Vertex Pharmaceuticals on Wednesday announced that a three-drug regimen combining the investigational next-generation corrector VX-445 with Kalydeco (ivacaftor) and tezacaftor met the primary endpoints of two Phase III studies in patients with cystic fibrosis (CF). Results showed that the triple combination therapy was associated with significant improvements in lung function versus placebo.
In one study, 405 patients aged 12 and older with one F508del mutation and one minimal function mutation were randomised to treatment with VX-445, Kalydeco and tezacaftor or placebo for 24 weeks. Top-line results for the primary endpoint showed that the mean absolute within-group change in percent predicted forced expiratory volume in one second (ppFEV1) in the triple combination group at week four from baseline was 13.8 percentage points versus placebo.
According to Vertex, the safety profile of the three-drug combination was in line with previous findings, while along with the main goal, the study will continue to evaluate a number of secondary endpoints, including the number of pulmonary exacerbations and changes in sweat chloride and patient-reported outcomes as assessed using the respiratory domain score of the Cystic Fibrosis Questionnaire-Revised, through 24 weeks.
In the second trial, 108 patients aged 12 years or older carrying two F508del mutations received Kalydeco and tezacaftor for four weeks followed by randomisation to treatment with VX-445, Kalydeco and tezacaftor or placebo for a further four weeks. Top-line results for the main goal illustrated that the combination regimen improved ppFEV1 by 10 percentage points from baseline to week four versus placebo. Vertex added that the VX-445 triple combination regimen was generally well tolerated in the study.
The findings follow top-line Phase III study results unveiled last year showing that a regimen combining Vertex's next-generation corrector VX-659 with Kalydeco and tezacaftor was also associated with significant improvements in lung function compared with placebo. In a study of patients with one F508del mutation and one minimal function mutation, the combination of VX-659, Kalydeco and tezacaftor demonstrated a mean absolute improvement in ppFEV1 of 14 percentage points from baseline at week four of treatment compared to placebo. Meanwhile, in the second study of patients with two F508del mutations, the triple regimen of VX-659, Kalydeco and tezacaftor resulted in a mean absolute improvement in ppFEV1 of 10 percentage points from baseline at week four versus placebo.
Vertex chief medical officer Reshma Kewalramani remarked "both the VX-659 and VX-445 triple combination regimens showed highly consistent and significant improvements in lung function across our Phase III programmes." The company indicated that it plans to submit regulatory filings in the US and EU in the third and fourth quarters, respectively, for one of the triple combinations after reviewing final 24-week data for both regimens, which are expected in the second quarter.
Commenting on the news, Leerink analyst Geoffrey Porges said "this triple data is, if anything, even better than the previously released VX-659 triple results, and in our view effectively guarantees the launch, approval...and adoption of one of these combinations with resulting multi-billion dollar sales." Jefferies analyst Michael Yee added "with the data looking similar between the two regimens to date, we think it is a prudent move by the company to wait for more data...given they will have a better picture." However, shares in the company fell up to 2 percent on the new timeline for a filing in the US, which had previously been pegged for mid-2019.
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