Interview / Dr. Menelas N. Pangalos | FRSB, FMedSci, EVP & President BioPharmaceuticals R&D, AstraZeneca
“Since I have been working for AstraZeneca, I am proud to say I have seen some huge, positive changes. We have launched nine new transformational medicines across a range of diseases including cancer, asthma, diabetes and heart disease, which have collectively helped to treat millions of patients. I’m really pleased to say the improvement in the quality of our pipeline has been remarkable. My goal continues to be to make sure we conduct the best science, which we then translate into life-changing medicines for patients.”
Dr. Menelas N. Pangalos: a member of the Greek Diaspora. Please talk to us about your life, your academic career and your work in the pharmaceutical industry.
I was born in London, to a Greek family who had settled in England. My mother was born on the island of Chios, and my father is descended from there; this is where I spent my summer childhoods and has been the single constant every year of my life.
I’ve always had a passion for science, and one of the things that fascinated me the most was understanding how the brain works. No one in my family had been to university, but I was fortunate that both my parents were very supportive of me continuing my higher education. My love for science really started to blossom after school, when I studied biochemistry at London Universities’ Imperial College of Science and Technology. To my pleasant surprise, I achieved a first-class honours degree which really gave me the confidence to pursue a scientific career.
After my degree, I applied for a PhD at the Institute of Neurology, which is part of University College London (UCL). The main project was supervised by Professor David Bowen, who was one of the first scientists to discover the cholinergic deficit in Alzheimer’s disease. His work led to one of the mainstay Alzheimer’s therapies of today: acetylcholinesterase inhibitors. I was delighted to be accepted into his lab, and was also lucky to have sponsorship from Merck. Having a pharmaceutical company co-sponsoring my work gave me unique insight into the applied side of research, and it was during this period that I realised my interest lay in helping turn science into medicine. To me, this felt truly meaningful and made me realise what an impact science could have on patients’ lives.
My route into pharmaceutical research was not a straight path from my PhD. My industrial supervisor from Merck, Dr Derek Middlemiss, suggested I do a post-doc in the US to further develop my knowledge and skills, but also importantly to experience a new culture and perspective – I now know how important this is in any scientific career.
I have worked in a number of companies including Janssen, GSK, Wyeth and Pfizer, with increasing levels of responsibility. Today, I work as President of BioPharmaceuticals R&D at AstraZeneca. I have overall responsibility for research and development, from discovery to launch, for all programs outside of oncology. This includes those in cardio, metabolic, renal, respiratory, immunology, neuroscience and infection. I have been with AstraZeneca since 2010, and have served as Executive Vice President of AstraZeneca’s Innovative Medicines and Early Development Biotech Unit and Global Business Development, where I had overall responsibility for research and early development across all therapy areas. Since I have been working for AstraZeneca, I am proud to say I have seen some huge, positive changes. We have launched nine new transformational medicines across a range of diseases including cancer, asthma, diabetes and heart disease, which have collectively helped to treat millions of patients. I’m really pleased to say the improvement in the quality of our pipeline has been remarkable. My goal continues to be to make sure we conduct the best science, which we then translate into life-changing medicines for patients.
Being able to help talented scientists realise their aspirations of bringing medicines to the clinic is one of the most satisfying aspects of my career – there is nothing more rewarding than seeing one of your medicines make a difference to patients’ lives. This is what motivates me to keep doing what I do.
Since you joined AstraZeneca in 2010, the company’s philosophy has changed. What are the main changes?
One of the biggest changes we have made is to focus on quality, not quantity. Instead of running a huge number of drug discovery programs and seeing many of them fail, we now work on a smaller number of projects but with scientific rationale that we believe gives each project a higher probability of success. By embedding something we call the 5R framework, we have dramatically decreased our failure rate; we have increased the percentage of successful programs (defined by launching a new medicines) by nearly five-fold. Our success rate for molecules entering man to launching a new medicine have risen from just 4% to 19%, while industry average has remained broadly flat at around 6%.
By focusing on this 5R framework, we have also changed the culture of the organisation and, in all honesty, it has probably delivered these impressive results a little faster than we were expecting. We rarely fail for safety reasons or for missing a proof of mechanism now. The primary reason for failure is that our scientific hypothesis was wrong – we have tested the target with a good molecule, but it just didn’t work in that patient population. We still fail sometimes, but not as often, and the failures are scientifically good because we have learnt something about the validity of our hypothesis.
