Work leading to GLPG2737, possible CFTR modulator, detailed

Therapy tested in Phase 1 and 2 trials, but no further studies in CF known

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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In a recent study, scientists described the process through which they discovered GLPG2737, an investigational CFTR modulator considered by Galapagos and AbbVie to be a possible treatment for cystic fibrosis (CF).

The molecule was found in early work to have an additive effect when combined with other types of CFTR modulators. It was evaluated in Phase 1 and 2 clinical trials in CF patients in combination with approved and experimental modulator therapies, but no current clinical trials appear to be active.

The study, “Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector,” was published in the Journal of Medicinal Chemistry.

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CFTR modulator therapy aims to correct the workings of the CFTR protein

CF is caused by mutations in the CFTR gene, leading to a missing or dysfunctional CFTR protein. CFTR normally acts as a channel through which chloride ions flow to regulate the balance of salts and water in cells.

When the protein is missing or faulty, as it is in CF, mucus that’s normally slippery and made mostly of water becomes thick, sticky, and difficult to clear.

CFTR modulators work in different ways to improve CFTR functionality. Correctors help to increase the number of CFTR channels that are transported to the cell’s surface, while potentiators help CFTR channels to remain open once they’re at the surface.

Combinations of modulator therapies with different mechanisms are considered be of benefit to patients. For example, the highly effective modulator Trikafta (sold as Kaftrio in Europe) contains three different molecules: the corrector tezacaftor, the potentiator ivacaftor, and elexacaftor, which is sometimes referred to as a co-corrector.

A co-corrector or a C2 corrector has a different mechanism than standard C1 correctors, like tezacaftor, and can enhance the benefits of a C1 corrector/potentiator combination, the scientists wrote.

Galapagos has developed a number of novel CFTR modulator molecules, including the co-corrector GLPG2737. Its development partner AbbVie obtained sole rights to the molecules for CF in 2018.

In the Phase 2 PELICAN clinical trial (NCT03474042), GLPG2737 added to Orkambi — a combination of the corrector lumacaftor and the potentiator ivacaftor — was associated with significant reductions in sweat chloride levels in treated CF patients. Some signs of improved lung function in these people, all with the most common CF-causing F508del mutation, also were reported in the trial, which concluded in 2018.

Scientists in this study, largely in France and Belgium, described the initial development and characterization of GLPG2737 in preclinical work.

GLPG2737 showed treatment potential in cell and animal lab studies

Through large-scale screenings, the researchers identified a compound that was able to boost trafficking of CFTR to the cell surface in a lung cell line expressing the F508del mutation.

They went on to develop a series of structurally similar molecules, looking for a final candidate showing high effectiveness and optimal pharmacological properties without signs of toxicity.

Ultimately, the team chose GLPG2737, which was found to be a potent corrector of F508del-CFTR. Specifically, when it was combined with a CFTR potentiator and a C1 corrector, GLPG2737 led to an eightfold increase in CFTR activity.

Importantly, the molecule was selective for CFTR, and did not appear to interact with any of the hundreds of other molecules evaluated. When tested in rats and dogs, it was found to be safe and well tolerated.

These findings supported its ultimate selection as a candidate for clinical trials, according to the scientists.

Positive findings in the PELICAN study were followed by the open-label Phase 1b FALCON trial (NCT03540524). This trial, which concluded in 2019, evaluated GLPG2737 in combination with Galapagos’ experimental potentiator GLPG2451 and the C1 corrector GLPG2222 in F508del-positive patients.

However, certain pharmacological issues with these molecules resulted “in limited benefit for patients,” according to the researchers. It could have a “potential for use in diseases other than CF,” they added.

Currently, no ongoing trials are known to be evaluating GLPG2737 in CF patients.

The study was funded by Galapagos, and a number its scientists are or were employees of Galapagos or AbbVie at the time of this work.