Drug and Market Development

By Alex Crawford

D&MD: Since Astex Technology is a very new company, it would be helpful if you could outline its progress from its start up to the present day, in general, and explain how you feel it’s been going.

HJ: It seems to have gone very well from where we are at the moment. If you were to look back at the original business plan, we’ve pretty much followed it, which is something that a lot of biotechs are probably unable to claim, as they’ve had to change direction.

The whole focus of Astex was to develop a new approach for rational drug design, using high-throughput X-ray crystallography. Three or four years ago, this is what we were saying the industry needed. There is a huge productivity gap in terms of new drugs, new medicines. It is interesting that, three years ago, the real focus appeared to be on genomics, rather than chemistry, so we were swimming against the mainstream. That’s why I think that we’ve not had to change our business plan – the field has come to us, rather than us having to go to the field.

We have put groups in place to develop the structural biology platform, to do high-throughput X-ray analysis on targets (which are associated with a variety of different diseases) and to build our chemistry capability. We have a medicinal chemistry team of around 20 people, making drug molecules using our fragment-based screening approach.

We have a variety of collaborations with pharma; this is also positive and is something that we clearly want to pursue, to get validation from pharma that we are building technology to be used by big pharma companies. We have collaborations with AstraZeneca, Aventis, Mitsubishi Pharma and Johnson & Johnson.

Overall, the company is going where we wanted it to go. Currently, we are 92 people, and very well funded, having raised $40m last year. We’re clearly focused on an IPO (initial public offering of shares) at some point, although the financial markets are being a little bit rough. We’ll obviously be pragmatic. But, for a three-year-old company with 90+ people to have a variety of collaborations, we couldn’t be happier really. It’s been very hard work, but it’s been a lot of fun as well.

D&MD: What was it that motivated you and your co-founders, Professors Sir Tom Blundell and Chris Abell, in the first place, as a couple of you were heads of departments and you were well placed in a big pharma company, so there didn’t seem that much reason for you actually to abandon all that and come into a start-up?

HJ: You’re right. It’s a question that I’m asked, as I’m sure many others are, having left secure jobs in pharma – although nothing is really secure as we all know. It’s very difficult to answer. I was head of structural biology and bioinformatics at GlaxoWellcome in the UK for 10 years. I joined in ’91, lived through one merger with Wellcome, and managed to get out just before the second one – about six months earlier, although there was a lot in the background about a possible merger (GlaxoWellcome and SmithKline Beecham).

What were the key drivers? Well, there were a number of issues, in terms of recognizing that research may be performed more productively in a smaller outfit than in a large organization – that’s not a criticism of major pharmaceutical companies, which are very powerful, as we all know. But, I’m not sure that research is scaleable, to provide what research scientists really need to keep that fire in their bellies, in the same sense as marketing forces are scaleable. It’s good to have a huge marketing force. Drug development might be scaleable as well, as long as it doesn’t get too large. But, research – I’m not convinced that you really need to be huge to be very productive. In fact, the data indicate that there is a critical size, probably between 150 and 250 research scientists, for drug discovery. That’s the size with which you can generate some very interesting drug leads.

It was a level of frustration, and, fundamentally, wanting to develop some new technologies - thinking that, actually, we could do better, and wanting to do the discovery in a slightly different way. I’ll come back later to the technical details of what we’re doing here at Astex. The opportunity came about to work with Professor Tom Blundell and Professor Chris Abell, and I don’t think that you get too many of those opportunities. The timing was right and the people were right, so I decided to give it a go.

D&MD: How easy was it to get that initial funding just to explore the concept of setting up Astex?

HJ: I’ve only done it once, so I can’t compare it with any other instance. But, from making observations about how difficult it has been for many other people, I think that we had a slightly easier ride to get the initial financing.

Why? I think that clearly we were in the right spot, the time was right, and, clearly, at the end of the day, the venture capitalists invest primarily in people. Given that I brought the industrial experience, obviously Prof. Blundell is an internationally renowned structural biologist, and Prof. Abell is a very talented academic scientist – it’s a good mix.

And the concept was different, in terms of the focus being lead discovery rather than just genomics. We were a little bit more farsighted from that point of view.

I think that the story was right, and therefore the financing was perhaps easier than it could have been.

D&MD: How much was the initial exploratory funding?

HJ: The seed financing was provided by Abingworth and Oxford Bioscience. That was £800,000, and was provided to fund just some very early experiments. The University of Cambridge was instrumental in that, because we were practically a virtual company doing some science in laboratories here.

