In a troubled economic environment the recipe for success in the biotech industry requires several key ingredients: take one part optimist, mix with some business innovation, cultural adaptability, and promising science in a significant therapeutic field, and allow time to brew. It’s this combination that makes James Sapirstein the right leader at the right time for Tobira Therapeutics, a company focused on developing and commercializing innovative antiviral compounds to treat HIV disease. “I’m an optimist; I always believe we can do better and innovate, and I continually challenge my staff to think of different options," he says. “I have a quote hanging in my office: Winners always find their road to victory. Because drug development is not a perfect science, things do go wrong, so it’s important to analyze what went wrong then find a different road to victory. I’ve followed this philosophy through my whole career; I think I’m pretty good at leading people through the jungle." Bolstering Mr. Sapirstein’s optimistic approach are Tobira’s unique offerings — a highly promising once-a-day therapy for HIV currently in Phase IIb trials and a senior management team with more than 100 years… Sidebar: A Worldly Perspective A Diverse Journey Expert on this topic James Sapirstein, President and CEO, Tobira Therapeutics n a troubled economic environment the recipe for success in the biotech industry requires several key ingredients: take one part optimist, mix with some business innovation, cultural adaptability, and promising science in a significant therapeutic field, and allow time to brew. It’s this combination that makes James Sapirstein the right leader at the right time for Tobira Therapeutics, a company focused on developing and commercializing innovative antiviral compounds to treat HIV disease. “I’m an optimist; I always believe we can do better and innovate, and I continually challenge my staff to think of different options," he says. “I have a quote hanging in my office: Winners always find their road to victory. Because drug development is not a perfect science, things do go wrong, so it’s important to analyze what went wrong then find a different road to victory. I’ve followed this philosophy through my whole career; I think I’m pretty good at leading people through the jungle." Bolstering Mr. Sapirstein’s optimistic approach are Tobira’s unique offerings — a highly promising once-a-day therapy for HIV currently in Phase IIb trials and a senior management team with more than 100 years of combined experience in HIV. “We’ve all touched almost every single HIV compound on the market in one way or another, from a research, clinical, or commercial perspective," he says. “We’re all very passionate about this disease. Unlike the big pharmaceutical companies, we don’t believe HIV is resolved; there are new patients every day. According to the Centers for Disease Control, the incidence of HIV in Washington, D.C., is 3%. If this percentage were as high for H1N1, for example, the national guard would have been called in to quarantine the city." Tobira is focusing its efforts on a next-generation class of compounds called CCR5 receptor antagonists, which are extracellular targets with five or six years of safety data to support them. The company’s lead compound TBR-652 has demonstrated a great deal of promise as a once-a-day therapy. At the 17th Conference on Retroviruses and Opportunistic Infections, Feb. 17, 2010, the company presented pharmacokinetic/pharmacodynamic (PK/PD) data for TBR-652, which showed a strong relationship between drug exposure and viral suppression. According to Tobira Therapeutics’ David Martin, Pharm.D., lead author of the PK/PD study, these data demonstrate a clear and consistent relationship between TBR-652 plasma concentrations and antiviral activity and TBR-652’s potent, dose-dependent decreases in viral load, obtained without the need for a ritonavir-boost, illustrate the potential for this compound in fixed-dose antiretroviral drug combinations for the treatment of HIV disease. “We’re excited we have a drug that’s not a me-too compound and one that’s going to make a difference to the lives of HIV patients," Mr. Sapirstein says. The Money Train The path for today’s emerging biotech companies is particularly onerous, given the growing regulatory and financial pressures. While Mr. Sapirstein appreciates the importance of many of the safety regulations that have evolved, he notes that they have added exponentially to costs, and that will likely limit innovation in the biotech field. At the same time, venture capitalists are less willing to take risks on early compounds. “The money isn’t there; because the pay off isn’t as lucrative as it was before, the stomach for risk isn’t there," he notes. “There’s money to be had elsewhere, for example in green energy and other technologies." Mr. Sapirstein warns that unless the government finds a way to ease the financing situation for biotech companies, or provide some form of funding, possibly in the form of tax credits, fewer innovative drugs will be developed. Tobira has experienced its own set of difficulties: in 2008 cash flow became a severe problem and the management team was not sure the company could survive. “Oddly enough, this was also the catalyst for the high point for Tobira," Mr. Sapirstein says. “In response, we came up with good strategic options of how we wanted to move the company forward. We then received the nod to proceed with our proof-of-concept study for TBR-652, which we not only conducted very quickly but also very successfully. Coming from the lowest of lows to the highest of highs in less than a year is a major highlight, and everything else pales in comparison." Poor cash flow is an issue that is affecting all