The first R in the framework is the right target. Target selection is one of the most important aspects of R&D. You need to have the correct basic understanding of disease biology, and ensure you are working on a pathway that has a key role in driving the disease process. The second R is the right tissue. Even if you identify the target correctly, you need to make sure you are modulating the target and engaging it in the correct tissue to properly test your hypothesis. The third R is the right safety. Spotting safety signals early in a programme is important, so you can remove the liability early on. Safety signals don’t tend to go away as clinical trials progress. Stopping projects with clearly visible safety issues is a smart decision; failing late in development for reasons of safety can be a tremendous drain on resources and money. The fourth R is the right patient – determining which patient is most likely to respond to your medicine and testing it in them first. If the drug doesn’t work in that selected population, it won’t work in a broader, more heterogeneous population either. More than 80% of our clinical programs now have a precision medicine approach to determine the most responsive patients. The final criteria in the 5R framework is the right commercial potential. This doesn’t mean we have to ask ourselves ‘is this drug going to be a blockbuster?’, but we need to understand why anyone would want to prescribe or reimburse the medicine, and think of the program we are running in the context of what other medicines will be available to patients at the time of launch. Any new medicine needs to be sufficiently differentiated that a payer will want to pay for the medicine, a doctor will want to prescribe it to a patient, and patient will want to take it.
We make sure to impart this framework into the everyday thinking of our scientists. Each of the five Rs is reasonably obvious when you think of it, but applying all five consistently across every project is more difficult in practice.
A top neuroscientist who has introduced philosophy in corporate development. Do you believe that a great researcher is also a great philosopher?
The philosophy or culture you create in a company is critically important. A broad variety of different mentalities and outlooks as a result of having multicultural, diverse teams leads to a richness in scientific thinking. For us it is all about leading scientifically, making sure our decisions are grounded in high quality science, and determining what it will take to deliver a clinically meaningful medicine to patients. We approach questions with a strong scientific hypothesis, test the hypothesis and then evolve it if we find out we are wrong. As industrial scientists where the failure rate of drug discovery projects is high, we have to be comfortable with constantly learning, dusting ourselves down when we fail, then getting up and trying again. It is this resilience that gives rise to ground-breaking new drugs from our teams.
Precision drugs and personalised treatment for each patient. How close are we? What are the benefits for patients and the healthcare system?
Precision medicine is here today. We and others have delivered novel medicines for cancer and asthma, based on a thorough understanding of the drivers of disease. Oncology definitely leads the way in this field, but we are now uncovering genetic drivers for more complex diseases such as chronic kidney disease and non-alcoholic steatohepatitis, (NASH), also known as fatty liver disease. Our understanding of the genetics and molecular pathophysiology of disease is enabling us identify drug targets specific to discrete patient populations. The benefits for the healthcare system, and for patients, is that we are tailoring medicines to subsets of patients and even individuals, not broad populations. This gives a more favourable risk–benefit ratio, and the value to patients and payers should be easier to demonstrate by delivering better outcomes for the patients taking the precision medicine.
What is your latest research interest? In which therapeutic categories are you focusing? Have you seen any tangible results?
At AstraZeneca, we work primarily on cardiovascular, respiratory, renal and metabolic disease, oncology, inflammation and autoimmunity. We also have small groups working in the areas of neuroscience and infectious disease. In terms of our latest interests, we are adopting new scientific platforms and technologies, such as CRISPR gene editing, dynamic ‘omics, PROTACS, and of course genomics, which can push medicines forward in these disease areas.
Advanced analytics and machine learning or artificial intelligence (AI) have huge potential to transform R&D across many areas, although it is still early days. It could enable us to create knowledge and identify new relationships within large data sets; it could help us improve the design of our molecules and medicines; it could help us identify and diagnose patients more accurately; it may help us execute our clinical trials more effectively.
As big data and AI start to take a more central role in R&D, it will be important for us to integrate computer scientists, physicists and mathematicians into our multidisciplinary teams, alongside the researchers who are more traditionally involved in medical and biopharmaceutical sciences. I think we will also start to see a lot more scientists with a hybrid background across both the life sciences and data sciences.
Another area of interest to us is the emergence of new drug modalities, which means we have an array of tools to use on challenging drug targets, previously thought to be ‘undruggable’. We want our scientists to be able to work on any biological target, so we need to look beyond the limits of small molecules and monoclonal antibodies. We have been expanding our drug modality toolbox by investing heavily in technologies such as CRISPR, PROTACS, modified RNA, antisense oligonucleotides and bicycle peptides to name but a few.
What is the median cost for the development of a drug? Could you provide us with an overview of the money invested? What should be done to reverse the failure of discovering major drugs?
