CTP-656 is the deuterated, or deuterium-modified, form of ivacaftor (Kalydeco), an FDA-approved treatment for cystic fibrosis (CF). It is under development by Concert Pharmaceuticals as a new version of ivacaftor, using a platform that modifies approved or widely studied drugs to create new products with more metabolic stability, lower toxic by-products, and increased half-life.

The drug is particularly targeted for individuals with gating mutations (e.g., G551D) of the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR). This  protein regulates components of sweat, mucus clearance, and digestion. Phase 2 studies accessing the efficacy and safety of the therapy are expected to begin soon, after Phase 1 results demonstrated improved pharmacokinetics when compared to ivacaftor.

History of CTP-656

Phase 1 studies for the deuterated form of ivacaftor began in March 2015. The study was a crossover, enrolling 45 healthy volunteers, whose first purpose was to assist Concert in choosing one of two deuterated forms for further trials, and then to study ascending doses.

Later, the pharmacokinetic superiority of CTP-656 was confirmed when compared to ivacaftor in healthy volunteers. The results also supported its tolerability and safety, and were presented at several conferences.  CTP-656 and other ivacaftor-deuteraded forms were also granted a U.S. patent, number 8865902, as potential CF treatments.

The company reported that, in crossover comparison with ivacaftor, CTP-656 demonstrated a superior pharmacokinetic profile, and data were presented at several international conferences.

How CTP-656 works

One way to overcome rapid absorption, distribution, metabolism and/or excretion (ADME) is to replace one or more hydrogen atoms with deuterium atoms. Deuterium is a stable isotope of hydrogen that forms stronger bonds to carbon when compared to hydrogen. The chemical stability of these bonds confers the possibility of enhanced ADME properties in a drug, because substituting hydrogen atoms with deuterium atoms is believed to improve its ADME properties. In the Phase 1 crossover comparison of CTP-656 and ivacaftor, for example, CTP-656 was reported to show a superior pharmacokinetic profile, including a reduced rate of clearance, longer half-life, and increased exposure and greater plasma levels at 24 hours.

Since deuterium is similar in size and shape to hydrogen, the biological activity of the drug is expected to remain the same.

CTP-656 is targeted for CF patients with gating mutations (e.g., G551D). This means that the individuals have full-length CFTR proteins, but the channel doesn’t open sufficiently to allow the passage of chloride through the cells.  The drug functions as a potentiator for this channel, and is a deuterated form of the approved drug ivacaftor (Kalydeco).

Next steps for CTP-656

Phase 2 studies are expected soon start in CF patients, accessing its safety and effectiveness.

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Graphic of molecule adapted from Concert Pharma website.