early-stage biotech companies, he notes. “Those who moved into biotech for the big reward at the end of rainbow now have to wait seven or eight years for the reward as opposed to three or four years," he says. “Venture capitalists recently have become very conservative and this has hurt the entrepreneurial spirit of the biotech field; there is a great deal of wariness on taking chances with a program even though it might improve the value of a compound or deliver better results. If there is any associated risk, VCs are not interested in taking that chance. “As the CEO of a biotech company, I don’t understand why this country doesn’t continue to support U.S. innovation to keep the science here," he continues. “We are world leaders in both pharmaceutical and biotech innovation, and we’re giving that advantage away." In the current climate, astute biotech CEOs are looking well beyond the confines of venture capitalists and pharma deals. To bolster Tobira, Mr. Sapirstein has been investigating multiple options, including potential collaborations with academia. By sharing his company’s IP or product knowledge with academia, which have outlets to publish results, Mr. Sapirstein believes this might be a way to potentially strengthen Tobira’s IP and assets at no cost to the company. As CEO, he is also looking at special grant programs, angel investors, and other types of public or private money. “We’re not looking solely in the United States for funding; we are also looking overseas," he says. “This might involve licensing specific rights in some countries." Having worked extensively in many parts of the world makes the task of seeking foreign investors less arduous than it might otherwise be for Mr. Sapirstein. “I know what to expect when I go to other parts of the world," he says. “I know that, for example, in Japan sometimes no means yes, and yes means no. This is a cultural nuance and it’s a question of understanding how companies like to do business and how they like to collaborate. I’ve been able to build a strong trust with companies overseas, which has had a direct bearing on my ability to in-license compounds from foreign countries." Hope and Grit Mr. Sapirstein certainly has the credentials to launch a product, having taken part in 23 drug launches and led six. Nevertheless, he is pragmatic enough to realize that in the current economic market, Tobira will need a pharma partner to progress its product to market. “If the IPO market gets better there’s always a chance based on our valuation that we could go public and launch TBR-652 on our own, but more than likely we’ll have to attract a big pharma partner to help us get to Phase III and beyond or look to a company to acquire us," he says. “I’d love to commercialize this drug and position it to do well. However, we’re a small company and the costs involved to bring a compound to market will make it difficult so we’ll seek a partner just before Phase III." But optimism is part and parcel of Mr. Sapirstein’s make up and he notes that while the financial market is still very flat, the first quarter of 2010 is better than the last quarter of 2009, which was much better than the first two quarters of 2009. “Some of the biotech companies that never had a chance were weeded out in 2008 and 2009," he says. “Companies like ours that have good compounds that are going to make a difference in the marketplace survived. There’s renewed interest from big pharma companies that have some big holes in their early pipelines and they obviously want to mitigate the risk, so there is a renewed appetite for Phase II compounds and early-stage companies." Generally, he believes that while a dearth of cash means few emerging biotech companies can take their own products to market, there are always opportunities. “For example, San Diego-based Trius discovered that its drug worked well against an important bacterium; it received some significant Department of Defense funding which carried it for several years, and just recently Trius filed an IPO," he says. “Trius went from a best-case scenario that it might be a buyout target to a company that is viable on its own." Were Tobira to experience a similar opportunity — perhaps discovering further great potential for the anti-inflammatory properties its product appears to have — it too could enjoy the chance to go it alone. Mr. Sapirstein works hard to keep his employees positive and motivated. “I don’t manage by e-mail; I tend to walk around the office to find out what’s going on that day," he says. “I’m not a micro-manager but I am a micro-monitor, because it’s my company and I like to know what’s going on. And because I don’t want my folks to be surprised I motivate them to think two steps ahead of what could potentially happen; this philosophy allows us to move quickly and in a very open and collegial atmosphere." F PharmaVOICE welcomes comments about this article. E-mail us at [email protected]. Managing a biotech company through the myriad obstacles companies must face is ­ difficult at the best of times; today it is even more taxing. But James Sapirstein is proving he has what it takes to put Tobira Therapeutics on the right track. Steering a Winning Course The immigrant experience has had a strong bearing on James Sapirstein’s career choices. Mr. Sapirstein’s family emigrated to the United States when he was 5. It was a somewhat inauspicious start — the immigration officials confused his name, renaming him James from Javier, and his birth date, which he later fixed, although James has stuck. His upbringing was far from cushy, but the results speak volumes. “I have worked since I was 12 years old in different jobs, including sweatshops and factories, and I decided when I was at high school that I never wanted to go from job