A Bright Outlook

Natalie Brandweiner talks to Lilly’s William Chin about personalized medicine, partnerships, and using the company’s PD2 initiative is generate new compounds.

“Lilly has 56 potential drugs in its clinical pipelines”

Eli Lilly and Company is well established in its R&D success. Currently ranked 122 in the Fortune 500, it has 56 potential drugs in its clinical pipelines. Armed with an array of knowledge and tools, Lilly is sizing up its disease targets.

However, this is not an easy task given the current economic climate, as well as the patent expiry pressures and safety hurdles beginning to weigh down almost every major drug firm.

The company is facing a number of pricing pressures, due to the loss of exclusivity on many of its drugs combined with the simultaneous shortening of drug life spans. The public is also increasingly demanding that drugs become safer and safer, signaling a shift in balance between benefit and risk. The industry is facing continuous skepticism regarding its productivity. Regardless of the investments Lilly has made, there have been certain periods, such as during 2007, in which low points are evident.

As the Vice President of Discovery Research and Clinical Investigation, William Chin is the man leading the company's drug developments, battling against the many industry pressures and media misgivings. Chin says the real challenge, both at Lilly and within the industry, is to continue to maintain a flow of high-quality molecules to test, and to understand what kinds of molecules will be able to help treat disease in patients.

"That is going to be a key challenge," he says, "but to do this in a more efficient and effective way unfortunately takes too long and costs too much to get the drugs that we get, and so we need to improve that. What I've been trying to do in that process is to take a group of very talented scientists, including physicians, and bring them together to join in on this process of making the whole journey better and more effective.

"In terms of my management style, I'm very fortunate to have really outstanding leaders in the various fields, whether it's biology, which includes cancer, metabolic diseases and neurosciences, but also leaders in chemistry, toxicology, ADME, experimental medicines/translational medicine and program/medical. I count on the excellence of these leaders to join in as a team to achieve our tasks, so my style is I trust my colleagues. I am, myself, proud of my own integrity and I hope that others would follow that. My decision-making style is a participatory one. I'm a firm believer that we need all the input of as many people as we can, within reason, to be able to make the best decisions. I believe in diversity of experience, of background, to be able to come together to provide the input so that we can make the best decisions for our own portfolio and for our products."

Academic achievements
Prior to joining Lilly, Chin was a member of the faculty at Harvard Medical School for 25 years and is proud of the achievements made during his academic career. His research in the nuclear hormone receptor field illuminated the process by which hormones work to regulate events in cells and pathways in the body. He also led a genetics program, one of the first in adult medicine in the United States, established 23 years ago. A pioneer indeed – at that time, genetics was thought of as a pediatric department, one that would be responsible for postnatal genetic diagnosis, for example.

"I learned that genetics is absolutely important to help us understand which may be the most important targets for drug discovery," he explains. "One of our challenges is that we need to be better at choosing targets for drug discovery, and part of the difficulty of this is, again, based on our still not complete knowledge of disease causation or pathogenesis. Genetics helps us begin to tease that out a little bit more.

"A classic example is an enzyme called PCSK9, which is a gene that regulates LDL cholesterol receptor function. As a result, it then follows the body's levels of LDL cholesterol, and we know how important that is in the cause of atherosclerosis. So we know that individuals who have defective PCSK9 genes have very low levels of cholesterol, and associated with that is almost absent cardiovascular disease and atherosclerosis.

"Conversely if you have too much of this activity then you can have the reverse. So, you can see how we might imagine that this could be a good target in addition to our statins. That's our standard treatment these days: diet, exercise and statins for control of cholesterol in the body. If you had a small molecule or an antibody that blocked the activity, or decreased the amount of PCSK9, you could mimic what happens in these few rare individuals who have the defect as a part of a genetic condition. So what I learned from my activities as head of genetics division is how to really utilize this kind of information to help us choose targets in a more intelligent way," says Chin.

