Interview with Dr. Klaus Edvardsen, Senior Vice President and Head for Global Medicine Developments, Oncology, AstraZeneca

Astra Zeneca is investing heavily in all aspects of precision medicine, from identifying new drug targets through genome sequencing, to the development of biomarkers for diagnostics and combinatorial treatments. In this interview, Senior Vice President and Head for Global Medicine Developments, Oncology, Dr. Klaus Edvardsen, outlines the opportunities and challenges associated with the advancement around implementing medical advancements, such as targeted therapies.

"We are in the beginning of a new era in medicine which provides enormous opportunities. Science is at the heart of everything we do, but it will be of no use to society if can´t deliver new medicines to patients. The new therapies are very costly, therefore we have to also be involved in delivery and in working out mechanisms for pricing that will work for different healthcare systems. But it is all in the beginning, we need to have a differentiated way of looking at it. As we develop an oncology medicine, we often develop it for different indications, the effect size may differ in various indications. Therefore, there has to be a mechanism in discussions with payers that the price will also be related to the effect size, which is a direct translation of the value it offers.

The pharmaceutical industry plays an important role in helping build the evidence-base needed for healthcare planners to make priorities and assign value to targeted therapies and biomarkers. This is necessary to know what treatments are efficacious and to avoid spending resources on giving medicine to patients that will not benefit. Fundamentally, we as an industry have an accountability to make sure that we deliver that value from a scientific perspective.

We do this through trials where biomarkers define patient populations to a large extent. As an example, Astra Zeneca and the investigators we are collaborating with are currently involved in more than 500 active oncology trials that enrolled almost 90,000 patients to date.

A concrete example, which really highlights the success we can have when we aim for something very specific is Astra Zeneca’s molecule which is targeting a specific mutation driving a number of cancers, especially non-small lung cancer. The Phase 3 AURA3 trial results show a median progression free survival of 10.1 months for patients on this new therapy versus only 4.4 months for patients using the second-line treatment of platinum-based chemotherapy."

An important part of precision medicine is the uncovering of the genetic drivers which creates unprecedented opportunities for drug discovery. Can you tell us about Astra Zeneca’s involvement here and the challenges to overcome before genome sequencing becomes an integrated part of general healthcare?

"Our AstraZeneca MedImmune Genomics Initiative is a partnership which was launched in 2016 together with the UK Biobank, the FinnGen consortium, Wellcome Trust Sanger Institute, University of Cambridge, UK, Columbia University, US, and several other partners with the bold ambition to analyze up to two million genomes by 2026. It will lead to new insights into the biology of disease and create a foundation from which we can create new medicines. It goes for all therapeutic areas, not just cancer, but cardiovascular and metabolic diseases as well. It will allow us to stratify our clinical trials and lead to an understanding why some patients respond to treatments when others don´t. It really is a crucial aspect of precision medicine. But it is not something the pharmaceutical companies can lift alone.

As an example, the MedImmune Genomics initiative, will be sequencing 500,000 genomic samples donated by patients from Astra Zeneca´s own clinical trials that we have collected over a 15 year period, so we have a huge amount of material internally. To make something out of it in the long-term, we are completely dependent on partnerships with the outside world; the academic research and hospital where the patients are. For the next step, and for genome sequencing to really be an integrated part of healthcare, we also need to get the healthcare financiers and the regulatory agencies into play. Each healthcare system will need to see the value of investing in the infrastructure that is needed to use the technology, including the biomarkers and diagnostic 49

testing to find the right patients, otherwise it will be like finding a needle in a haystack. The pharma industry can help in building the evidence-base that all healthcare planners need for any investment.

So we have a big task ahead of us of developing pricing mechanisms and regulatory processes around precision medicine to make it available for all the patient groups it holds promises for."

With genetic testing and biomarkers comes the opportunity to use combinatorial treatments. What are the obstacles associated with taking these treatments from the lab to the patient?

"If you really want to make sure that you tailor treatments, you have to have a very broad approach and partnerships, because it will unlikely be one single company that has all of the compounds that can target all of the genetic abnormalities that drives one phenotype. Imagine that as a doctor, I have a complete understanding of the genetic make-up of what drives a specific phenotype in the patient in front of me. The best treatment would be to perhaps combine compound X from Astra Zeneca with compound Y from another company. But how do you conduct clinical trials around these possibilities? We don’t yet have a good mechanism for how to handle these opportunities because that is not how drug development is traditionally done.

I think one important aspect of combinatorial treatments is to look at the diagnostic part. The use of circulating tumour DNA Biomarkers, liquid biopsies, might be what enables the use of the combination therapies. Improving and facilitating the process of biomarkers is an integrated part of our strategy, which has to go hand in hand with the development of medicine. You need to find the patient in the real world setting that would benefit from your medicine, so it is complex and we are not quite there yet, but it is an ambition."

Despite the complexities and challenges that we need to overcome, are you hopeful that in a not too distant future we will be able to bridge the advancement in technology with the growing cancer patient population globally?

"I am extremely hopeful. To take the example of lung cancer, not that many years back, we didn’t even have the wildest believing that we could cure non-small cell lung cancer patients or transforming them into long term survivors. Over the past years there has been a tremendous development in targeted therapies that are really substantially benefitting patients that we never thought we could manage before, so I am very hopeful.

I believe that we are just in the beginning of all of this and the more we get involved in genomics and the more we understand about the drivers of disease, the better we can tailor treatments. It is an extremely exciting moment. I am not denying the obstacles; there are obviously many things that needs to go hand in hand to be successful here, but I fundamentally believe that we all work for the same goal and we are making progress every day towards curing cancer."