ETX001 is a potentiator of a chloride channel called TMEM16A. Because TMEM16A’s production and function are independent of CFTR — the protein that is deficient in CF patients — the findings validate TMEM16A’s activation as a potential therapy for all CF patients, regardless of CFTR mutation.
The study, “TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis,” was published in the American Journal of Respiratory and Critical Care Medicine.
CF is caused by mutations in the CFTR gene resulting in a deficient CFTR protein. The protein acts as a channel involved in the regulation of salt and water transport in and out of cells, and the deficiency results in thick, sticky secretions and mucus that are poorly removed from the airways (impaired mucus clearance), leading to chronic bacterial infections and a progressive loss of lung function.
While most CF-specific therapies target CFTR’s function, they do not cover all CFTR mutations, meaning that some patients are not eligible for these therapies.
The activation of other channels controlling the amount of salt and water in the airways has been thought to be a potential therapeutic strategy for improving mucus hydration and clearance in all CF patients. TMEM16A, a calcium-dependent chloride channel present in airway cells, is one of these candidates.
Enterprise, along with researchers in the U.K. and the U.S., validated this hypothesis by boosting TMEM16A’s activity through ETX001, a newly discovered and optimized compound.
The compound was first identified through the screening of large chemical libraries for positive modulators of TMEM16A, and was then optimized to promote a potent activation of TMEM16A.
Researchers evaluated the effects of ETX001 in CF patients’ airway cells grown in the lab, and in a sheep model of impaired mucus clearance.
Exposing airway cells from CF patients to ETX001 increased the cells’ fluid secretion, specifically through calcium-dependent chloride TMEM16A channels. ETX001’s effects were independent of inflammation, which was previously proposed to increase TMEM16A activity.
ETX001 treatment, delivered through inhalation, also promoted mucus clearance both in healthy sheep and in sheep with impaired mucus clearance.
“These data support the concept of positive modulation of TMEM16A as a target for respiratory diseases [characterized by mucus obstruction] and that compounds such as ETX001 represent therapeutic candidates for clinical development,” the researchers wrote.
Boosting the activation of TMEM16A holds promise as a non-CFTR mediated approach for the treatment of CF, which can be delivered alone or in combination with CFTR-targeted therapies, the data suggest.
“Given the percentage of the population of CF patients who are not genetically matched to existing CFTR repair therapies, this paper builds a strong case for testing TMEM16A potentiation in the clinic,” Henry Danahay, MD, Enterprise’s head of biology and the study’s lead author, said in a press release.
This work was partly funded by an award given to Enterprise by the Cystic Fibrosis Foundation. The grant of up to $7 million is intended to support the clinical development of a TMEM16A potentiator up to the end of Phase 2 clinical trials.
Enterprise is also evaluating other potential non-CFTR therapies, including those targeting ENaC — a sodium transport channel that is overactivated in the lungs of people with CF — and those focused on cells that produce mucus, with the aim of lessening mucus production and complementing mucus hydration therapies.
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