Drug discovery is a time consuming and expensive undertaking. Currently it commonly takes between 10 to 15 years to get from the start of the discovery process through to launch (if you make it !) and the cost can range from $2 billion to $5 billion depending upon whose statistics you reference. The preclinical discovery phase tends to be short and relatively cost effective, the output of which then runs the gauntlet of a battery of toxicity and safety tests before being allowed to enter testing in humans. After what is usually a relatively short efficacy study in a small number of patients provides a suggestion that the drug may work, a series of larger and longer clinical studies ensure that the drug is both safe and effective. If all goes well in these studies the regulatory authorities, usually FDA or the EMEA, will review the extensive data package and if opinion is positive, give approval for the drug to be launched for use in routine clinical practice.
We all want this process to be faster and more effective but without any compromise on safety and determination of efficacy – and by ‘we’ I mean drug discovers, patients, the pharmaceutical industry and regulators. We also want the process ideally to be more efficient and predictive with less chance of failure, particularly in late stage, expensive studies (one of the major reasons the costs above are in the billions – if every drug that entered clinical studies worked the cost of discovering a new drug would be ~$350 million). A focus on orphan diseases where patients are more homogeneous and we have strong understanding of the genetic basis of their disease is delivering higher success rates. Perhaps the poster child for this approach has been cystic fibrosis and the introduction of therapies that effectively address the genetic defect by repairing the defective protein – in CF it’s the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel. Vertex Pharmaceuticals introduced the first of its expanding portfolio of CFTR repair therapies in 2012 – this was the CFTR potentiator, ivacaftor (tradename Kalydeco). Ivacaftor demonstrated impressive clinical effects in patients with a specific CFTR mutation (G551D) and has demonstrated efficacy in a number of follow on trials in CF patients with mutations which are biophysically similar to G551D (a CFTR protein that makes it to the cell membrane but is loathe to open). G551D is the third most common CF disease causing mutation that accounts for somewhere between 2 – 5% of the CF population so relatively rare as there are estimated to be ~70,000 patients worldwide.
So what happens if you have a medicine which you believe will deliver benefit to additional patients but they are few and far between, with not enough to undertake a robust phase 3 trial ? This was the conundrum facing Vertex when looking to expand the labelling for Ivacaftor. In what is the first of its kind the FDA granted expanded approval to Vertex for Ivacaftor based upon in vitro data only. This could be a landmark step and the FDA has acknowledged that this approach could have implication for other drugs that have a well understood safety profile and address well characterised diseases. With Ivacaftor Vertex have a drug with a robust safety package, a strong understanding of its mechanism of action and have put considerable effort into assessing the correlation between preclinical cellular assays, clinical biomarkers and registerable endpoints. To support the request for expanded labelling Vertex expressed ~50 mutations in Fisher rat thyroid cells, a cell system widely used by the CF field as it has low expression of background chloride channels and can be used in a variety of assays (including Ussing chamber ion transport). Mutations that delivered a 10% increase in chloride transport when treated with Ivacaftor were considered responsive. This wasn’t an arbitrarily selected figure but one borne out by Vertex’s clinical experience with Ivacaftor and other compounds from their developing CFTR repair portfolio. Of those tested 23 mutations have been added to Ivacaftors labelling (26 failed to meet the criteria).
In real terms this means that ~900 CF patients in the US alone will now have the opportunity to access this breakthrough medicine – my congratulations to Vertex for pioneering the approach and my congratulations to the FDA for entertaining it….let’s hope it can be pursued for many other diseases.
Blog written by Martin Gosling
Durmowicz A.G et al (2018) The FDA’s experience with Icavaftor in cystic fibrosis: establishing efficacy using in vitro data in lieu of a clinical trial. Ann Am Thorac Soc. 2018 Jan;15(1):1-2. doi: 10.1513/AnnalsATS.201708-668PS.
Kingwell K (2017) FDA Oks first in vitro route to expanded approval. Nature Reviews Drug Discovery; doi:10.1038/nrd.2017.140