Chin says his focus during his time at Harvard, whether he practiced as a physician, researcher or educator, was always the patient. His realization of the huge amount of unmet medical need propelled him to look for solutions; as a scientist, Chin notes that the greatest of discoveries are made through serendipity. "In order for you to have great innovation you've got to create a climate to allow our scientists to be able to almost play a little bit," he says.

He notes the tendency, due to tighter budgets and time constraints, to rush through discovery developments, but says the correct atmosphere and environment must be created in order for those random acts to occur that often provide the most insight. Because he is no longer a scientist working in an academic environment, but is head of a corporate department, Chin must be aware of these constraints, as he points out, "After all we do have a business to run, and we do need to make sure that we provide this flow of innovation to our patients and shareholders."

Lilly is currently keen to promote its phenotypic drug discovery initiative, PD2. The company's success in drug development over the last several years is more than apparent – a large number of molecules have been tested in both human subjects and patients. Determined to continue in its success, the company is doggedly providing this stream of information, transforming itself in order to meet the industry challenges Chin has already noted.

"One answer is to focus on patients," explains Chin. "We like to talk about improved outcomes for individual patients. We know that even if we have the most innovative drug but our patients have no access to it, for whatever reason, because they can't afford it or governments or third-party payers are not willing to reimburse for it, then we really haven't done anything."

Networking
He also notes the importance of providing patients with tailored therapies, and the need for collaboration in order to understand these new ideas. Collaboration has long been a trend within the pharmaceutical industry, but Lilly is now entering into much deeper partnerships, sharing risks as well as rewards. Chin explains that this is called a FIPNET – fully integrated pharmaceutical network – which encompasses collaborative partnerships with academics, biotech companies and government agencies, or even with larger pharma companies. "Another level is to have shared risk and reward, so in other words, everybody has a bit of stake in the game as opposed to just paying a group for services. And the third level is to take an equity position in our partner company," he explains.

"We made Lilly a FIPCO – a fully-integrated pharmaceutical company – that is both self-contained and self-sufficient. However, we realized that we're going into an era where this may not be the best approach, and so we are morphing towards a network approach, a FIPNET.

"As part of this FIPNET, we think that PD2 is an opportunity to increase our innovation flow by basically bringing together the talent that's present throughout the world. That seems like a very ambitious goal, but there are a lot of ideas and compounds out there in the scientific community that remain untapped but could really help patients.

"What this program does is provide free testing of compounds that are designed by largely academic investigators, that may be very different than the kinds of compounds that we normally have; they're tested in four or five assays, which are called antitypic assays. Normally in our business we decide on a particular target, such as a molecular target, and then find molecules for that target. Whether they're small or large molecules, we then test to see whether they work in biochemical and cell assays and then ultimately in animals.

"If that does well and it's safe enough, we then move these molecules into humans. One of the assays is to see how compounds affect cell proliferation, how cells multiply and so on. So you can see how this would be very valuable in cancer.

"We have another assay that looks at what we call angiogenesis, which is the production of new blood vessels. Many cancers are very good at making new blood vessels and depend on that in order to thrive; our job is to find drugs that block new blood vessels in formation, and so that's another assay. Instead of focusing on a specific molecular target, it's looking at a cell behavior."

Approximately 60 institutions and laboratories have signed into PD2, providing opportunity to have their molecules tested. If at the end of the testing there is enough mutual interest, the molecules are novel enough and the activities interesting enough, Lilly will then engage in a discussion and have a certain amount of time in which it can agree or disagree with the investigator in order to proceed with a research contract.

"If we agree not to continue, the investigator gets all the data and gets to publish at will, which becomes a way of increasing our knowledge base for everybody. In this sense, this is a model of open collaboration with a much larger network of scientists that increases the likelihood of innovating. This will provide what I like to call a win/win/win - it's a win for our partners, our academic and other collaborators, because they get more information about their compounds and improve our overall knowledge base. It's a win for Lilly because we have access, potentially, to ideas that we might not have, and we create relationships with investigators that we might otherwise not have had. Most importantly, the third part of the win is that ultimately we hope this will lead to new therapies and treatments for our patients," says Chin.

