Achondroplasia is a serious growth disorder for which there is currently no FDA-approved therapy, presenting a high unmet medical need. Achondroplasia results from an autosomal dominant mutation that causes an increase in signaling in the FGFR3 pathway. This pathway has a negative effect on chondrocyte growth and thus bone growth. C-Type Natriuretic Peptide (CNP) is a target for drug therapy, as downstream signaling of CNP inhibits the FGFR3 pathway and promotes proliferation and differentiation of the chondrocytes, resulting in bone growth. High levels of CNP in humans are associated with skeletal overgrowth; in addition, CNP has been shown to reverse the achondroplasia phenotype in animal models.
Once-weekly TransCon CNP leverages the TransCon technology platform to develop a long-acting CNP for achondroplasia. TransCon CNP is being investigated as a once-weekly prodrug to provide continuous exposure to CNP to potentially improve efficacy, safety and/or convenience over first-generation CNP analogues.
TransCon technology has the potential to offer solutions to challenges of developing long-acting CNP:
- To obtain growth velocity, CNP needs to have a long enough half-life and maintain a small enough size to penetrate into growth plates
- Achieve effective shielding of CNP from neutral endopeptidase degradation in subcutaneous tissue and the blood compartment
- Minimize binding of CNP to the NPR-C receptor to decrease clearance
- Reduce binding of CNP to vascular NPR-B receptors to avoid hypotension caused by activation of this receptor
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 CNP.
Building on these positive results, Ascendis Pharma plans to submit an Investigational New Drug Application for TransCon CNP in the fourth quarter of 2017.
Achondroplasia is the most common form of human dwarfism. It is a skeletal disease characterized by an average-size trunk and short limbs. In patients with this condition, disproportionate growth between endochondral bone and underlying organs can lead to a number of orthopedic, neurological, respiratory, ear, nose and throat (ENT) and dental issues. Spinal stenosis, foramen magnum stenosis, ear infections, scoliosis and joint problems are common.