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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 370; no. 3; pp. 459 - 471
• Main Authors: Breinholt, Vibeke Miller, Rasmussen, Caroline E., Mygind, Per Holse, Kjelgaard-Hansen, Mads, Faltinger, Frank, Bernhard, Ana, Zettler, Joachim, Hersel, Ulrich
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Achondroplasia - drug therapy; Achondroplasia - epidemiology; Achondroplasia - metabolism; Achondroplasia - physiopathology; Amino Acid Sequence; Animals; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone and Bones - physiopathology; Bone Development - drug effects; Bone Remodeling - drug effects; Comorbidity; Delayed-Action Preparations; Macaca fascicularis; Male; Mice; Natriuretic Peptide, C-Type - adverse effects; Natriuretic Peptide, C-Type - metabolism; Natriuretic Peptide, C-Type - pharmacokinetics; Natriuretic Peptide, C-Type - pharmacology; NIH 3T3 Cells; Prodrugs - metabolism; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Safety; Tissue Distribution; Tomography, X-Ray Computed; LLOQ; SAP; CNP; CTX; cGMP; HR; WCX; BP; QC; OC; vBMD; BMD; DSI; HPLC; PINP; ACH; RIA; BAP; VOI; HPLC-MS/MS; NTx; PEG; NPR-B; NPR-C; NEP; PK; FGFR3; MAP
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.119.258251

TransCon CNP is a C-type natriuretic peptide (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic CNP levels upon weekly subcutaneous administration. TransCon CNP is in clinical development for the treatment of comorbidities associated with achondroplasia. In both mice and cynomolgus monkeys, sustained exposure to CNP via TransCon CNP was more efficacious in stimulating bone growth than intermittent CNP exposure. TransCon CNP was well tolerated with no adverse cardiovascular effects observed at exposure levels exceeding the expected clinical therapeutic exposure. At equivalent dose levels, reductions in blood pressure and/or an increase in heart rate were seen following single subcutaneous injections of the unconjugated CNP-38 molecule or a daily CNP-39 molecule (same amino acid sequence as Vosoritide, USAN:INN). The half-life of the daily CNP-39 molecule in cynomolgus monkey was estimated to be 20 minutes, compared with 90 hours for CNP-38, released from TransCon CNP. Cmax for the CNP-39 molecule (20 µg/kg) was approximately 100-fold higher, compared with the peak CNP level associated with administration of 100 µg/kg CNP as TransCon CNP. Furthermore, CNP exposure for the daily CNP-39 molecule was only evident for up to 2 hours postdose (lower limit of quantification 37 pmol/l), whereas TransCon CNP gave rise to systemic exposure to CNP-38 for at least 7 days postdose. The prolonged CNP exposure and associated hemodynamically safe peak serum concentrations associated with TransCon CNP administration are suggested to improve efficacy, compared with short-lived CNP molecules, due to better therapeutic drug coverage and decreased risk of hypotension. The hormone C-type natriuretic peptide (CNP) is in clinical development for the treatment of comorbidities associated with achondroplasia, the most common form of human dwarfism. The TransCon Technology was used to design TransCon CNP, a prodrug that slowly releases active CNP in the body over several days. Preclinical data show great promise for TransCon CNP to be an effective and well-tolerated drug that provides sustained levels of CNP in a convenient once-weekly dose, while avoiding high systemic CNP bolus concentrations that can induce cardiovascular side effects.