D&MD: But I’ve picked up that you’re rather keen not to be seen as a university spin-out company, although you have the association with two of the professors involved.

HJ: That’s a good point. A company is usually spun-out because some technology or a breakthrough has been made in a university, and clearly the university looks to generate value from that. This was a very different scenario, where there was no technology that was taken from the university. The concept, the ideas and the experiments were actually devised after I left Glaxo and initially started the company. So we are not a spin-out, although we have very strong links with the university, and have access to a variety of different research programs from Prof. Blundell’s and Prof. Abell’s labs.

D&MD: What was the next tranche of finance that you received, the subsequent financing?

HJ: The seed money was just to get going, so immediately we started to arrange our first-round financing. We pretty much went out and got other investors – Advent International, Alta, and GIMV – which, together with Oxford and Abingworth, provided the $40m.

D&MD: I was wondering why it ($40m) was done in two steps, because you got most of the money in the first tranche?

HJ: It was really to provide an opportunity for other investors to come on board.

D&MD: It wasn’t to do with having to meet particular milestones?

HJ: No, it wasn’t, because our key milestones had been met well before that.

D&MD: You mentioned earlier an IPO, But, if you are getting all this support from major pharma companies, why should you be particularly interested in going for an IPO because you’re getting finance coming into the company anyway?

HJ: Some of those collaborations, certainly the earlier ones, are research collaborations, which cover the research costs and bring value to the company.

Later collaborations are more milestone-based; we are currently negotiating more of this type. But we won’t see the financial benefits of these for a few years, until the drugs that we discover actually get onto the market place.

We also have a variety of internal discovery programs, and are aiming to discover compounds to take forward into the clinic. But it’s an expensive business, so we’re focusing on doing an IPO to raise sufficient funds for that activity.

D&MD: In the normal course, you would be looking at an IPO next year (2003). But in the current climate, do you have a feeling for that?

HJ: The general view of IPO from bankers and analysts is that it will be very surprising if an IPO window opened next year (2003). So, looking past next year, our current finances will take us well into 2004. But obviously, we’re always looking for quality investors, in the same way everyone is.

D&MD: What is it that is particularly special about Astex, because I’ve come across quite a few examples of companies that aim to be making the drug-discovery process that much more efficient? What is different about Astex?

HJ: You need to cast your mind back perhaps to the 90s. When we sat in big pharma companies, we were all in awe of combinatorial chemistry, massive parallel synthesis of compounds, and this belief that the industry could make enough compounds, and that with ultra-high-throughput screening we would find more and more drugs. But in the mid-90s, it became apparent, at least to several of us, that it wasn’t the magical solution, that the data wasn’t actually supporting it. There are fundamental issues with that approach. Nevertheless, combinatorial chemistry has had an overall positive impact in the industry, but it wasn’t going to generate a plethora of drugs by itself.

One of the issues was that the chemistries that you can do using parallel synthesis or combichem are not necessarily the chemistries that you need to use. If you look at molecular weights of the resulting compounds in corporate collections, the average molecular weight was increasing; so the compounds were getting larger and larger. What you were actually finding was that, when you did a high-throughput screen against the target, there were, maybe, micromolar affinities against the target. The molecular weight of the compounds was already 400-500, and, as we know, 500 is approaching the upper end of a suitable drug candidate.

The challenge for the chemists was to strip back the bits that were not important in the drug molecule and build in the bits that were needed , to continue to hone the potency, the selectivity and the ADME/Tox profile of the drug. People were struggling with this concept. So we said, OK, if we stop looking at large molecules and look at molecular fragments, take drugs that are 400-500 molecular weight and split them up into fragments that are maybe 150 – very small entities – then, if we can find some that look like interesting leads, we can add on just what we want.

The problem with trying to identify fragments in a conventional bioassay screen is that, because these fragments are small, they are not very potent, so they bind very weakly. Quite often, they may have high micromolar or even millimolar affinity. Chemists have got used to working with potency; they very rarely work on weakly-binding fragments.

But we think that as long as you know what you can do to the fragment to build it up, you shouldn’t be worrying about the potency. You need to have a technology that allows you to image the binding of the fragment - the fundamental sciences are X-ray crystallography and NMR (nuclear magnetic resonance). People were exploring NMR as an approach to fragment-based drug discovery, but nobody had really thought about using X-ray crystallography.

The whole concept of Astex’s approach is to use high-throughput X-ray analysis to look at the binding of these fragments into the active sites of target proteins. The structural information is useful to the chemists who then look to grow fragments in a particular way, keeping the molecular weight of the compound down, to help it downstream, in terms of attrition.

