Three triple-combination treatments from Vertex Pharmaceuticals showed promising results in Phase 1 and Phase 2 clinical trials in cystic fibrosis (CF) patients with one F508del mutation and one so-called minimal function mutation (F508del/Min) in the CFTR gene, the defective gene that causes CF.
Vertex announced that these are the first data to demonstrate that it is possible to treat the underlying cause of CF in patients with these mutations, which are particularly difficult to treat.
Minimal function mutations are gene changes that leave the CFTR protein minimally functional or unable to function at all. Earlier studies showed that patients with these types of mutations are not responsive to treatment with Kalydeco (ivacaftor), tezacaftor, or the combination of the two.
The trials showed that patients improved their lung function, as measured by percent predicted forced expiratory volume in 1 second (ppFEV1), and lowered the amount of chloride in their sweat, a measure of how well the CFTR protein works.
A Phase 1 clinical trial explored a triple combination with VX-659, which is another corrector. This study showed similar improvements in lung function and sweat chloride analyses.
The trials showed that all of the treatments were relatively safe, with the majority of adverse events being mild or moderate.
“These safety and efficacy data are clear and compelling, indicating significant potential benefit for people with CF from each of these three different triple combination regimens,” Jeffrey Chodakewitz, MD, executive vice president and chief medical officer at Vertex, said in a press release.
“We will be collecting and evaluating additional data from these and other studies and will make a decision on which regimen(s) to take forward into pivotal program(s), which we expect to begin in the first half of 2018,” Chodakewitz added.
The Phase 2 study (NCT02951182) is evaluating two doses of VX-440 — 200 mg and 600 mg every 12 hours — in combination with tezacaftor and Kalydeco. The trial includes adult patients who have either two F508del mutations or the F508del/Min combination of mutations.
Among 47 patients with minimal function mutations analyzed so far, the average lung function was found to be improved by about 10-12%. Meanwhile, the amount of chloride in patients’ sweat decreased, indicating improved activity of the CFTR protein.
Researchers noted both of these positive effects in both dose groups (200 and 600 mg). In contrast, those who received a placebo had no changes in these parameters during four weeks of treatment.
The treatment was also beneficial to 26 patients with two F508del mutations who were already receiving treatment with the tezacaftor-Kalydeco combo. These patients were randomized to receive either VX-440 or a placebo for four weeks.
Like the other patient group, the addition of VX-440 to the treatment plan improved lung function by 9.5%. It also significantly lowered sweat chloride levels.
A second Phase 2 trial (NCT02951195) studied three doses of VX-152 — 100 mg, 200 mg, and 300 mg every 12 hours — together with tezacaftor and Kalydeco. Patients are adults with either two F508del mutations or a F508del/Min mutation combination.
In patients with F508del/Min mutations, two weeks of treatment allowed those in the lower dose group to improve by 5.6% on lung function tests, while those in the higher group improved by 9.7%. Sweat chloride levels also decreased in this study.
A similar result was observed in patients with two F508del mutations: 7.3% improvement in lung function and a decrease in sweat chloride levels.
The Phase 1 study (NCT03029455) differs in design from the Phase 2 trials as it evaluates increasing doses of VX-659 alone and in triple combination with tezacaftor and Kalydeco in healthy volunteers. The trial also includes patients with the F508del/Min mutations.
As in the other studies, preliminary results showed an improvement of 9.6% in patients’ lung function after two weeks of treatment.
“Patients with minimal function mutations have been waiting for a medicine to treat the underlying cause of their disease, which makes these data, showing pronounced improvements in lung function particularly important,” said Steven M. Rowe, MD, co-chair of a steering committee of global CF experts who advise Vertex on the development of the triple combination treatments.
“It’s also encouraging to see that the addition of a next-generation corrector may lead to substantial additional benefits for patients with two copies of the F508del mutation, who were already receiving tezacaftor and ivacaftor,” added Rowe, who is also a professor of medicine, pediatrics, and cell developmental and integrative biology at the University of Alabama at Birmingham.