Joe Miletich tells Next Generation Pharmaceuticals why it’s more important than ever for pharmaceutical R&D to pursue the highest levels of innovation.
 |
| Joe Miletich |
In 1999 he moved into the pharmaceutical industry, taking a position at Merck in the toxicology group and then heading up the company's worldwide pre-clinical development. Miletich joined Amgen in 2002, and for the first four years was responsible for discovery research all the way through the first introduction of medicines into people. Since 2006 he has focused on translational medicine. To top it all off, he is also a board-certified clinical pathologist.
This wealth of experience should come in handy as he shepherds Amgen's R&D through what are shaping up to be some turbulent years for the industry. Like most top 20 pharma companies, Amgen rode the wave of blockbuster success in the late 1990s and early 2000s, but now finds itself staring at the twin threat of patent expiries and a lack of big earners coming out of the drug pipeline. Amgen's answer is to "reignite" its innovation engine. But what does this actually mean?
In its largest sense, any change can be labeled as innovation; as Miletich points out, you're not going to get very far by doing things the same way they've always been done. In this way, innovation is essential to a company's survival.
His definition of the term 'innovation' as it is used in the current context of drug discovery means not just bringing in change but bringing in change at a very significant level: changing the practice of medicine and changing what people understand and believe about what can be done in disease conditions.
"That's the highest level of innovation when you're in the drug discovery and development business," says Miletich. "You want to change the way people think about a disease and make things possible that weren't possible before.
"I think society truly wants our industry to focus on the highest level of innovation, but in our current climate there are a couple of things that are acting against that larger goal. The first is a fear of being reckless and having an insufficient regard to safety; and the second is a concern about how we are going to pay for it, because it's very costly to be this innovative.
"The only reason people might be reluctant to be highly innovative now is because of a worry that we're at a temporary phase where the concerns about safety and reimbursement have become so prominent in our thinking that what we would normally expect as rewards for innovation might not be there."
Against the odds
Miletich believes it is more important than ever to be innovative in the current climate. He underlines the obvious fact that discovering and developing drugs is a long cycle business: the time from an original idea until a drug reaches the market might be 12 or 15 years. Companies work constantly to reduce that time, yet at the same time ever more stringent safety and efficacy requirements act to increase it.
He remains optimistic, however, that the need for innovation will win out in the end. "In the long term," he says, "what we fundamentally need as a society and human beings will prevail and the truly innovative things will be rewarded. When you think about this as a long-cycle business, as a company we need to pay attention to that and bet heavily on it.
"That doesn't mean we won't do anything that isn't the most highly innovative thing we can think of. There are very practical benefits to being innovative on a less expansive scale, and we do make improvements to medicines. We've done this in the past, and we'll continue to do so where it brings benefit.
"It's all in how you weight your portfolio. We weight our portfolio so that roughly two-thirds of what we're doing are highly innovative things. It's a conscious choice. We make the choice to do that and then set ourselves up so that we can find people in our own research labs and in all the connections we make with small companies and with academic collaborators around the world - find those innovative insights that will help change the practice of medicine."
A major focus of Miletich's role at Amgen is to oversee the translation of drugs from discovery through early stage clinical trials. He points out that at Amgen, translational medicine is not limited to early clinical trials and biomarker research.
"Of course we have a terrific medical sciences group that places an enormous emphasis on biomarkers and we concentrate on our experiments in people to discover whether that fundamental idea that we started with back in the research labs actually does have enough impact in human biology to let us change the practice of medicine.
"But that's not the only thing that's important when you're trying to translate that original idea. You also have to understand how to make a molecule at large scale, how to formulate it and what the attributes are that will become important in human biology, and how you would recognize if you needed to make something that was changed.
"You have to incorporate all you learned from your pharmacokinetics and drug metabolism studies to know and appreciate the characteristics of those molecules and how they behave, and you certainly have to understand all of your toxicology assessments so that you can clearly make a weighted judgment about what risk you will expose patients to and become very convincing and fluent and provide appropriate scientific evidence about the safety factor that you're employing when you embark on those experiments.
"Even more than all of that, when you integrate your learning from all of these different sciences that go into what molecule you want to make and how it performs, as well as what actually happens when you do this in biology, you can learn a great deal more. You can learn a great deal about how things work in the human body."
Miletich and his team work to integrate the different sciences needed to move a candidate molecule forward and develop it with the optimal properties for a potential human therapeutic, in order to learn as much as they can about what goes on in human biology and to carry out the most informative experiments. They then use that information to make judgments about how to weight the portfolio and where to make the investments that are the most likely to pay off with the greatest benefit to people.
Forging ahead
Producing breakthrough drugs that radically change the way we look at disease might be every R&D team's dream, but what about the challenges in then bringing that drug to market? Only about one in every 10 drug candidates that enter clinical trials are eventually approved by the FDA, and the cost of all these failed drugs is another major challenge for the industry. How can pharma companies raise their success rates and cut down the amount of money spent conducting trials for drugs that never come to market?
"Companies may understandably try to reduce drug discovery and development to a methodology that can be repeated for project after project," Miletich says. "There is great efficiency in doing that so you don't relearn how to do things, and we do that when it is appropriate as well and have no qualms about it. Where things are repetitive and we can learn to do them in a repeatable, efficient fashion, we do that at every opportunity.
"Every one of these innovative projects, however, is a new adventure. It's a pioneering discovery, and in order to optimize how much you can do with the resources you have you need to make decisions all along the way about what your level of investment is going to be.
"That means that when you integrate all this information that's coming in in real time as you're in this early stage of drug development, you should have a sense, if you're paying attention to all the information you have, about what your likelihood of success is, and about what your potential for doing good in how many people might be. My firm belief is that you should adjust your investment to those opportunities as you see them in real time.