It is also another way of getting far more novelty, because these type s of scaffolds have actually been found by large pharma. It’s a fragment-based, lead-discovery approach. And, it’s fundamentally different from what you’d find if you were to walk into a typical large pharma company. They know of this approach, but it’s not generally in their mainstream.

D&MD: I interviewed Sir James Black three or four years ago, when I went to his laboratories in South London. He explained to me basically that combinatorial chemistry was flawed because it was producing millions of compounds without very much intelligence. Yours is also a screening approach. How do you make sure that it doesn’t become mindless in that kind of way?

HJ: We only have a few hundred compounds, 500-1000 fragments, and these screens are just start points really to see something that binds. Then the medicinal chemists use their intuition and intelligence to say: “This is our anchor point. How are we going to build this up?” We’re not screening to find the end product. We’re screening to find the start. All the experience that our chemists have will go into building-up the drug.

We now have several examples where we’ve taken these weakly-binding fragments and grown them into very potent drug leads, which are active in cells against a few targets in cancer and inflammation. We established a proof of concept two years ago.

It’s interesting that, in the past year or two, it has become more of interest to the big pharma guys. This harks back to why we left big pharma; we couldn’t have achieved this if we’d stayed there.

D&MD: How important have your pharmaceutical partners been to the success of Astex? Could you not have done this without the involvement of big pharma?

HJ: I think that it’s been very important that many of us came from that side. We have credibility. People know who we are, so, when we go back and tell them what we’re finding, there is a genuine trust. These are the same guys that we used to work with.

It is slightly different for some other biotechs; those who were more academic and were spin-outs from university found it difficult to speak to big pharma. But that’s not happened to us. We’ve not suffered from that communication issue.

D&MD: Quite often, small biotechs look to big pharma to give them credibility because they’ve actually got a contract, whereas I sense that it’s not the same in your case. Because your technology’s so very much different, you could actually have ploughed your own furrow, so to speak.

HJ: We could’ve done that, but we never really tried to do it in isolation. You’re not going to build one technology that’s going to completely change the game plan.

It’s very important to be linked into these big pharma companies, because, at the end of the day, the feedback that we get from them will actually help us in how we hone this technology to address real issues.

D&MD: Can you give some particular examples of success at this stage?

HJ: In lead discovery, we now have some programs with chemistries that are in lead optimization, and we’ve identified a lot of these compounds using very simple fragments, so we have enough data to show that this approach works. The challenge is (to determine) how broadly applicable is this approach, and that’s what we’re hoping to continue to develop as we go forward. No technology works in every case.

Another area where we have had success is drug metabolism. I’ve talked, up to now, about lead generation. Most attrition occurs as you try to take these compounds forward, and drug metabolism is a key area. The proteins that are responsible for metabolizing drugs are in the P450 family. There are four or five isoforms that turn over drugs, quite unpredictably sometimes, and the industry is constantly trying to optimize chemistries to avoid this.

So what we figured was that, if we could determine the crystal structure of these human cytochrome enzymes, and try to determine the principles of their recognition of small molecules, it might give us some idea of how to design chemistries that are not affected too much by these enzymes. This was quite a new concept, a new idea. Many people have been trying to solve these structures for years. But we put a team together here and, at the end of last year (2001), we announced that we’d solved the first crystal structure. More recently we solved the second, and also explained which isoforms of P450 we had solved – 2C9 and 3A4.

Isoform 3A4 particularly is regarded as the “Holy Grail” in terms of seeking an understanding of form, as it turns over a lot of different drugs. 50% of all drugs are affected by these P450s. Quite often, when you have drugs that have been withdrawn from the market, their adverse reactions are due to these P450-related issues.

There is a huge interest in this area, reflected in collaborations we have established with AstraZeneca, Aventis and Mitsubishi Pharma. They recognize that we clearly are leading the field, so they’re working with us. They’re giving us compounds which they can’t optimize, and we’re taking these compounds and showing them how they can fit into the P450s, giving them an insight that they didn’t have before. That would be the basis by which they could devise new chemistries to overcome these problems.

D&MD: You mentioned briefly your own drug-development programs. Can you say anything about which areas they’re going to be in?

HJ: A lot of the analysis has been focused on targets in protein families. We’ve been working on protein kinases, phosphatases and proteases, so we’ve been focused less on therapeutic areas and more on protein families really. However, we are now beginning to evolve a therapeutic focus within the company, given that we have chemistries that are being further progressed into optimization, and they’ll be pre-clinical probably by the end of next year (2003).

