Deuterium-modified ivacaftor tested in cystic fibrosis

LEXINGTON, Mass.—Concert Pharmaceuticals, Inc. today announced positive data from a Phase 1 single ascending dose clinical trial of CTP-656, a novel deuterium-modified version of ivacaftor, which is commercially available as a single agent under the name Kalydeco and as part of a fixed-dose combination therapy called Orkambi. The clinical results continue to support the development of CTP-656 as a once daily potentiator for the treatment of certain cystic fibrosis genotypes as monotherapy or in combination with other CFTR (cystic fibrosis transmembrane conductance regulator) modulators. CTP-656 demonstrated a superior pharmacokinetic profile compared to Kalydeco, current standard of care. Results of the Phase 1 trial also showed that CTP-656 was well-tolerated and its safety profile was comparable to Kalydeco. The Phase 1 single dose results were presented during the “hot off the press” session at the Cystic Fibrosis Trusts UK Conference 2015 in Manchester, England.

“CTP-656 is a new chemical entity that we designed to provide superior pharmacokinetic properties while leveraging the known safety and efficacy of Kalydeco. Based on data from our initial clinical evaluation, we are extremely pleased with the compound’s profile,” stated James V. Cassella, Ph.D., chief development officer at Concert.

“With the favorable safety and pharmacokinetic profile of CTP-656 observed in our single ascending dose trial, we look forward to the completion of our Phase 1 multiple dose clinical evaluation and advancement of this drug candidate into a Phase 2 clinical efficacy study in 2016,” said Cassella. “We intend to develop CTP-656 to improve patient outcomes and expand therapeutic options as a potential single agent treatment, as well as to enable new combination medications so that patients with cystic fibrosis can have a range of treatment options."

The Phase 1 clinical trial was designed to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of CTP-656 as well as to provide a comparison with a single dose of Kalydeco in ten healthy volunteers. Three doses (75, 150 and 300 mg) of CTP-656 were administered as an aqueous suspension. Additionally, a 150 mg dose of CTP-656 was compared to a 150 mg solid dose of Kalydeco in nine subjects. CTP-656 was well-tolerated across all dose groups. There were no serious adverse events reported in subjects who received CTP-656.

In the Phase 1 cross-over comparison of CTP-656 and Kalydeco, CTP-656 demonstrated a superior pharmacokinetic profile compared to Kalydeco including a reduced rate of clearance, longer half-life, substantially increased exposure and greater plasma levels at 24 hours. An analysis of metabolites in plasma also showed that the overall exposure profile of CTP-656 differed from that of Kalydeco in that the majority of plasma exposure in the case of CTP-656 was due to parent drug, whereas with Kalydeco the majority of plasma exposure was due to a less-active metabolite and an approximately equivalent amount of an inactive metabolite was also observed.

“We believe that the longer half-life and lower metabolite levels measured for CTP-656 are clear demonstrations of a positive deuterium effect and might offer a dosing advantage to the patient,” said Cassella.

A previously completed Phase 1 clinical trial compared a single dose of CTP-656 and another deuterated ivacaftor analog, which led to the selection of CTP-656 for further clinical evaluation. The data from the crossover trial and the single ascending dose trial will be presented in the poster session at the North American Cystic Fibrosis Conference being held October 8-10, 2015. A future Phase 1 trial evaluating multiple ascending doses of CTP-656 in healthy volunteers is expected to begin in the fourth quarter of 2015. That trial will include a single dose crossover comparison of a tablet formulation of CTP-656 versus Kalydeco. Concert expects to report top-line results from this multiple ascending dose Phase 1 trial in the first half of 2016.

The U.S. Patent and Trademark Office has issued U.S. Patent No. 8,865,902 claiming CTP-656 and other deuterium-modified ivacaftor analogs as novel composition of matter.

CTP-656 is a novel potentiator that may enable once-daily dosing and was developed by applying deuterium chemistry to modify ivacaftor. Concert is initially developing CTP-656 as a potential treatment for cystic fibrosis as monotherapy in class III (gating) mutations (e.g., G551D) of the gene that encodes for cystic fibrosis transmembrane conductance regulator (CFTR), a protein which regulates components of sweat, mucus clearance and digestion. Cystic fibrosis is a life-threatening, hereditary genetic disease that has systemic effects and can cause significantly reduced lung and digestive system function. According to the Cystic Fibrosis Foundation, an estimated 70,000 people worldwide have cystic fibrosis.

Concert Pharmaceuticals is a clinical stage biopharmaceutical company focused on applying its DCE Platform (deuterated chemical entity platform) to create novel small molecule drugs. This approach starts with approved drugs, advanced clinical candidates or previously studied compounds that have the potential to be improved with deuterium substitution to enhance clinical safety, tolerability and efficacy. The company is developing a broad pipeline targeting CNS disorders, genetic diseases, renal disease, inflammatory diseases and cancer.