The UK Cystic Fibrosis Gene Therapy Consortium: Single Dose Clincal Trial

Single Dose Clinical Trial

Pilot study for gene therapy

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Patients receive the gene therapy via a nebuliser.

The aim of this study is to assess the safety of a single dose of the Wave 1 product. To date, over 30 patients have a received a dose of the gene therapy. Patients have been treated with different quantities of the gene therapy formulation to assess the optimal dose going forward to the multi-dose clinical trial.

The gene therapy is administered in a filtered cubicle through a nebuliser and some patients also have a small dose in the nose from a nasal spray. A 20ml dose takes around 1 ½ hours to administer. Each patient has any symptoms recorded and has physical examinations, oxygen saturation levels, spirometry, CT scans and numerous blood and sputum tests. A subgroup of patients were kept in hospital for overnight monitoring after dosing.

Although the primary purpose of the study was not to check for efficacy, the clinicians have also been taking some measurements to see if the single dose is having any effect (at a molecular level, not for clinical benefit).

Patients on the pilot study underwent the following tests at study visits (some of the patients did not undergo all of these procedures):

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Nasal Potential Difference Analysis. A measurement taken as part of the Single Dose Clinical Trial (Pilot Study)

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Some patients receive a small dose of gene therapy in the nose via nasal spray.

- Medical history and clinical examination
-Blood and urine samples taken
- Spirometry
- Lung function tests
- Nasal Potential Difference analysis
- Bronchoscopies
- Nasal brushings
- Sputum analysis
- Completion of diary card
- Lung clearance index (LCI)
- Airway mucosal blood flow
- Gas transfer tests

A gas transfer test. A measurement as part of the Single Dose Clinical Trial (Pilot Study)

Some patients had a mild flu-like reaction to the dose with a temporarily raised temperature and drop in FEV1 (which were noticed more by clinical measurements than the patients themselves) along with other mild symptoms. The response in the patients who had a lower dose was less than in those who had a higher dose. The symptoms were short lived and mostly gone in one or two days.

One of the areas of work the Consortium has undertaken was to refine the plasmid DNA (the correct version of the gene) to remove elements which are believed to cause this flu-like reaction, which was also seen in a previous lung trial. The changes made in the plasmid were successful in reducing these flu-like reactions in animal models. However in the CF patients, there is likely to be another important component, namely the amount of gloopy, fatty substance (the gene transfer agent) being delivered to the lungs. The pilot study is using a new and highly efficient nebuliser, which deposits about 75% more of the gene into the airways than occurred in the first trial. Both the Consortium and the CF Trust's Scientific Advisory Committee think it likely that we are now being over-efficient and the lungs are simply responding to the large volume of this material. Once the amount delivered is reduced, the expectation is that the symptoms will reduce or disappear.

A pharmacy ready box of GL67A and pGM169 plasmid.

The pilot study is now completed and the data is being analysed. Results will be presented at the North American Cystic Fibrosis Conference.

The Consortium will present the results from this study to the CF Trust's Scientific Advisory Committee to agree on the optimal dose to take forward to the
multi-dose clinical trial.