Treatment with ABBV-2222, an investigational CFTR corrector formerly known as GLPG2222, was well-tolerated and partially corrected the function of the CFTR protein, both alone and in combination with Kalydeco (ivacaftor), in a group of patients with cystic fibrosis (CF), Phase 2 clinical trials show.
Trial findings were published in the study, “CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials,” in the Journal of Cystic Fibrosis.
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. This protein is transported to the cell membrane where it works as a channel for molecules, such as chloride and water, to move in and out of cells.
The F508 deletion is the most common mutation associated with the disease, in which a single amino acid (the building blocks of proteins) is deleted from the CFTR protein sequence at position 508. This leads to incorrect protein folding and premature protein degradation, which prevent CFTR from reaching the cell membrane and performing its function.
ABBV-2222, a therapy originally developed by Galapagos and Abbvie, is a CFTR corrector that helps abnormal CFTR protein fold correctly, so it won’t be destroyed by cellular agents and will be safely transported to the cell membrane, resulting in an increase in chloride transport.
In the study, the researchers reported the findings of two randomized, double-blind, placebo-controlled Phase 2a clinical trials — FLAMINGO (NCT03119649) and ALBATROSS (NCT03045523) — assessing the safety and efficacy of ABBV-2222, either alone or in combination with Kalydeco (marketed by Vertex Pharmaceuticals), in a group of CF patients.
In both studies, patients carrying either one (ALBATROSS) or two (FLAMINGO) copies of the F508 deletion took ABBV-2222 orally once a day for 29 days. Patients participating in the ALBATROSS trial were also carriers of another gating mutation in CFTR, and were being treated with Kalydeco.
The trials’ primary outcome was to assess the treatment’s tolerability and safety. Secondary goals included assessing the pharmacokinetic properties of the compound, meaning how the therapy is absorbed, distributed, metabolized, and eliminated from the body, as well as the effects of ABBV-2222 on sweat chloride, patients’ lung function, and respiratory symptoms.
Sweat chloride concentrations are considered a biomarker of CF severity — the higher the levels of chloride in a patient’s sweat, the more severe the disease.
A total of 59 patients were enrolled in FLAMINGO and 37 into ALBATROSS.
Results showed that treatment with ABBV-2222 led to a significant reduction in patients’ sweat chloride concentrations (maximum decrease of 17.6 mmol/L in FLAMINGO, and 7.4 mmol/L in ALBATROSS), indicating that ABBV-2222 at least partially corrected the function of the CFTR protein.
However, no significant improvements were found in patients’ lung function, nor in their respiratory symptoms. The pharmacokinetic profile of ABBV-2222 in both trials was consistent with previous studies on healthy volunteers and CF patients.
Treatment-related adverse events were reported in 29.2% of patients in FLAMINGO and 40% in ALBATROSS. Most were mild to moderate in severity, and included respiratory, gastrointestinal, and infection complications. No deaths or therapy discontinuation associated with treatment adverse events were reported in any of the trials.
“Findings from FLAMINGO and ALBATROSS demonstrated that GLPG2222 is well tolerated both alone and in combination with [Kalydeco], with preliminary data suggesting partial correction of CFTR function and on-target activity. These outcomes will inform the future clinical evaluation of GLPG2222 within this dynamic environment, in particular with regards to its use in combinations with additional CFTR modulators,” the researchers wrote.