GLPG3221 is an investigational therapy being developed by Galapagos in collaboration with AbbVie for the treatment of cystic fibrosis (CF).

How GLPG3221 works

CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which provides instructions for the CFTR protein. The role of this protein is to transport chloride ions across cell membranes. This movement through membranes is essential for the correct balance of water and salt on the surface of cells in many organs in the body.

There are six classes of CFTR gene mutations; the majority of CF patients have class 2 mutations, also called the F508delta mutation. Class 2 mutations affect the processing of the CFTR protein once it is made inside the cell, leading to very little or no protein being transported to the cell surface where it would normally function.

GLPG3221 is a CFTR modulator therapy, which are intended to correct the function of the faulty protein made by the defective CFTR gene in cystic fibrosis patients. Specifically, GLPG3221 is a type 2 corrector (C2) that is being studied as part of a triple combination therapy, along with a type 1 corrector (C1) and a potentiator molecule.

C1 and C2 function at the level of class 2 mutations, while potentiators function at the level of class 3 mutations, where the CFTR protein is present at the cell surface but is malfunctioning. Both Class 2 and Class 3 mutations cause a reduction in the flux of salts, leading to the production of a thicker than normal mucus and the symptoms of CF.

The triple action in the combination therapy is intended to correct the misshaped protein to be transported to the surface of the cells using the combination of C1 and C2 molecules. The use of both correctors is aimed at maximizing channel restoration, thereby increasing the amount of functional CFTR channels on the surface of the cells.

The potentiator allows the flow of ions through the channels that are present on the cells’ surface. In other words, the potentiator binds to the channels on the surface of the cells and induces them to open properly and do their work.

GLPG3221 in clinical trials

The Phase 1 trial of the triple combination of the potentiator plus C1 and C2 resulted in an increase in chloride transport in lab studies and in the restoration of protein levels on the surface of human bronchial epithelial (HBE) cells from patients with the F508del mutation, grown in the laboratory.

These effects were superior to the ones observed with Vertex PharmaceuticalsOrkambi (lumacaftor/ivacaftor) and the investigational TEZ/IVA (tezacaftor/ivacaftor combo therapy).

Galapagos announced in November 2017 that it will now initiate a Phase 1 clinical trial to assess the safety and efficacy of GLPG3221 in healthy volunteers before advancing to clinical trials in CF patients.

Other information

Galapagos and AbbVie joined forces in 2013 to discover, develop, and commercialize new potentiator and corrector molecules for the treatment of CF. GLPG3221 is the second C2 molecule developed by the two companies; the first was GLPG2737.

The companies have an extensive program of clinical trials testing their other products, including the potentiators GLPG1837 and GLPG2451, and the C1 molecule GLPG2222 on their own or in combination.


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