Making the Leap

Brian Kotzin, Vice President of Medical Sciences at Amgen, tells EHM how biomarkers help translate basic science into medicine, and how increased funding for research has led to an explosion in innovation.

“It became almost an irrational fear of new clinical trials, and we had to get beyond that using really strong science to convince people that our trials are safe”
-Brian Kotzin, Amgen

Brian Kotzin is the first to admit that his background is a little unusual compared to that of his senior colleagues at Amgen. “I was at the University of Colorado, at The National Jewish Center for Immunology, now called the National Jewish Medical and Research Center,” he explains. “I was a physician scientist and did the usual things they do in academic medicine. I’m a clinician, a rheumatologist, so I saw patients within the internal medicine and rheumatology setting. I also ran a laboratory, and I did a lot of teaching.”

Kotzin’s appointments were in medicine, immunology and genetics. Over 25 years, he headed clinical immunology and rheumatology groups, as well as a center of excellence devoted to autoimmune diseases. As this research developed, he realized the next step would be to develop it into a therapeutic, which can be hard to do in an academic setting.

“At some point in your career, you want to do something that’s a little bit more broad-based and has more applicability to more people, and this seemed like a great opportunity,” he says. “When I came to Amgen, I headed up the development group for inflammation therapeutics. The main therapeutic that Amgen had at that time was Enbrel, which is a TNF inhibitor, which had dramatic effects for certain diseases like rheumatoid arthritis. After a short time, I became Vice President of Medical Sciences, which was a much larger group focused on the early development of Amgen’s pipeline in all therapeutic areas and the science needed to put molecules into humans. My background seemed to be suited for this job – it seemed a natural position for me because it is right at the interface between research and clinical development.”

Biomarkers
Much of the work that Kotzin and his team carry out in medical sciences is related to biomarkers. “Our group is composed of combined groups from research and clinical development,” he points out. “For example, we have a molecular sciences group that’s devoted to molecular biomarkers, we have an imaging sciences group that’s devoted to advanced imaging biomarkers, we have a clinical immunology group that includes a group focused on cellular biomarkers, and we have the development group. It’s a very biomarker-oriented function here in medical sciences.”

The goal of Kotzin’s studies is to maximize the information he gets from early clinical trials. Because the therapeutics are being introduced into a small number of people, it’s important to get as much information as possible, which is accomplished by dividing biomarkers up into different categories. “One of our biomarker-directed questions is, when we introduce a therapeutic into people, did we hit the target? Did we do what we really thought we did?” says Kotzin. “Then we ask, did we cover the biochemical pathway? Were the intracellular signaling pathways inhibited to the full extent that we thought they were?

“Then we have biomarkers that are a measure of clinical activity. We can’t do large clinical studies where we use a clinical endpoint, like survival – we don’t do that in these early clinical trials. Instead, we try to incorporate biomarkers that will give us a clue as to whether we have a clinical effect. For example, if it’s a cancer therapeutic, did we shrink the tumor, or were the tumor cells killed within the tumor?

“The last group of biomarkers that we try to get insight into are those that might predict who’s going to respond to a therapeutic. We call them stratification biomarkers or predictive biomarkers.”

One other important category of biomarker is that related to safety. Most therapeutics at this early stage do not work out: they fail for one reason or another, and the importance of being able to make a strong conclusion regarding that failed molecule is critical. The team needs to know, if it has a failure, is it because the target that they chose was not the right target, or is it because the therapeutic they developed wasn’t the right therapeutic?

“By knowing whether you hit the target and whether you covered the pathway, this gives you essential information you need to know whether the approach is going to be useful. If there was no effect on the disease, we don’t want to develop another molecule to hit that particular target. And you only discover that by having those biomarkers that tell you whether you did hit the target.

“We may have a molecule, for example, where we have a safety concern. The question is, did we use it at a dose that was much higher than we need, or was it the right dose, or was it not enough? By having the information that says yes, we did hit the target, or we didn’t even reach the dose that we needed to hit the target, this will tell us what the next step is in terms of trying to develop something for the same pathway.”

Predictions
Kotzin and his colleagues have had successes in which they have used biomarkers that predict the clinical effect. For example, instead of going to a several hundred-patient study that measures hemoglobin A1c for a diabetes drug, he has been able to measure the effect in a study with only 20 to 30 subjects, using biomarkers. “We were able to come to the conclusion that the drug really didn’t work, and it wasn’t going to work even if we studied many more subjects. That’s a great help. It’s much faster, and we expose fewer people to the therapeutic.

“We get to make our conclusion earlier and faster, and we get to move on to other molecules within the portfolio. Within our cancer therapeutics, we’ve been able to see tumor shrinkage. We’ve been able to measure the death of cancer cells within the tumor. And that’s really important early information that says, ‘Yes, this potentially important cancer therapeutic should be moved forward, so that we do larger studies and measure clinical effects like progression-free survival and overall survival.’”

Kotzin’s definition of translational medicine is very closely tied to medical sciences. He defines it as the interface between research and clinical development. “When I think of the term ‘translational medicine’, I think of discovery research: animal studies, basic research at the bench. And then you move that science into clinical trials, trying to understand whether there’s going to be a benefit in patients. Translational medicine is that interface, moving it all forward. And it’s all the science that goes along with that transition.

