by Kim Ribbink A Lifetime of Adventure With a number of ground- breaking technologies under its belt, Nektar Therapeutics is vying to be the No. 1 drug-delivery company in the world. And the company’s cofounder and chief scientific officer, John Patton, Ph.D., has led the push to unearth solutions to drug-delivery challenges that go beyond today’s capabilities. Where there is discovery, there is adventure. And while life-sciences research and development also includes more laborious aspects of proof of concept, not to mention the excruciating process of regulatory approval, there is more than enough adventure to capture the imagination of John S. Patton, Ph.D., cofounder and chief scientific officer of Nektar Therapeutics. “The life sciences are so awe inspiring,” Dr. Patton says. “I’m not a religious person but when I look deeply into the workings of the body, the immune system, cells, nerves, and the brain, I become religious. The way the body works is so clever. What’s really inspiring is the great leaps in the understanding that continue to be reached. I’m convinced that 100 years from now diabetes will be gone, asthma will be gone, and cancer will be suppressed. We really are at the dawn of a new age.” From the High Seas to Lab Discoveries For Dr. Patton, the adventure, which has involved such exotic pursuits as research in the Amazon and the Great Barrier Reef during his marine biology studies, culminated in the formation of his own company. Nektar Therapeutics, formerly Inhale Therapeutic Systems, brings together many of Dr. Patton’s most distinct goals — the desire to formulate drug-delivery solutions to make drugs safer, more effective, and easier to administer; a keenness to create an organization that encourages excellent science; and a yearning to have Nektar explore new opportunities and excel in it accomplishments. Dr. Patton’s quest for adventure began early. He grew up in the mountains of Pennsylvania, where he enjoyed outdoor pursuits such as hunting, fishing, and bird watching. “When I was growing up, Jacques Cousteau was famous and the marine world was a total romance for me,” Dr. Patton says. “My goal was to see the world, not be stuck in an office. And for me and my friends, money was never something that interested us. We were all about having fun.” During his research as a marine biologist, Dr. Patton had investigated fat digestion in animals, and he decided to continue in that field, shifting the focus to humans. Though the research was fascinating, Dr. Patton says he realized he wanted to make his work more relevant to people. With that in mind, Dr. Patton returned to academia to focus on biomedicine. Dr. Patton’s interests led him to his post-doctoral work with Professor Bent Borgstrom at the University of Lund in Sweden, who was an expert in the field, and later to Professor Martin Carey at Harvard. “These were the gurus in the field of fat digestion,” Dr. Patton explains. “At the University of Lund, I received very good training in protein chemistry. It was a wonderful experience. At Harvard, I started looking at fat digestion under the microscope, and our research ended up on the cover of Science magazine.” Dr. Patton credits his postdoctoral work and the years he spent as a tenured professor at the University of Georgia as critical to his training as a scientist. He believes academia is where scientists develop not only their creativity, but their ability to handle adversity. “Scientists who are so anxious to get into industry and who don’t realize the value of postdoctorate degrees, sell themselves short,” he says. “A critical aspect of academia is the peer review and critiques from fellow scientists. This is where young scientists hone their craft, gain a rigor and perspective about science and data that are lacking in industry, and, develop a thick skin, which makes them stronger as scientists.” Teaching also provided Dr. Patton with a wealth of experiences that he would not have gained by going straight into industry. “Teaching was hard for me, particularly since the subjects I was teaching were a huge stretch for me — physical and chemical oceanography, and microbial ecology, and a host of strange courses that I didn’t have a lot of experience in,” he says. “But I found that each year my teacher evaluations improved because, more and more, I turned the class over to the students. I learned early on how critical it is to involve them in the teaching process.” After six years as an associate professor, working with students and producing a critical mass of research material, Dr. Patton decided it was time to gain industry experience. He joined the team of scientists at Genentech, then a fairly young biotech company that had a reputation for cutting-edge research. “Genentech had more papers published in Science and Nature than Harvard or Stanford or any other entity at the time,” he says. Dr. Patton’s task was to look at the delivery of proteins and during his time at Genentech he led two major strategic planning efforts for drug delivery. An early breakthrough during an experiment to put growth hormone in the lungs of a rat led to Dr. Patton’s long-term interest in finding alternative ways to deliver proteins into the body. “I spent four years gathering data showing that inhaled growth hormones in animals was safe and convincing the company to develop a formulation for humans,” he says. “The project had a lot of champions, but it also had a number of