Navepegritide for Achondroplasia

Recruiting in Palo Alto (17 mi)

+15 other locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Ascendis Pharma A/S

Must be taking: Vitamin D

Must not be taking: Corticosteroids, Growth hormone

Disqualifiers: Premature birth, Surgery, Heart disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is a Phase 2, multicenter, double-blind, randomized (ratio 2:1 TransCon CNP vs. placebo), placebo-controlled trial, designed to evaluate the safety, tolerability, and efficacy of 100 μg CNP/kg of Navepegritide (TransCon CNP) administered SC once-weekly for 52 weeks in infants with genetically verified heterozygous ACH, aged 0 to \< 2 years at the time of randomization.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking medications that affect growth or require long-term corticosteroid use, you may not be eligible to participate.

What data supports the effectiveness of the drug Navepegritide (TransCon CNP) for treating achondroplasia?

Research shows that TransCon CNP, a drug that slowly releases C-type natriuretic peptide (CNP) in the body, has been effective in stimulating bone growth in animal models and is well-tolerated in humans. It provides sustained CNP levels with once-weekly dosing, which may improve bone growth in children with achondroplasia. ^{1 2 3 4 5}

Is Navepegritide (TransCon CNP) safe for humans?

Navepegritide (TransCon CNP) has been tested in clinical trials and was generally well tolerated in humans, with no significant adverse cardiovascular effects observed. It provides a sustained release of CNP, which helps avoid high concentrations that could cause side effects like low blood pressure. ^{1 2 3 5 6}

How is the drug Navepegritide (TransCon CNP) different from other treatments for achondroplasia?

Navepegritide (TransCon CNP) is unique because it is a prodrug that provides a sustained release of C-type natriuretic peptide (CNP) with a convenient once-weekly injection, allowing for continuous exposure that promotes bone growth without causing cardiovascular side effects. This contrasts with other treatments that may require more frequent dosing and can lead to higher peak concentrations that might affect blood pressure. ^{1 2 3 4 7}

Research Team

Eligibility Criteria

This trial is for infants under 2 years with achondroplasia, a form of dwarfism. Parents must consent and be able to give weekly shots at home. Babies up to 1 year old need daily Vitamin D; older ones with low levels must start supplements before joining.

Inclusion Criteria

I am under 2 years old.

My caregiver is ready to follow the study rules and give me weekly shots.

Written, signed informed consent by the parent(s)/caregiver(s) of the participant, and as required by the institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC)

Exclusion Criteria

My genetic test shows I have two copies of the ACH gene.

Known or suspected hypersensitivity to the investigational product or related products (trehalose, tris[hydroxymethyl]aminomethane, succinate, and polyethylene glycol [PEG])

History or presence of injury or disease of the growth plate(s), other than ACH, affecting growth potential of long bones, as determined by Investigator and confirmed with the Medical Monitor

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly subcutaneous injections of TransCon CNP or placebo for 52 weeks

52 weeks

Once weekly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment long-term

Treatment Details

Interventions

• TransCon CNP (Growth Hormone Therapy)

Trial Overview The trial tests Navepegritide (TransCon CNP) against a placebo in babies with achondroplasia. It's given as a shot once a week for a year. The goal is to see if it's safe and works better than no treatment.

Participant Groups

Group I: Navepegritide Experimental Treatment 1 Intervention

Once weekly double-blinded treatment with SC injection of 100 µg/kg of Navepegritide for 52 weeks

Group II: Placebo for Navepegritide Placebo Group 1 Intervention

Once weekly double-blinded treatment with SC injection of 100 µg/kg of Placebo for Navepegritide for 52 weeks

Who Is Running the Clinical Trial?

Ascendis Pharma A/S

Lead Sponsor

Trials

15

Recruited

1,600+

Ascendis Pharma Growth Disorders A/S

Lead Sponsor

Trials

4

Recruited

320+

Findings from Research

TransCon CNP (navepegritide) is a promising once-weekly treatment for children with achondroplasia, showing a significant improvement in annualized growth velocity (AGV) compared to placebo after 52 weeks, particularly at the highest dose of 100 μg/kg/week.

The treatment was found to be safe, with mostly mild to moderate side effects and no serious adverse events related to the drug, indicating a favorable safety profile for this new therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. Savarirayan, R., Hoernschemeyer, DG., Ljungberg, M., et al.[2023]

TransCon CNP, a novel prodrug for achondroplasia, was found to be well-tolerated in a phase 1 trial with 45 healthy adult males, showing no serious adverse events and no clinically relevant cardiac effects.

The treatment provided sustained release of C-type natriuretic peptide (CNP) for at least 7 days, significantly increasing levels of cGMP, indicating effective engagement with the target receptor, which supports its potential for once-weekly therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long-acting C-type natriuretic peptide prodrug, TransCon CNP. Breinholt, VM., Mygind, PH., Christoffersen, ED., et al.[2022]

TransCon CNP, a sustained-release formulation of C-type natriuretic peptide, has shown to be more effective in stimulating bone growth compared to intermittent CNP exposure in preclinical studies with mice and cynomolgus monkeys.

The drug was well tolerated with no adverse cardiovascular effects at therapeutic levels, and it provides prolonged systemic exposure to CNP-38 for at least 7 days, which may enhance its efficacy while minimizing the risk of hypotension associated with short-acting CNP formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. Breinholt, VM., Rasmussen, CE., Mygind, PH., et al.[2019]

C-type natriuretic peptide (CNP) significantly stimulates endochondral bone growth, as demonstrated in studies using transgenic and knockout mice.

Targeted overexpression or systemic administration of CNP has been shown to reverse impaired skeletal growth in mouse models of achondroplasia, suggesting potential therapeutic applications for this condition in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Genetic basis for skeletal disease. CNP therapy for achondroplasia]. Yasoda, A., Nakao, K.[2010]

Targeted overexpression of C-type natriuretic peptide (CNP) in chondrocytes effectively counteracts dwarfism in a mouse model of achondroplasia by preventing bone shortening and correcting extracellular matrix synthesis in the growth plate.

CNP works by inhibiting the MAPK pathway of FGF signaling, which is responsible for the bone growth issues in achondroplasia, suggesting that activating the CNP-GC-B system could be a promising new therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Yasoda, A., Komatsu, Y., Chusho, H., et al.[2012]

Systemic administration of C-type natriuretic peptide (CNP) significantly improved bone growth in a mouse model of achondroplasia, a common skeletal dysplasia, suggesting its potential as a novel treatment.

The study showed that both increased plasma CNP from the liver and intravenous administration of synthetic CNP-22 effectively rescued impaired bone growth without significant adverse effects, indicating a promising therapeutic strategy for skeletal dysplasias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Yasoda, A., Kitamura, H., Fujii, T., et al.[2021]

C-type natriuretic peptide (CNP) promotes skeletal growth and can rescue dwarfism in a transgenic model of achondroplasia, indicating its potential as a treatment for this condition.

In a specially designed mouse model with high blood CNP levels, skeletal overgrowth occurred without negative effects on blood pressure or heart weight, suggesting that CNP could stimulate bone growth safely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. Kake, T., Kitamura, H., Adachi, Y., et al.[2009]

References

1. England pubmed.ncbi.nlm.nih.gov

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long-acting C-type natriuretic peptide prodrug, TransCon CNP. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. [2019]

4. Japan pubmed.ncbi.nlm.nih.gov

[Genetic basis for skeletal disease. CNP therapy for achondroplasia]. [2010]

5. United States pubmed.ncbi.nlm.nih.gov

Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. [2012]

6. United States pubmed.ncbi.nlm.nih.gov

Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. [2009]