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George Rosenkranz (center) displays a test tube of yam-derived , the substance needed to produce hormones, and its raw source material, Mexican yams. Grouped around him from left to right are Alex Nussbaum, Mercedes Velasco, Gilbert Stork, Jan Pataki, Enrique Batres, Juan Berlin, , Rosa Yashin, Octavio Mancera, Jesùs Romo. CHF Collections. Courtesy of Roche. LifeLife afterafter SyntexSyntex By Alejandro Zaffaroni

Early Years of age. My father was in the banking business, Alejandro Zaffaroni at My life started in Montevideo, , many and our family enjoyed a good standard of living. CHF in 2004. Photo by years ago. Uruguay is a small country; today Early in my life, I lost both my parents. My Steven Begleiter. it has three million people. Back then life in mother passed away when I was 12 years of age, Uruguay was wonderful. It was a great place to and my father when I was 18. Now, when I look live—safe and peaceful—and the standard of back, I think that loss forced me to learn to be on living was high. For many years, Uruguay was my own. I was also lucky enough to have an uncle known as the Switzerland of South America. and an older sister who supported and encour- The social and political organizations were aged me to continue my education. very progressive: women were allowed to vote; After earning a B.Sc. at the University of it had the highest rates of literacy; it was the Montevideo in 1941, I began studying at the first social democracy on the continent; pri- school of medicine. I soon realized, however, that mary, secondary, and university education was anatomy was not one of my favorite courses. I (and still is) free. had taken some chemistry and The population was and still is mainly of courses while in premed, and I decided to study European descent, mostly Italians and Span- biochemistry instead. Since there was no bio- iards. My grandfather emigrated from Italy chemistry degree in Uruguay or South America, TheThe EarlyEarly DaysDays and arrived in Uruguay when he was 16 years I started to inquire about studying abroad. of Syntex Continued on page 11 By

Flashbacks from My Life The reaction of the owner, Angel Vieta, dean If I examine my early youth, I can detect hardly of the University of Havana medical school, was any signs of entrepreneurship. Sure, critical deci- negative. To quote: “In the 18 successful years at sions had to be made: first, to leave Hungary to my firm, I never had a chemist. Why should I hire study in Switzerland over the strong objections you now?” My answer was short and bold: “Give of my parents; later, to abandon my academic me a chance and I’ll show you.” career, my wonderful mentor, Leopold Ruzicka, Apparently impressed, he offered me the and the old continent for an essentially unknown glorious salary of $20 a week. I did not fail him. future. In retrospect, I consider the causes of A dozen products later, I was making $1,000 a these events, speaking in chemical terms, more month and 15% on those products’ sales. The the push-pull effect of the grave political circum- university offered me a professorship. I declined stances of that time than entrepreneurship. but eventually agreed to direct a research program When Pearl Harbor was attacked, I was in Summer 2005 Summer for Ph.D. candidates in my laboratories. The most 2005 Summer Havana waiting for a boat to Ecuador, where I famous of my two dozen students of those days George Rosenkranz at had been offered a chair in organic chemistry at was Ernest Eliel, who became a president of the CHF in 2004. Photo by Steven Begleiter. the University of Quito. After a futile wait, I de- American Chemical Society. 23:2 cided to take advantage of President Fulgencio My Zurich-born interest in led me to 23:2 Batista’s decree allowing refugees to settle in look for domestic sources of steroidal sapogenins Cuba. And when the national university showed suitable for hormone synthesis. Finding none, I no interest in me, I tried to get a job at the largest imported sarsaparilla root from Mexico and made local pharmaceutical firm—Laboratorios Vieta- small quantities of progesterone and testosterone. Plascencia. Rumors of these activities led to an invitation to Chemical Heritage Chemical Heritage visit a start-up firm in Mexico named Syntex. Alejandro Zaffaroni (left) and Carl Djerassi discuss norethindrone, Chemical Heritage the first orally effective progestational agent and the first wholly Continued on page 10 synthetic hormone. Sold by Syntex as Norinyl. CHF Collections. Courtesy of Carl Djerassi. 8 9 23-2 CHF 2005 9/8/05 2:45 PM Page 10

The Early Days of Syntex Life after Syntex Continued from page 8 Continued from page 9