to job like my father did," he says. With an interest in health, Mr. Sapirstein enrolled in Rutgers College of Pharmacy (now the Ernest Mario School of Pharmacy at Rutgers University) because it offered several alternative paths, including retail, hospital, and industry. While he began with the intention of becoming a retail pharmacist, the advent of third-party reimbursement and the squeeze this started having on independent pharmacists caused Mr. Sapirstein to reconsider his choice. In the end, he went straight from college to Eli Lilly as a field sales representative. Mr. Sapirstein’s pharmacy background gave him good a scientific overview, but he quickly realized he didn’t have the business background to prepare him for the commercial side of the industry. “The language of business is very different from the language of science, and that’s really why I went back to get my MBA, so I could better understand my colleagues, the business, and financial processes that motivate a company to move forward," he says. As the son of Spanish-speaking immigrants, Mr. Sapirstein is able to draw on many valuable lessons. He is fluent in Spanish and adept at cultural nuance. After Lilly, he took a position at Roche before moving on to Bristol-Myers Squibb. “Spanish helped me in my career at Roche because my first international assignment was in Latin America," he says. During the course of his career, he has been to more than 60 countries, including Japan, where he spent an extensive period of time as director of infectious diseases, international marketing, with Bristol-Myers Squibb. “The opportunity to understand and experience different cultures has been helpful to me," Mr. Sapirstein says. “Before I went to work in Japan, I asked my company to send me to cultural training so I could understand how to bow correctly and to whom." No matter where he goes, Mr. Sapirstein presents himself as a citizen of the world. When possible he seeks to speak the local language — he speaks some French and Portuguese, in addition to Spanish. “Even though I grew up in the United States, I grew up as an Argentinean and that aspect gave me a broader world perspective," he says. His upbringing also impacted his outlook when it comes to giving back to those in need. “I grew up without a lot of money, so I know what it’s like to watch one’s parents be disappointed that they can’t give you what they want to — whether it’s a good meal or a new pair of shoes," he says. Over the years, he has met many people around the world for whom there is little opportunity; these interactions have compelled him to give back. The ideal avenue for doing so presented itself while he was at Bristol-Myers Squibb — not-for-profit HIV and infectious disease projects in Africa. Today, among other advisory and board roles, Mr. Sapirstein is on the board of Prescription for Hope, which is working to build pharmacies in Rwanda. Kim Ribbink Resume — James E. Sapirstein 2006 – Present. President and CEO, Tobira Therapeutics 2005 – 2006. CEO in residence, Paramount Capital; President and CEO, Xaviro Biosciences, hired by Paramount to start new clinical development company in infectious diseases 2002 – 2005. Executive VP, Metabolic & Endocrinology North America, Serono Inc. 2000 – 2002. Senior Director, Global Marketing, Gilead Sciences Inc. 1996 – 2000. Director, Infectious Diseases, International Marketing, Bristol-Myers Squibb 1995 – 1996. Product Director and Market Intelligence Analyst, Hoffmann-La Roche 1994 – 1995. International Operations Manager – Latin America, Hoffmann-La Roche 1993 – 1994. BioScience Regional Manager, Hoffmann-La Roche 1992 – 1993. Zone Sales Manager – New York/ New Jersey, Hoffmann-La Roche 1991 – 1992. Division Sales Manager – Chicago, Hoffmann-La Roche 1990 – 1991. Career Development Sales Trainer, Roche Laboratories 1987 – 1990. Field Sales Positions, Roche Laboratories 1984 – 1987. Field Sales Positions, Eli Lilly and Co. Education: 1997. MBA, Management, Fairleigh Dickinson Un versity 1984. B.S. Pharmacy, Rutgers University Boards and Professional Memberships: BIO (Biotechnology Industry Organization) Biotechnology High School (NJ Magnet School for gifted students) Business Development and Capital Formation committees Emerging Companies Board Fairleigh Dickinson University – Becton ­College of Pharmacy – Advisory Board FreedomScope (Medical Device Company) Prescription For Hope (nonprofit supplier for African HIV/AIDS patients) Rutgers Chief Executive Officer Roundtable obira Therapeutics, a clinical-stage bio­technology company led by James Sapirstein, CEO, that is committed to research and product discovery for the treatment of life-threatening and life-altering infectious diseases, has made a significant scientific breakthrough with its promising HIV treatment TBR-652. On Feb. 17, 2010, at the Conference on Retroviruses and Opportunistic Infections, Tobira released the first Phase II data for the product, which demonstrates that the CCR5 receptor antagonist provides potent antiviral activity and is generally safe and well-tolerated in its proof-of-concept trial. In a Phase IIa trial, involving 54 treatment-experienced HIV infected patients, a 10-day course of once-daily TBR-652 monotherapy produced a median nadir decline from baseline in HIV viral load of up to 1.8 log10 copies/mL. There were no serious adverse events, deaths, or drug-related discontinuations in the study. Dose-dependent changes in MCP-1 concentrations were also observed, demonstrating TBR-652’s dual CCR5/CCR2 mechanism of action and potential anti-inflammatory benefits. Calvin J. Cohen, M.D., M.Sc., of the Community Research Initiative of New England, presented data from Study 652-2-201, a double-blind, placebo-controlled, dose-escalation trial in which patients