A phase IIb Double-Blind Placebo-Controlled Trial of Non-Viral Gene Transfer for Cystic Fibrosis.

Pringle IA, Alton EW, Boyd AC, Cheng SH, Cunningham S, Gill DR, Griesenbach U, Higgins TE, Hyde SC, Inness AJ, Porteous DD, Scheule RK

Molecular Therapy, Vol 22, S1a, Abstract 593


The American Society of Gene and Cell Therapy Annual Conference, Washington DC, 2014

StagedFrontPageDelivery.jpgThe UK CF Gene Therapy Consortium is developing both non-viral and lentivirus-mediated CFTR gene transfer to the lung as a potential treatment for cystic fibrosis (CF). Non-viral CFTR gene transfer, where cationic liposomes are complexed with plasmid DNA, can partially correct the ion-transport defects associated with CF, although the effects to date have been transient.

In order to offer patients realistic clinical benefit, we further developed our non-viral formulation by:

  1. Generating the novel hCEFI enhancer/promoter sequence capable of directing persistent in vivo lung CFTR expression;
  2. Constructing pGM169, a novel plasmid entirely free of CG dinucleotides (CpGs detected by TLR-9) to minimise inflammatory responses, containing a CFTR cDNA under the control of the hCEFI enhancer/promoter;
  3. Identifying the optimal non-viral liposomal formulation (GL67A) for lung plasmid delivery;
  4. Selecting the optimal nebuliser (Trudell AeroEclipseII) for delivery of pGM169/GL67A aerosol to the CF lung.

In a Phase I/IIa open-label clinical study, we identified a safe dose of the pGM169/GL67A formulation (5ml containing 13.25mg pGM169 & 75mg GL67A) which directed changes in nasal and lung potential difference measurements consistent with correction of the CF chloride channel defect and improvement in lung function as determined by lung clearance index. Subsequently, a multi-dose toxicology programme in mice has shown a cumulative effect of repeated administration, with 12 pGM169/GL67A doses resulting in human CFTR expression at levels equivalent to ∼100% of endogenous Cftr levels.

These studies supported initiation of a Phase IIb double-blind placebo-controlled trial which began in June 2012. CF patients with 50% ≤ FEV1 ≤ 90% receive 12 monthly administrations of either pGM169/GL67A (n≥60) or 0.9% saline (n≥60) in a 1:1 randomisation; all CF mutation classes are included. The primary outcome is change in FEV1 with multiple secondary outcomes for clinical efficacy and safety. Twenty-four patients also receive a monthly 2ml nasal dose, to allow sequential measurement of nasal PD, and a further 24 have measurements of bronchial PD pre- and post-treatment (randomisation 2:1 for these mechanistic studies).

This subgroup will address whether: a) changes in nasal PD predict those in bronchial PD, and b) whether either measurement predicts any clinical changes following treatment. In total, 166 patients have attended screening visits, of which 136 progressed to dosing. 61 patients have completed the study and the remainder have had at least 8 doses.
All pre-treatment bronchoscopies for bronchial PD measurements have been successfully undertaken, and three independent Data Safety Monitoring Board reviews have not identified any problems. The study is on track to be completed in summer 2014. The trial is funded by the National Institute for Health Research's EME programme. Work leading up to the trial was funded by the UK CF Trust.