Syntex Going to the United States retire. The new head of our depart- utilized my paper chromatography On my arrival in Mexico I found a I managed to get a scholarship to come ment, Elmer Stotz, formerly of technique to produce cortisone at the small family enterprise dedicated to the to the United States thanks to the Insti- Harvard, told us at one of our first lowest cost and in the shortest time and manufacture of progesterone based on tute of International Education. My meetings that he was working on cy- thus was able to upstage all other methods of a brilliant but tempera- two options were Harvard University tochrome C and wanted all of us to “pharmas.” mental chemist, Russell E. Marker (see or the University of Rochester. work on his project. This created a To Mexico—and Back CH, Summer 1987, pp 3–6). However, I boarded a Liberty ship in Monte- problem for me because I had already The early years of Syntex in Mexico the owners had had a bitter falling-out video while World War II was still go- started working on my paper chroma- were a great experience for me. We with Marker, who left and shortly ing on and arrived in the United States tography idea and was convinced it were doing transformative science and thereafter set up a competitive venture. at the port of New York on 16 August would work out. I asked Stotz if I could had an incredible group of very smart In a burst of true entrepreneurial 1945, two days after the Japanese had still work on my own project on my and talented scientists. The progress we spirit, I accepted the offer to take over surrendered. For me, arriving in New own time at night, and he agreed. After made in the area of steroids made us the technical part of direction. My York at that time was an unforgettable a few months he reviewed my own realize that Syntex could become an compensation was roughly equivalent experience. It was like a big party: peo- work, saw that I was onto something, important company at the edge of new to the one in Havana but included the ple were celebrating in the streets; there and told me to forget about his project technology. Once we realized this po- option of buying 15% of Syntex stock was music; it was incredible. After a and to continue with my own work. I Russell Marker with his Syntex lab assistants, 1945. CHF Collections. Courtesy of Roche. tential, George and I started to trans- at book value. No big deal, since the couple of weeks I went on to Harvard. have always appreciated the opportu- form Syntex from a chemical company company was $330,000 in the red and Since profits selling hormones and There I met a young professor who ex- nity he gave me. Going Public into a pharmaceutical company. practically broke. For years to come, steroid intermediates were significant, plained my options. I would be part of I finished my Ph.D. in 1949 and The stage was set for the next big step in At one point, we realized that to my darling wife, Edith, and I faced the nobody questioned my budget. I in- a group of six students following a re- stayed at Rochester while I continued Syntex’s history: the change of owner- become a top-tier pharmaceutical com- dilemma of whether to buy a new vested in research, bringing the most search program under the guidance of my postdoctoral work. I developed a ship. This occurred when the legendary pany we needed to move to the United household item or invest in company talented scientists available to Mexico. the professor. paper chromatography technique that Wall Street entrepreneur Charles Allen States. Carl Djerassi, one of our distin- stock. Interestingly, organic chemists, in con- I then went to visit the University became very useful in the synthesis of decided to acquire the promising Mexi- guished Syntex scientists, had recently There were no manuals, no process trast to biologists, were more ready to of Rochester. During those times, the steroids; it allowed for much cheaper can upstart and eventually take it public. started teaching at Stanford University descriptions, and reagents and inter- assume risks. entire medical school was working on and faster analyses than the methods This group acquired 100% of the in Palo Alto, California. Carl encour- mediates bore coded labels. My staff The big exception was an outstand- the Manhattan Project. As a foreign developed by others at about the same Syntex stock for $2 million in cash and aged us to settle in Palo Alto. The next consisted of nine female laboratory as- ing biochemist: Alejandro Zaffaroni. student I could not participate in that time. Unexpectedly, the technique had $2 million in notes payable from future decision was who should establish the