GLPG2451 is an investigational therapy for the treatment of cystic fibrosis (CF), a genetic condition caused by defects in a protein channel called the cystic fibrosis transmembrane conductance regulator (CFTR). It is being co-developed by Galapagos and AbbVie.

CFTR works to transport chloride ions across cell membranes, regulating the secretion of such fluids as mucus and sweat. Defects in the CFTR protein can affect how well the channel works in transporting chloride ions. In CF, decreased channel activity results in the abnormally thick mucus secretions that are a disease characteristic.

How GLPG2451 works

GLPG2451 works as a potentiator of the CFTR channel, meaning that it enhances the activity of the defective CFTR at the cell surface to improve the transport of chloride ions.

In laboratory (in vitro) studies, GLPG2451 demonstrated significant activity in primary cells with defective CFTR taken from cystic fibrosis patients. GLPG2451 was found to be metabolized to an active component called M31, which had a similar efficacy to its parent drug.

GLPG2451 in clinical trials

Two randomized, double-blind Phase 1 studies (NCT02788721 and NCT03214614) were designed to evaluate the safety, tolerability, and pharmacokinetics (how the drug moves in the body) of single and multiple ascending oral doses of GLPG2451, and combined doses of GLPG2451 plus GLPG2222, in about 40 healthy participants in Belgium.

GLPG2222 is another potential CF therapy being developed by Galapagos and AbbVie. It is an investigational CFTR corrector, meaning that it overcomes the defective folding of CFTR and increases the density of CFTR on the cell surface. In cellular assays, GLPG222 used in combination with another CFTR potentiator was shown to restore the function of defective CFTR.

Results of the second Phase 1 study (NCT03214614) showed that GLPG2451 was safe and well-tolerated when administered alone or in combination with GLPG2222 for 14 days and at six-month follow-up. Side effects were manageable, and of mild or moderate intensity. The pharmacokinetic profile of GLPG2451 favored a low-dose once-daily treatment schedule.

The company, in partnership with Abbvie, also plans to initiate a triple combination therapy consisting of corrector and potentiator drugs seen in cellular analyses to restore CFTR activity. These combinations in such preclinical studies resulted in a significant increase in chloride transport compared, for example, to Orkambi, an approved therapy for patients with CF.

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