Head to head: with big pharma

Julia Puppe spoke with Dr. Joseph Miletich about the ‘Best Biotech Pipeline’ and how the company managed to establish itself among the big drugmakers.

Total drug sales in 2006, according to IMS Health, increased by 8.3 percent from 2005 to $274.9 billion. Amgen’s antianemia injectable drug Aranesp led all gainers among the top 20 earners by an increase in revenues of 42 percent. The bad news is that today, as many as one in three drugs fail in phase I trials, despite extensive pre-clinical testing and the screening of potential drugs. In phase II trials, 10 percent of potential drugs fail due to pharmacokinetics with an additional 25 percent failing for safety reasons.

With ever-increasing drug development costs, failing drugs faster ranks high on the drug industry’s agenda. “No one likes to find out, after some substantial burn of resource and time, that a potential new medicine might have a fatal flaw. Every company is trying to understand where those flaws might be and uncover them sooner. But the focus, at least for us at Amgen, has changed,” says Dr. Joseph Miletich, SVP of Research and Development (R&D) at Amgen.

Complex biologics

One of the biggest challenges, Miletich believes, is identifying how much good medicines can do. He is concentrating his efforts on understanding and developing conviction about whether a medicine is worthwhile taking forward into the commercial landscape. “That’s a shift in focus because especially with biologics, the number of times that the molecule is inadequate in terms of its specificity, or some detrimental unintended activity, is lower. We have become much more fluent in being able to develop very complex biologics. As we delve into more and more molecular mechanisms, we find that the same pathways come up fairly frequently in different clinical settings. Finding out whether or not influencing those pathways can truly make a difference in a particular disease state is our principal focus now.”

Crucial for Miletich is a translational approach, and so he concentrates on identifying whether the potential new therapeutic hits its target molecule, if it interacts in the appropriate tissues, if there is a dose response, and if it shows the results that had been hypothesized. “Then you have to have the tools in place to see whether the diseases you’re investigating are actually altered in a beneficial way. There’s sometimes an assumption that the tools to do all of that would be in place because of the way that medicine is practiced. But the assays, imaging modalities, and the information that you need about the baseline characteristics of a disease population versus a normal population, often actually aren’t in place. So we begin developing the tools we will need to explore that when we start thinking about developing a target.”

The ‘molecular science’ group at Amgen is charged from the early phases of its R&D programs to assemble the tools needed to test molecules in human models. Miletich: “It’s important to start that even before the molecule is ready, because the effort can sometimes take several years. You do not want that to be rate-limiting. The amount of resource we devote to that effort, and the way we integrate that effort into the whole drug discovery and development process, I believe to be best in class.”

Better than the rest

Amgen is certainly doing something right, and the title of ‘Best Biotech Pipeline’ in 2006 by R&D Directions magazine proves it. What makes Amgen’s pipeline better than anyone else’s? For Miletich, the answer is innovation. “It is really difficult to improve medicines, and it is really difficult to discover new ones. However, making improvements in a medicine, once you know the clinical reason for developing it is there, is probably only about a fifth as hard as developing an entirely new medicine. We decided to be innovative, so the vast majority of our early and emerging pipeline involves potential new therapeutics that work by mechanisms that do things in people that no one has commercialized medicines for yet. And in that regard, ours is probably the most innovative pipeline in the industry.”

It certainly is a high risk venture. Amgen, however, has a large early and emerging pipeline, which is beneficial because not all ideas work. “It’s important to have both a very innovative and a very large pipeline. When you combine those two elements, that’s what makes our pipeline the best.”

Miletich’s main responsibility at Amgen has been to build and develop the company’s emerging pipeline. “We have a number of oncology therapeutic agents that will enter phase II trials this year. We have a very promising molecule in bone health, and we have quite a few very early-stage molecules that hold enormous promise in Inflammatory diseases and in diabetes. In broad strokes, those are the areas that have most promise for our emerging pipeline.”

Late-stage pipeline

Looking at Amgen’s late-stage pipeline, in recent years the company has spent the most effort on denosumab, a fully human monoclonal antibody that targets RANK Ligand. “This is an enormously promising molecule that will allow us to control osteoclast function and bone resorption, and will have a great deal of impact across all aspects of bone health. Much of the science and biology was discovered here at Amgen. It’s taken a long time to bring that molecule forward, simply because of the large number and breadth of registrational studies that is required. But it’ll be an extremely important molecule.”