"You don't just set up a drug discovery and development organization and turn a crank. You learn how to turn the cranks very efficiently where it's important, but you continuously review your portfolio and continuously monitor what the opportunity actually looks like relative to your original idea and adjust your investments accordingly."
Miletich says that when this is done well and a good stable of candidates is selected at the very beginning, a fraction of these emerge quite early as having very promising characteristics that can then be invested in heavily and pushed aggressively and quickly, thanks to the conviction that this drug should be developed and made available as fast as possible.
"With some, another fraction, you find the idea simply wasn't good enough or your molecule wasn't good enough, and when you find that early you can stop that investment, rethink what you want to do, and see if there's an adjustment you can make. Then there's a group in the middle, which can encompass 40-50 percent of the molecules, where you discover that there's something else that you need to understand before you can gage the value of the opportunity. For these candidates, you adjust and modify your investment and decide what that next piece of information is to allow you to make a decision about whether it's worth investing in or not.
"You have to manage this portfolio in a very dynamic way. When you do that, you'll increase your overall success rate, and you'll increase the efficiency of the resource base you use. I'm optimistic that in another five or six years we will be able to point back and say it did result in an improved success rate."
Although Miletich makes this process sound quite straightforward, in reality it is anything but. He explains that for a typical project at this stage there can be as many as 1000 different work streams. His team could be working on 30, 40, or 50 different projects and many of those work streams are interconnected, so that one that's about to begin depends on the results from another one that has just been completed, which makes managing this resource base in real time an incredibly complex project management task.
On target
The use of biomarkers is often touted as essential weapon in this struggle to cut waste by ensuring more drugs hit their targets, but Miletich is quick to point out that biomarkers are not magic bullets. "Biomarkers are just tools," he says. "They allow you to gage whether you're doing what you wanted to do and whether it's as impactful as you wanted it to be.
"Sometimes when people talk about biomarkers, they make it sound as though they can solve all our problems, and that it's the biomarkers themselves that are important. But in fact the important thing is deciding what you want to do, what your idea is, whether it works and whether it is impactful. Biomarkers help you determine whether you're doing that or not, and you have to have a full toolset of biomarkers to do that.
"One of the things that might not be evident to people who aren't familiar with the business is that while in human medicine we have a large number of tests that are available through physicians and hospitals and we have a lot of imaging tools, those tools, assays and tests were developed for very specific purposes and often don't answer the questions we're asking now.
"So we have to set up new assays, new tools, new tests, and we have to understand how they perform in populations of people. All that work has to start very early on because it can take years to set up. Our goal is to always have those tests and assays in place by the time we are ready to do that experiment in people."
All of this hard work has resulted in some interesting drug candidates moving through Amgen's pipeline, including an osteoporosis drug known as AMG-785, which is now in phase II trials and about which Miletich is very excited. "We're investigating AMG-785 along with our partner UCB, to find out what dose and schedule of this new therapeutic will enable us to restore a good level of baseline bone health to women with moderate to severe osteoporosis, and we're also studying it in a phase II trial where we're looking at very hard-to-heal fractures. In particular, we're looking at fractures that happen in the tibial plateau, the top of the lower leg bone.
"Fractures there can often be problematic, not healing adequately or taking too long to heal. We're investigating AMG-785 to see if we can improve the speed or quality of healing in that setting."
Amgen has a large number of therapeutic candidates in phase II trials in oncology, as well as a portfolio of molecules being studied in a variety of inflammatory and autoimmune diseases, including an extensive program of molecules in asthma. The company recently licensed a molecule from Cytokinetics and is studying patients with severe congestive heart failure to improve heart function.
"We've also recently introduced an antibody called AMG-145, which helps us lower cholesterol levels in patients that can't otherwise reach target," Miletich says. "We're in phase I studies with that molecule. So we're making some meaningful ventures into the cardiovascular arena, again where we're using mechanisms that have never been explored in human biology, to do things in ways that were never possible. We continue to have new efforts in the diabetes, such as the deal we concluded in December with Array BioPharma to license their glucokinase activator, which is a very promising molecule that, if it is successful, will allow treatment of diabetes in a new and meaningful way as well."
When asked how he sees pharmaceutical R&D developing over the next couple of years, Miletich smiles, and calls it an intriguing question. "In one sense if you take the pulse of the industry, there are pressures there that are unprecedented: concerns around safety, around reimbursement, around the productivity of the industry as a whole.
"At the same time, from someone in my position the prospect of doing important things for patients who suffer from grievous illnesses has never, ever been better, and it feels like a very unusual time to be in the pharmaceutical industry: our fears and concerns are at a peak at the same time that our hopes and aspirations are also at a peak, and no one knows how this will play out.
"If you look at previous examples of how humankind has reacted in other situations that are even remotely parallel to this, I would say that there will be tremendous advances, and there will be some things that we can't predict that will take place in ways we can't foresee. My guess is that some time over the next 10 years we might see some consolidation in the industry, but we'll also see out of the next four or five years of effort some winning scenarios emerge, and those companies that are nimble and can adapt and that aren't afraid of the opportunities will manage to be highly successful even though there are great concerns about the pressures on the industry at the moment.
"I hope, and will work diligently with all of my colleagues here at Amgen to ensure, that we are one of those companies that emerges with the success rate that's necessary to move on to even greater things."
Joseph Miletich is Amgen's Senior Vice President for Research and Development.
Happy anniversary
In 2010 Amgen celebrates its 30th anniversary, having been established as a corporation on April 8, 1980. Since then, the company has grown to become one of the world's leading independent biotechnology companies.
