Something old and something new: ENaC & TMEM16A as targets to hydrate mucus in the CF airway
Henry Danahay, Enterprise Therapeutics, Brighton, UK
In the absence of functional CFTR in the apical membrane, the epithelial sodium channel (ENaC) and TMEM16A, a calcium activated chloride channel, are key regulators of airway mucosal hydration. As drug targets, both ENaC blockers and TMEM16A potentiators would provide an opportunity to treat CF patients who are unsuitable for CFTR repair therapies.
Inhaled ENaC blockers are predicted to attenuate fluid absorption out of the airway mucosa and improve mucus clearance. Clinical studies using the ENaC blocker amiloride, were first reported >30 years ago although since then novel inhibitors have failed to deliver efficacy in Phase 2. In contrast, positive modulators of TMEM16A as an alternative anion conductance to compensate for the loss of CFTR function in the airway epithelium are only now becoming available to begin to ask whether this mechanism could provide adequate anion and fluid secretion to hydrate airway mucus.
Why have novel, inhaled ENaC blockers failed to deliver any clinical benefit in Phase 2 studies? Is ENaC simply just not a good target for restoring mucus hydration or have we not developed the right drug candidates yet? Human genetics would support the negative regulation of ENaC as being a core mechanism by which to enhance mucus clearance, in which case the drug candidates are presumably the issue. To this end, we have evaluated the in vivo potency and efficacy of several ENaC blockers that have entered clinical development. A common finding is that doses used for the clinical studies are low when compared to the predicted ‘minimally efficacious dose’ derived from the pre-clinical dose-response relationships. This may be because of safety concerns commonly associated with ENaC blockers, specifically the potential for inducing hyperkalaemia as a side effect of ENaC block in the kidney. Moving forward, perhaps we should consider advancing only candidates with a broader safety window, offering the potential to dose significantly higher than a predicted minimally efficacious dose? Furthermore, clinical studies to confirm target engagement and duration of action would help to understand whether ENaC does represent a meaningful target to inhibit and thereby restore mucus hydration.
TMEM16A-based drug discovery is at a much earlier stage. High-throughput screening has identified novel potentiators of the channel. These compounds do not directly open the channel but rather ‘sensitize’ it to elevations in [Ca2+]i under the control of normal physiology. We can demonstrate that TMEM16A potentiators will enhance airway epithelial anion and fluid secretion and improve mucus clearance with the opportunity to treat patients currently unsuitable for CFTR repair drugs.