In “Achondroplasia: A view to the future options emerging from the benchside”, Narayana, J., Horton, W.A, 2013, there is a very interesting point that reflects the challenges of bringing FGFR3-based therapies to the bedside.
“Despite the considerable recent progress in the development of strategies to treat achondroplasia with drugs, there remain significant barriers to their implementation. The greatest challenge may be the ethical considerations of conducting long-term clinical trials in children who do not have a terminal illness. Thus, any potential treatment must be thoroughly tested in preclinical models and prove safe and effective for children. Even when efficacy and safety are established, performing pharmacodynamic and pharmacokinetic studies to optimize treatment protocols in children is challenging because growth and metabolic rates vary by age and developmental stage.
These factors all complicate the design of clinical trials of potential drugs, as does the relative rarity of the condition, which hinders recruitment. Another complicating factor is the inherent slowness of bone growth; without the benefit of biomarkers or other indicators that accurately reflect linear bone growth, many months are typically required to demonstrate increased bone growth velocity during a therapeutic trial.
Receptor and tissue specificity is another issue. Clearly, a drug that acts only on FGFR-3 in growing bones has advantages over drugs that poorly distinguish FGFR-3 signaling activity from that of other FGFRs, or target FGFR-3 activity in tissues unrelated to bone growth. In the first case, drugs such as CNP (like BMN-111 that target signaling pathways down-stream of FGFR-3 not known to be utilized by other FGFRs may have fewer side effects related to suppression of other FGFRs than tyrosine kinase inhibitors and antisense strategies that lack complete selectivity for FGFR-3.
However, such drugs may be more likely to disturb functions of other receptors and signaling pathwaysthat are modulated by CNP. At this point in time, these questions are largely theoretical, but they will need to be addressed in the future.”
Questions to keep in mind.