactating or breastfeeding.