A phase 2 trial of Enterprise Therapeutics’ cystic fibrosis (CF) drug candidate has hit its primary endpoint, furthering the biotech’s pursuit of a target that companies including Vertex have worked on previously.
U.K.-based Enterprise enrolled 57 people with CF across the two-part trial. After assessing safety and tolerability in the first part of the study, the biotech randomized patients to receive ETD001 or placebo to evaluate the effect of its inhaled ENaC blocker on lung function. Patients took ETD001 or placebo twice daily for 27 days, followed by one dose on Day 28 before the assessment of the primary endpoint.
Enterprise saw a statistically significant 3.4-percentage-point improvement in lung function, as measured by ppFEV1, in people taking ETD001 compared to placebo, hitting its primary endpoint. An exploratory analysis showed that patients were three times more likely to improve ppFEV1 when receiving ETD001 compared to placebo.
The level of improvement is below the improvement seen in studies of CFTR modulators—where Vertex has reported double-digit jumps—but Enterprise is targeting the 10% of CF patients who are ineligible for such drugs. The biotech excluded patients who had received CFTR modulator therapy in the 60 days before screening.
Patients who are ineligible for drugs such as Vertex’s Alyftrek lack disease-modifying therapies, leading to declining lung function and worse outcomes than for people treated with CFTR modulators. Leading drug developers have flagged ENaC inhibitors as a way to help patients without the mutations that make CFTR modulation viable. Yet, after a flurry of activity about a decade ago, the ENaC inhibitor field faded.
Vertex paid Parion Sciences $80 million upfront for rights to ENaC inhibitors in 2015, only to cut (PDF) its ties to programs five years later. In 2023, Parion outlined (PDF) plans to start a phase 3 trial in primary ciliary dyskinesia, but the biotech hasn’t published a press release since then. Parion ran phase 2 trials of the asset in cystic fibrosis during the Vertex partnership.
Boehringer Ingelheim took another ENaC inhibitor into phase 2. However, the drugmaker terminated development after failing to show the potential for clinical benefit in the midphase cystic fibrosis study. AstraZeneca ended development of its ENaC inhibitor after seeing data from phase 1 and phase 1b trials.
Novartis’ candidate never made it past a phase 1/2 trial that was terminated over “resource issues.” The ENaC inhibitor didn’t have “a meaningful effect on how easily participants could breathe compared to the placebo,” Novartis said (PDF), although the small size of the study precluded firm conclusions.
The investigators in Boehringer’s trial named inadequate dosing and bronchiolar deposition as problems that may have caused earlier ENaC inhibitor studies to fail. While Boehringer took steps to avoid those pitfalls, the investigators admitted that the dose and duration of Boehringer’s inhaled ENaC inhibitor may have fallen short of the level needed to drive therapeutic benefits.
Enterprise compared ETD001 to earlier ENaC inhibitors in sheep to evaluate its chances of succeeding where others stumbled. Having designed ETD001 to be retained in the airways following inhaled dosing, the biotech reported a single low dose enhanced mucus clearance in sheep airways for at least 16 hours. The readout convinced Enterprise that the candidate has the long duration of action needed to succeed.
With 28-day data in hand, the company plans to run longer phase 2b dose-ranging trials and assess the effect of giving ETD001 in combination with CFTR modulators. A trial in non-CF bronchiectasis is also on Enterprise’s to-do list.