Beyond Achondroplasia

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The TransCon CNP for achondroplasia – Ascendis Pharma publications


Ascendis Pharma, a company funded in 2007, applies the TransCon technology which combines a prodrug with a sustained-release technology. This way, the company can offer products with a predictable and sustained release of an unmodified parent drug.

Before heading for the publications the company released in 2017 in selected events, is important to explain some concepts.

What is a prodrug?

A prodrug is an inactive medication or compound (the same as having no action), and after being administrated, it is converted within the body (metabolized) into a pharmacologic active drug.

Prodrugs undergo an enzymatic and/or chemical transformation in vivo (inside the body) to release the active drug: the parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving several properties of active agents: physicochemical, biopharmaceutical or pharmacokinetic.1

Example of a prodrug. Credits:

During 2017 Ascendis Pharma released relevant information on the TransCon CNP. Through selected publications, the company shows high expectations on the efficacy of TransCon CNP in improving the quality of life in achondroplasia and reducing complications. In the company website it can be read the following:

Our preclinical studies of TransCon CNP have been encouraging. Continuous exposure to TransCon CNP has been found in preclinical studies to be more efficacious at inducing skeletal growth compared to once-daily injections. In preclinical safety studies, a low Cmax due to slow release of CNP has been shown to improve hemodynamic tolerability. And, the half-life extension observed confirms the potential of convenient weekly dosing in patients with achondroplasia. Additionally, preclinical data suggest a trend toward bone growth associated with TransCon CNPBuilding on these positive results, Ascendis Pharma plans to submit an Investigational New Drug Application for TransCon CNP in the fourth quarter of 2017. Ascendis pharma

What is the Cmax?

Is the maximum concentration of the drug that is measured in the plasma after one dose administration. 2 The concentration of a drug is the abundance of a compound divided by the total volume of a mixture. The following image gives a simple example how to reach the concentration value of a mixture.


So, once the TransCon CNP shows a low Cmax, this avoids side effects in the body after the administration of CNP, namely the reduction of blood pressure and an increase of heart rate has shown by other CNP (as BMN-111).

And what is the plasma?

Is the clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma.3 Blood is composed of blood cells suspended in blood plasma, that can be separated by centrifugation (a process used to separate substances that as mixed together).


What is the half-life of a drug?

Is the time that takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. 4

So due to an increased half-life of the TransCon CNP, the company sees the potential of having one administration per week of the drug instead of a daily administration.


Structural Optimization of TransCon CNP – Development of a Sustained-Release Prodrug of CNP for Achondroplasia


The TransCon technology. Credits: Ascendis Pharma

The reduced drop in the blood pressure after Vosoritide and TransCon CNP administration. A preclinical study conducted in monkeys.  Credits: Ascendis Pharma

Main conclusions

  1. The TransCon CNP prodrug has minimal binding to the NPR-B and NPR-C receptors and improved NEP stability in vitro compared to unmodified CNP.
  2. In vivo TransCon CNP demonstrated the desired half-life extension without adverse hemodynamic effects.
  3. These data support clinical development for weekly dosing and suggest TransCon CNP may be a safe and efficacious option for children with ACH. Ascendis Pharma

TransCon CNP, a sustained-release prodrug of C-type natriuretic peptide, prevents premature synchondroses closure in an achondroplasia mouse model

The reduction of the ossification of the areas around the foramen magnum, the synchondroses (IOSA). Credits: Ascendis Pharma

Main conclusions:

  1. In a murine model of ACH, TransCon CNP prevented the closure of synchondroses and resulted in an improvement in foramen magnum and skull shape, suggesting normalization of the overall skull contour.
  2. These results suggest that the early administration of TransCon CNP may alleviate the risk of foramen magnum stenosis that leads to some of the most serious clinical complications of ACH. Ascendis Pharma

Pharmacokinetics and Cardiovascular Assessment of TransCon CNP, a Sustained-Release C-type Natriuretic Peptide Prodrug, for the Treatment of Achondroplasia

Main conclusion:

  1. Continuous exposure to CNP showed better efficacy and CV tolerability than intermittent, daily injections.
  2. TransCon CNP exhibited a substantially longer half-life in cynomolgus monkeys compared to daily CNP analogs, supporting once-weekly dosing in humans
  3. TransCon CNP showed no adverse hemodynamic effects in cynomolgus monkeys or mice at doses exceeding the expected therapeutic dose
  4. TransCon CNP may improve efficacy and safety over daily administered CNP. Ascendis Pharma

TransCon CNP, a Sustained-Release Prodrug of C-Type Natriuretic Peptide, exerts Positive Effects on Bone in Juvenile Cynomolgus Monkeys and in a Mouse Model of Achondroplasia

TransCon CNP administration to Fgfr3Y367C/+ mice from birth to day 15 increased the naso-anal length and bone length (femur; blue arrows, tibia; red arrows). Credits: Ascendis Pharma

Main conclusions:

  1. In young healthy monkeys, once weekly TransCon CNP increased long bone growth in a dose-dependent fashion.
  2. In a murine model of ACH, TransCon CNP improved growth plate architecture and improved phenotypical features.
  3. These data support further development of TransCon CNP as a potential therapy for ACH, providing efficacious CNP levels with weekly administration. Ascendis Pharma



1. Rautio J et al, 2008, Prodrugs: design and clinical applications.

2. Science Direct – Cmax (pharmacology)

3. Pubmed Health – Blood Plasma

4. UNIL-Université de Lausanne


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