A triple combination of dirocaftor (PTI-808), Proteostasis Therapeutics’ investigational CFTR potentiator, with a proprietary CFTR amplifier and corrector led to significant improvements in lung function in patients with cystic fibrosis (CF) carrying the F508del mutation, according to topline data from a Phase 2 trial.
CF is a genetic disorder caused by mutations in the CFTR gene, which provides instructions to make the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although several mutations can cause CF, the F508del mutation is the most common, with up to 90% of CF patients worldwide estimated to carry at least one copy of this mutation.
In people with CF, the F508del mutation leads to the incorrect folding and premature degradation of the CFTR protein, effectively preventing it from reaching the cell membrane and performing its normal function of transporting molecules and water in and out of cells.
Over the past few years, several therapies designed to correct the defects caused by mutations in the CFTR gene, known as CFTR correctors, have been developed. These medications have been found to be more effective when used in combination with CFTR potentiators and amplifiers.
The safety, tolerability, and efficacy of dirocaftor (PTI-808), an experimental CFTR potentiator, is being tested in a Phase 2 trial in combination with one or two other CFTR modulators, also developed by Proteostasis, in adults with CF carrying the F508del mutation.
A total of 68 adults with CF, including 28 carrying two copies of the F508del mutation and 40 carrying a single copy of the mutation, were enrolled in the trial. Following enrollment, participants were assigned to receive a daily combination treatment of dirocaftor (300 mg) and posenacaftor (PTI-801; 600 mg), with or without nesolicaftor (PTI-428; 10 mg), or a placebo, over four weeks.
Among those carrying two copies of the F508del mutation, the triple combination therapy led to stronger improvements in lung function (measured by the percentage predicted forced expiratory volume in 1 second, ppFEV1), and in the levels of sweat chloride (a measure of CFTR activity) compared to the double combination therapy.
In this group of patients, the triple combination therapy led to a mean absolute improvement of eight percentage points in ppFEV1, and to a mean reduction of 29 mmol/L in the levels of sweat chloride, compared to the placebo at day 28.
Improvements in lung function were also found to be higher among those with high disease burden, which included those whose ppFEV1 was lower than 70% at baseline, those who had had at least two exacerbations in the year before enrolling in the study, and those who responded poorly to previous treatment with other CFTR modulators.
Among those carrying one copy of the F508del mutation, the effects of the triple combination therapy on patients’ lung function and sweat chloride levels were more variable. The effects of treatment on lung function ranged from a decrease of 13 to an increase of 20 percentage points in ppFEV1, while sweat chloride levels ranged from a reduction of 79 mmol/L to an increase of 12 mmol/L.
All experimental compounds were found to be generally safe and well-tolerated, with the majority of reported adverse events being mild or moderate in severity.
“Evidenced by the variability of subject response and tolerability to currently approved CFTR modulators, it remains clear that the CF community is in need of additional CFTR modulator options,” Jennifer Taylor-Cousar, MD, professor of medicine and pediatrics, and co-director and CF Therapeutics Development Network Center Director of the Adult CF Program at National Jewish Health, said in a press release.
“The latest data from the dirocaftor, posenacaftor and nesolicaftor combination suggests that, even in a population with high disease burden and including subjects who were not eligible for studies of currently approved CFTR modulators, this triple combination demonstrated remarkable outcomes across key study endpoints and performed well in the most challenging disease settings,” Taylor-Cousar added.
Based on these promising findings, Proteostasis is planning to launch a global, randomized, placebo-controlled, Phase 3 study called MORE (Modulator Options to RestorE CFTR study) to investigate the effects of the triple combination therapy in a larger group of CF patients carrying two copies of the F508del mutation. This trial should start in the beginning of next year.
In parallel, the company will also launch the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF – Efficacy Study), which is designed to evaluate if positive organoid ex-vivo responses may be translated to potential clinical benefit in CF patients carrying rare CFTR mutations. CHOICES will be the first study based on personalized medicine to be performed in CF patients.
“We look forward to advancing our triple combination into a pivotal study next year, while simultaneously pursuing a personalized medicine clinical and regulatory pathway,” said Geoffrey Gilmartin, MD, chief medical officer of Proteostasis.
“We are very grateful to the patients, their families and healthcare providers who have supported [Proteostasis] in our pursuit of delivering more choices to people with CF, and to providing the benefit of CFTR modulators to all, regardless of mutation status,” he added.