A Phase 2b clinical trial of non-viral gene therapy in Cystic Fibrosis patients: randomized, double-blind, placebo-controlled repeated aerosol delivery to the lungs.

Gill DR

The European Society of Gene and Cell Therapy Conference, Helsinki, 2015

The UK Cystic Fibrosis Gene Therapy Consortium has undertaken an extensive pre-clinical programme, including repeat-dose toxicology studies in mice and sheep, together with a Phase 1/2a safety study in Cystic Fibrosis (CF) patients to assess aerosol delivery of non-viral plasmid DNA/liposomes to the lungs.

The formulation is composed of GL67A liposomes complexed with plasmid pGM169, which is completely free of CpG dinucleotides and directs persistent high-level expression of codon-optimised CFTR under the control of the hCEFI promoter/enhancer (Hyde et al 2008 Nature Biotechnology 26: 549-551).

The Phase 1/2a trial in CF patients identified a safe (5ml) aerosol dose delivered to the lungs via a Trudell AeroEclipse II nebuliser. In a follow-on Phase 2b study, CF patients with an FEV1 % predicted lung function of between 50 and 90% were recruited to measure potential clinical benefit following delivery of 12 aerosol doses at monthly (28 ± 5 day) intervals.

The double-blind, placebo-controlled trial compared the above formulation with 0.9% saline in a 1:1 randomisation. The Per Protocol patient group (pre-defined as receiving 9 or more doses) consisted of 116 patients (52 Placebo and 64 Active). Two small (n=24) patient sub-groups also underwent either additional nasal administration, or bronchoscopic measurements, to evaluate molecular surrogates (2:1 randomisation Active: Placebo).

Data for safety and primary/secondary efficacy outcome measures will be presented.

Supported by the NIHR EME programme and the CF Trust.


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