Phase 2 Results of CFTR Potentiator Show Evidence of Comparable Efficacy to Kalydeco

Galapagos NV recently reported positive topline results from SAPHIRA 1, a Phase 2 clinical trial assessing the company’s potentiator molecule, GLPG1837, in patients with cystic fibrosis (CF) who have the G551D mutation. Data showed results comparable to an approved CF treatment, the company announced.

SAPHIRA 1 (NCT02707562) was an open-label, four-week clinical trial testing three successive doses of GLPG1837 in 26 CF patients with the G551D mutation. The molecule is being considered as part of a triple combination therapy that Galapagos, together with AbbVie, are working to develop to treat almost all CF cases, regardless of underlying mutation.

Primary endpoints included the safety and tolerability of GLPG1837, and secondary endpoints included the drug’s effectiveness and properties as determined through changes in sweat chloride from baseline — sweat chloride being a measure of the function of the CFTR ion channel (which is defective in CF patients) — and of changes in pulmonary function (forced expiratory volume in one second [FEV1]) from baseline.

The study included 25 subjects who have been treated with Kalydeco (ivacaftor), a U.S. Food and Drug Administration-approved CF treatment, and one patient naïve to the drug. Patients on Kalydeco underwent a one-week washout period before starting treatment with GLPG1837.

All patients received GLPG1837 at 125 mg (twice-daily) for seven days, at 250 mg for another seven days, and at 500 mg for the final 14 days of treatment.

The results showed that the treatment resulted in a statistically significant dose-dependent decrease in sweat chloride concentration, with the 500 mg dose level registering a drop from 98 mmol/L at baseline to 66 mmol/L at nine weeks.

Patients on Kalydeco treatment started the study — pre-washout phase — with an average percent predicted FEV1 (ppFEV1) level of 74 percent. Immediately following the one-week washout, these patients had a 5.4 percent mean decrease in absolute ppFEV1 levels. Upon completion of GLPG1837 treatment, results found their ppFEV1 levels had again returned to pre-washout levels.

Regarding safety, the company reported that GLPG1837 was well-tolerated. Treatment-related adverse events were mild to moderate, and typical for a CF patient population. One patient left from the trial due to an increase in non-cardiac creatine phosphokinase (an enzyme that, when at increased levels, might mean that the person may have brain injury, pulmonary infarction, or other life-threatening conditions).

“The success of this trial is an important milestone in two regards; firstly, GLPG1837 has shown safety and significant efficacy as a novel CFTR potentiator. Secondly, it demonstrates that the CF community is committed to the further development of CFTR modulators despite the complexities related to evolving standards of care,” Jane Davies, with the Royal Brompton & Harefield NHS Trust in London and principal investigator for SAPHIRA 1, said in a press release.

“The SAPHIRA 1 results show this is the first new potentiator since Kalydeco to demonstrate competitive results in patients harboring the G551D mutation. … Galapagos and AbbVie will further study the data before deciding which potentiator will be included in the triple combination,” Piet Wigerinck, CSO of Galapagos, said. “The clinical validation of our in vitro systems reinforces our belief in our approach to get to a triple combination therapy.”

CF is triggered by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in abnormal transport of chloride across cell membranes. Normally, the CFTR channel transports chloride ions to the outside of the cell, but mutant CFTR does not, leading to the build-up of a sticky mucous.

Galapagos and AbbVie entered into an alliance in 2013 to develop a triple CFTR combination therapy that might treat 90% of all CF patients.