Promising clinical data from a Phase 1 multiple ascending trial of a deuterium-modified version of the commercially available Kalydeco® (ivacaftor), a drug used to treat cystic fibrosis (CF) in patients with a specific mutation, has been announced by Concert Pharmaceuticals.
CF is a hereditary genetic disease estimated to affect about 70,000 people worldwide. It significantly reduces the function of the digestive and respiratory systems, often leading to death. Ivacaftor, available in the market as Kalydeco®, was approved by the U.S. Food and Drug Administration (FDA) in 2012 as the first medicine that directly affects the genetic defect that causes the disease. It is particularly directed against a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, found in approximately 4% of the patients with CF.
Selective replacement of hydrogen atoms with deuterium — a less common but naturally occurring form of hydrogen — has been shown, in certain cases, to positively modify the metabolic fate of physiologically active compounds, and improve their safety, efficacy and/or tolerability, while retaining their pharmacological profile. Using this approach in approved drugs with well defined human pharmacological effects can, therefore be a way to provide new medicines that better suit the patients needs.
Concert has created a deuterium-modified version of ivacaftor, called CTP-656, and conducted a Phase 1 trial that enrolled 38 healthy volunteers, and was divided in two parts to assess the safety, tolerability and pharmacokinetics of CTP-656 in a tablet formulation.
In the first part, a pharmacokinetic comparison of a single dose of 150 mg of CTP-656 versus 150 mg of Kalydeco was assessed. The results have been previously reported, revealing a superior pharmacokinetic profile for CTP-656, including longer half-live, reduced rate of clearance, and greater plasma levels at 24 hours.
“We are pleased with the profile of CTP-656 emerging from the Phase 1 program,” said James Cassella, PhD, Chief Development Officer of Concert Pharmaceuticals, in a press release. “We believe its potential to be dosed once-daily as well as its improved metabolite profile may provide important patient benefits, including ease of adherence and potentially improved efficacy.”
Concert has now revealed the results from the second part, where three doses of CTP-656 (75 mg, 150 mg, and 225 mg) were administered daily, for seven days, and compared to placebo. After repeated dosing, CTP-656 demonstrated a dose-proportional increase in concentration when 75 mg and 150 mg doses were given, enhanced exposure to the parent drug, and less exposure to metabolites. In terms of safety, CTP-656 was found to have a similar safety profile to that of Kalydeco.
The company expects to present the results of the Phase 1 multiple ascending trial in the upcoming 39th European Cystic Fibrosis Conference being held in Basel, Switzerland in June 8-11, 2016.
“We believe that we have identified a safe and well-tolerated dose range for CTP-656 that will provide effective clinical CFTR potentiation. Importantly, we believe we have the necessary data to select the doses for our Phase 2 trial that bracket parent drug exposure associated with the commercial dose of Kalydeco,” said Dr. Cassella.
Another Concert Phase 1 trial that was recently completed evaluated the phamacokinetics and bioavailability of CTP-656 in healthy volunteers that were fasted or given a low or medium fat-containing meal. Results revealed that subjects dosed with either low or moderate-fat containing food had consistent CTP-656 exposure, which was also consistent with previous analysis made in subjects dosed with a high fat meal.
“We are pleased to see that full bioavailability of CTP-656 was retained even with a low fat meal,” concluded Dr. Cassella.