How ABBV-2222 works
CF is a heritable disease caused by mutations in the CFTR gene. This gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), which transports chloride ions across cell membranes. Mutations in the CFTR gene cause the protein to be made incorrectly, or not at all. Without CFTR, chloride ions cannot be transported efficiently across cell membranes, causing the buildup of thick mucus in organs.
The most common CF-causing mutation is the F508del mutation where a single amino acid (amino acids are building blocks of proteins) is deleted at position 508 in the protein. This causes the CFTR protein to fold incorrectly. The misfolded protein is degraded by the cell, meaning that very little CFTR reaches the cell membrane.
ABBV-2222 acts as a CFTR corrector. It is designed to bind to abnormally folded CFTR protein as it is being made by the cell and help it fold correctly. The corrected protein is transported normally to the cell membrane resulting in increased chloride ion transport. Often, CFTR correctors are used in combination with other CFTR modulators to increase chloride ion transport.
ABBV-2222 in clinical trials
A Phase 1 clinical trial (NCT02662452) was conducted to evaluate the safety and pharmacokinetics, or movement through the body, of ABBV-2222. Healthy volunteers received single and multiple ascending doses of the therapy. The results showed that ABBV-2222 was safe and well-tolerated, with the treatment causing only mild side effects.
Another Phase 1 trial (NCT02788721) compared the effects of a combination of ABBV-2222 and a CFTR potentiator, GLPG2451, to that of GLPG2451 alone. CFTR potentiators are designed to hold the CFTR channel open so that more chloride ions can be transported through them.
Researchers evaluated the safety and pharmacokinetics of single and multiple ascending doses of the combination and monotherapy in 40 healthy volunteers. Participants tolerated GLPG2451 well at all doses in this trial.
A Phase 2a clinical trial (NCT03045523) evaluated the safety and tolerability of ABBV-2222 in CF patients who were being treated with Kalydeco (ivacaftor). During the trial, patients received one of two dose levels of ABBV-2222 or a placebo once a day for 28 days.
Results showed that ABBV-2222 was safe and that patients tolerated it well, with only mild side effects. Patients displayed a dose-dependent increase in lung function from treatment, meaning that the larger the dose, the higher the benefit. The lung-function yardstick that researchers used was forced expiratory volume in one second, or FEV1, the amount of air a person can forcibly exhale in one second after taking a deep breath. Patients who took ABBV-2222 had higher FEV1 scores.
Patients also experienced statistically significant dose-dependent decreases in sweat chloride. People with CF have high levels of chloride in their sweat, which is why sweat chloride is a biomarker of the disease’s severity. A decrease in sweat chloride indicated that ABBV-2222 was benefiting patients.
Another Phase 2a trial (NCT03119649) assessed ABBV-2222 as a treatment for CF patients whose disease stemmed from an F508del gene mutation. The treatment lasted four weeks. The study included 59 patients, who were randomly assigned to receive one of four doses of ABBV-2222 or a placebo for four weeks. Patients were monitored for an additional two weeks after treatment had ended.
Results of the trial indicated that ABBV-2222 was well-tolerated and reduced sweat chloride levels, though no changes in FEV1 were observed. Most side effects were mild or moderate. Two patients on placebo experienced lung exacerbations caused by an infection.
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