The Pharmafocus Interview: Jan Lundberg

pharmafile | October 10, 2008 | Feature | Research and Development |  AstraZeneca, clinical trials, drug discover 

AstraZeneca's head of global drug discovery Jan Lundberg says his younger years as a sportsman have made him a determined individual, and one who doesn't accept failure easily. "I used to be an athlete, I played a lot of ice-hockey – so I don't like to lose!"

But Lundberg and other senior figures at the company have had to endure a series of failures in recent years, with no fewer than five late-stage drugs having to be abandoned between 2004 and 2007.

This series of late-stage failures knocked investor confidence, and caused a major re-think at AstraZeneca in how it conducted research and development.

Lundberg says the company is now combining an array of novel drug discovery technologies with streamlined and improved internal practices, which he believes will pay off in the long-term.

'Predictive science' (which includes the development of biomarkers) is an example of the key strategic tools the company is now employing.

"Predictive science is one of our key strategic areas for the future. We have seen that we are very good at predicting what type of chemical structure you should avoid. And in the end that will help patients in maybe ten years time," he says.

Another key component of the strategy is a target to have biotech drugs represent 25% of its pipeline by 2010.

"We need a portfolio to balance failures with some successes. And that's what we are working very hard on," says Lundberg.

Nine years as head of drug discovery

Lundberg has headed up drug discovery at the company since 1999, when Swedish company Astra merged with the British company Zeneca. At Astra, Lundberg had led the pre-clinical affairs department, with responsibilities for discovery, build up of enabling technologies, project co-ordination and evaluation.

His extensive research experience stems from his academic days as professor of pharmacology at the Karolinska Institute in Stockholm. But Lundberg credits his earlier medical training for prompting his leap into drug research.

During his medical training he saw a lot of patients, and the inadequate treatment options presented to them and he decided that he wanted to try to improve the situation. Moving into academic research enabled him to decipher disease mechanisms and test new pharmacological agents at the early stage, allowing him to help patients in the long-term by going beyond hands-on medical treatment.

For Lundberg, the opportunity to use his expertise to lead and help people is a key motivation for working in industry.

"The opportunity of leading people to help patients is much more obvious in this role, which I think is a unique opportunity for me.

"It's [also] about meeting phenomenally competent people inside and through external partners – to be able to interact with the best scientists in the world. That's something you can do from a pharma background much more easily than if you are an academic."

Lundberg also relishes working in a big organisation – "because drugs are not created by one person."

An issue of safety

AstraZeneca had to abandon five late-stage drugs between 2004 and 2007. All were highly innovative, but had to be scrapped because of doubts about either their safety or efficacy.

Lung cancer drug Iressa, anti-clotting treatment Exanta, diabetes medicine Galida, stroke treatment Cerovive and atherosclerosis drug AG-1067 all fell by the wayside.

Looking back, Lundberg is philosophical about failure: "It's part of the industry reality, unfortunately – our task is to reduce the failure rate. But failure is also a way of learning, and some of the follow-on compounds in our pipeline have learned from failed frontrunners and have much better capabilities."

So what went wrong with the recent late stage drug failures?

"The safety issues were from compounds that were nominated in the mid nineties – pre-merger compounds. And you know, once you have the compound there's not very much to do with it – you just have to accept these properties."

The company had already started to specifically focus on safety at the time of the merger, says Lundberg.

AstraZeneca now monitors the safety of compounds very early on, and anticipates problems with their particular mechanism. Lundberg says the company can detect molecules with potential safety problems at a much earlier stage, resulting in a significant reduction in safety concerns in its recently nominated compounds.

In the year 2000, about 40% of AstraZeneca's candidate drugs being considered for clinical development would have to be abandoned, usually because of potential safety concerns. The company has now dramatically reduced this wastage, with just 12% being discontinued in 2007. This has helped the number of candidates entering phase I development to hit a record high – 36 in 2007, up from the previous record of 22 candidates the year before.

The company says it is on track to reduce its average drug development time to launch to just eight years by 2010, which if achieved will mean several years and many millions of dollars saved compared to current standard practice.

These are dramatic improvements, but they are being matched by several of AstraZeneca's peers, so the company must aim to reduce attrition and speed to market in clinical development as well.

An area of drug safety testing which remains of central importance is in avoiding heart arrhythmias. These have been a problem for some compounds on the market, for example some anti-histamines. The company is also looking at geno-toxicity by testing anti-metabolites, and there are now rapid screening measures in place for a variety of toxicities.

Testing these properties at an early stage is helping, says Lundberg, not only to select, but also to make compounds that don't have these properties.

Lundberg says that chemical compounds can be subjected to a battery of tests that scientists working on biologicals still do not have at their disposal.

"In contrast to biotech we have thousands of experiments that we can gather; scientists can use that data to decide on the right compounds, or at least they know which elements they should avoid."

