FDA has dosing questions for Vertex’s Kalydeco follow-up

Against a backdrop of strong first-quarter sales for its cystic fibrosis drug, Vertex has revealed that its longer-acting version of Kalydeco has been held up by an FDA request for more data—but analysts suggest it could be a bigger issue for rival developers.

The regulator wants to see additional dose-ranging data for VX-561, a ‘potentiator’ version of ivacaftor, which is the active ingredient in Kalydeco and a component of Vertex’s two-drug therapies Orkambi and Symdeko. It’s a more stable, deuterated version of ivacaftor that Vertex says will help it create once-daily versions its CF drugs, including three-drug combinations that aim to expand the pool of CF patients eligible for treatment.

Phase 2 studies of VX-561 in three-drug combinations have demonstrated that once-daily administration is feasible, but the FDA has requested “additional dose-ranging for VX-561 including potential evaluations of monotherapy before allowing evaluation of [the drug] in late-stage development,” said Vertex’s CMO Reshma Kewalramani, M.D., on a conference call.

The interpretation is that the FDA views VX-561 as a new chemical entity (NCE) and will want to see the level of dose-ranging work typically required of a novel drug, said Jeff Leiden M.D., Ph.D., Vertex’s CEO.

“Having said that, the data for VX0561 is quite compelling,” Leiden continued, pointing to efficacy data showing an 11% to 12% improvement in lung function (FEV) and food safety. “We’re still in discussions with the FDA about exactly what they are going to need in the phase 1 and phase 2 studies, but we think it’s highly doable.”

Once the requirements are known, the company will come up with a bridging strategy to push forward VX-561 as quickly as possible, said Leiden.

The request was a relatively minor fly in the ointment for what was overall a positive first-quarter update, according to analysts at Jefferies, who say the FDA’s greater scrutiny may in fact have greater implications for other CF drug developers such as Galapagos.

The move suggests the FDA “wants new drug [developers] to have to do lots of work on components before they can take these into pivotals,” they write in a research note. As Vertex already has two phase 3 studies ongoing for its other three-drug CF combinations based on original ivacaftor, tezacaftor and either VX-659 or VX-445, that means it could “pull away” from its rivals.

The news “has important read through to Vertex leadership in our view, and also to a reality that … Vertex or competitors probably can't just quickly start any phase 3 for any triple,” say the analysts. They think Vertex may be able to complete the necessary work this year, allowing them to move ahead with phase 3 for once-daily triples “later in 2018 or in 2019.”

Vertex said on the call that it is also making progress in its non-CF pipeline, saying it is preparing for a European phase 1/2 trial of CRISPR/Cas9 candidate CTX001 in beta thalassemia in collaboration with CRISPR Therapeutics, and is also advancing its pain programs.