Tezacaftor (VX-661) for Cystic Fibrosis

Tezacaftor (VX-661) is an oral medication for cystic fibrosis (CF) developed by Vertex Pharmaceuticals. In a combination therapy formulation called Symdeko (tezacaftor plus ivacaftor), it is approved in the U.S. and Canada for CF patients, ages 12 and older, who have two copies of the F508del mutation in the CFTR gene and one minimal function mutation. Symdeko is approved and marketed in the EU as Symkevi.

Tezacaftor is not approved as a stand-alone treatment, but as part of a combination therapy.

How tezacaftor works

The transport of charged ions across cell membranes is achieved through a protein called the cystic fibrosis transmembrane regulator (CFTR). This protein’s main role is to function as a channel across cell membranes, allowing the passage of charged ions such as chlorine or sodium, which are important in the movement of water in tissues. Proper functioning of the channel maintains the viscosity of the mucus lining various organs, including the lungs.

In CF, mutations in the CFTR gene that encodes for this protein results in the production of a defective CFTR protein. This hinders the workings of the channel and compromises the transport of water and salts across cell membranes. The result is the formation of thick, sticky mucus that can accumulate in the lungs, pancreas, kidneys, and other organs.

The most common mutation in the CFTR gene is the so-called F508del mutation, which results in one amino acid missing in the CFTR protein at position 508. (Amino acids are building blocks of proteins.)

CFTR modulators are a specialized group of therapeutics that address the underlying cause of CFTR protein dysfunction. Tezacaftor is one type of CFTR modulator —  a so-called corrector. Its function is to correct the positioning of the CFTR protein on the cell surface to permit proper channel formation and improved flow of water and salts across the cell membrane. (Ivacaftor, which is a stand-alone treatment for those with gating mutations and available under the brand name Kalydeco, is a potentiator, meaning it helps ions to flow through the channel.)

Tezacaftor in clinical trials

Several clinical trials have tested the efficacy of tezacaftor in combination with other therapeutics in CF patients.

In a Phase 2 study (NCT01531673), researchers evaluated the safety and efficacy of tezacaftor alone or in combination with Kalydeco (ivacaftor) in patients with CF who carry one or two F508del mutations. The study also monitored the movement of the medications in the body (pharmacokinetics) and the way the body processes the therapeutic (pharmacodynamics). Researchers reported that tezacaftor as a combination therapy with Kalydeco fared significantly better than tezacaftor alone in alleviating CF symptoms.

Positive results from two Phase 3 studies (EVOLVE and EXPAND) led to the approval of Symdeko in the U.S., Canada, and the E.U.

In the EVOLVE study (NCT02347657), researchers assessed the efficacy and safety of Symdeko in CF patients with two copies of the F508del CFTR mutation. A total of 510 patients (ages  12 and older) were included in this study. They were randomly grouped to treatment with Symdeko, Kalydeco alone, or a placebo. Patients in the combo treatment group received an oral dose of tezacaftor at 100 mg once a day plus ivacaftor at 150 mg every 12 hours for 24 weeks. The team evaluated the change in the percentage of the predicted forced expiratory volume in 1 second (ppFEV1) from the start of the study (baseline) as a measure of lung function.

Those given the combination therapy had a significant improvement in lung function as seen by a ppFEV1 change from study start of 4 percent compared to the placebo group. The rate of pulmonary exacerbations was also 35 percent lower in the combination therapy group compared to the placebo. Adverse events were rare in both groups.

The EXPAND study (NCT02392234) compared the safety and efficacy of tezacaftor/ivacaftor combination therapy, Kalydeco monotherapy, and placebo. A total of 248 CF patients, ages 12 and older, with one mutation that results in residual CFTR function and one F508del mutation were included in this study. Participants were randomly assigned to one of the treatment groups — tezacaftor/ivacaftor, Kalydeco alone, or placebo — for eight weeks, followed by eight weeks of no treatment (a washout period). Patients were then switched to one of the other two treatment regimens for another eight weeks. Participants in the tezacaftor/ivacaftor combination therapy group received one oral dose of tezacaftor at 100 mg daily plus 150 mg Kalydeco every 12 hours. Patients on Kalydeco alone were given 150 mg tablets every 12 hours.

The primary outcome measure of EXPAND was lung function improvement. The ppFEV1 of participants was measured at the start of the study, at week 4, and at week 8. An average of week 4 and week 8 ppFEV1 values were calculated and used to measure the change in ppFEV1 from baseline. The tezacaftor/ivacaftor combination therapy group showed a significant improvement of 6.8 percentage points compared to placebo, while the Kalydeco alone group had a mean absolute increase of 4.7 percentage points compared to placebo, confirming better efficacy of the combination therapy.

Of the 235 people who completed the EXPAND, 227 chose to enroll in a rollover study (NCT02565914)for long-term Symdeko treatment.

In both EVOLVE and EXPAND, the combination tezacaftor/ivacaftor was generally well-tolerated. The most common adverse events were pulmonary exacerbations and coughing. The rates of treatment discontinuation due to adverse events were low and similar between placebo and treatment groups, as were rates of respiratory adverse events.

A separate Phase 3 study (NCT02953314) tested the safety and efficacy of tezacaftor/ivacaftor combination treatment in 70 children with CF, ages 6 to 11, who have one or two copies of the F508del-CFTR mutation. This multi-center study is thought to have ending in August 2018, but results have not yet been published.

Several Phase 2 and Phase 3 clinical trials evaluating tezacaftor as a triple combination therapy other CFTR modulators are also underway. More information about these trials can be found here.


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