Vertex Will Advance CF Therapies VX-659 and VX-445 to Phase 3 Clinical Trials

Vertex Pharmaceuticals will advance to the next clinical-trial stage two therapies designed to correct faulty mechanisms underlying cystic fibrosis.

The company said it plans Phase 3 trials of its next-generation correctors VX-659 and VX-445. They will be part of two triple combo therapy regimens that Vertex tests in CF patients. The combos have the potential to treat patients with mutations that fail to respond to VX-661 (tezacaftor) or Kalydeco (ivacaftor), the company said.

Vertex said it is designing the Phase 3 program in close collaboration with regulators.

It hopes to start the VX-659 trial before July 2018. It will test VX-659, VX-661 and Kalydeco as a triple combination therapy.

Vertex also expects to start the trial of VX-445 combined with VX-661 and VX-561 in the middle of 2018. Participants will receive it once a day.

In addition, the company expects to have the results of previous trials in the first half of 2018. They include a Phase 2 trial investigating the VX-445, VX-661 and VX-561 combo.

In that trial, Vertex is testing the combination in patients with two copies of the F508del mutation of the CFTR gene — the one that is defective in CF patients.

Vertex said the decision to advance VX-659 and VX-445 to Phase 3 trials was based on positive results from the Phase 2 studies. These include two ongoing trials showing that the therapies led to improvements in patients’ lung function.

The VX-659 trial led to a 13.3 percentage-point improvement and the VX-445 trial to a 13.8 percentage-point improvement over four weeks. The lung function measure that researchers used was predicted forced expiratory volume in one second, or FEV_1. This is the amount of air that a person can force out of their lungs in one second after a deep breath.

VX-659 Phase 2 Study

The ongoing three-stage Phase 2 trial (NCT03224351) of VX-659 is covering two groups of CF patients. Those in the first stage of testing have an F508del-CFTR mutation and a minimal function mutation. Those in the second have two copies of the F508del mutation.

Researchers are looking at VX-659 in combination with VX-661 and Kalydeco. Patients are receiving one of three oral tablets of VX-659 — either 80, 240 or 400 mg — once a day. The treatment lasts four weeks.

Minimal function mutations lead to little-to-no functioning CFTR protein, so patients who carry it are unable to respond to Kalydeco or VX-661 treatment alone — or both therapies combined.

In a third stage of the trial, researchers are evaluating VX-659 combined with VX-661 and VX-561 as a once-a-day treatment for F508del/Min patients. VX-561 is a new formulation of Kalydeco that has more stability in the body.

The study’s primary objectives are to see how safe the combo is, how well patients tolerate it and how effective it is. The safety measures are the number of participants who experience adverse events or serious adverse events. The effectiveness yardstick will be whether the combo can improve patients’ FEV₁ scores.

Secondary objectives include whether the combo leads to improvements in patients’ sweat chloride and Cystic Fibrosis Questionnaire-Revised index scores. Sweat chloride scores are a measure of CFTR function.

Stages 2 and 3 of the study are continuing. Results are expected before July 2018.

Vertex has reported the initial results of Stage 1 of the study, which covered 63 patients with one F508del mutation and one minimal function mutation. Patients were randomly assigned to one of four groups. Eleven patients received 80 mg of VX-659, 20 received 240 mg, 22 received 400 mg, and 10 a placebo.

All of the groups receiving VX-659 showed significant improvements in FEV₁ after 29 days of treatment, compared with the placebo, meeting the trial’s primary objective.

The most significant changes were in patients receiving 240-mg and 400-mg doses of VX-659 as part of the triple combo therapy. The 240-mg group had a 11.6 percentage-point improvement in FEV₁ and the 400-mg group a 13.3 percentage-point improvement, compared with the placebo.

In addition, the VX-659 400-mg triple combo led to a major improvement in patients’ sweat chloride concentration — a measure of CFTR function — compared with the controls.

Researchers added that in general patients tolerated the combo well.

VX-445 Phase 2 Study

There are six stages in the ongoing Phase 2 trial (NCT03227471) of VX-445. Parts A, B and C are looking at the safety of single and multiple ascending doses of VX-445 alone, and in combination with VX-661 and Kalydeco, in healthy volunteers. Researchers are also assessing participants’ ability to tolerate the regimens.

Part D is evaluating the safety of VX-445 administered in three once-a-day doses — either 50, 100, or 200 mg — combined with VX-661 and Kalydeco. The four weeks of treatment cover adults with CF who have one F508del mutation and one minimal function mutation.

Patients with two copies of the F508del mutation are being evaluated in Part E of the study. And Part F is looking at VX-445 combined with VX-661 and VX-561 as a once-a-day triple combo treatment for F508del/Min patients.

Parts E and F are continuing. Results are expected in the first half of 2018.

Part D of the study covered 65 patients with one F508del mutation and one minimal function mutation. Researchers randomized them so that 10 were in a VX-445 50-mg group, 22 in a 100-mg group, 21 in a 200-mg group, and 12 in a placebo group.

The VX-445 100-mg triple combo group achieved a 7.8 percentage-point improvement in FEV₁ and the VX-445 200-mg group a 13.8 percentage-point improvement, compared with the placebo.

The VX-445 200-mg triple combo therapy also led to a major improvement in patients’ sweat chloride concentration, compared with controls.

In addition, researchers said participants generally tolerated the combo well.

“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, Vertex’s executive vice president and chief medical officer, said in a press release. “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.”

“Together, all the Phase 2 data to date provide further evidence that the addition of a next-generation corrector to tezacaftor [VX-661] and ivacaftor [Kalydeco] 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, an associate professor of Medicine and Pediatrics at National Jewish Health, Colorado. She is also co-chair of Vertex’s Triple Combination Steering Committee.