Single Dose Pilot Study

A pharmacy ready box of GL67A and pGM169 plasmid.

Pilot study for gene therapy
So far, the Gene Therapy Consortium has given 10ml doses of the gene therapy product to three patients and 20ml doses to 13 patients. The main aim of this study is to assess the safety of the Wave 1 product.

The doses are given in a filtered cubicle through a nebuliser and each patient also has a small dose in the nose from a nasal spray every five minutes. The 20ml doses have taken 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. The first six patients were kept in hospital for overnight monitoring.

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

Results so far
All the patients have had a mild flu-like reaction to the dose with temporarily raised temperature and a temporary 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 10ml was less than in those who had 20ml. The symptoms were short lived and mostly gone in one or two days. One patient felt tired for several days following the dose, another reported feeling better than before dosing, and another went swimming the following morning.

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 (as has already been seen with the 10ml dose) or disappear.

With regards to looking for molecular efficiency (ie. was the CFTR protein made), the intention had been to assess this either two days or 14 days after gene delivery. After the first few patients had this reaction, the Consortium changed the design of the trial to perform bronchoscopies on day six or day 14 because it was felt unwise to give a general anaesthetic (necessary to undertake the bronchoscopy) to people just at the time of this flu-like reaction. This led to a delay whilst this was approved by the Medicines and Healthcare Products Regulation Agency (MHRA) and the Gene Therapy Advisory Committee (GTAC) - two Government bodies who regulate clinical trials and who have very exacting and time-consuming regulations to help ensure patient safety. All new treatments have to be approved by the MHRA and any gene therapy additionally has to satisfy GTAC.

Encouragingly, many of the patients are showing evidence for new normal CFTR protein being produced in their nose and lungs following the gene therapy. In some cases, the amount of protein has been up to the level of that in people without CF - the largest changes ever recorded using any type of therapy worldwide in Cystic Fibrosis. We must be quite clear that this only happened in a few of the subjects.

Where next?
Although the flu-like reaction is not severe, and not a problem for a one-off dose, the Consortium concluded that it may not be advisable to repeat this dose of treatment monthly to people who have Cystic Fibrosis. The next few patients in the Pilot Study will therefore have the dosing time, or the dose itself altered, to find an acceptable way of delivering the gene repeatedly. This change in the design of the Pilot study means that the likely end date for this study will now be in late spring/early summer 2010.

Importantly, the overall gene therapy programme will not be delayed as a result of this, because based on the evidence and the likelihood that the flu-like reaction can be markedly reduced or prevented altogether, the Scientific Advisory Committee advised the Trustees of the CF Trust that we should proceed with the multidose trial. In order to prevent delay, we will now proceed with the preclinical toxicology programme that must precede the multi-dose trial in people with Cystic Fibrosis. Previously, the product for this was not going to be ordered until after the pilot study was completed. This is encouraging news, although as is hardly surprising with a therapy that is breaking new scientific ground, there will always be challenges to overcome.


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