“It’s this interface of translating the discoveries you have – either in cell culture or in animals – into human disease. It’s a very difficult thing because the animal models are frequently not predictive of the human disease.

“We’re measuring pathways in animals, and we have to measure the same pathways in humans. All of the science we do here is centered around how do we take what we’ve learned in the animal studies, or in the preclinical studies, and move that into humans, so that we can truly understand things. And it’s much more difficult. In an animal study, you can look at the whole animal to see whether your drug has had an effect. But in human studies, you may be limited to sampling blood. You have to be very ingenious, very innovative in how you get the information. This whole process is translational medicine.

Approval
How difficult is it to get approval to carry out these early clinical trials? Kotzin explains that there are extensive regulations that govern this process. This is to ensure the safety of the participants when investigating a therapeutic that has never been put into people before. Patient safety is paramount. Because of this, there are many regulations regarding what doses you can start at and what types of animal preclinical studies you need in order to know that the therapeutic is likely to be safe.

These regulations have become much more stringent in the last few years, because of the tragic outcome of TeGenero’s TGN1412 study. TGN1412 was a therapeutic that was designed to target T-cells, but instead of inducing the lymphocytes to not respond, it triggered them to release massive amounts of cytokines. One of the study’s major flaws was in the decision to inject all of the participants at the same time, and all who received the active drug became seriously ill.

“That catastrophe understandably colored early development around the world,” says Kotzin. “Although at Amgen we’re very stringent and we like to believe we would not have done anything like that, everyone became afraid of approving new therapeutics, especially biologics. Now nearly every time we apply to put a new biologic into people, the specter of the TeGenero catastrophe comes up. This has resulted in new regulations being put into place around the globe that delay the process.

“I remember traveling to the MHRA and presenting a molecule that was an immunologic molecule, and we arrived shortly after the TeGenero tragedy. The regulatory group in the UK just didn’t know what to do. They were faced with the results of this tragedy and how to prevent something like that from ever happening again.

“It became almost an irrational fear of new clinical trials, and we had to get beyond that using really strong science to convince people that our trials are safe. We’ve been trying to convince regulatory groups – for example, when we come forward with a new therapeutic – that the science predicts that this will be safe. We’ve been successful, but sometimes there has been an inordinate delay related to the fact that people are still afraid.”

Certainly one way to improve safety is not to inject all study participants at the same time at the beginning of the study. Instead, one individual is exposed to a very low dose, and if that causes no ill effects, researchers can feel more comfortable about exposing several people to that therapeutic. The dose can be gradually increased after the first subjects have been safely dosed.

Animal studies are often carried out to provide enough information to ensure that the compound will not cause problems in people. But as Kotzin explains, sometimes a negative result in animals will not necessarily translate into humans.

“This is challenging because we’re sometimes faced with situations where we have an animal toxicity which we don’t believe will translate into humans. When this happens, we have to figure out how to get beyond the problem and convince ourselves, investigators and regulators that this shouldn’t prevent us from going into people, especially when the illness is grievous, such as a cancer therapeutic.

“Another example of regulations that have been challenging is related to biologics.  Amgen is a leader in the development of  biologic therapies, and these types of molecules are a major portion of our portfolio., Sometimes,   regulatory groups apply principles used for small molecules,  the usual types of drugs taken orally, to biologics. Sometimes, these regulations are just not applicable. It’s a teaching process. You have to explain to them why the same rules that they use for small molecules don’t apply to these large protein molecules.”

Developments
There has been an explosion in basic science, which has had a big impact in translational medicine, because there are so many new ideas and new discoveries that can now be translated to humans. As Kotzin says, “The whole understanding of disease has been an important development for translational medicine. That’s very dependent on new research technologies, which give us the ability to develop new molecular techniques.

“There have been tremendous advances in proteomics, and in how to measure intracellular pathways by measuring proteins that get phosphorylated. And there’s been a tremendous explosion in genetics in terms of the tools you can use. Now, you can screen the whole genome for polymorphisms that might affect whether your therapeutic will work in certain people and not others.

“There are also new sequencing machines that sequence at an unbelievable rate, something that nobody even a few years ago could believe that we could do. And that’s added to the information we can add in our early clinical trials. We can sample tumors, for example, and do unbelievable amounts of sequencing of all the different genes that have changed in those tumor cells.”

“We’ve also become more innovative in our clinical trials. We’re no longer fixed into the same type of experiments. We’re doing clinical trials where we learn as we go, right in the same clinical trial. We’ve combined different, single dose and multiple doses in the same trial. Again, ensuring safety at the same time we go, but increasing the information that we get, as well as the speed that we can move in terms of getting the information that we need.”

Brian Kotzin joined Amgen in 2004, as Vice President and Head, Global Inflammation Development, before transitioning to his current position as Vice President, Medical Sciences. He leads this integrated function comprised of Early Clinical Development, Molecular Sciences, Imaging Sciences, Clinical Immunology, and Computational Biology. Medical Sciences is responsible for the planning and execution of early-phase clinical development as well as the discovery and implementation of pharmacodynamic  biomarkers in clinical studies at Amgen.