Mene PangalosWith such high levels of investment, commercial pressures can cause one to lose sight of basic research principles. With a failing pipeline, Mene Pangalos, Executive Vice President of Innovative Medicines and Early Development at AstraZeneca was one of the key people behind AstraZeneca’s truth-seeking revolution.

Since joining AstraZeneca in 2010, Mene has been an instrumental figure in transforming the company’s commitment to science. As well as driving collaborations with academic, NGO, and peer organisations, he has also been leading the truth-seeking revolution that has been transforming the company’s R&D productivity. Ahead of his plenary presentation at Festival of Genomics London, we caught up with Mene to find out what it takes to put an organisation back on the right path.

This interview was originally published in Issue 6 of Front Line Genomics Magazine

 FLG: I understand you are a fellow graduate of the UCL Ph.D. programme. What attracted you to take that first step into a life of research?

MP: That’s right – I got my degree from Imperial and PhD from the Institute of Neurology, which is part of University College London. I’ve enjoyed science since my early school days and was always particularly interested in understanding how the brain works. I had no idea how a passion for science would translate into a career, given there were no scientists in my family, but when I achieved a first in biochemistry I thought it would be a shame not to continue my training – particularly since I enjoyed it so much. I was accepted for a PhD at the Institute of Neurology, supervised by Professor David Bowen – he was one of the first scientists to discover the cholinergic deficit in Alzheimer’s Disease – a breakthrough that led to one of the mainstay Alzheimer’s therapies of today, acetylcholinesterase inhibitors. I was also sponsored by Merck through my PhD which gave me an invaluable insight into the applied side of research alongside the basic academic research I was doing. And from there I’ve never looked back!

FLG: What prompted you to make the jump into industry?

MP: As I said, during my PhD I was sponsored by Merck. It was during this time I realised that what really interested me was translating research. The opportunity to take basic research and translate that understanding into the discovery of a medicine that could transform the lives of patients really excited me – it felt useful, meaningful and real. I didn’t go straight into pharmaceutical research. My industrial supervisor from Merck, Dr Derek Middlemiss, advised me to do a post-doc in the US – to further my scientific knowledge, but also to experience a new culture and a new way of working. It was great advice which encouraged me to think about my development and career and take some risks. New York where I worked for a few years was wonderful and his advice to be adventurous and take risks has stayed with me over the years. I encourage individuals that work with me to think about their development and challenge them to take leaps that can accelerate their careers.

FLG: It feels like the drug discovery and development paradigm has shifted significantly, now that we’re moving past the ‘blockbuster’ era. Rather than taking a ‘try it and see’ approach or developing ‘one size fits all’ therapies, there seems to be much more focus on developing a more in-depth understanding of a disease and its pharmacogenomics properties earlier on in the process. How would you characterise the change in approach to discovery and development over the past few years?

MP: I think oncology research has been a key driver of this change – and cancer patients have seen the benefits of what we have been able to do. Lung cancer is an area we’re very passionate about and exemplifies what’s been happening in terms of a change in the landscape. Go back 20-30 years and lung cancer would have been defined by histopathology. Do you have small cell or non-small cell? Squamous or non-squamous? You would have taken your biopsy, taken it to a pathologist and they would have diagnosed you and received the devastating news that you have 6-12 months to live. Fast forward to the early 2000s and you’ve got the first oncogenes defined such as KRAS – the first genetic driver of lung cancer. Fast-forward another few years and you’ve got the second one in EGFR receptors, which yielded drugs like Iressa and Tarceva. Go forward to today and we’ve gone from having a couple of genes identified to more than 20 genes known to drive subsets of lung cancer. And what we’ve seen is that when we start to develop molecules that hit those specific subsets change the way we conduct clinical trials, enhance our patient selection, the efficacy relative to the risk and non-response is much much higher.

If you’re on a drug like Iressa, you have EGFR driven disease but after 6-12 months of taking the drug your tumour may develop resistance to the drug. Two thirds of that resistance is driven by a very specific mutation called T790M. 

By understanding that biology and that mutation we were able to develop a molecule that specifically targets the resistance mechanism. That molecule went into man two and half years ago, and it was approved as Tagrisso on Friday 13th November 2015. That’s two and a half years from first in man to launch, which is the fastest-ever approval in the history of our company and our industry. This shows you the power of personalised medicine.

It’s a breakthrough that we are applying in other disease areas such as asthma and COPD where the first drugs are getting approved now for patient populations stratified by how many inflammatory cells patients have in their blood or sputum. We’re starting to stratify patients with lupus, Alzheimer’s disease, patients with diabetes and cardiovascular disease. We are seeing it happen in more and more areas as we build a deeper understanding of the drivers of disease, even in complex non-monogenetic diseases. That’s the excitement of what we see, and with the added benefit of next generation sequencing, where we can sequence not tens or hundreds of genomes but thousands and millions of genomes, the power of the data we can generate becomes even greater so we can hopefully start to see the impact of even subtle levels in genetic variation

Click here to read more of the interview on page 37, including Mene’s take on the differences between the British and American research environments, and how the research direction is applying pressure to the drug development industry.