Friday, 3 July 2015

Phase 2b Gene Therapy Results

Today the results of the UK CF Gene Therapy Consortium’s Phase 2b clinical trial were published in Lancet Respiratory Medicine. The trial achieved its primary endpoint by showing gene therapy improves FEV1 in a statistically significant way. It is a big step forward for CF science.

·         The CF gene is essentially an instruction to cells to produce a certain protein (CFTR) that is needed to allow salt and water to pass across cell membranes. Without this protein, airways and other important tubes get clogged with sticky mucus that a) obstructs the tubes; and b) acts as a breeding ground for bugs. Researchers are trying to find CF therapies to address the underlying defect at both the gene and the protein level. There is also an intermediate step where the CF gene produces a copy of itself (called RNA) and that copy is used by the cell to manufacture the CFTR protein. Researchers are looking to design therapies that work at the RNA-level too (e.g. ProQR).  

·         CFTR modulators like Ivacaftor are thought to work by attaching to the defective CFTR protein and encouraging it to work properly. They do not do anything at a genetic level. Since different CF mutations mean different defects in the CFTR protein, CFTR modulators are developed for specific mutations. This is one reason why they are extremely high priced. Gene therapy works by putting a working copy of the CFTR gene into cells so that the cells themselves produce normal CFTR protein (just like someone who does not have CF) so the individual CF mutation is irrelevant. This should also make the therapy more cost effective.

·         It is hard to get the gene therapy into the airways where it can actually work because the lungs have evolved very effective self-defence mechanisms. Getting gene therapy into the lungs means penetrating these natural defences as well as getting through all the mucus that clogs the airways of people with CF. This needs to be done without triggering an immune response that creates problems which outweigh any benefit of the therapy. So the key challenges are delivery and safety.

·         While gene therapy is not yet a finished product and patients on the Phase 2b trial probably did not feel major improvements in themselves, the results show that gene therapy can safely deliver statistically significant treatment effects. Scientists think the efficacy can be improved by increasing the dose/frequency of administration and tweaking the vector (i.e. the design of the “missile” that delivers the gene therapy “payload”). It is an important stepping stone in the development of gene-based therapies that seek to correct the underlying defect and achieve a functional cure for all CF mutations.

·         The 3.7% difference in mean relative % predicted FEV1 in the gene therapy group compared to placebo is only slightly lower than that seen in the Phase 3 trials of Lumacaftor/Ivacaftor in homozygous F508dels (4.3-6.7%).

·         There were no safety issues.

·         The gene therapy essentially stabilised lung function – the 3.7% difference was driven by deterioration in the placebo group.

·         There was a wide variation in response. The gene therapy benefited some much more than others and it is not clear why.

·         A wide range of mutations were included in the trial and treatment effects were independent of mutation.

·         Those with more severe disease (less than 70% FEV1) saw bigger effects but it is not clear why this is. Intuitively, it makes sense that greater mucus obstruction in the smaller airways of those with more sever disease would mean more drug dwelling in the larger airways with a greater opportunity to act. It may also be harder to show benefit in patients who are already relatively well.

·         This trial has shown repeat doses of gene therapy can be delivered into the lungs in a way that is safe and produces benefits in terms of key health markers. Hopefully it will give researchers and funders confidence to build on this work and explore the potential to tweak the dose and/or the frequency of administration; develop superior vectors; and also find an efficient way to test gene therapy in combination with CFTR modulators like Ivacaftor.

·         Further out, the data should have positive implications for future iterations of gene therapy, RNA-based therapies and gene editing approaches; and the UK GTC’s data, know-how and experience is a community asset that will inform work in all these areas.

·         It is an exciting time in CF because Ivacaftor has shown that, in certain mutations, the functionality of the CFTR protein can be rescued and that, when this is done, people with CF get a lot better. It has shown us what the destination looks like. However, the recent results from Vertex’s Phase 3 trials of Lumacaftor and Ivacaftor in combination for people with two copies of DF508del, the most common mutation, show there is a long way to go before people with that mutation and other rarer ones have a CFTR modulator therapy that does for them what Ivacaftor monotherapy does for G551Ds. Even if they work, we may not be able to afford them. 

·         While Ivacaftor for G551Ds has set expectations sky high, in reality for most people alive today with CF, stabilisation would be a very successful outcome. Stabilisation, if maintained over a number of years (as compared to the standard annual 2-3% decline), could mean that a person with CF takes, say, 60 years to get to the point where they need a transplant rather than, say, 40 years and that is a big deal – it could mean a very different kind of life for them and those around them.

·         For mutations which are not responsive to Ivacaftor monotherapy, it is unlikely that a single pill or other form of treatment will have all the answers. It is likely we will need combinations of different forms of therapies (gene-based, RNA-based and protein-based) working together and some form of gene therapy could be a component of the overall solution.

·         This trial and the openness in relation to the data is a huge credit to the UK CF community and it makes me proud to be part of it. While the Phase 2b trial itself was funded by MRC/NIHR, a huge amount of work has taken place over the last 15 years to get to this point and 90% of the overall funding has come directly from the UK CF community. Indeed, it was the Cystic Fibrosis Trust that put the UK Gene Therapy Consortium together in the first place. Adults with CF and parents of children with CF have made this happen.

·         It has cost around £45m to get to this point. This is much less than the figures usually sited by industry for getting through Phase 2.


·         Patients from 18 UK hospitals were able to take part in the trial. Not many hospitals have the facilities or the capability to do trials like this but allowing local hospitals (acting as “Patient Identification Centres”) to refer willing and eligible patients to one of the two participating centres meant the trial could recruit to target and it extended the opportunity to participate to a much wider group of patients. There is going to be an increasing bottleneck in CF drug development as the big CF centres are unable to cope with all the trials that will need to be done to convert the pipeline and exciting science behind it into therapies for patients. There is also an issue of equality of access to trials - it is not fair that only patients at the big CF centres should have the opportunity to take part in clinical trials. The Patient Identification Centre model, used for the first time in the Phase 2b gene therapy trial, may be a way to address some of these important issues.