With little in the clinical pipeline for achondroplasia beyond BioMarin Pharmaceutical Inc.’s late-stage vosoritide, startups Therachon AG and BioClin Therapeutics Inc. are rethinking how to tackle the disease. By targeting FGFR3 directly, the two companies think they can block a signal vosoritide misses, and produce compounds that have better efficacy and require less frequent dosing.
The field appears poised for an uptick of activity, triggered by BioMarin’s positive Phase II data and recent publications that validate the FGFR3 biology underlying the disorder.
Achondroplasia is the most common form of short-limb dwarfism, and is caused by a single point mutation in FGFR3 that constitutively activates the receptor and inhibits bone growth. The treatment landscape involves either painful limb-lengthening surgery or, typically, a one-year course of human growth hormone, which has limited benefit.
BioMarin’s approach is to block a downstream mediator in the FGFR3 pathway that is responsible for chondrocyte growth. Its candidate, vosoritide, is a stable analog of the peptide agonist CNP that acts via the cell surface receptor NPR2 to inhibit a ras-driven cascade downstream of FGFR3. In December, BioMarin initiated a Phase III trial of vosoritide in patients aged 5-14.