Personalized medicine
The idea of tailored therapeutics – providing the right drug at the right time and for the right patient - is gaining support industry-wide. However, Chin notes that often Lilly's commercial colleagues would prefer that he and his team think in terms of expanding the business rather than from a patient perspective. In order to create good outcomes for all, Chin says Lilly has taken deliberate steps to ensure that every project that is started has a multiple of outcomes.

The first of these is improving outcomes for individual patients – understanding how the drug will excel against any others that are on the market, and looking at which patients will benefit more than others. The second outcome involves incorporating biomarkers, which allow researchers to follow both the efficacy of treatments in animals, as well as human subjects and patients. Chin provides an example of how this can be applied in cancer drugs:

"In colorectal cancer, for example, there are a number of agents that have been shown to be effective, including an antibody against the EGF receptor known as cetuximab. It's been shown that this drug is useful in patients with colorectal cancer, if you have a certain gene called K-RAS. If there is a normal copy of that gene in the tumor in these patients, then you have a better likelihood of response with these agents, but if you have a mutated or abnormal form of K-RAS, then it is not likely that you'll benefit.

"The FDA, as well as the EMEA, has allowed us to be a part of the approach that we can take in terms of personalized medicine. That's a really good example of how this is going to be applied. Sixty percent of individuals with colorectal cancer have a normal form of K-RAS, which means 40 percent through this testing wouldn't respond and or benefit and so probably shouldn't take this medicine," says Chin. 

Chin explains that the success of these developments is Lilly's strategy to meet the considerable challenges that continue to dominate the industry. For Chin, the correct organization of staffing is necessary to ensure the company remains ahead of its competitors. "I have an outstanding scientific and physician staff and ultimately it starts there: if you have the best people in the business then you at least stand a chance of being hailed to be competitive, but you can have all the best people in the world and if they're not organized well, if they're not working together in an optimal way as part of a true team, then you've lost the benefit. So what Lilly has done is to create an environment where our biologists working in cancer and neurosciences are working closely with our chemists and our toxicologists; and our folks who work on ADME, PK/PD, experimental medicine and medical work together in a cluster concept of activity.

"About four or five years ago I wanted to reorganize our group because I felt that we had groups that were much too large. That they'd created silos that diminished the synergies that I thought we could have by having more integration, and so we created smaller groups called drug-hunting teams. This is largely the biologists; the groups were much smaller and focus on specific areas such as diabetes or psychiatric diseases.

"These smaller groups would have with them a set of colleagues in chemistry and so on, and they would work together to provide more flexibility, with the ability to respond to changes more rapidly. In large part it has allowed us to do that, and I believe this has been a reason why we have been more successful lately in our pipeline," explains Chin.

He also reiterates that a continued focus on patient outcomes, as well as FIPNET, are other factors behind the company's success, before citing the fourth reason as being the result of "a rare company that has a true balance of therapeutic modalities focusing on small and large molecules."

Most pharma companies have largely focused on small organic molecules as drugs, and those drugs mostly been taken orally in the form of a pill. However, Lilly is opting to take a different direction, focusing on large molecules such as antibodies, peptides and therapeutic proteins to treat disease. Lilly's recent acquisition of Applied Molecular Evolution to aid the company with the optimization of proteins for the large molecules has been supported by its additional acquiring of Structural Genomics, a technology used as a structure for finding new molecules.

Chin finally describes the company's focus on being excellent partners, understanding that the future depends not on doing things as a sole company, but through collaborative partnership. "What we are trying to find out is how can we share in knowledge, share in work, share in the risk of projects and hopefully, then, share in the reward," he concludes.

William Chin became Vice President of Discovery Research and Clinical Investigation at Eli Lilly and Company. He also serves as a member of the company's senior management council. Prior to joining Lilly in January 1999, Chin was Professor of Medicine and Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School Chief of the Division of Genetics and Senior Physician at the Brigham and Women's Hospital, Boston.