Efficacy and Safety Evaluation of Navepegritide and Lonapegsomatropin in Pediatric Achondroplasia: A 156-Week, Phase 2, Open-Label, Single-Arm Study
- Trial ID
- 2023-508341-40-00
- Protocol
- ASND0042
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **navepegritide** and **lonapegsomatropin** on linear growth in children with **achondroplasia**, compared to **navepegritide** alone. Additionally, the study aims to assess the safety profile of these treatments. This is clinically relevant as it addresses the potential for improved growth outcomes and safety in a pediatric population affected by this genetic disorder.
Secondary objectives include:
- Evaluating the effect of combination therapy on linear growth compared to placebo.
- Assessing the impact on **ACH** experience measures, quality of life, and sleep.
- Investigating the effect on growth of dysplastic bone and body composition.
- Evaluating the treatment impact on physical functioning.
- Assessing the safety and tolerability of the combination therapy.
- Characterizing the pharmacokinetics (**PK**) and pharmacodynamics (**PD**) biomarkers of the treatments.
- Assessing potential immunogenic response to the therapies.
Participants
The clinical trial involves a total of **8 participants** diagnosed with **achondroplasia**, a genetic condition characterized by short stature. The study population includes both male and female children aged between **2 to 11 years**. Participants were selected based on their ability to stand without assistance and the availability of at least six months of growth and disease history. The trial population is considered vulnerable due to the young age of the participants. The selection criteria required a clinical diagnosis of achondroplasia with genetic confirmation of a heterozygote genotype. Participants' parents or legal guardians provided written, signed informed consent, and they are responsible for administering weekly subcutaneous injections as part of the study protocol. The trial aims to evaluate the effect of navepegritide and lonapegsomatropin on linear growth and assess the safety profile of these treatments.
Plans and Procedures
The clinical trial is designed as a **Phase 2, open-label, single-arm** study to evaluate the efficacy, safety, and tolerability of combined once-weekly administration of navepegritide and **lonapegsomatropin** in children diagnosed with achondroplasia. The trial will span a total duration of 156 weeks, with the primary objective being to assess the effect of the treatment on linear growth and to evaluate the safety profile of the investigational medicinal products. Participants will be administered the treatment via **subcutaneous injection**. The trial will include a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis, and the ability to stand without assistance. Follow-up visits will occur at regular intervals to monitor growth velocity, safety assessments, and other secondary endpoints, including changes in height Z-score and body composition. The end-of-study visit will conclude the participant's involvement, with comprehensive assessments to evaluate the overall impact of the treatment. The expected length of participant involvement is the full 156 weeks unless conditions arise that necessitate early termination, such as adverse events or withdrawal of consent. The trial will adhere to rigorous safety monitoring, including vital signs, ECG, and laboratory tests, to ensure participant well-being throughout the study period. The trial is not categorized as low intervention, reflecting the complexity and investigational nature of the treatment regimen. Participants will be required to comply with all protocol requirements, including the administration of weekly injections and attendance at scheduled study visits. The trial aims to provide valuable insights into the potential benefits and risks associated with the combined treatment approach in this pediatric population.
Treatment
The clinical trial involves the administration of **TransCon CNP**, a **solution for injection** containing the active substance **C-type natriuretic peptide** conjugated to a multi-arm polyethylene glycol carrier molecule through a cleavable linker. This experimental medication is administered via **subcutaneous injection**. The dosage is calculated based on body weight, with a maximum daily dose of 14.3 µg/kg. The treatment period extends up to 156 weeks. The formulation is not specifically designed for pediatric use, although it is being tested in a pediatric population. The medication is synthetically manufactured and classified as a protein of other origin.
Another experimental treatment in the trial is **TransCon hGH**, also a **solution for injection**. The active substance in this formulation is **lonapegsomatropin**, which is administered through **subcutaneous injection**. The dosing regimen is weight-based, with a maximum daily dose of 0.04 mg/kg and a total maximum dose of 0.05 mg/kg. The treatment duration is up to 156 weeks. Similar to TransCon CNP, this formulation is not specifically pediatric but is being evaluated in children. The active substance is a protein of other origin, and the product is authorized for use in the trial.
Both TransCon CNP and TransCon hGH are being evaluated for their efficacy, safety, and tolerability in children with **achondroplasia**. The trial aims to assess the effect of these treatments on linear growth and to compare the outcomes of combined therapy with navepegritide and lonapegsomatropin versus navepegritide alone. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the annual growth velocity (AGV) measured in centimeters per year at Week 52. Secondary endpoints include AGV at Weeks 26, 104, and 156, as well as changes from baseline in height Z-score at Weeks 13, 26, 52, 104, and 156. Additional secondary endpoints involve the Achondroplasia Child Experience Measures (ACEM) and Achondroplasia Parent Experience Measure (APEM) at Weeks 26, 52, 104, and 156. Changes from baseline in various clinical outcome assessments (COAs) such as QoLISSY, SF-10, PGIS, PGIC, HCRU, and CGI-S will also be evaluated at the same timepoints.
Further assessments include changes from baseline in sleep apnea, quality of sleep, and snoring patterns, as well as changes in the length of long bones and other skeletal measurements using standardized radiologic assessments at Weeks 52, 104, and 156. Body composition changes, including body fat, lean mass, skeletal muscle, and bone mineral density, will be measured using DXA assessments. The number of rises during a 1-MSTST and maximal knee extensor muscle strength will also be evaluated. Safety assessments will be conducted throughout the trial, including vital signs, ECG, safety laboratory tests, physical and skeletal examinations, injection site reactions, and fundoscopy. Bone age will be assessed via X-ray at Weeks 26, 52, 104, and 156.
