A clinical study to evaluate the safety and efficacy of pGM169/GL67A administered to the nose and lungs of individuals with cystic fibrosis.

Hyde SC, Davies JC, Griesenbach U, Higgins T, Alton EW, Boyd AC, Innes A, Porteous D, Gill DR

Molecular Therapy, 18 S1 Late Breaking

The American Society of Gene and Cell Therapy Annual Conference, Washington DC, 2010

The UK CF Gene Therapy Consortium is committed to the development of a safe and effective gene therapy treatment for individuals with cystic fibrosis (CF). Extensive pre-clinical studies have led to the selection of our currently preferred non-viral gene transfer product pGM169/GL67A; which consists of pGM169, an entirely CpG-free plasmid DNA containing the human CFTR cDNA under the control of the hCEFI promoter (Hyde et al Nature Biotechnology 26:549), complexed with GL67A, a mixture of three lipids: GL67, DOPE and DMPE-PEG5000.

We are currently undertaking a single-dose safety and efficacy clinical study in which we are assessing delivery of up to 20mL of pGM169/GL67A (containing 2.65mg/mL pGM169 and 14.41mg/mL GL67A) to the lungs via an AeroEclipse II breath-actuated nebuliser (Trudell Medical International) and a nasal dose of 10% of the nebulised volume administered on the same occasion using a standard nasal spray device. Safety measures include physical examination, chest CT, lung physiology (spirometry, pulse oximetry, lung clearance index), systemic and sputum inflammatory markers, renal and hepatic function, anti-nuclear and anti-double stranded DNA antibodies and specific CFTR-related T cell responses.

Efficacy measures include assessment of vector specific CFTR mRNA levels by QRT-PCR on nasal and bronchial brushings, CFTR protein levels by immunohistochemistry and CFTR function by potential difference (PD) measurements. Safety and efficacy measures are made at intervals prior to dosing and during a 28 day follow up period, bronchoscopies for lower airway measurements are performed under general anaesthesia prior to and either 6 or 14 days post-dosing. To date, 16 subjects have completed the study, 3 receiving a 10mL lung dose and 13 receiving a 20mL lung dose.

The study is ongoing. An interim analysis reveals that, as in our previous clinical studies with GL67A, the majority of subjects have experienced transient mild flu-like symptoms with raised temperature and a drop in FEV1. These symptoms were self-limiting and short lived - typically resolving within 24-48 hours. Changes in nasal PD consistent with the correction of the CF chloride secretion defect have been observed in 5 of 13 subjects receiving the 20mL lung dose. Encouragingly, PD changes have been sustained in the best cases for up to 6 weeks post-dosing. In subsequent subjects, dosing delivery time and/or dose delivered will be varied in attempts to further reduce the mild-flu like symptoms while retaining the observed efficacy.

It is anticipated that the safety and efficacy profile of pGM169/GL67A will support a planned multi-dose clinical study, the endpoint of which, rather than being a surrogate molecular or electrophysiological assay, will be, for the first time in a CF gene therapy study, to detect clinical benefit.