detractors who wanted answers to impossible questions, such as if an inhaled growth hormone was put into the lungs of children how would this affect them when they were 45.” Genentech ended up tabling the work and that was when Dr. Patton decided it was time to display the confidence he felt in the research by starting his own company. Waiting to Inhale Inhale Therapeutic Systems was cofounded by Dr. Patton and Bob Platz, an aerosol physicist. Starting a company is far from easy, particularly when the grounding science is little known or understood by venture capitalists. “Starting Inhale was a struggle, and it didn’t help that we weren’t very well-known,” Dr. Patton says. Inhale was started with money from Dr. Patton’s Genentech stock until Terry Opdendyk from Onset Ventures came up with enough funding to help Dr. Patton keep going. “That was in September 1991, and we haven’t deviated too much from the original business plan, which involved the delivery of proteins and small-molecule drugs,” he says. The company began by focusing on the development of drug-delivery systems that delivered a range of inhalable drugs — including peptides, proteins, and small molecules — to treat systemic and respiratory diseases. In the past few years the company has broadened its drug-delivery and development capabilities with the acquisition of two other companies — Shearwater Corp. and Bradford Particle Design. These acquisitions added proprietary PEGylation-based molecule engineering and supercritical fluids (SCF) technology and advanced Inhale’s position in pulmonary technology. Early this year, Inhale changed its name to Nektar Therapeutics to reflect the expanded drug-delivery solutions. “Most of Shearwater’s products are improved injectables, which expands the type of drug-delivery technologies we offer, and the company has real expertise in PEGylation technologies, which is an important field for us,” Dr. Patton says. “Bradford offered a specialty in particles that were applicable to oral, pulmonary, and injection delivery. This expanded the company’s scope beyond pulmonary, though pulmonary is still a big part of Nektar’s business.” Nektar provides a broad portfolio of drug-delivery technologies and expertise to enable pharmaceutical and biotechnology companies to optimize the performance of their drug products, improve delivery, extend product franchises, and increase product pipelines. The company’s suite of technologies encompasses molecule engineering, particle engineering, and drug-delivery solutions for both large and small molecules. These technologies and capabilities are a source of great pride to Dr. Patton. “I like to bring the word to new people and new organizations about what we do and what we’ve accomplished,” he says. In addition, Dr. Patton sees his role as one of product champion and product identifier. But while as chief scientific officer Dr. Patton oversees a number of direct reports, he believes his true talents lie more in visualizing ideas, concepts, and goals for the company than in managing staff. “I’m more of a vision keeper; I’m the keeper of the flame,” he says. “Management requires constantly thinking about people — how to better structure staff, improve performance — these are important functions that take a full-time effort. At the same time, solving problems inherent to a disease state or developing a drug-delivery system requires a lot of thought and effort, as does the struggle to get funds for a specific project. So to try to tackle all those roles leaves a leader conflicted.” Nevertheless, Dr. Patton understands the importance of a caring and spirited work environment. “Corporate America has a heart of stone and often the individual is not treated as warmly as he or she should be,” he says. “I try to consider the individual so that even if a person has to be laid off because of downsizing, I’m committed to helping that person find a new job. It’s important to care about staff as human beings and that doesn’t happen all that often.” Future of Drug Delivery Under the thoughtful guidance of its founder and other dedicated men and women, Nektar has grown leaps and bounds since the early battle to secure funding. And while Dr. Patton remains fairly modest about his own contributions to the company’s successes — giving attribution to the efforts of all Nektar’s senior staff — he has a truly ambitious vision for Nektar’s future. “We aspire to be the No. 1 drug-delivery company in the world, and I believe Nektar is well on the way to achieving that goal,” he says. Nektar uses its various technologies to help pharmaceutical and biotech companies realize the full potential of their drug molecules. Central to the company’s technology platform are Nektar Molecule Engineering, which improves drug performance using Nektar Advanced PEGylation and PEG-based delivery systems; Nektar Particle Engineering, which designs precise drug particles and optimizes delivery using the company’s expertise in Pulmonary Particle Technology and Supercriticial Fluid Technology; and Nektar Delivery Solutions, which improves therapeutic outcomes by enhancing the delivery of products using Nektar’s advanced delivery solutions for pulmonary, oral, and injectable administration. “Our understanding and capabilities of particle engineering are unparalleled in the business, though we have a long way to go to exploit all the opportunities,” Dr. Patton says. Once the particles are delivered to the