Cystic fibrosis gene therapy associated with stabilization of lung function

1. In patients with cystic fibrosis, monthly use of non-viral pGM169/GL67A gene therapy was associated with a significant, but modest, benefit in forced expiratory volume in one second (FEV₁) at one year, compared to a decline with placebo.

2. Though this treatment effect was significant, it represented stabilization in lung function for one year rather than an improvement. Therefore, more investigation is warranted to see if this treatment effect is maintained over time.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Cystic fibrosis is caused by a mutation in the CFTR gene. Therapy targeting the CTFR gene, by utilizing inhaled gene-liposome complexes to deliver treatment, has been under investigation. This phase 2b trial investigated the clinical efficacy of the non-viral CFTR pGM169/GL67A gene-liposome complex after repeated delivery to the airways. Over one year, 140 patients with cystic fibrosis were randomly assigned to either a treatment group that received nebulized gene-liposome complex or a control group that received nebulized 0.9% saline every 28 days. Relative change in FEV₁ was the primary endpoint.

At 12 months follow-up, a modest yet significant treatment effect was observed in the group that received the gene-liposome complex compared to placebo. This effect was correlated with stabilization (rather than improvement) of lung function in the treatment group compared to a decline in the placebo group. This trial is important, as it reports the results of the first non-viral based gene therapy for cystic fibrosis. However, this trial required clinical stability at point of entry and may have reflected patients with optimum respiratory health, and therefore may not be generalizable.

Click to read the study in The Lancet Respiratory Medicine

Relevant Reading: Cystic fibrosis transmembrane conductance regulator-mRNA delivery: a novel alternative for cystic fibrosis gene therapy

In-Depth [randomized controlled trial]: This randomized, double-blind, placebo-controlled phase 2b trial, conducted in two cystic fibrosis centers at 18 sites in the UK, aimed to analyze the efficacy of non-viral CFTR gene therapy in individuals with cystic fibrosis. 140 patients aged 12 years or older with FEV₁ 50-90% predicted who had any combination of CFTR gene mutations were randomized to receive either 5ml of nebulized pGM169/GL67A gene-liposome complex (n=78) or 0.9% saline placebo (n=62) every 28 days for 12 months. Primary endpoint was relative change in percent predicted FEV₁.

At 12 months follow-up, a significant treatment effect was observed in the pGM169/GL67A group compared to the control group (3.7%, 95% Confidence Interval [CI] 0.1–7.3; p=0.046. The relative changes for each group were -4.0% in the control group (95% CI -6.6 to -1.4) and -0.4% in the pGM169/GL67A group (-2.8 to 2.1). Retrospective analysis demonstrated that 21 patients (18%; n=6 in the control group and n=15 in the pGM169/GL67A group) experienced an improvement in percent predicted FEV₁ of 5% or more from their baseline values.

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