AstraZeneca is now spending heavily on predictive science, both through internal investment but also with external partners including industry consortia and private academic partners.

The scientists behind the drugs

Drug discovery has also become more productive, more predictable in the last five years.

"You can do things faster and better, potentially to a lower cost. There has been a lot of automation and also a great number of scientific findings in the external world that have helped us understand diseases better."

"You can create a compound today in about half the time you could five years ago and at half the cost – and with at least the same quality.

"So that's a huge advantage, but of course the key challenge is to ensure these new compounds become differentiated products. They need to retain a meaningful impact on patients and convince payers that they will add value."

Lundberg says the twin fields of biology and chemistry are now propelling drug discovery forward, with new targets and new technologies.

In biology, he says the genomic applications have had a huge effect – from understanding disease mechanisms based on genetics, to expressing target proteins using genomic technologies, to creating animal models via transgenic technologies.

The whole area of biologicals as therapeutics is, in a way, now very much dependent on genomics, he says.

In chemistry, scientists can now predict the structural properties of compounds, making it easier and quicker to select those that will be worth pursuing.

"Because of the increased knowledge of structure activity relationships, the design of compounds today can be done in a much cleverer way, giving them the right properties for selectivity, pharmacokinetics and safety."

Chemistry has advanced a lot in relation to automation – robotics, for example, but also detection systems. So things that you used to do five years ago with some difficulty are routine today.

There have also been big developments in screening compounds, and the emergence of highly sophisticated technologies, such as high content biology. This allows several different parameters to be measured in parallel in the same cell using fluorescent markers.

"If you go into a lab today, there are huge amounts of equipment," says Lundberg. "And very few lab benches. That is the obvious difference in the lab these days, and some of the improvements have certainly been spearheaded by the evolution of technology."

Pipeline potential

Lundberg is optimistic about potential success stories but doesn't want to speak too soon.

"I think we need to wait for the clinical data to get the authorities' view. You should really try a drug on 100,000 patients to know the benefit on the real life situation. Because they could be better than you think but there could be unique non-responders. I shouldn't over-promise until we have a product."

But there are of course a number of phase III drugs for which expectations are inevitably rising: platelet inhibitor AZD6140, Recentin for cancer and ZD4054 for prostate cancer.

Most important to Lundberg is that AZ has a solid base in its early development pipeline so that discovery compounds are now progressing.

"Externally it is being recognised that we have a strong early development pipeline. So that has had a major impact on the company."

AstraZeneca now focuses on seven major research areas, having decided to reduce or exit some other therapy areas.

The seven major research areas are: cardiovascular, gastrointestinal, respiratory, oncology, inflammation, neuroscience and infection, with staff focussed on specific disease areas.

Lundberg feels the company has particularly competitive ideas in the field of infection treatment. AstraZeneca is expanding its infection capability with a new building in Boston, with a focus on bacterial infections that are resistant to existing treatments.

They've also been recruiting "some of the best infection scientists, from other companies mainly" and Lundberg clearly feels excited by what might be achieved by these top scientific minds.

Asked if there are any breakthroughs at AstraZeneca that he has been particularly proud of his involvement in, Lundberg is quick to credit the discovery organisation as a whole.

But of his own aspirations, Lundberg is clear: "I want to see compounds coming onto market that we have nominated at AstraZeneca. That would be my biggest reward. My motivation is to have influence in helping patients, and many scientists share that [drive]. So that we can exploit science for the benefit of patients and of business.

"Also I would personally like to see a better Alzheimer's treatment, which we are working on. Having close relatives dying of that disease, it's a motivational factor."

Partnerships

AstraZeneca now has a target of 25% of biologicals in the pipeline by 2010. The MedImmune and CAT acquisitions mean the company has achieved this target in the early phase of its pipeline. But now they need to see progress into later phases, says Lundberg.

AZ's strategy for acquiring companies has been different in each case. MedImmune was a big acquisition for the company, and one that will be run as a stand-alone biologicals unit. But AZ has also acquired some smaller companies like Kudos, for its anti-virals expertise, which have become part of the small molecule discovery organisation.

Lundberg says the companies have been left to run with an independent 'power drome' to deliver in their speciality areas, but with the support of a larger organisation.

"Now they have access to strong capabilities, informatics capabilities and much more expertise in population and safety assessment etc."

"But in the end I think it's more about the philosophy – how can you work well together with certain people, and to have a scientific angle to that. Science speaks – that is the key thing."

The resignation of David Mott, the head of MedImmune, in July – only a year after its acquisition was an unwelcome disruption.

"Dave Mott was a very influential person for MedImmune and has been with the company more or less since it started, so that's a major change for many of the staff," says Lundberg.

