Concert developing ‘improved’ version of Vertex’s Kalydeco

Launched in 2012, Vertex's Kalydeco has been a breakthrough in treating cystic fibrosis, being the first drug to target defective proteins which lead to damaging chest infections.

Kalydeco (ivacaftor) has been a success for Vertex, and is expected to earn $575-$590 million this year. A follow-up drug, Okambi, was launched earlier this year, and combines ivacaftor with another molecule, lumacaftor, broadening the number of cystic fibrosis (CF) patients who can benefit from the treatment.

Until now, Vertex has had the field to itself, but that's set to change with the arrival of Concert Pharmaceuticals, which is developing a rival CF treatment.

Concert's tactic is to create a modified and improved version of ivacaftor – the molecule being sufficiently different to not infringe Vertex's patent, but close enough to piggyback on its proven efficacy.

Concert is led by Roger Tung, who served as Vertex's vice president of drug discovery from 1989 to 2005, and was also one of its founding scientists.

Tung set up Concert shortly after leaving Vertex, and has built the company on a simple insight based on deuterium substitution: by strategically replacing hydrogen molecules in existing drugs with deuterium, a drug candidate can bind better with carbon, thereby improving efficacy and side-effect profiles.

Concert's molecule CTP-656 is a deuterium-modified version of ivacaftor, a tweak which allows the drug to stay longer in the body and provide more benefits for the patient, with potentially fewer drug interactions.

Results from a phase I trial of CTP-656 has been presented at the Cystic Fibrosis Trust's conference in Manchester, England, which showed the drug was well-tolerated, with a safety profile similar to Kalydeco.

"CTP-656 is a new chemical entity that we designed to provide superior pharmacokinetic properties while leveraging the known safety and efficacy of Kalydeco," said James V Cassella, chief development officer at Concert.

The company says the drug's pharmacokinetic profile shows it has a longer half-life and lower metabolite levels than Kalydeco, which might allow it to be taken less frequently. Kalydeco must be taken every 12 hours, and if Concert can improve on this profile, it could steal market share from Vertex.

Responding to the announcement made at the conference, Janet Allen, director of Strategic Innovation for the Cystic Fibrosis Trust said the CTP-656 were encouraging: "The way this potentially superior treatment is processed by the body means that fewer doses may be required, potentially leading to once-a-day dosing, as well as a reduced risk of interaction with other drugs. This will likely result in easier clinical use for a drug which has similar pharmacological activity to ivacaftor in cells outside the body. We are looking forward to seeing how the trials progress."

Concert says a further phase I trial evaluating multiple ascending doses of CTP-656 in healthy volunteers is expected to begin later this year.

The trial will include a single dose crossover comparison of a tablet formulation of CTP-656 versus Kalydeco, with top-line results expected in the first half of 2016.

There is still lots more room for progress in CF: Kalydeco only works for 4-5 per cent of CF patients who have the G551D mutation, but Vertex is seeking to expand the sub-groups of patients it is licensed to treat. Orkambi is licensed for patients with two copies of the F508del mutation, a much larger group of patients, but still only accounting for around 28 per cent of CF sufferers.

Vertex has a number of new CF treatments in its pipeline, but Concert's rival could seriously undermine its dominance in the therapy area if and when CTP-656 is approved.