Enterprise Therapeutics awarded up to £5.7M ($7M) from Cystic Fibrosis Foundation to Support Clinical Development of Novel Chloride Channel Modulator

  • Support for clinical development up to end of Phase 2 for ETD002, first-in-class TMEM16A potentiator for the treatment of cystic fibrosis
  • Milestone Funding through Cystic Fibrosis Foundation’s Therapeutics Development Award programme

Brighton, UK, 15 October 2019: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of patients suffering with respiratory disease, today announced it has been awarded up to £5.7M ($7M) funding under the Therapeutics Development Award programme from the Cystic Fibrosis Foundation. The milestone-related funding will support clinical development up to the end of Phase 2 for ETD002 – a first-in-class TMEM16A potentiator that has the potential to treat all persons with cystic fibrosis (CF), independent of their cystic fibrosis transmembrane conductance regulator (CFTR) genotype.

Enterprise Therapeutics is developing novel disease-modifying therapies which target underlying mechanisms of mucus congestion, enhancing the clearance of mucus from the airways, thereby restoring lung function and to reduce morbidity and mortality in CF. The Company’s first-in-class ETD002 programme is targeting the calcium-activated chloride ion channel TMEM16A. By enhancing the activity of TMEM16A, there is increased anion and fluid flow into the airways, thinning the mucus and increasing its clearance from the airways.

CF is a devastating and life-limiting genetic disease. CF patients have a significant reduction in the hydration of their airway mucus, leading to failed clearance, a high incidence of infections, and rapid decline in lung function.

Dr John Ford, CEO, Enterprise Therapeutics, said:

“We are delighted to receive such a significant award from the CF Foundation. This funding will enable critical clinical research to be undertaken on our novel TMEM16A programme, and highlights the potential of chloride channel modulation via alternative channels to deliver innovative and effective treatments for all CF patients.”

ECFS Clinical Meeting Liverpool TMEM16A potentiator

ECFS Clinical Meeting Liverpool TMEM16A potentiator

Objectives: TMEM16A (ANO1) is a Ca2+-activated, alternative chloride channel expressed in the human airway epithelium. A potentiator of TMEM16A is predicted to enhance the secretion of chloride and thereby increase mucus hydration and clearance in the CF lung. Our aim is to discover and test the efficacy of novel TMEM16A potentiator compounds as a new therapeutic option for the treatment of CF lung disease.

Methods: Four, parallel high-throughput screening approaches were used to identify novel TMEM16A potentiator compounds. Compounds were then optimised and tested in primary CF bronchial epithelial cells for effects on both ion transport and airway surface liquid secretion.

Results: Several classes of TMEM16A potentiators were identified from the high-throughput screens. Only compound series that potentiated TMEM16A activity in a patch-clamp electrophysiology assay and which had no effect on intra-cellular Ca2+, were progressed for lead optimization. Pre-treatment of CF-HBE with TMEM16A potentiators for between 5 min to 96h resulted in an enhancement of Ca2+-mediated anion-secretory responses that were sensitive to the TMEM16A blocker, Ani9. Measurements of [Ca2+]i confirmed that TMEM16A potentiators had no effect on calcium mobilization, consistent with a direct effect on the channel. A Series 1 TMEM16A potentiator, ETX001, increased the secretion of airway surface liquid (ASL) in CF-HBE. The ETX001-driven increase in ASL height was further enhanced in cells that had been pre-treated with IL-13 to boost TMEM16A expression. A close structural analogue of ETX001, ETX002, that is inactive on TMEM16A, did not increase ASL height.

Conclusions: Together, these data support the concept that potentiators of the alternative airway chloride conductance, TMEM16A, can restore anion conductance and fluid secretion in both primary CF cells. Enterprise Therapeutics are advancing TMEM16A potentiators into clinical development.

A systematic comparison of the profiles of inhaled ENaC blocker candidates on mucociliary clearance: are we under-dosing in clinical studies?

A systematic comparison of the profiles of inhaled ENaC blocker candidates on mucociliary clearance: are we under-dosing in clinical studies?

Henry Danahay1, Clive McCarthy1 and Martin Gosling1

1Enterprise Therapeutics, UK

Objectives: Recent clinical studies with ENaC modulator compounds have challenged the validity of the target for treating CF lung disease. Our aim was to establish retrospective human dose predictions for several of these compounds to understand whether this might be a factor in the failure of the clinical studies to show benefit.

Methods: ENaC modulators used in recent CF clinical studies were assessed in a sheep model of mucociliary clearance (MCC) and were compared with ETD001, a novel, non-amiloride based inhaled ENaC blocker (Enterprise Therapeutics), entering clinical development in 2019. Test compounds were administered directly into the sheep airways by aerosolization and MCC was measured by gamma-scintigraphy between 4-6h after the completion of dosing. Using the dose required to achieve a maximal increase in MCC in the sheep, an estimated ‘minimal effective clinical dose’ was calculated for each ENaC modulator.

Results: Each of the compounds studied induced a dose-dependent increase in MCC, typically reaching a maximum of between 20-25% clearance of the 99mTc-sulfur colloid tracer. Combining the predicted clinical dose (based on the sheep MCC model) with the actual dose/nebuliser used in the respective clinical study (www.clintrials.gov), suggests that all the ENaC modulators tested in the clinic to date have potentially been under-dosed by as much as 90%. This analysis further assumes that the healthy sheep airways in the MCC model predict for a clinical dose in a CF lung on a 1:1 basis. If a CF lung requires a higher dose than a sheep airway, the potential for under-dosing increases.

Conclusions: The pre-clinical safety profile of ETD001 currently enables doses of between 30-40x above the minimum predicted clinically efficacious dose to be tested in clinical studies. This profile provides a good opportunity to test the ENaC therapeutic hypothesis and ultimately provide a new therapy for CF patients.

Something old and something new: ENaC & TMEM16A as targets to hydrate mucus in the CF airway

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.