Biomarker analysis will include plasma concentrations of Total CNP, Free CNP, and mPEG, as well as serum concentrations of hGH, lonapegsomatropin, IGF-1, and IGFBP3. The detection and characterization of both antidrug and anti-prodrug antibodies will also be part of the efficacy assessment. These parameters will be measured and analyzed at specified timepoints to determine the efficacy of the investigational medicinal products in children with **achondroplasia**.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written, signed informed consent and/or assent (if applicable) by the parent(s) or legal representative(s) of the participant, and as required by the IRB/HREC/IEC.
- Male or female between 2 to 11 years of age (inclusive) at the time of Visit 1.
- Clinical diagnosis of ACH with genetic confirmation of heterozygote genotype present at Visit 1. Documentation of historic test results are acceptable for proof of diagnosis.
- Able to stand without assistance.
- Parent(s)/caregiver(s)/legal guardian(s) willing and able to administer weekly SC injections of IMP and comply with all protocol requirements.
- At least 6 months of growth and disease history from TCC-NHS-01 or TCC-201 or comparable growth and disease history available from medical records.
Exclusion Criteria
- Participation in any interventional clinical trial within three months prior to screening (except TCC-201 or ASND0039).
- Cervicomedullary decompression surgery within 6 months prior to Screening or with anticipated need for repeat decompression surgery during the time of the trial.
- Evidence at screening consistent with severe cervicomedullary junction compression based on clinical and/or radiologic findings that indicate immediate surgical intervention is required.
- Ventriculoperitoneal shunt and laminectomy with full recovery within 6 months prior to Screening.
- Salter-Harris fracture within 6 months prior to screening (within 2 months for fracture of digits and buckle fractures).
- Clinically significant musculoskeletal disease, such as Salter-Harris fractures or clinical and/or radiographic evidence of severe hip pathology
- Planned or expected surgical intervention during trial participation that may significantly affect trial parameters (confounding of safety events) or would prevent the participant from performing trial procedures. Minimally invasive surgeries such as insertion of grommets, adenoidectomy, tonsillectomy, or myringotomy tube placement, are permitted during the trial.
- Severe untreated sleep apnoea or newly initiated sleep apnoea treatment (e.g., Continuous Positive Airway Pressure [CPAP] in the previous 2 months prior to screening).
- Clinically significant finding or arrhythmia as determined by the investigator that indicates abnormal cardiac function or conduction that includes, but is not exclusive to: a. Repaired or unrepaired coarctation. b. 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 haemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
- Closed epiphysis at screening.
- Known history or presence at screening of the following: a. Chronic anaemia (iron deficiency anaemia that is resolved or considered adequately treated in the Investigator’s opinion is allowed). b. Chronic renal insufficiency defined as estimated glomerular filtration rate (eGFR) according to the revised bedside Schwartz equation less than <60 mL/min/1.73 m2 for >3 months. c. Chronic or recurrent illness that can affect hydration or volume status, including conditions associated with decreased nutritional intake or increased volume loss. d. Acute critical illness following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions for which lonapegsomatropin treatment is contraindicated.
- Known history or presence of malignant disease.
- Hepatic transaminases (aspartate aminotransferase (AST) or alanine transferase (ALT)) greater than 3x upper limit of normal (ULN) at screening.
- Serum 25-hydroxy-vitamin D (25OHD) level of <30 nmol/L (<12 ng/mL) at screening. Participants with 25OHD levels between 30-50 nmol/L (12-20 ng/mL) may be enrolled provided treatment with Vitamin D supplementation is initiated.
- 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 who are unwilling or unable to use a highly effective form of contraception for the entire trial period and for 90 days after last dose of trial treatment
- Female participants who are pregnant, lactating or breastfeeding.
- History of or suspected hypersensitivity to the IMP or related products.
- Findings on fundoscopy at screening consistent with intracranial hypertension, papilledema, or evidence of any other retinal disease for which GH therapy is contraindicated.
- Have a growth disorder or medical condition other than ACH that results in short stature or abnormal growth such as severe ACH with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia, GHD, Turner syndrome, pseudoachondroplasia, inflammatory bowel disease, celiac disease, hypothyroidism, hyperthyroidism, pre-diabetes, or diabetes mellitus.
- Have received any dose of prescription and/or investigational medications or device intended to affect stature, growth, or body proportionality at any time prior to screening, except for those participants enrolled in Cohort B who will have prior navepegritide exposure.
- Receiving concurrent treatment with any agent that might influence growth or interfere with GH secretion or action: a. Inhaled corticosteroid therapy at a dose of >400 µg/day of inhaled budesonide or equivalent for more than 28 consecutive days total over the course of 12 months prior to screening. b. Require, 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. c. Currently using or have used within 12 months prior to screening any sex steroids (for example estrogen), non-steroidal anabolic agents (for example, oxandrolone) or gonadotropin-releasing hormone (GnRH) analogues treatment. d. Treatment for attention-deficit hyperactive disorder (ADHD) such as methylphenidate.
- Known history or 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 Orthopaedic reconstructive surgery for bone lengthening (procedures for leg bowing such as 8-plate are not exclusionary).
- Known or suspected intracranial pathology. Participants with a history of known intracranial pathology, such as a tumour or significant hydrocephalus, clinical resolution must be confirmed by an MRI scan at screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 May 2024 | 4 |
 Ireland | Not Recruiting | 01 May 2024 | 6 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TransCon hGH | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 0.04 | 156 | PRD4938660 |
Navepegritide 2.8 mg CNP89-126 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 14.3 | 156 | PRD12903335 |
TransCon CNP 3.9 mg CNP-38/vial | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 14.3 | 156 | PRD9278536 |
Navepegritide 5.5 mg CNP89-126 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 14.3 | 156 | PRD12903336 |
TransCon hGH | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 0.04 | 156 | PRD4938659 |