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Combination of Tezacaftor and Ivacaftor met primary endpoints with improvements in lung function in patients with cystic fibrosis


Results from two phase 3 studies of the Tezacaftor ( VX-661 ) / Ivacaftor combination treatment that showed statistically significant improvements in lung function ( percent predicted forced expiratory volume in one second, or ppFEV1 ) in people with cystic fibrosis ( CF ) ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, were announced.
The 24-week EVOLVE study evaluated the combination treatment in people who have two copies of the F508del mutation. This study met its primary endpoint with a mean absolute improvement in ppFEV1 through 24 weeks of 4.0 percentage points from baseline compared to placebo ( p less than 0.0001 ).
The second study, EXPAND, was an 8-week crossover study that evaluated the combination treatment in people who have one mutation that results in residual CFTR function and one F508del mutation. This study met the primary endpoints of absolute change in ppFEV1 from baseline to the average of the Week 4 and Week 8 measurements, with the Tezacaftor and Ivacaftor combination treatment demonstrating a mean absolute improvement of 6.8 percentage points compared to placebo ( p less than 0.0001 ) and the Ivacaftor monotherapy group demonstrating a mean absolute improvement of 4.7 percentage points compared to placebo ( p less than 0.0001 ).

Across both studies, the Tezacaftor and Ivacaftor combination treatment was generally well tolerated. The most common adverse events, regardless of treatment group, were infective pulmonary exacerbation and cough.
In both studies, rates of discontinuations due to adverse events were low and similar between placebo and treatment groups ( 2.1% for placebo vs 1.7% for the Tezacaftor and Ivacaftor combination ).
Rates of respiratory adverse events were similar between placebo and treatment groups ( 15.0% for placebo vs 11.4% for the Tezacaftor and Ivacaftor combination ).

EVOLVE trial

EVOLVE was a global phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Tezacaftor and Ivacaftor combination treatment in people with cystic fibrosis ages 12 and older who have two copies of the F508del mutation.

The combination group received Tezacaftor 100 mg once daily ( QD ) in combination with Ivacaftor 150 mg every 12 hours ( q12h ).
In the study, more than 500 people were treated at more than 90 sites in North America and Europe.
The primary endpoint was absolute change in ppFEV1 from baseline through Week 24 for those treated with the Tezacaftor and Ivacaftor combination treatment compared to placebo.
The mean ppFEV1 at baseline was approximately 60% for each study arm.
Of the 477 people who completed the 24-week study, 461 chose to enroll in a rollover study to receive the combination treatment.

Through 24 weeks of the study, the mean absolute improvement in ppFEV1 was 4.0 percentage points from baseline for those treated with the Tezacaftor and Ivacaftor combination compared to placebo ( p less than 0.0001 ).

Statistically significant improvements were seen in multiple key secondary endpoints, including a 35 percent reduction in the annualized rate of pulmonary exacerbations with the Tezacaftor and Ivacaftor combination treatment compared to placebo.

The Tezacaftor and Ivacaftor combination treatment was generally well tolerated. The majority of adverse events were mild or moderate.
The most common adverse events ( greater than or equal to 15% ), regardless of treatment group, were infective pulmonary exacerbation, cough, headache, nasopharyngitis and sputum increased.
The rate of discontinuations due to adverse events was low and similar between the placebo group and the combination treatment group.
Rates of adverse events, serious adverse events and respiratory-related adverse events were similar between the placebo and the Tezacaftor and Ivacaftor combination treatment groups.

EXPAND trial

EXPAND was a global phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study designed to evaluate the efficacy and safety of Tezacaftor and Ivacaftor combination treatment as well as Ivacaftor monotherapy in people with cystic fibrosis ages 12 and older who have one mutation that results in residual CFTR function and one copy of the F508del mutation.

Patients were randomized to one of six treatment groups to receive Tezacaftor and Ivacaftor, Ivacaftor monotherapy or placebo for eight weeks, followed by an 8-week washout period.
Following the washout period, patients switched to one of the other two treatment regimens for another eight weeks.
The combination treatment group evaluated Tezacaftor 100 mg once daily ( QD ) in combination with Ivacaftor 150 mg every 12 hours ( q12h ), and the monotherapy group evaluated Ivacaftor 150 mg every 12 hours ( q12h ).
In the study, approximately 250 people were treated at more than 80 sites, mainly in North America and Europe.
The primary endpoints were absolute change in ppFEV1 from baseline to the average of the Week 4 and Week 8 measurements for each of the treatment groups ( Tezacaftor and Ivacaftor combination treatment and Ivacaftor monotherapy ) compared to placebo.
The mean ppFEV1 at baseline was approximately 62% for each study arm.
Of the 235 people who completed the study, 227 chose to enroll in a rollover study to receive Tezacaftor and Ivacaftor combination treatment.

The mean absolute improvement in ppFEV1 was 6.8 percentage points from baseline compared to placebo ( p less than 0.0001 ) for those receiving the Tezacaftor and Ivacaftor combination and was 4.7 percentage points compared to placebo ( p less than 0.0001 ) for those receiving Ivacaftor alone.

An additional pre-specified analysis of the combination group compared to the monotherapy group showed that the Tezacaftor and Ivacaftor combination treatment provided a statistically significant improvement in ppFEV1 over the use of Ivacaftor alone ( 2.1 percentage points, p less than 0.0001 ).

The key secondary endpoint was absolute change in the Cystic Fibrosis Questionnaire-Revised ( CFQ-R ) respiratory domain score from baseline to the average of the Week 4 and Week 8 measurements for each of the treatment groups ( Tezacaftor and Ivacaftor combination treatment and Ivacaftor monotherapy ) compared to placebo.

In the EXPAND study, the safety profile observed for the Tezacaftor and Ivacaftor combination treatment was favorable and similar to that seen in the EVOLVE study.
The Tezacaftor and Ivacaftor combination treatment as well as Ivacaftor monotherapy were both generally well tolerated.
The majority of adverse events were mild or moderate.
The most common adverse events ( greater than or equal to 15% ), regardless of treatment group, were cough and infective pulmonary exacerbation.
There were no discontinuations due to adverse events in the combination treatment group. Discontinuations due to adverse events were low and similar between the placebo group and the Ivacaftor monotherapy group.
The incidence of adverse events, serious adverse events and respiratory-related adverse events was similar between the placebo, Tezacaftor and Ivacaftor combination and Ivacaftor monotherapy groups.

Cystic fibrosis is a rare, life-shortening genetic disease affecting approximately 75,000 people in North America, Europe and Australia.
Cystic fibrosis is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes ( one from each parent ) to have cystic fibrosis.
There are approximately 2,000 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic test, or genotyping test, lead to cystic fibrosis by creating non-working or too few CFTR protein at the cell surface.
The defective function or absence of CFTR protein results in poor flow of salt and water into and out of the cell in a number of organs.
In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death.
The median age of death is in the mid-to-late 20s.
In people with the F508del mutation, the CFTR protein is not processed, or folded, normally within the cell and generally does not reach the cell surface.
Tezacaftor is designed to address the processing defect of F508del-CFTR to enable it to reach the cell surface where Ivacaftor can further enhance the protein's function.
In North America, Europe and Australia, there are more than 22,000 people ages 12 and older who have two copies of the F508del mutation, and there are more than 1,500 people ages 12 and older who have one mutation that results in residual CFTR function and one copy of the F508del mutation. ( Xagena )

Source: Vertex, 2017

XagenaMedicine_2017



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