The two therapeutic areas in which we look to take our own compounds forward will be cancer and inflammation. We’ll continue to work on targets outside these therapeutic areas, but will look to partner these targets in programs. A very good example,, which we will again announce in the New Year (2003), is a key target in Alzheimer’s disease. We don’t have any particular expertise in the biology of Alzheimer’s, which is a very difficult area, so that’s a program that we’re looking to partner.

D&MD: I picked up that you’re aiming to have drug candidates in the clinic next year?

HJ: We’ll certainly have a few candidates in the preclinical stage by next year. It depends on progress, if we’re in the clinic by 2004,that will be going some.

I’m very nervous about trying to push hard to get a compound in the clinic so as to have a compound in Phase I. I’d rather have a much more robust portfolio of several compounds that we move forward, perhaps more slowly, but then you have several shots on goal. The whole biotech model - get one compound, get it in the clinic and then push forward – is such a fragile model because, if it falls, what do you have left?

D&MD: From what I’ve seen, big pharma has these very powerful marketing teams that can push drugs into the market. Why don’t you go along with a partnership model, rather than trying to take your own drugs through to the market?

HJ: The business model we have is a hybrid one, where we will be looking to partner very early on some of our chemistries for the big pharma to take forward, as we recognize that they have immense power and expertise in that area.

But, as the company evolves and grows bigger, we may take our own drugs to the market. If we truly believe that we have a discovery approach that is coming up with novel chemistries, novel drugs, our investors will rightly ask us “Are you sure that you want to be letting them go at this stage?” There is this balance to be struck, whereby we take forward our own programs as well.

But we’re very pragmatic and realistic about where our strength lies as a company of just over 90 people. We’ll grow to 130 or 140 in the next 12-18 months, but we’re still pretty small.

D&MD: In terms of the location in Cambridge, that seems to make sense, but most of big pharma seems to be shifting towards America. Is there a case for having some operations in America?

HJ: It’s an interesting point. The way we’ve been looking at it is in terms of our profile in the USA, our exposure. We definitely have a lower profile than some of our US peers, and, as you said, pharma is huge there, so we don’t want to be isolated. But I think that is a long way off for us. This year (2002), we consciously this year went out to raise our profile in the States, in the West Coast particularly. We’re fairly well known in the East Coast. Three of our investors are American, for example, so they know us pretty well. Now, we get invited to a variety of conferences and we talk in the US and Europe, so I don’t think we’re suffering.

D&MD: How is the construction of your new, purpose-built facilities progressing? When do you expect to move there?

HJ: Our new building is on schedule for occupation in February. We have two buildings at the moment, so we are looking forward to getting both parties together in the new labs. The facility will be 36,000 square feet (3600 square meters), which is double the amount of space that we have currently, and it will allow us to grow up to 150-160, or maybe more, people. The plan is for 130-140 in the next 12-18 months. We have options to extend the facility; we’re all looking forward to the move.

D&MD: I noticed that you had announced participation in the European Synchrotron Radiation Facility. How important is that to Astex, given that it is such a long way off?

HJ: These radiation facilities, the synchrotrons, are actually key to us. We don’t have to be geographically close to them, given that there is only one or two in each country, so that it is difficult to be close.

We use the European facility in Grenoble. We have a collaboration, a relationship with the Partnership for Structural Biology (PSB)there, which is a broader collaboration that the European Union have formed to bring industrialists together to guarantee access to a radiation source.

We also use a synchrotron facility in the UK, which is at Daresbury. It’s a key part of our science program.

D&MD: How does it fit in with your high-throughput screening, because I understood that involved robots?

HJ: Some 80% of our X-ray crystallography is carried out in-house, so our X-ray crystallography suite, which we built here, has the robots, for manipulation of crystals, etc. All of our X-ray screening is done internally.

We use the synchrotrons for specific experiments for more advanced crystallography problems.

Having said that, a lot of the synchrotron facilities are also investing in robotic systems to improve their efficiency, for example, at Daresbury.

D&MD: Having answered all my questions, are there any areas that you would like particularly to mention?

HJ: The key messages for us are that people should view our company as a structure-based lead-discovery company, clearly making key breakthroughs in structural biology.

Specifically, our fragment-based approach to drug discovery is something that we’ve pioneered. Like all things that tend to work, the approach is increasing in popularity, and it is amazing how many companies are now flying that flag. I’m excited that Astex is at the forefront of this new area of drug discovery.

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