TransCon CNP for Achondroplasia

(AttaCH Trial)

Recruiting at 14 trial locations

Overseen By Vibeke Breinholt

Age: < 18

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Ascendis Pharma Growth Disorders A/S

Must be taking: Vitamin D

Must not be taking: Prescription medications

Disqualifiers: Hypersensitivity, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: Individualized per participant, up to 10 years

140 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses TransCon CNP to help children and adolescents with achondroplasia grow their bones properly. It is for those who have already been part of a previous trial. The treatment continues for an extended period.

Will I have to stop taking my current medications?

The trial requires that participants have not received any dose of prescription medications or investigational products other than TransCon CNP. This suggests you may need to stop taking other medications, but the protocol does not specify a washout period.

What data supports the effectiveness of the drug TransCon CNP for 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 studies and is well-tolerated in humans. It provides sustained CNP levels, which may improve bone growth in achondroplasia without causing heart-related side effects. ^{1 2 3 4 5}

Is TransCon CNP safe for humans?

TransCon CNP has been tested in clinical trials and was generally well tolerated in humans, with no major safety concerns reported. In animal studies, it showed no adverse cardiovascular effects, which are often a concern with similar treatments. ^{1 2 3 4 6}

What makes the drug TransCon CNP unique for treating achondroplasia?

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 dose, maintaining continuous CNP exposure to stimulate bone growth without causing cardiovascular side effects, unlike other treatments that require more frequent dosing and can lead to high peak concentrations. ^{1 2 3 4 5}

Research Team

Vibeke Breinholt

Principal Investigator

Ascendis Pharma

Eligibility Criteria

This trial is for children and adolescents with achondroplasia who have already been part of a previous TransCon CNP study. They must be able to receive weekly injections, have parental consent, and meet safety criteria from the prior trial. Those unable to complete the study or at risk due to other conditions are excluded.

Inclusion Criteria

My guardian can give me weekly shots and follow the study rules.

I have achondroplasia and finished a trial with TransCon CNP.

My guardian has signed the consent form, and I will too when I'm of age.

Exclusion Criteria

I have taken prescription or investigational drugs other than TransCon CNP.

I am not allergic to the trial drug or its components.

I am not using effective birth control and am able to have children.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly subcutaneous doses of TransCon CNP until femur and tibial epiphyseal closure is confirmed

Individualized per participant, up to 10 years

Visits every 12-14 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue receiving TransCon CNP in a long-term open-label extension

Up to 10 years

Treatment Details

Interventions

• TransCon CNP

Trial Overview The long-term safety, tolerability, and effectiveness of TransCon CNP given once a week are being tested in young patients with achondroplasia until they reach skeletal maturity (16 years for females, 18 years for males), confirmed by radiographic imaging.

Participant Groups

Group I: TransCon CNP 100 mcg Experimental Treatment 1 Intervention

TransCon CNP 100 mcg delivered once weekly by subcutaneous injection

Who Is Running the Clinical Trial?

Ascendis Pharma Growth Disorders A/S

Lead Sponsor

Trials

4

Recruited

320+

Findings from Research

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 (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 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]

References

1. 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]

2. 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]

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

A long-acting C-natriuretic peptide for achondroplasia. [2023]