"On the other hand MedImmune has many capable people, so it's going to be strengthened in various ways by the ongoing build up, and it should be an attractive place to work for other candidates in the role. There are not many other companies in the biotech industry today where such an expansion going on."

But AstraZeneca is not only interested in biologicals. "If you look at external partnering, certainly on the small molecule side, we are constantly looking at opportunities. And for us as a company it is all about the quality of the opportunity and how attractive it is from a commercial aspect and the quality of the opportunity."

So what makes a good biotech partnership? "Strategically aligned, [remaining] operationally independent and collaborating where it makes sense," says Lundberg.

Emerging markets

I ask Lundberg about AstraZeneca's expansion of research in emerging markets, where pharma investment is accelerating.

He dismisses the idea that it's a new concept for the company, saying: "We have been in India doing drug discovery for almost 20 years. In Bangalore for TB in particular, and we have recently expanded the process of R&D chemical upscaling – an area where India has strong competence."

As for Asia's other economic powerhouse, Lundberg repeats AstraZeneca's corporate line on its investment in the country.

"We have taken the approach that we want to be in China for China," he says.

"People may think [we are in] China because of cheaper labour or the cost aspect. But I think, with the demands for high salaries, that argument may not be long lived. It's more about looking at access to the huge pool of talent and the growing market.

"I look upon China very positively. I was there [recently] and saw great progress. But on the other hand we have high capabilities in the west that we also need to be sure we can delivery in the future.

"Certainly we want to see stepwise progress before we build up huge capabilities. If you look in the drug hunting area – which is what we call designing a new drug and developing it – Europe and US are clearly ahead of local Chinese expertise. There are people that are moving back to China from the West, that are attractive but they also want western salaries!"

The company has opened in China an innovation centre in oncology – mainly translational science to understand what are the most rational treatments in China.

Asian populations have different prevalence of tumours to western populations. In particular, cancers of the liver and of the stomach are more prevalent in China and Asia compared to the west.

"We have a number of new compounds so we are testing them to see if they are particularly suitable for the Chinese or Asian populations. I think that's an activity which is very well received locally in China, and it also has a lot of scientific rationale."

Currently AstraZeneca are also collaborating with a number of biotech companies in China in creating compound libraries.

Facing challenges

As everyone in pharma knows, along with failures comes bad press. What about the scientists behind the scenes – how have people in AZ drug discovery been affected by the criticism of recent years?

Lundberg accepts it as reality. "Bad press is something that affects all of us in a company like AZ. It depends on what is the specific topic, whether it's described in a reasonable way or positioned in a way that is exaggerated."

He concedes the company could do more to improve its image by illustrating more effectively the benefits to society of medicines.

"It's unfortunate that the value of the pharma industry is hidden by discussion about price," he says.

"Most drugs are not more expensive than buying a packet of cigarettes every day or alcohol or cosmetics. Why shouldn't people be more concerned about their health, even pay for them when they are not available because of government constraints?"

Lundberg reveals that he sometimes goes with sales representatives to visit doctors in general practice and hospitals to see for himself the reaction to products, and to hear how real-life patients respond to AstraZeneca's products.

As a medic turned 'drug hunter', he says he finds it useful to return to the frontline occasionally and says the feedback he gets from doctors is very strong, and something he can take back to his work.

Lundberg restates his belief that the most important work remains back in the laboratory.

"The scientists behind the scenes are the real heroes in our company, even if it's not communicated directly."

AZ pipeline products: ones to watch

Cardiovascular

AZD6140, an anti-platelet receptor antagonist for arterial thrombosis, which could eventually take on BMS/Sanofi's blockbuster Plavix.

Onglyza (saxagliptin), an selective inhibitor being developed in conjunction with BMS for type II diabetes was submitted for US and European approval in June 2008.

Neuroscience

Pn400 is a new non-steroidal anti-inflammation pain product for osteo and rheumatoid arthritis that combines naproxen and esomeprazole in a single tablet.

AstraZeneca are developing the drug in conjunction with Pozen, using the smaller company's proprietary formulation technology. The treatment is particularly for those at risk of NSAID associated gastric ulcers and is currently in phase III trials.

Oncology

Zactima, a combined EGF, VEGF and RET inhibitor for non-small cell lung cancer treatment, is expected to be filed early next year.

Recentin, a VEGF signalling inhibitor for recurrent glioblastoma, and ZD4054, which offers a new approach to treating hormone-resistant prostate cancer, are both in phase III development.

Motavizumab, a MedImmune humanised monoclonal antibody for infection was submitted for regulatory approval in 2008.

Respiratory and Inflammation

AZ have a number of compounds in phase II trials for COPD, the fifth biggest killer worldwide. Drugs on the horizon are CRTh2 receptor antagonist, CCR1 receptor antagonist AZD1981, AZD4818, neutrophil elastase inhibitor AZD9668 and matrix metallo-proteinase inhibitor AZD1236.