There’s also the multikinase inhibitor motesanib diphosphate, a highly selective oral agent that is being evaluated for its ability to inhibit angiogenesis by targeting vascular endothelial growth factor receptors one, two and three. And Amgen’s platelet stimulating agent AMG 531, an Fc-peptide fusion protein that is being investigated for its potential to increase platelet production through activation of the thrombopoietin receptor. “This is an enormously interesting molecule because it enables treating idiopathic thrombocytopenic purpura in a new paradogm. Medical practice has been focused on trying to quiet down the destructive process that clears the platelets from patients. We’ve focused on stimulating the production of platelets to get the number of platelets back into a safe range, which dramatically alters the way people think about the disease.”

Last year, Amgen received approval in its first indication for Vectibix. Miletich is certain that this first fully human anti-EGFR monoclonal anitbody still has a lot of potential ahead of it for other indications.

An integrated approach

Although Pfizer’s Lipitor once again topped the lists of most commonly prescribed and purchased medications in 2006, the drug giant last year only produced two of the top 20 drugs in the US1. Amgen is the only company with four products among the best-selling 20 (Aranesp, Epogen, Neulasta and Enbrel). How has the young company established itself over a remarkably short time? “We have an integrated approach to how we not only discover but develop and then eventually commercialize the therapies. The combination of focusing on innovation and on having a small company that still feels nimble always has been, and still is, an extremely powerful way to do that. When you focus on that, and if you have a bit of luck as well, good things can happen. That’s the story of Amgen.”

A true innovator, Miletich believes, needs to have what he calls “the right kind of pioneering entrepreneurial risk-taking spirit,” because no one truly understands what will happen in human biology. “What we do have is a lot of clues about pathways or particular molecular interactions that often come up in different disease states. But knowing whether or not altering those will really change the course of disease is something that nobody can predict well yet. Our risk-taking strategy is that we will develop molecules in a very quick facile manner, and we’re willing to try those ideas in people as long as the molecules are safe and we don’t jeopardize anybody’s health. But our willingness to try those as quickly as we can, with the tools required to get a meaningful answer, is risky simply in the fact that a majority of those ideas won’t work. That’s where our fundamental risk is.”

For Miletich, this is the biggest bottleneck in effective drug discovery from an early stage point of view. Beyond that, there is pressure on reimbursement. “The revenues from successful drugs is what pays the bill for these fairly expensive but truly life changing therapies. There is considerable pressure while we’re doing all of the discovery work to sustain everything that’s necessary to prove benefit to payers around the world, and to continue to prove the safety of the medicines. It’s an understandable and logical burden.”

Biomarkers

And there’s another cloud on Amgen’s blue biotech sky. Sales of the company’s blockbuster anemia drug Aranesp face pressure as US health officials review its risks. Miletich stresses that everyone at Amgen is working hard to provide the necessary data. “We try to not focus on this in any kind of an emotional or reactive way, but to simply respond to any questions or queries we have with the most robust data so that everyone from payers to physicians to patients can make up their own minds about what’s going on. It certainly also energizes us to redouble our efforts to bring the best of our portfolio of early and emerging molecules forward.”

Biomarkers, Miletich says, are extremely important. But they mean different things to different people. “They have always been significant in the study of human disease and in the development of potential interventions. And they are certainly one very strong leg of what enables us to do a high-quality ethical experiment in people when we introduce a new therapeutic. In a narrower sense, biomarkers mean something that might act as a surrogate for a disease endpoint or an early readout for a disease endpoint. In an even narrower sense, a biomarker might serve as a regulatory surrogate. Those are more complicated questions, but in the broadest sense, we’re interested in all aspects of biomarker development and use them as robustly as possible.”

At the same time, Miletich emphasizes, his focus is not on hoping that biomarkers will solve his problems. Rather, he aims to understand how his potential new therapeutics alter or do not alter disease. Biomarkers, he stresses, are just another tool in the quest to do this efficiently.

Some analysts forecast that by 2010, the Amgen will be as big as Merck. Miletich laughs. Competition, he says, is a good thing. “But we are going to keep our focus on patients, on bringing medicines forward that can benefit the most patients as quickly as possible. If we do that better than others, then we’ll be bigger. There’s a very good possibility that this will happen. It will depend mostly on how many patients we can help. So far our track record is good, and I believe very strongly in the promise for the future.”

IMS Health, press release, March 8, 2007.

Dr. Joseph Miletich joined Amgen from Merck Research Laboratories, where he was SVP, Worldwide Preclinical Development.