Issues in Dry Eye Adrienne Graves, PhD President, Santen Incorporated Adrienne Graves, who recently became President and CEO of Santen Incorporated, the US branch of Japanese ophthalmic drug manufacturer, Santen, Ltd., has been studying vision since undergraduate days. She recently came to prominence when she and her team shepherded two drugs through the FDA approval process in surprisingly little time. As one of the people who will shape the future of both ocular surface research and clinical practice, she talked to us about her vision of what is to come for herself and her company.
THE OCULAR SURFACE It’s a long way from undergraduate to pharmaceutical company CEO. How did you get started? ADRIENNE GRAVES, PhD As an undergraduate, I studied experimental psychology at Brown University. My particular interests were sensory and physiological psychology, and my original intent was to pursue a career in clinical psychology. However, I soon became fascinated with the visual system. I completed my senior thesis at Brown under Lorrain A. Riggs, PhD, who was well known for his work in visual psychophysics and electrophysiology. When I presented the results of my small project at the big ARVO meeting, it was a tremendously exciting moment. It ignited a passion for further study of the visual system. I spent the next year working at Harvard Medical School for Anne Fulton, MD, a pediatric ophthalmolo©2002 Ethis Communications, Inc. All rights reserved.
gist who studies the development of the visual system and electrophysiology. This experience helped solidify my interests, and I began looking for appropriate graduate programs. The University of Michigan’s program in visual science held great appeal because it was so wonderfully interdisciplinary. My advisor there, Daniel G. Green, PhD, had appointments in three departments: ophthalmology, psychology, and engineering. This was an ideal combination for me, given that I not only wanted to continue my studies in sensory psychology but also wanted a deeper understanding of neurophysiology and of the visual system itself. I consider myself extremely fortunate that my career has allowed me to continue to work toward understanding the visual system. I still attend conferences and interact with this field’s thought leaders, many of whom I met or read about when I was still a student. TOS When you completed your PhD training, how did you imagine your career would develop? GRAVES I assumed I would remain in academia as a researcher. I loved the work so much that it didn’t seem like work at all. In fact, I was completing a post-doctoral fellowship in visual neuroscience at the University of Paris when I received a call from a headhunter about a position at Alcon Laboratories. Until that point, I had not given any thought to a career in the pharmaceutical industry—I didn’t even know, for example, that oph-
thalmic pharmaceutical companies were engaged in extensive basic research. That came as a surprise to me. TOS Would the person you were 20 years ago be surprised at where you are today? GRAVES I think the person I was a year ago would be surprised. . . surprised but not shocked. I am an explorer at heart; that is why I gravitated toward the sciences. It is also why I love travel. Although my career path is, in some regards, different than I would have predicted, it is still very much about exploration and new possibilities. I’m still exploring visual science, but with greater focus on therapeutic applications and concurrently enjoying the challenges and rewards of running a business. TOS What was your role at Alcon? GRAVES They hired me to start a basic visual function laboratory, so one of my first tasks was to establish neurophysiological and psychophysical methodologies for animal studies. This initial work was in diabetic retinopathy, but I immediately became intrigued with glaucoma. It represented a significant research opportunity and key area for investment of resources. As I moved up the learning curve, I was increasingly struck by the fact that while we were doing extensive research on lowering intraocular pressure (IOP) and the effects of various drugs on IOP, we were ignoring the effects on visual function. I soon established a collaboration between Alcon and two scientists I knew from my early days at graduate school, Drs. Ron Harwerth and Earl Smith. Using Alcon’s glaucomatous monkeys, we
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began studying the long-term effects of elevated IOP on the visual system and visual function. As this work progressed, I wondered why our clinical glaucoma studies were not evaluating visual function. After all, glaucoma patients are not necessarily thinking about IOP numbers; they are worried about their ability to see and function. The process of instituting long-term studies of drug effects on visual fields sparked my interest in clinical trial design. TOS How did this experience influence your vision of the industry? GRAVES When I started working in clinical studies, it was like starting graduate school all over again. There was so much that was new: the drug application and approval process, interacting with the FDA, working extensively with sales and marketing. It certainly gave me a greater appreciation not only for the drug approval process but also for the way in which the various disciplines within the pharmaceutical industry operate together. Again, as in graduate school, I was drawn to multifaceted interactions—which continues to motivate my leadership at Santen. TOS How long were you at Alcon? GRAVES Almost 10 years. Over that time I held several positions, including Director of International Ophthalmology and Clinical Sciences. TOS And from there you went to Santen. Tell us about that transition. GRAVES I started at Santen in 1995 when the company began operations in the US. It was a unique opportunity to work with a company that has been a leader in ophthalmology for over 100 years (Santen Ltd. was founded in Osaka, Japan in 1890) and, yet, in the US, was a small startup enterprise. With Santen unknown in the US and having no product on the domestic market, I was hired to organize a clinical research group, conduct trials, and get products on
the US market as quickly as possible. Within five years, our team had three products on the market: Alamast™ (pemirolast), a mast cell stabilizer, Quixin™ (levofloxacin), a fluoroquinolone anti-infective, and Betimol® timolol), a topical beta blocker. (Betimol was initially licensed to CIBA Vision.) TOS What did you learn through this experience of three successive fast-track approvals? GRAVES I learned several things. The experience showed me what teamwork can do, especially because we were the “little guys.” We started with a very small operation, but this proved to be an advantage, as we were able to work together closely and move quickly. I think this achievement also shows that drugs are approved because of their merits rather than because a huge corporate entity is behind them. For me, it also underscored the importance of clinical trial design. The success and speed of the approval process depends heavily on sound clinical trial design at the front end and then careful monitoring as the study progresses. TOS What are some of the challenges in achieving sound clinical trial design for an ocular pharmaceutical? GRAVES I think it’s essential to listen to the experts and really understand the disease you are studying before embarking. The more you understand the disease process and what it is your drug purportedly does to that disease process, the better able you are to pinpoint the best means of defining endpoints and capturing the drug’s efficacy. I’ve always found the FDA to be a strong partner in the clinical design process, because having sound data upon which to make a properly informed decision is a shared goal. It is important, therefore, to work with the FDA in the very early stages of study design in order to come to an agreement about mutually acceptable ways of demonstrating drug efficacy.
