A personalised approach

By Frances Davies, Deputy Editor

Personalised medicines tailored to suit an individual’s genetic make-up could revolutionise the future of drug discovery. Frances Davies of NGP talks to Jan Lundberg of AstraZeneca about the revolutionary research needed to take advantage of this potential new direction.

New breakthroughs in drug discovery are becoming more rare, as a focus on blockbuster drugs, faster sales growth, and ploughing more money into advertising and marketing overtake that of invention. Generic drug makers in the US and in developing markets such as India are also muscling in on the profitability of many pharma’s thus becoming a worrying concern.

These trends highlight the need for many companies to strengthen their new product pipelines and investment in R&D to ensure they maintain a steady flow of new drugs and innovations. In his role as Executive Vice President of Discovery Research at AstraZeneca, Jan Lundberg is at the forefront of some of the most revolutionary research into drug discovery. His role is to ensure accountability for innovative candidate drugs. He is also responsible for supporting these drugs throughout development with a variety of technologies, including imaging.

Lundberg believes that genomics and personalised medicine is an exciting new area for the pharmaceutical industry and one that could hold a great deal of potential for patient treatment. Although estimates suggest we could be 10-15 years away from widespread adoption, studies are already taking place into the usefulness of personalised medicines for the treatment of some cancers.

The hope is that one day doctors will be able to prescribe drugs perfectly suited to patients, thus optimising effect while reducing the risk of side effects. “Genomics is part of the personalised medicine approach, or a prerequisite for that approach. It gives us tools to characterise patients with, for instance, cancer tumours specific to groups or individual patients. In the future, we want to tailor the right medicines for the right patient in the right dose at the right time. There is also a need to recognise that combination treatments should be individualised based on sensitivities, for instance, to various types of drug metabolism.”

These new approaches should mean better and safer drugs for patients. These kinds of medicines could revolutionise the industry and differentiate the drugs that are currently available. “We can build on not only the genomics revolution, but the overall advances in science and technology for the future,” enthuses Lundberg.  “With every new molecule we nominate for clinical development, we have a plan, whether it makes sense for either a combination approach or an approach for a biomarker to obtain an early clinical readout or obtain a selected patient population that could be more responsive to these particular types of treatments. This could help us to develop compounds at a lower cost if the number of patients having to be exposed can be reduced. The caveat with this latter approach is that there is a need for a substantial range of patients to establish the right type of safety for these new types of treatment.”

Close collaborations
Another area in which AstraZeneca is focusing its attention is in biologicals, which are playing an increasingly important role in drug discovery and development. According to Lundberg, biologicals go hand in hand with the traditional small molecule approach. As a result, the company has pursued a number of projects to advance its biological therapies interests, beginning with a collaboration with Abgenix in oncology to develop therapeutic antibodies for up to 36 cancer targets.

Other projects include the acquisition of Cambridge Antibody Technology (CAT), with the intention of combining the biologics discovery and early development of CAT with AstraZeneca’s capabilities in respiratory and inflammation. The  recent acquisition of MedImmune, a Maryland-based biotech firm that the company hopes will enhance its research and development base and help the company deliver a much stronger biologicals product pipeline. MedImmune has been combined with CAT to create a fully integrated biologics and vaccine business, which is strategically aligned but operationally independent from the rest of AstraZeneca.

“There are a number of attractive disease mechanisms that can be addressed with either small molecules or biologicals,” highlights Lundberg, “However, one should recognise that there are specific characteristics that favour one approach compared to another; for example, for an intra-cellular target. If this is the case, then you probably need a small chemical molecule, which can penetrate membranes, while if it’s a circulating larger protein, a monoclonal antibody could be a better approach to take. In my opinion, to be a fully-fledged pharma company, you need to have access to both types of capabilities.”

According to Lundberg, biological drug development today is particularly advantageous for cancer and inflammatory diseases, in comparison to other areas, such as chronic cardiovascular disease or psychiatry, in which small molecules are likely to have much more of an impact. But new opportunities for biologicals are also appearing in additional disease areas.

Several technologies are helping to speed up the drug discovery process and lower the costs of development. Of these, high throughput screening combined with more rational structure-based design is proving particularly beneficial. Another development that Lundberg has witnessed is the impact of the early front-loading of safety parameters, so chemists can create compounds that are less prone to be toxic.

