Tezacaftor (VX-661) is a corrector developed by Vertex Pharmaceuticals. Tezacaftor aims to restore CFTR (cystic fibrosis transmembrane conductance regulator) gene function by moving the protein into the correct position on the cell surface. Tezacaftor is designed to treat people with cystic fibrosis (CF) who carry the F508del mutation.

History of tezacaftor

According to the U.S. National Institutes of Health clinical trials website, a Phase 2 study was completed in March 2014 to evaluate the tolerability of VX-661 alone and in combination with Kalydeco (ivacaftor) in patients with CF who carry one or two F508del mutations. The data gathered from the study was presented by the research team and sponsor and supports the combination of the two therapies for CF patients with the F508del mutation.

Results from two Phase 3 studies of a tezacaftor/ ivacaftor combination treatment were announced with statistically significant improvements in lung function, as measured by percent predicted forced expiratory volume in one second, ppFEV1 in people with CF with 12 years and older who have certain mutations in the CFTR gene.

The EVOLVE study (NCT02347657) was a Phase 3, randomized, double blind, placebo-controlled, parallel group study assessed the efficacy and safety of tezacaftor (VX-661) in combination with Kalydeco (ivacaftor) in people with 12 years and older with CF, and two copies of the F508del CFTR mutation. The combination group received tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every 12 hours.  The primary endpoint was absolute change in ppFEV1 from baseline through week 24 for those treated with the tezacaftor/ivacaftor combination treatment compared to placebo. The mean absolute improvement in ppFEV1 was 4,0% from baseline for those treated with the combination treatment compared to placebo. Of the 477 people who completed the 24-week study, 461 chose to enroll in a rollover study to receive the combination treatment.

The EXPAND study (NCT02392234) was a Phase 3, randomized, double-blind, placebo-controlled, crossover study that assessed the efficacy and safety of ivacaftor and tezacaftor in combination with ivacaftor in people with 12 years and older with CF, have one mutation that results in residual CFTR function and one F508del mutation. Participants were randomized to one of six treatment groups to receive tezacaftor/ivacaftor, ivacaftor alone or placebo for eight weeks, followed by an 8-week of no treatment (washout period). Following the washout period, participants switched to one of the other two treatment regimens for another eight weeks. The combination treatment group evaluated tezacaftor 100 mg once daily  in combination with ivacaftor 150 mg every 12 hours, and the ivacaftor alone group assessed ivacaftor 150 mg every 12 hours. 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/ivacaftor combination treatment and ivacaftor alone) compared to placebo. This study met the primary endpoints of absolute change in ppFEV1from baseline to the average of the Week 4 and Week 8 measurements, with the tezacaftor/ivacaftor combination treatment demonstrating a mean absolute improvement of 6.8 percentage points compared to placebo and the ivacaftor alone group demonstrating a mean absolute improvement of 4.7 percentage points compared to placebo. Of the 235 people who completed the study, 227 chose to enroll in a rollover study to receive tezacaftor/ivacaftor combination treatment.

In both studies the combination tezacaftor/ ivacaftor was generally well tolerated. The most common adverse events were infective pulmonary exacerbation and cough. Also, rates of discontinuations  due to adverse events were low and similar between placebo and treatment groups, as were rates of respiratory adverse events.

“The tezacaftor/ivacaftor combination treatment demonstrated clinically meaningful benefits, with a favorable safety profile, across multiple patient groups,” said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex. “This combination treatment may provide a promising new option for treating the underlying cause of CF in the future and brings us increasingly closer to our goal of developing new medicines for all people with the disease.” he added.

How tezacaftor works

In healthy people, the transport of charged ions across cell membranes is achieved through a protein called cystic fibrosis transmembrane regulator (CFTR). The main role of this protein is to serve as a channel, allowing the passage of charged ions such as chlorine or sodium, which are important in the movement of water in the tissues. In this way, thin mucus is produced whose main function is to protect and lubricate the reproductive and other systems; organs such as the lungs and pancreas; and body tissues.

When a mutation occurs in the gene that encodes this protein (the CFTR gene), a defective CFTR protein is produced. The most common of these mutations is the F508del mutation, where an amino acid is deleted in the 508 position of the protein. The channel then doesn’t function properly and the passage of water through the cell membranes is compromised. As a result, thick mucus is produced.

Tezacaftor (or VX-661) is aimed at restoring the CFTR function by correcting the CFTR protein.

Next steps for tezacaftor

Based on these Phase 3 studies results, Vertex plans to submit a New Drug Application (NDA) to the Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the third quarter of 2017 for the tezacaftor/ivacaftor combination treatment in people with CF ages 12 and older who have two copies of the F508del mutation and in people who have one mutation that results in residual CFTR function and F508del mutation.

According to ClinicalTrials.gov, there are ongoing Phase 2 and Phase 3 studies to further investigate tezacaftor’s effectiveness, safety and tolerability in combination with Kalydeco for CF patients with the F508del mutation.

Additional studies will include a triple combination of tezacaftor with other therapies. Vertex announced in October 2016 the start of a Phase 2 study that will include a triple combination of next-generation correctors VX-152 and VX-440, with tezacaftor and Kalydeco.

Vertex also plans to start developing a Phase 1 study of next-generation corrector VX-659 by the end of 2016, and a initiate a Phase 1 trial of a fourth next-gen corrector in 2017, the company announced.

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