TOS Did this experience of bringing three ocular pharmaceuticals to market in a compressed time frame change any presuppositions you may have had about the process? GRAVES Before this experience, I would have presumed that a larger company with more resources would get through clinical trials more quickly than a small company. My thinking shifted in that regard. Fortunately, putting together a successful formula doesn’t necessarily require a company with a lot of infrastructure. A company needs several things to succeed: the wisdom to listen carefully to (and the courage to rely upon) the experts; a solid understanding of the fundamentals of clinical trial design; and the ability to hire good people to carry out the studies. As in so many things, sticking to fundamentals is the foundation of success. TOS Ah, you make it all sound so easy. GRAVES Well, then there is the drug itself. It actually does have to work! TOS Now that you have three approved drugs, what’s next for Santen? GRAVES With three drugs on the US market, we are still the “little guys” in terms of a product portfolio. But, for the eight short years we’ve been established, it is a good track record. We have a story to get out. In addition to presenting new products to the US market, we are still in the process of introducing American doctors to the company. Establishing a market presence for both new products and a “new” company simultaneously is a tremendous challenge. And we have to do this in the context of strong competition (on both fronts) from established companies. The image of Santen in the Japanese market is that of a company completely dedicated to ophthalmology and innovative ophthalmic research. We are working hard to establish this image in the US. TOS As an ocular surface publication, are there other agents in the
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pipeline we should know about? GRAVES Our next product will be levofloxacin in a 1.5% concentration. This will be preservative-free, because the drug itself is so potent that preservatives are not needed. In addition, it is a broad-spectrum agent that retains the safety profile of the 0.5% solution. Because preservative can interfere with the healing process, we think the 1.5% concentration should prove beneficial for both surgical prophylaxis and the treatment of ocular infections. We think that higher concentration will also help to forestall the development of resistance. A drug so strong that it knocks out infection quickly and completely gives bacteria no opportunity to develop resistance. The 1.5% solution will have that capability. This is of particular importance in ophthalmology, where there is growing concern about bacterial resistance. We are working on the new drug application for this levofloxacin product right now. TOS Other products in development or preparation for market? GRAVES We also have a dry eye product in the pipeline and are obviously excited about that because there is currently no prescription dry eye product available in the US. This is a significant unmet need. TOS Can you tell us more about the dry eye product?
GRAVES Not at this point. But, as many people know, Santen’s hyaluronic acid formulation for dry eye is one of the company’s largest, most successful prescription products in Japan. The product we develop for approval in the US will be similar. TOS Of the considerable body of work now being done concerning the ocular surface, what strikes you as most important? GRAVES We believe future therapies for dry eye and other ocular surface conditions will be etiology-based. Therefore, Santen is very interested in understanding the mechanisms that underlie ocular surface dysfunction. A more developed understanding of the complex mechanisms at play is essential, as are better methodologies by which to identify the disorders. The more accurately we can characterize the disorders, the more effective our treatments will be. It is with etiology-based therapies that I think we will have hope of someday curing the disorders that we are still battling to understand. TOS How do we get to this future of etiology-based therapies? GRAVES It will take a significant investment in basic research. At this point, nearly 15% of Santen’s revenue from sales is invested back into research and development. To focus that research appropriately, we will need to select areas of clinical need on which to concentrate. We can only do that by listening care-
fully to the physicians who are seeing and treating patients. To that end, we encourage and maintain an open dialogue with the key thought leaders in ophthalmology. One advantage of being a smaller company (at least in the US) is that we can listen better. When ophthalmologists meet with us, we can convene all levels of the company in a single room. This allows thought leaders from both sides of the table to communicate directly. We can also act on what we hear quickly, without having to shepherd fresh ideas through multiple layers of bureaucracy. The relative immediacy of the process is not only gratifying to us, it’s exciting to the ophthalmologists with whom we work. TOS What is next for you? GRAVES Clearly, my challenge is to solidify the success of Santen in the US. My focus is to advance our corporate image as a company that is not only dedicated to ophthalmology but one that partners with—and really listens to—ophthalmologists and ophthalmic researchers. By listening to these experts, we’re advancing our understanding of patients’ needs, physicians’ needs, and disease mechanisms. I use the word “listen” a lot to describe what I try to do both in working with thought leaders and in working with our management team at Santen. I think it is by truly listening and acting upon what we hear that we will take Santen to the next level. 䢇
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