Golden Age of Discovery

Martin Mackay, Pfizer’s President of Global R&D, explains how in the age of tailored therapies, the end of diseases is in sight, and how the merger with Wyeth will set the company at the forefront of drug discovery.

“We're on the cusp of the golden age of drug discovery and of producing medicines that are going to alter the nature of disease”
-Martin Mackay, President of Global Research and Development at Pfizer

Martin Mackay assumed his role as President of Global Research & Development in 2007 at Pfizer, but being an internal candidate for the position, had thought hard about his responsibilities and aims long before his appointment. Working within the company, his main objective was to understand why, as an R&D department, Pfizer was not getting its return on investment, and how as a department they could address that.

Plan of discovery

Mackay explains the implementation of what he describes as his "highly tactical plan" from day one. "The first day I was in the job I laid out my five-point plan, which people thoroughly enjoy at Pfizer, and it was a very simple plan based on everything that we had learned over a period. It basically came down to executing what we had in the pipeline.

"The simple first thing was to deliver the late-stage portfolio: at the beginning of 2007 we had eight entities in phase III; by the end of 2008 we had 26 entities in phase III. That first part of the plan of delivering was very important and as part of that we made some commitments to what we were going to deliver as an R&D organization. We did that on March 5th 2008, and we've been very public about them; we're on track to deliver on all of these publicly made commitments, something that we hadn't done before."

The second part of the plan was to make sure the company was working in the right areas: those of the highest medical need and those that could be attacked from our scientific and drug discovery point of view. This resulted in Novartis cutting its portfolio considerably to focus on areas that would be best for patients and for the company.

MacKay notes the third part of the plan was to focus on becoming a top-tier company in biotherapeutics. Historically, Pfizer has focused on small molecule drug discovery with a large biotherapeutics pipeline, but Mackay wanted more, and to take the company to the next level. His fourth agenda was to increase productivity. Despite this receiving the least attention, he notes how it received the biggest amount of effort, particularly in terms of improving attrition.

"The fifth part of the plan was to access external science much more productively and efficiently, and whist we had always had collaborations, again, it was a case of taking it to the next level. In our five largest therapeutic areas we formed therapeutic area scientific advisory panels, each lead by a leading academic and in turn those academics having a number of really top-notch scientists. This group works directly with the leaders of those five therapeutic areas – whom we call chief scientific officers – that has really gained us access to the very best minds.

"We've got terrific talent within Pfizer, and a great history of drug discovery," explains Mackay. "However, most discoveries happen outside because even with our terrific budgets it's relatively small compared to everything that's invested in the life sciences. I'm very pleased with the number of great collaborations that we have, both with academia biotech and actually with some of our competitors.

"So over that period we've focused on execution at attacking the issues of productivity that has dogged the industry, engaged our colleagues, and I have to say they've risen to this task. I couldn't ask for more effort and more result coming out of our laboratories, and obviously all the people that support that have been really excellent."

In addition to improving the company's problem areas, Mackay has also been determined to address those external challenges that face every pharma company. He notes the increase in regulatory hurdles, and the company's response to this of running more patients in its studies. "We have always had a very simple philosophy that our drugs have to be both safe and effective, and we put a lot of effort into making sure they are," he explains.

Pfizer's work with agencies across the world and its multi-center operations does not come without its challenges, but Mackay notes that providing the company continues to produce good medicines, then they will be approved through the regulatory process. "Sure, there will be discussions and meetings and appropriately the data will be scrutinized, but I like to think we scrutinize our own data more than anybody else does," he says. "We're on the cusp of the golden age of drug discovery and of producing medicines that are going to alter the nature of disease."

Personalized medicine

Discovering and developing the right medicines and ensuring the right patients receive these is Mackay's essential goal; Pfizer's laboratories now examine, very early on in the process, the patient population that will best be served by each medicine. "This is going to be a real change for the true benefit of patients in then near future," he says..

Pfizer's portfolio of pipeline products currently spans 11 therapeutic areas, ensuring the tailored therapies approach is begun in the very early stages of clinical development. Mackay gives examples of this, of drugs both in the market and also within early stage clinical development. Selzentry, which is also known as maraviroc, is Pfizer's CCR5 antagonist for the treatment of HIV/AIDS. Mackay explains how the virus enters the immune cells of some humans via the CCRF receptor, but there is another portal of entry, for which the company has an assay that it conducts before treatment starts.

"This ensures that the virus actually would enter the patient by this receptor," explains Mackay. "Therefore for any patient that takes Selzentry, we essentially know that it's going to be effective because of this test that we do beforehand. Selzentry was the first new treatment, first new mechanism, in HIV/AIDS for a decade. We launched around 18 months ago, but right from the beginning (and I was there on day one of this project) we had an eye on making sure that the right patient got the treatments. I'd like to think that in future the vast majority of the compounds we launch will have aspects in them of this.