Lunderg is also enthusiastic about the efforts being made to predict the right pharmacokinetic properties much earlier than in the past. Equally, having markers that can predict the clinical readout earlier and better is advantageous, as they can help decide whether to progress with further research. “Some of these technologies, including imaging, clearly help us to study the progress of disease over longer time periods, both in experimental animals and in patients in a non-invasive way, which certainly is helpful.”

The robotisation and automisation of a variety of screens is also making a great impact. For the company, these technologies are helping to generate much more data than ever before to characterise compounds early in relation to the type of properties that are needed to become a successful product.

Exciting developments
Another development at AstraZeneca has been the formation of a new company, Albireo, through a partnership between AstraZeneca and Nomura Phase 4 Ventures. The intention of the venture is to develop new treatments for lower gastrointestinal (GI) disorders. Based in Gothenburg, Sweden, the company has secured one clinical and a number of pre-clinical GI programmes for AstraZeneca as well as researchers with extensive experience in AstraZeneca’s GI research area.

Lundberg describes how AstraZeneca took the decision not to continue independently with research into lower gastrointestinal tract disorders. “This decision was based on an overall judegment of the likelihood of success for us in this area. In comparison to other areas, we had a less clear understanding of the mechanisms underlying the pathophysiology of, for instance, irritable bowel syndrome. The venture for us is actually an opportunity to test a new hypothesis, while focusing our internal resources on other areas.”

The company is committed to continuing its research around the proton pump inhibitor, Nexium, and gastroesophagel reflux disease, and has been taking additional novel approaches in this area. Reflux disease is a common ailment in Western countries, and occurs when the oesophagus becomes irritated or inflamed because of acid and other components backing up from the stomach.

Causes of the condition are multiple and may vary from patient to patient. One of the research approaches the company has been looking into in this area has been to reduce openings of the lower oesophageal sphincter.

Research has proven fruitful and the company now has novel approaches that have been proven to influence reflux from the stomach up into the oesophagus. “We have a compound, code named AZD3355, which in the initial clinical studies showed some promising properties in relation to reflux symptoms. As a result, we are progressing this compound further into later development.”

Future plans
Bringing new medicines to market is a long, costly and complex process; however, the introduction of a successful product can drastically improve and transform life. With this in mind, Lundberg is enthusiastic about some of the opportunities likely to present themselves in the future. The company has several compounds in late phase development in the cardiovascular arena: “The first one is a platelet inhibitor with the code name AZD6140, which in initial clinical trials has been shown to have a very rapid onset of effect and much less variability than the current market leader, Plavix. This is a major product to prevent patients from having reoccurrence of myocardial infarction, for instance. This compound (AZD6140) is now in a very large phase III trial, and of course we have great hopes that we can come up with a market leader.”

In the area of diabetes, the company has two promising compounds in the type II diabetes area from their partnership with Bristol-Myers Squibb. The first of these is Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor currently in phase III development, which is able to lower blood glucose. The second is Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, also currently in phase III development.

This solution means that more glucose enters the urine and thereby lowers blood glucose in a very novel way in patients with diabetes type II. Lundberg is enthusiastic that both of these agents could have a considerable therapeutic impact, which is particularly exciting due to the major increase in the patient population of diabetes type II due to the ongoing global obesity epidemic.

In terms of oncology, Lundberg describes how the company has three approaches in late phases: “The first one is an endothelin A receptor antagonist, which has had some very interesting improvement of survival in late stage patients with prostate cancer. The second one is called Zactima, the VEGF/EGFR inhibitor that is tested in non-small cell lung cancer. Third, is the VEGF inhibitor Recentin, which is tested in several tumours including colorectal cancer. So we have some clear opportunities in the oncology arena to improve life expectancy for patients with cancers.”

The increasing R&D projects currently being undertaken by AstraZeneca may contradict the global trend toward reduction in new drug approvals. As the company proves it is taking a lead, others are sure to follow, and this should ensure that investment and interest in innovation stay at healthy levels.

Jan Lundberg is EVP Discovery Research at AstraZeneca. He was previously SVP, Head of Global Discovery, a position he had held since the Astra-Zeneca merger in 1999. Before the merger, Jan was Head of Preclinical Affairs, Astra AB. He was a professor in the Department of Pharmacology at the Karolinska Institute in Stockholm before joining Astra AB, and has published more than 500 scientific articles.