Transcon CNP, a Sustained-Release C-Type Natriuretic Peptide Analogue, for the Treatment of Achondroplasia

Presentation Number: MON 331
Date of Presentation: April 3rd, 2017

Kennett Sprogoe*1, Caroline Elisabeth Rasmussen2, Ulrich Hersel2 and Vibeke Miller Breinholt2
1Ascendis Pharma A/S, Hellerup, Denmark, 2Ascendis Pharma

Abstract

Background

Currently, no FDA-approved therapy exists for achondroplasia (ACH), the most common form of dwarfism. Administration of C-Type Natriuretic Peptide (CNP) to ACH patients and animals has been shown to stimulate endochondral bone growth and improve adverse skeletal manifestations of the disease. Given that continuous CNP exposure has demonstrated better efficacy than bolus administration, TransCon CNP, a prodrug in development that releases unmodified CNP, could provide patients with a safe and effective treatment with once-weekly dosing.

Objectives

The aims of these nonclinical studies were to investigate the pharmacokinetics of TransCon CNP in cynomologus monkeys and compare cardiovascular safety parameters to that of a daily administered CNP.

Design and Methods

In its prodrug form, TransCon CNP was developed to shield the CNP molecule from neutral endopeptidase degradation leading to decreased bioactivity, while simultaneously having low affinity for the natriuretic peptide clearance receptor (NPR-C). Following non-enzymatic hydrolysis of CNP from the proprietary TransCon Linker, the CNP molecule regains full bioactivity.

The pharmacokinetic (PK) profile of TransCon CNP was investigated following the administration of single and multiple doses to cynomolgus monkeys. Further, cynomolgus monkeys were surgically implanted with a telemetry device and given single escalating doses while a detailed hemodynamic assessment was performed.

Results

As predicted from in vitro results, TransCon CNP in cynomolgus monkeys exhibited a long half-life, supporting the use of TransCon CNP for once-weekly dosing. In cynomolgus monkeys, no clinical signs or hemodynamic effects were detected at TransCon CNP doses up to 100 µg CNP/kg/week (highest dose tested). This was in contrast to daily CNP, which at an equivalent dose led to hypotension.

Conclusion

TransCon CNP exhibits a substantial half-life extension compared to daily CNP analogues, supporting once weekly dosing in humans. The favorable PK profile was obtained by shielding CNP from enzymatic degradation and reducing receptor-mediated clearance. Prolonged drug exposure of TransCon CNP combined with low peak serum concentrations may widen the therapeutic window and decrease the risk of hypotension, thereby improving efficacy and tolerability; nonclinical studies in cynomolgus monkeys support weekly dosing in humans.

 

Disclosure: KS: Employee, Ascendis Pharma. CER: Employee, Ascendis Pharma. UH: Employee, Ascendis Pharma. VMB: Employee, Ascendis Pharma.