Several studies have highlighted the huge cost of drug development across the industry; a range of estimates for the average cost of bringing a new drug to market have been made, with a widely cited average of $2.6 billion dollars1 calculated in 2016. This is driven largely by the very high cost of failure.
Our success rates are better than most at almost 20%, but we are in no way complacent and will not settle for this figure as it means we are still failing 80% of the time. We aspire to continually improve, and have set ourselves ambitious goals in this regard for the next seven years. I am optimistic that as our scientific understanding of disease improves, as the tools at our disposal expand, as we diagnose patients earlier in their disease, we can push our success rates higher. This will hopefully mean we can deliver our medicines to patients more quickly and cost effectively.
What is your focus area when referring to access to innovation?
Collaboration and freedom of exchange of ideas is key to scientific success; we aim to create a culture of cross-pollination. Often the result of scientific collaboration is much greater than the sum of its parts. At AstraZeneca our scientists work side by side with academics at leading institutions such as the Laboratories for Molecular Biology in Cambridge, the Karolinska Institute, Max Planck, Imperial College London, the Crick Institute, and many others. We share data, publish together and train postdocs and PhD students together. We also share many of our compounds, equipment and capabilities with others. We don’t lose our competitive edge by collaborating, on the contrary – this is the key to advancing science and coming up with the best ideas in the field.
We have also made many of our molecules available to investigators from the NIH (National Institute of Health) and the MRC (Medical Research Council) through our Open Innovation programmes. We have created ‘BioHubs’ on our Gothenburg and Boston sites, where we aim to develop an environment in which we help smaller biotech companies with shared interests, and encourage them to engage with our scientists.
To what extent is scientific knowledge utilised? What do you anticipate for the near future? Can we be optimistic for a more qualitative and longer life?
We are seeing dramatic changes in medical practice and dramatic improvements in patient outcomes across many different diseases. I’ve never been more excited to be a scientist in the pharmaceutical industry. When you look at the progress we have made in oncology, diabetes, heart failure, asthma… it really is incredible.
New technologies are advancing rapidly to expand our understanding of biology. Gene and cell-based therapies are becoming established across multiple disease areas. Generation of genomic and multi-omic data is becoming the norm, and this data is being combined with electronic health records giving us access to complex datasets that will accelerate our understanding of disease. Human-derived, cell-based systems are refining research strategy, and genetic screens are enabling us to validate or invalidate drug targets faster than ever. Regulatory agencies are also becoming more agile and innovative, which helps us conduct more effective clinical trials and speed up the development of new medicines for patients.
We still have far to go but looking at recent developments, I am optimistic about the future trajectory of our industry. We are at a point where we can actually start to think about finding cures or, at the very least, effective treatments for some of the world’s deadliest and most difficult-to-treat diseases.
Having international experience, how could Greece develop in the field of research and clinical research?
In the last few years, we have seen some positive changes within the research community in Greece, and I am really heartened by this. More young people are returning to Greece after studying or working abroad, thanks to money being made available for research as part of an agreement with the European Investment bank.2
Greece has always exported talented physicians and scientists with many having hugely successful international careers. The most important thing any government can do to increase its future prosperity is to invest in science, innovation and health. I fundamentally believe that investment in these areas is one of the key economic drivers for any developed country. If more resources can be made available to the country’s scientists and physicians, if the government can find ways to increase its investment in human capital and infrastructure, it can reverse the negative trends in research and development that were caused by the economic downturn over the last decade. Even during more difficult times, Greece has shown tenacity and continued to produce excellent people-Greek scientists contribute to the top 1% most cited papers in the world. This is a testament to the talent that the country has, and a sure sign that it needs to be nurtured.3
Prix Galien Greece will award you the Galien Scientific Research Award, highlighting and honouring the leadership of a prominent scientist and researcher of the Hellenism of the Diaspora. How do you feel about it?
I am truly honoured to receive this award. I was born in the UK to a family hugely proud of its Greek heritage. My roots are Greek and an important part of my being, even if I feel I am a citizen of the world. Being nominated for this award is one of the biggest accolades of my career and I am humbled by this. All of the projects I have worked on through my career have been with amazing teams and I have been lucky to work with many outstanding scientists and physicians. I chose a career in science because I found it fascinating, and I am lucky that I still love what I do. I really do think I have the best job in the world! For those of us working in this industry, we are privileged to do work which has the opportunity to transform patients’ lives for the better; to create ground-breaking medicines that impact not just our friends and families, but all of humanity.
- DiMasi, et al. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of health economics. 2016 47; 20-33.