"We have a very interesting approach in oncology now for non-small cell one carcinoma. We showed how in a particular group of patients with non-small cell lung carcinoma that our phase I compound worked remarkably well and better than anything else that is currently being used, and we were able to isolate a particular genetic translocation in that group of patients. We've subsequently partnered up with Abbott on a diagnostic that will identify those patients ahead of time.

"Another example that demonstrates how we approach diseases or conditions from a discovery perspective, which is a particular program called NaV 1.7, is a sodium channel approach that we have in the pain area. We did some seminal work with leading academics in the United Kingdom, looking at a family in Pakistan who had what's called a chronic indifference to pain. Essentially they couldn't feel any pain, and whilst that sounds a good thing it's actually a really terrible thing. It leads to mutilation of fingers and the like, because children growing up can't feel the normal sensory touches that protect us.

"The seminal work that led to the identification of the problem was that the sodium channel, this NaV 1.7 channel, was the gene responsible for the condition. We did other work that was also genetic analysis; there's another condition where people are acutely aware of pain: even at the slightest touch they feel it quite badly, and again this was when the NaV 1.7 channel was implicated, so here we had genetic validation both in terms of a loss of function and a gain of function. We started a program in the UK whereby we launched a very large program because we thought this was a leading target in pain treatment.

"More and more our early discovery portfolio is predicated on a genetic analysis which shows some genetic validation, but also was an acute eye right in the beginning to get to the right patient population, so those are examples of much of the work in our laboratories," he says.

Discovery methods

Pfizer's methods for discovery have also matched its products. In the early 1990s the company was one of the leaders in high-throughput screening. Mackay notes that during his early days with Beecham Pharmaceuticals, in the 1970s, chemists would only make a few compounds a week. As time has gone on and tests have become more high tech, there was greater accuracy in the correct chemical matter in addressing particular targets, and this became achievable on a much greater scale.

Medicinal chemists and chemists could now make tens of thousands of compounds rather than the previous few, with the biologists matching this with the creation of assays that could tests hundreds of thousands of compounds, referred to as high-throughput screening.

"There's a whole host of different ways we screen millions of compounds, which gives you a much earlier clue as to the type of chemical matter that you're going to have to work on, to come up with what will be a medicine," he says.

"Interestingly there are very few occasions now that we run a high-throughput screen. We have a file of about three million what we believe to be excellent compounds and we can run those and a whole array of different types of screening technologies, but much more we use computation and selected parts of the files.

"For example, let's say the target is a kinase target, which is a particular type of enzyme in the body which is very well known to be a good source of new medicines, we can now have a targeted library purely for kinases and if we're starting any de novo kinase we will just screen against those compounds first before ever going to the full file. So high-throughput screening has moved in the last few years onto the next plane, which is much more selective screening but still using the power of numbers and the power of combinatorial chemistry.

"Most of our new projects, certainly from a small molecule perspective, start in this way and it's really very impressive how we're using computational biology, computational chemistry to really narrow down on the types of chemicals that make great medicines."

Future of discovery

Staying at the forefront of drug discovery in an industry of giants is no mean feat, but Pfizer's merger with Wyeth is sure to set them in good stead. The deal is due to close over the next three months and the results of this for the R&D department is due to give, what Mackay describes as, a huge boost.

"Point three of the five-point plan was to become top-tier in biotherapeutics. Wyeth has a really impressive record in both biotherapeutics and prophylactic vaccines, so when you ask what will set us aside and what I'm optimistic about, I see us being a really terrific company in small molecule drug discovery and development, in biotherapeutics, and in prophylactic vaccines, which really gives us the span of the modalities that we will need to attack disease.

"The head of R&D at Wyeth, Michael Dohlsten, is joining Pfizer, and Michael and I have decided to split R&D into two components, a small molecule group and a large molecule group. I will lead the former and he will lead the latter, but these groups are inextricably linked and we have just a golden mission to really attack the diseases that dog us. I truly believe that by the end of the century we will cure most of the diseases that plague us, and it's our challenge in an R&D environment to make that happen in our lifetimes.

"We have never had a better chance to do that, and Michael and I are on an absolute mission to be a forefront R&D organization that really addresses the needs in oncology, Alzheimer's disease, diabetes, pain and inflammation, and we've never had so many tools at our fingertips to be able to do this. I'm very optimistic about the future of medicine and our role in it."

Martin Mackay is President of Global Research and Development at Pfizer.