CTP-656, now known as VX-561, is the deuterated, or deuterium-modified form of Kalydeco (ivacaftor), an FDA-approved treatment for cystic fibrosis (CF). Concert Pharmaceuticals was developing CTP-656 as a new version of Kalydeco using its DCE platform that modifies approved or widely studied drugs to create improved products with higher metabolic stability, lower toxic byproducts, and increased half-life. Vertex Pharmaceuticals has since taken over its development.
CTP-656 is targeted for CF patients with gating mutations (e.g., G551D) of the gene that encodes for the CFTR (cystic fibrosis transmembrane conductance regulator) protein. This means patients have full-length CFTR proteins, but the channel doesn’t open sufficiently to allow the passage of chloride through the cells.
CTP-656 functions as a potentiator for this channel, keeping the channel open for the molecules to pass through. (CFTR regulates components of sweating, mucus clearance, and digestion).
How VX-561 works
One way to overcome rapid absorption, distribution, metabolism or excretion (ADME) of a drug is to replace one or more of its hydrogen atoms with deuterium atoms. Deuterium is a stable form of hydrogen that forms stronger bonds with carbon atoms compared to hydrogen. The chemical stability of these bonds offers the possibility of enhanced ADME properties in a drug.
In a Phase 1 crossover comparison of CTP-656 and Kalydeco, 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.
Clinical studies with VX-561
A Phase 1 trial (NCT02680249) for the deuterated form of Kalydeco began in March 2015. The trial was a crossover study enrolling 15 healthy volunteers. Its first purpose was to assist Concert in choosing one of the two deuterated forms of the molecule for further trials and then to study the effect of ascending doses.
The trial confirmed the pharmacokinetic superiority of CTP-656 over Kalydeco including a reduced rate of clearance (removal from the blood circulation), longer half-life, and greater blood plasma levels. The results, which were presented at several conferences also supported the drug’s tolerability and safety. The results also supported the use of a single daily dose of CTP-656 regardless of the fat content of the food consumed by the patients, unlike Kalydeco, increasing the possibility of treatment adherence.
CTP-656 and other Kalydeco-deuterated forms were granted a U.S. patent as potential CF treatments.
In November 2015, a multiple ascending dose Phase 1 study (NCT02599792) was conducted in two parts and enrolled 38 healthy volunteers to assess the safety, tolerability, and pharmacokinetics of CTP-656 in a tablet form.
The first part assessed a single dose of pharmacokinetic comparison of 150 mg of CTP-656 vs. 150 mg of Kalydeco. The second part assessed three daily doses of CTP-656 (75 mg, 150 mg, and 225 mg) for seven days compared to placebo. The results supported the use of a single daily dose and demonstrated enhanced exposure to the parent drug in each repeated dosing (instead of the metabolites arising from the breakdown of the drug from the previous dose), unlike Kalydeco. The results also showed that CTP-656 was safe and well tolerated.
In December 2016, a randomized, double-blind, placebo-controlled Phase 2 clinical trial (NCT02971839) was started to evaluate the safety and effectiveness of CTP-656 in patients with gating mutations. The ongoing Phase 2 trial is being conducted at multiple U.S. study sites within the Cystic Fibrosis Foundation’s Therapeutic Development Network, and results are expected by the end of 2017.
Next steps for VX-561
Concert plans to initiate an open-label Phase 2 trial in Europe, also in 2017. The trial is expected to enroll 14 CF patients with gating mutations stable on Kalydeco. Patients will be given one dose of CTP-656 for two weeks followed by a switch to a higher dose for an additional two weeks. Patients will then resume treatment with Kalydeco.
Recently, Concert Pharmaceuticals signed a purchase agreement with Vertex Pharmaceuticals, a company with clinical expertise in CF, under which Vertex will acquire CTP-656 by paying $160 million for all worldwide development and commercialization rights for the investigational drug. The agreement with Vertex will significantly advance the development of CTP-656. The transaction is expected to close by Oct. 31, 2017.
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Graphic of molecule adapted from Concert Pharmaceuticals’ website.