were randomized four-to-one to receive doses of TBR-652 of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and placebo. All patients were HIV treatment-experienced, although none had previously been treated with a CCR5 antagonist. Most adverse events in the study were mild in severity (Grade 1). There were no clinically significant trends in adverse events, laboratory tests, vital signs, or electrocardiogram measurements. Additionally, there were no liver function test elevations greater than Grade 1. Mr. Sapirstein says the product is a once-a-day treatment so it can be combined with just about any other HIV drug, as well as other once-a-day drugs. “We can put TBR-652 into a fixed-dose combination — this is really the future of personalized HIV therapy," he says. In commenting on the findings, Dr. Cohen said TBR-652 does not need a pharmacologic boosting agent and this is an important benefit for simplified dosing and ease of administration in early-stage disease. During Phase II trials the company also discovered that there is an anti-inflammatory component to the drug. While at this stage Tobira hasn’t resolved exactly how that will be put into use, the advantage this component presents has potentially vast implications. “HIV patients are no longer dying of rare infections, such as Kaposi’s sarcoma, which people used to regard as AIDS-related diseases," Mr. Sapirstein says. “On the other hand, HIV patients are having heart attacks at age 40, many are dying from diabetic complications, and these patients tend to age faster." He is hopeful TBR-652 can make some inroads into some of these problems that patients continue to face. “TBR-652’s unique properties, including once-daily dosing, which may facilitate co-formulation with other antiretrovirals, such as nucleoside-sparing or ritonavir-sparing combinations, distinguish it from the early CCR5 antagonists," he says. “Further, TBR-652’s added CCR2 antagonism and potential anti-inflammatory benefits suggest a bright future for this high-potential compound." “I’d like to say our drug is ahead of its time," he tells PharmaVOICE. The company had also been working on another platform, CXCR4 antagonists, although a tight financial market has forced Tobira to put this project on the back burner for the time being. A Progressive Focus Mr. Sapirstein says he has always had an interest in infectious disease and HIV research. The move after 17 years in big pharma to a biotech setting — as senior director of global marketing for Gilead Sciences — was an eye-opener but also allowed him to pursue his interests. “I found out that I had to do the job of four or five people as opposed to the job of one person with three assistants," he says. While the resources in biotech were more restricted, the boundaries were far more munificent. It was apparent that few of his ideas would see the light of day had he stayed in the big pharma setting; in biotech, with direct access to senior VPs, there was a real opportunity to contribute. “Toward the latter part of my career at Gilead, the company started looking at the Triangle Pharmaceuticals’ acquisition, and I was part of the team that presented the CEO with some avant-garde ideas on what we could do with this acquisition," he says. “To his credit, he accepted those ideas, moved them forward, and the rest is history." The history to which Mr. Sapirstein refers is the $464 million acquisition of Triangle in 2002 and the subsequent launch of Coviracil (emtricitabine) into the competitive HIV marketplace. Mr. Sapirstein’s experience has led him to consider biotech a better environment for the pursuit of HIV treatments. Because HIV drugs tend to progress through clinical trials more rapidly than primary-care drugs, companies need to be nimble in order to make decisions quickly. “Big pharma companies are very process oriented, and the processes for both clinical development and commercialization are the same for a specialty compound or primary-care compound," he says. “Resources are allocated depending on forecasted sales for a drug, and while specialty products don’t need a lot of resources, what there are have to be very directed. A small company can direct resources specifically to these specialty programs and projects because they aren’t competing for big dollars with the primary-care compounds that are integral to the growth of large pharma companies." Typically, big pharmaceutical companies aren’t very good at developing specialty drugs, however he concedes that some big companies have adopted more flexible models to manage specialty areas. “For example, David Epstein was given the opportunity to run a specialty department — the oncology division — within Novartis, which is now the most successful business unit and therapeutic area within Novartis, because he was allowed to nourish the division and run it like a specialty company," he says. Personnel consistency is critical in specialty fields, Mr. Sapirstein maintains. While executives in big pharma companies tend to rotate through divisions, this is not conducive to success in the specialty area. In biotech companies, on the other hand, there tends to be the same core of individuals who nourish and grow a company for several years. Carving out a Market In a crowded marketplace, it is the differentiators that define which companies will succeed and which won’t, and for Mr. Sapirstein that differentiator lies in the area of personalized medicine. “Infectious disease, oncology, and even dermatology are areas that require personalized medicine," he says. “The future lies in finding ways to personalize medicine, particularly in primary-care areas, for example diabetes and cardiology." F Breakthrough on HIV Treatment

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