lungs, they must fall apart to release the drug molecules and the molecules then run off into the body, sometimes too fast. To combat that, Nektar started to re-engineer the molecules, to further control their behavior. “By engineering the molecules in the dosage form going into the body, there is a second chance to put substances on the molecule to slow it down, protect it, and make it safer as it is dispersed in the body,” he says. “That’s where our Advanced PEGylation comes in.” Advanced PEGylation, including site-specific PEGylation, can improve drug performance by optimizing pharmacokinetics, increasing bioavailability, and decreasing immunogenicity and dosing frequency. “We’ve developed this holistic ability to design great new delivery systems through particle engineering and molecule engineering,” he continues. Nektar also has a healthy pipeline of drugs it has developed and continues to develop, often in collaboration with industry leaders. “The partner model is still our business model,” Dr. Patton explains. “But what we like to do is take the drug and prove to the potential partner that it works. This way we have a product package that’s very sellable — we’ve done human trials, we’ve looked at the biology, and demonstrated that the proof of concept is real.” Currently, Nektar has five products approved in the United States and an additional product that has been improved in Europe. The company also has four products in late-stage trials, four in mid-stage trials, and eight in early-stage clinical trials. (See box on page 34 for a representation of products in development.) All of Nektar’s marketed products and many of the products in its pipeline are based on the company’s PEGylation technology. Nektar is collaborating with Pfizer on Exubera, an inhaled insulin. Pfizer also is partnering with Aventis to codevelop, copromote, and comanufacture inhaled insulin. Nektar also is investigating some exciting new areas in partnership with other drug companies. One such program is to develop inhaled tobramycin for delivery through a very small, dry-powder device in collaboration with Chiron. Tobramycin is an aminoglycoside antibiotic used to treat infections caused by many different bacteria. “This is a monster field,” Dr. Patton says. “About 20% of the world’s population is diagnosed with lung disease every year. We’re extremely excited about our efforts with inhaled tobramycin and the possibility to get much higher concentrations of the antibiotic into the lungs, sparing the body from very high concentrations of oral antibiotics.” Currently Chiron markets a nebulized form of tobramycin under the brand name TOBI for treating cystic fibrosis patients with Pseudomonas aeruginosa. Elsewhere, Nektar is embarking on research into inhaled THC, the active ingredient in medical marijuana, through a meter-dose inhaler. “Nektar’s capability to conduct experiments internally and prove that the technology works for a particular drug makes the company an attractive partner,” Dr. Patton says. F PharmaVoice welcomes comments about this article. E-mail us at [email protected]. What we like to do is take the drug and prove to the potential partner that it really works. Nektar: A Product Review Nektar’s pipeline contains more than 50 partnered programs, including 21 programs that have been completed or are in human clinical testing. Included below is a selection of highlighted programs. Partner — Brand/molecule Indication On the U.S. Market Amgen — Neulasta (pegfilgrastim) Neutropenia Bristol-Myers Squibb — Definity Vial (perflutren lipid microsphere, injectable suspension, PEG) Contrast enhancement for indicated echocardiographic procedures Pfizer — Somavert (pegvisomant)* Acromegaly Roche — Pegasys (peginterferon alfa-2a)* Hepatitis C Schering-Plough — PEG-Intron (peginterferon alfa-2b) Hepatitis C Phase III Pfizer — Exubera (inhaled insulin) Type 1 and Type 2 Diabetes Partner — Brand/molecule Indication Pfizer — CDP 870 (PEG-anti-TNF alpha antibody fragment) Rheumatoid arthritis Phase II/III Confluent Surgical — SprayGel Adhesion Barrier System (PEG-hydrogel)* Prevention of postsurgical adhesions Eyetech — Macugen (pegaptanib sodium) Age-related macular degeneration Phase II Celltech — CDP 860 (PEG-anti-PDGF beta-receptor antibody fragment) Cancer tumors Phase I Celltech — (PEG CDP 791) Cancer Chiron — (Inhaled tobramycin) Lung infections associated with cystic fibrosis Partner — Brand/molecule Indication Enzon — (Inhaled leuprolide)** Prostate cancer, endometriosis InterMune — PEG-Infergen (PEG-interfe on alfacon-1) Hepatitis C Regeneron Pharmaceuticals –(PEG-axokine) Obesity Serono — (PEG-interferon beta 1a) Undisclosed Unimed Pharmaceuticals –(inhaled dronabinol) Undisclosed Notes: * Product also approved in Europe; ** Initial Phase I trials completed by Nektar; additional Phase I trials with partner to commence. Source: Nektar Therapeutics, San Carlos, Calif. For more information, visit nektar.com. We aspire to be the No. 1 drug-delivery company in the world, and I believe Nektar is well on the way to achieving that goal. Conscious Exploration John Patton — resume 1990 — present. Cofounder and chief scientific officer, Nektar Therapeutics, San Carlos, Calif. (formerly, Inhale Therapeutic Systems) 1985 — 1990. Scientist, Genentech Inc., South San Francisco, Calif.; head of drug-delivery physiology group, project team leader of nasal and aerosol growth hormone projects and intramuscular tPA