Combined Tezacaftor, Kalydeco Therapy Significantly Improved CF Lung Function in Clinical Trials

Combined Tezacaftor, Kalydeco Therapy Significantly Improved CF Lung Function in Clinical Trials

Vertex Pharmaceuticals recently announced positive results of two Phase 3 clinical trials, the EVOLVE and EXPAND studies, evaluating the effects of a combination of tezacaftor (VX-661) and ivacaftor (sold under the brand name Kalydeco) in cystic fibrosis (CF).

The results showed that the new combined therapy significantly improved lung function in CF patients carrying either one or two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is the defective gene underlying cystic fibrosis.

The EVOLVE trial (NCT02347657) studied the effects of tezacaftor/Kalydeco in CF patients carrying two copies of the F508del mutation in their CFTR gene. Over 24 weeks, these patients (who were at least 12 years old) were randomly assigned to receive tezacaftor 100 mg once daily in combination with Kalydeco 150 mg every 12 hours. The effects of the treatment were compared to those receiving a placebo control.

The group who received the tezacaftor/Kalydeco combination showed an improvement of 4% from baseline in the percent predicted forced expiratory volume in one second, or ppFEV1 (a parameter that measures lung function), compared to placebo controls. Researchers also observed that the treated group showed a 35% reduction in the annualized rate of pulmonary exacerbations relative to the placebo group.

In the EXPAND study (NCT02392234) researchers evaluated the effectiveness and safety of the tezacaftor/Kalydeco combination, but also the effects of Kalydeco as a single therapy, in patients with CF who had one copy of the F508del mutation and one mutation that impacted CFTR function. Patients were randomly assigned to receive tezacaftor/Kalydeco, Kalydeco monotherapy, or placebo for eight weeks. Afterward, they underwent an eight-week washout period and switched to one of the other two treatment regimens for another eight weeks.

The treatments were as follows: tezacaftor 100 mg once a day in combination with Kalydeco 150 mg every 12 hours, while the monotherapy group received Kalydeco 150 mg every 12 hours.

Both treatments showed a significant improvement in ppFEV1 from baseline when compared to placebo – specifically, a 6.8% improvement in patients treated with the combination of tezacaftor/Kalydeco, and 4.7% for the monotherapy.

When comparing the combination of tezacaftor/Kalydeco with Kalydeco alone, the combined therapy was more efficient, with a 2.1% improvement relative to the single therapy of Kalydeco.

“The tezacaftor/ivacaftor combination treatment demonstrated clinically meaningful benefits, with a favorable safety profile, across multiple patient groups,” Jeffrey Chodakewitz, MD, executive vice president and chief medical officer at Vertex, said in a press release.

“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.” Chodakewitz added.

Vertex now plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), as well as a Marketing Authorization Application to the European Medicines Agency (EMA), both in the third quarter of 2017, for tezacaftor/Kalydeco combination therapy for CF patients ages 12 and older with either two copies of the F508del mutation or one copy of the F508del mutation and one mutation that results in residual CFTR function.

3 comments

  1. Catherine says:

    What mutations result in “residual function of the CFTR protein”?
    Does either of these drug combos help those with one delta F508 mutation plus a Stop mutation: R1162X ?
    Thank you.

    • Scott Wakefield says:

      According to the article, “Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients”, at:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964615/
      “Predicted CFTR function: ‘Residual’: carrying at least one partial function CFTR mutation (class IV or V).”
      Here is a “Classification of CFTR alleles”:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964615/table/T1/
      Class IV Decreased Channel Conductance
      Class V Reduced Synthesis and/or Trafficking
      Class IV A800G, D1152H, D1154G, D614G, delM1140, E822K, G314E, G576A, G622D, G85E, H620Q, I1139V, I1234V, L1335P, M1137V, P67L, R117C, R117P, R117H, R334W, R347H, R347P, R347P/R347H, R792G, S1251N, V232D
      Class V 2789+5G > A, 3120G > A, 3272-26A > G, 3849+10kbC > T, 5T variant, 621+3A > G, 711+3A > G, A445E, A455E, IVS8 poly T, P574H
      Catherine, unfortunately, the chart lists both R1162X and 1078delT as:
      Class I Defective Protein Synthesis (nonsense, frameshift, aberrant splicing)

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