Vertex Pharmaceuticals has selected two of its next-generation correctors, VX-659 and VX-445, for Phase 3 trial development as part of two triple combination regimens for the treatment of cystic fibrosis.
This decision was based on initial data from two Phase 2 ongoing clinical trials in people with one F508del mutation and one minimal function mutation (F508del/Min) in the CFTR gene, which is defective in CF patients.
These Phase 2 studies have shown that treatment with triple combination regimens of VX-659 (400 mg daily) (NCT03224351) and VX-445 (200 mg daily) (NCT03227471) led to a 13.3 percent and 13.8 percent increase, respectively, in mean absolute improvement in percent predicted forced expiratory volume in one second (ppFEV1; a measure of lung function) from baseline to four weeks after treatment began.
The trials also showed that these triple combination regimens are generally well tolerated, with the majority of adverse events being mild to moderate in severity. The discontinuation rate due to adverse events associated with the treatment was low.
“These results support the selection of both the VX-659 and VX-445 triple combination regimens and underscore the potential for these regimens to provide significant clinical benefits for up to 90 percent of people with CF,” Jeffrey Chodakewitz, MD, executive vice president and chief medical officer at Vertex, said in a press release.
“Together, all the Phase 2 data to date provide further evidence that the addition of a next-generation corrector to tezacaftor and ivacaftor has the potential to provide substantial clinical benefits to patients with one F508del and one minimal function mutation who don’t currently have a medicine to treat the underlying cause of their CF, as well as to provide additional benefits to patients with at least one F508del mutation who are already eligible for CFTR modulator therapies,” said Jennifer Taylor-Cousar, MD, MSCS, an associate professor of medicine and pediatrics at National Jewish Health, Colorado, and co-chair of Vertex’s Triple Combination Steering Committee.
Regulatory discussions are underway to finalize the design of Phase 3 trials including VX-659 and VX-445. Once finalized, Vertex will start a Phase 3 program in the first half of 2018 to assess VX-659 in a triple combo with Kalydeco and tezacaftor. Another study, also set to begin in the first half of 2018, will again evaluate this triple combination, but in patients with two copies of the F508del mutation (F508del/F508del).
In mid-2018, depending on data from an ongoing Phase 2 study, Vertex plans to initiate a Phase 3 program to evaluate VX-445 with tezacaftor and VX-561 as a once-daily treatment in F508del/Min and F508del/F508del patients.
“We look forward to concluding our discussions with regulators and initiating Phase 3 development in the first half of the year, with the goal of bringing a triple combination regimen to patients as quickly as possible,” Chodakewitz added.