Reducing Safety-Related Drug Attrition
Gareth Waldron is Gareth Waldron, Non-Clinical Safety Lead at Pfizer Neusentis. We spoke to Gareth about about in vitro pharmacological profiling, how it could be implemented to reduce this attrition and the success stories so far.
Gerald Clarke So, Gareth, what are the main causes of safety related drug attrition?
Gareth Waldron So, I think the pharma industry has lived through the era of QT related attrition, and some of the old favourites such as drug induced liver injury, and cardio tox continuing to cause attrition. Also, I think there’s now increased scrutiny on increases in blood pressure, which sometimes means being very conservative in not want to take forward compounds that cause what are, in fact, fairly modest increases in blood pressure in preclinical species, they’re only finding this out in humans in large phase three trials where the levels of the stringency for increased blood pressure are pretty high.
Clarke So what role can in vitro pharmacological profiling play in reducing this?
Waldron In vitro pharmacological profiling can have pivotal roles in decreasing attrition, but two of the largest roles are in early characterisation of the chemical series to determine how promiscuous the chemical scaffold is, i.e. Is the end compound likely to have many of the targets that would cause attrition? Or is it going to be very selective and have few off target liabilities. We think the second role is characterisation of that potential final compound, to identify any particularly large liabilities that it may hold, to allow one to go out and look for those liabilities in vivo studies, or even in early human studies.
Clarke So, what are the main challenges of this method?
Waldron I think the main challenges for in vitro pharmacological profiling, as with any predictive technology, is the building up of a robust set of data from which knowledge can be gained. With the variety of in vitro technology that can be used, different in vitro numbers, for example IC50s or KIs can be obtained from target. This, coupled with the in vitro to animal, then animal to human translation, where in the human the data can be either poor in resolution or rare in occurrence, can make the building and translation of knowledge pretty difficult.
Clarke Have there been any success stories so far?
Waldron I think many people think hERG is a special case for in vitro safety, but my view is in fact it’s a prototypical example for an off target pharmacology. An FDA colleague put it this way: Who would have thought that an anti-histamine, targeted at hayfever, would block cardiac ion channel? At the time he was referring to terfenadine or seldane which were the main compounds which brought the QTC issues to the forefront of pharmas thinking about drug safety. It did take the industry around ten years to understand hERG prolongation, but we did it, and now we know where we stand. And we’re now looking to move forward and streamline the scheme paradigm with the use of normal technologies, such as in silico modelling, use of stem cells, cardiomyocytes. Even questioning the utility of the thorough QT study, such that we can decrease the screening burden whilst not losing any of the stringency on human drug safety.
Clarke So what do you think will be the main changes in this field in the coming 18 months?
Waldron I hope we’ll see more expansion into newer classes of targets, such as further extensions to kinase space, assessment of epiphetic targets and transporters, outside of the monoamine transporters of DATs, NETs and SERTs, into transporters that are more traditionally viewed as being in ADME space. This hopefully will bring together experts with opinions from outside the classical GPCR and ion channel screening fields, along with the pharmacologists that have been running those in vitro pharmacological profiling in such a way that the former can bring some new science and the latter can pass on the experience in setting up the panels and targets, and how we start building that translational knowledge.
Clarke So you’re speaking at the Predictive Toxicology Summit 2014 in London, England. What topics are you most looking forward to discussing with the other attendees?
Waldron I think I’m looking forward to discussing how we identify and best use opportunities for future sharing. I think even the creation of a robust translational knowledge for a single target is probably beyond a single company, so we have to work together. There are already many initiatives in this base, and I’d look forward to learning from others what has worked and not worked in those data sharing initiatives. That would be great.
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First published: 18/12/2013