Inhaled therapy ETD001 well tolerated in healthy volunteers
Phase 1 trial data also indicate prolonged exposure of drug to lungs
ETD001, Enterprise Therapeutics’ inhaled investigational therapy to improve mucus clearance in people with cystic fibrosis (CF) — regardless of the underlying CF-causing mutation — was well tolerated in healthy individuals at doses higher than those predicted to be therapeutic, a study showed.
The now-complete Phase 1 safety study (NCT04926701) also showed the inhaled drug was slowly absorbed from the lungs into the bloodstream, indicating prolonged airway exposure.
Researchers noted that ETD001, at any tested dose, did not alter blood potassium levels, a common side effect associated with other therapies that have the same mechanism of action.
“We are passionate about working [toward] treatments that will benefit all people with cystic fibrosis and are excited to publish these promising results from our Phase 1 trial,” Henry Danahay, PhD, head of biology at Enterprise and the study’s lead author, said in a company press release.
Meanwhile, Enterprise recently completed a Phase 2 trial (NCT06478706) investigating whether 28 days of ETD001 treatment improves lung function in 57 adults with CF. Interim data is expected early next year.
Phase 1 data were reported in the study, “ETD001, a long-acting inhaled ENaC blocker, is well tolerated in a first human, healthy participant trial,” published in the Journal of Cystic Fibrosis.
EDT001 takes different approach by targeting key protein
CF is caused by mutations that result in absent or faulty production of the CFTR protein. Because CFTR normally helps regulate the water content of mucus, its loss leads to thick, sticky mucus that accumulates in various organs, driving a wide range of symptoms.
CFTR modulators are therapies designed to boost the function of defective CFTR proteins. Although transformative for many people, these therapies don’t work for those with certain CF-causing mutations, while others are unable to tolerate the side effects.
“There is an urgent need for new therapies to treat mucus obstruction in the lungs of people with CF, and especially those who are genetically unsuited to CFTR modulators,” Danahay said.
EDT001 takes a different approach by targeting the epithelial sodium channel, a protein that also contributes to the balance of water and mucus on cell surfaces. By blocking this channel, the therapy aims to increase the water content of mucus, thereby independently counteracting CFTR deficiency, regardless of the specific CFTR mutation.
Last year, EDT001 received rare pediatric disease designation from the U.S. Food and Drug Administration. This designation supports the development of treatments for serious, rare pediatric diseases in the U.S.
Single dose found safe, with no adverse events
The therapy was first tested in sheep, demonstrating that low doses of inhaled EDT001 remained active for more than 16 hours, which was longer than expected, and helped clear mucus from the airways.
Enterprise then launched the first-in-human Phase 1 study to assess EDT001’s safety, tolerability, and pharmacokinetics — the movement of the drug into, through, and out of the body — in 98 healthy adult volunteers.
Part A of the study was a single-ascending-dose assessment, in which 14 participants received a single inhaled placebo dose and 42 received a single inhaled ETD001 dose ranging from 0.06 mg to 10.8 mg.
ETD001 was safe and well tolerated, with no serious adverse events or treatment-related withdrawals. No clinically significant changes or dose-related trends were observed in laboratory tests, vital signs, or cardiac and pulmonary function.
No changes in potassium levels were detected across the evaluated doses. This finding is important because other experimental therapies that block the epithelial sodium channel have been associated with elevated potassium, known as hyperkalaemia, the team noted.
Multiple-dose design also yielded positive results
Part B of the study employed a multiple-ascending-dose design, in which 11 participants received a placebo, and 31 participants received an ETD001 dose of 0.6 mg to 4.65 mg twice daily for up to 14 days.
Nearly half of the participants (45.2%) experienced at least one treatment-emergent adverse event (TEAE); all were mild or moderate, and none were serious. ETD001 was generally well tolerated, with no dose-related trends or differences in severity across groups.
The most common TEAEs were general disorders/administration site conditions (14.3%) and nervous system disorders (11.9%), with headache the most frequent event (9.5%). Chest discomfort occurred in three participants (7.1%). One mild case following a 1.55 mg dose of ETD001 was considered possibly related and resolved within eight hours without treatment.
In general, there were no dose-related trends in laboratory tests, vital signs, or cardiac and pulmonary function. Although the mean blood potassium levels were higher in ETD001-treated groups than in the placebo group, no cases of hyperkalaemia were reported.
he results from this Phase 1 study highlight that ETD001 is well tolerated at doses up to and including 4.65 mg [twice daily] for 14 days with no evidence of significant accumulation.
In contrast to earlier inhaled epithelial sodium channel blockers, ETD001 demonstrated a pharmacokinetic profile after inhalation characterized by slow absorption from the lung into the bloodstream, indicating prolonged retention in the lungs and the potential for an extended duration of action.
Urinary excretion of ETD001 occurred in all cases, with kidney clearance consistent across doses, study days, and between single- and repeat-dose phases.
“The results from this Phase 1 study highlight that ETD001 is well tolerated at doses up to and including 4.65 mg [twice daily] for 14 days with no evidence of significant accumulation,” the researchers wrote. “The drug shows a slow absorption from the lung into the circulation that is consistent with a prolonged residence time in the airways.”
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