project 1979 — 1985. Associate Professor (Tenured), University of Georgia, Athens, Ga. EDUCATION 1977 — 1979. Post doctorate, biomedicine, Harvard Medical School, Boston 1976 — 1977. Post doctorate, biomedicine, University of Lund, Sweden 1976. Ph.D., Marine biology, University of California, Scripps Institution of Oceanography, San Diego 1973. M.S., Oceanography, University of Rhode Island, Kingston, R.I. 1968. B.S., Zoology, Pennsylvania State University, University Park, Pa. RESEARCH EXPEDITIONS Summer 1981. R/V Acheron — Coral Symbiosis Expedition, Great Barrier Reef, Australia Summer 1976. R/V Alpha Helix — Amazon River Expedition Leg III, Brazil Spring 1976. R/V Severiana — Clarion Expedition II, Isla Clarion, Eastern Pacific Spring 1975. R/V Agassiz — Expedition Aftershot II, California Coast Fall 1974. R/V Alpha Helix — Clarion Expedition, Isla Clarion, Eastern Pacific Summer 1974. R/V Alpha Helix — Salmon Expedition, British Columbia, Canada Winter 1974. R/V Alpha Helix — Kona Expedition, Kona, Hawaii Winter 1974. R/V Trident — Bermuda-Gulf Stream Leg IV, North Atlantic Fall 1973. R/V Dolphin — Salmon Expedition II, British Columbia, Canada A Journey of Exploration In an exclusive interview with PharmaVOICE, John Patton, Ph.D., founder and chief scientific officer of Nektar Therapeutics, talks about his concerns for the industry, the difficulties involved in drug discovery, the people who have inspired him, and how he seeks to inspire others. What are some of the difficulties involved in moving from concept, to research, to product? One of the perennial issues surrounding bioscience and biotech is the tendency to underestimate how complex biology is and how redundant it can be. The body is at once very simple on the surface and, in terms of how it works, enormously complex. Wall Street and venture capitalists are being seduced constantly by sexy new breakthroughs that will probably take 30 years to bear fruit. Gene delivery is a classic example of a technology that will not produce drugs in the timeframe that everybody hoped. This was going to be the great panacea, but research is proving that it’s very difficult to stick a gene back into a body and get it to work properly. How important is it for companies to foster individuality and risk taking? A Pulitzer Prize-winning book called “Founding Brothers” profiled some of America’s founders, people such as George Washington and Thomas Jefferson. The gist was that these individuals by themselves could not have achieved what was accomplished by them collectively. Rather, it was the mix of all of them together — one was a socialist, one was an imperialist who wanted to be king, one was a communist, one was a conservative republican. The idea is that it takes all types of people working together to achieve greatness, and that’s true of pharmaceutical organizations. Companies need a mix of people. At times, companies have a tendency to weed out the wilder, free spirits, but it’s important to keep these people around. The industry needs to give individuals the freedom to come up with great new ideas, new thinking, and new solutions. Who has been an inspiration to you? My father, who is 83 now, is an important influence on me. He is a scientist and has studied milk all his life. He has about 400 publications under his belt, with a new book coming out soon. Graduate students were in our home as far back as I can remember. I love talking to my dad about science.ß We can go on and on, often talking about esoteric, obscure things. He’s a great inspiration. When I was a child, he would often come home excited about an experiment, and that excitement had a real impact on the choices I made throughout my life. I’ve had so many good mentors. My advisor when I was at Rhode Island University was Jim Quinn, a professor of oceanography, who taught me the basics — how to set up experiments and the need for sound documentation. There are so many others, including Dr. Andy Benson, who I did my postdoctoral work with. What I’ve found most inspiring is spending time with people who have the same ridiculous calling as I do. People who are consumed with science and the quest are the people who fuel my enthusiasm. How do you inspire others? All my mentors used to ask what the results meant to me and were they the best results that could be achieved? These are important questions to put to scientists. Being a good mentor means not pulling any punches when it comes to people’s work. Mentors need to reinforce good work and at the same time question results when they don’t make sense. I have a reputation for caring more about the science than I do about the politics, and I believe it’s vital to look after the future of the scientists in a company. Aside from science, what other creative outlets do you enjoy? I love to paint. I work in a variety of styles, as a colorist, producing large, colorful canvases, to more realistic work. At the company, we are developing an art collection. We have a tremendous amount of art, mostly from local artists. None of it is very expensive, but it’s very colorful and humorous. The collection always makes an impression on people when they come into the company. I’m very proud of that. The life sciences are so awe inspiring. I’m not a religious person but when I look deeply into the workings of the body, the immune system, cells, nerves, and the brain, I become religious.

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