sistants, three workers for moving the We met at the 1951 Laurentian Hor- project, so the chairman of the chem- a great impact in steroid chemistry, profits. I became president and CEO, company. I took the step to leave Mex- heavy stuff, and one chemist. mone Conference in New Hampton, istry department, Walter R. Bloor, told which at the time was focused on what and Alex was executive vice president. ico and moved back to the United As chemical archaeology was not New Hampshire, after a long corre- me they would give me a lab, and that later became known as the “race for Allen’s words to us were: “Boys, you States. We started Syntex Laboratories my area of expertise, I started from spondence involving steroid samples the research for my Ph.D. had to relate cortisone.” All the big pharmaceutical have all my support, all my help; just in 1958, and from then on there was no square one, developing my own pro- for Alex’s paper chromatography. This to the field of lipids. Having my own companies were trying to win the cor- don’t ask for money, because you won’t looking back. cesses. Soon we were back in produc- encounter turned out to be one of the get any.” During the following decades lab and the freedom to choose what I tisone race. In 1948 scientists at the tion. The high price of progesterone most significant events in our lives; the he became a cherished friend and in- wanted to work on sounded great: it Mayo Clinic had used cortisone to heal ALZA—and After —$18 a gram, though way down from empathy and friendship we built has valuable adviser, sharing our problems convinced me to decide on the Univer- severely arthritic patients. In 1950 the After about 10 years of being with Syn- the original price of $180 a gram— carried through all these years. and enjoying with keen interest our suc- sity of Rochester. Nobel Prize in medicine was awarded tex in Palo Alto, I started to think about produced handsome profits and I will not describe in detail the two cesses. After I had lived in Rochester for to the three who had discovered the ways to optimize the delivery of med- allowed me to expand my staff. With monumental events in Syntex’s history: We were on our own—our dreams one year, I decided to invite my fiancée, hormones of the adrenal cortex: Philip ications to and within the body. I had the help of a few newly hired Mexican the cortisone race and the pill. These had come true! It is impossible to de- Lida, to join me. We got married via S. Hench, Edward C. Kendall, and the belief that a novel drug-delivery and foreign chemists, we soon devel- are well known. For a short time, they scribe our joy, elation, and enthusiasm. proxy, and she arrived in the United Tadeus Reichstein. It was a very hot technology could overcome the body’s oped novel, patentable, kilogram-scale focused the attention of the world on Our first big decision was to become a States after a three-day trip by airplane. area to be working in. natural barriers and thereby improve syntheses of all the sex hormones with our company, our achievements, and pharmaceutical company built on re- Having Lida with me in Rochester was During my postdoc years I attended existing medicines, creating a whole the exception of estrone. Mexico. search. I brought back Carl, who had one of the important factors that influ- the Laurentian Hormone Conference in range of new therapies. When I pre- While tackling this last problem, At this stage we had an outstanding moved to Wayne State University, to- enced my success. New Hampton, New Hampshire, in sented my concept to the Syntex board, Summer 2005 Summer my attention was drawn to a young team of scientists and consultants, an gether with eight of his best postdocs. At Rochester I became interested in 1951 to present my paper chromatog- however, the investor group decided 2005 Summer chemist, Carl Djerassi. Following a astounding number of patent applica- The collaboration between Alex, better analytical methods for finding raphy technique, and I met George not to participate in this new technol- hunch, I invited him to Mexico. He tions and publications, and an impres- Carl, and me became an incredibly cre- produced and secreted Rosenkranz. George and I clicked right ogy. I felt so passionate about these was charmed and accepted my offer to sive number of new compounds that by the adrenal cortex. I had read about away: it was the beginning of a wonder- novel concepts that I decided to branch 23:2 ative driving force. We got so close to 23:2 come to work with us. Soon we solved resulted from what I used to call “mo- each other that anyone could finish a a new technology invented by two ful friendship. To make the story short, out from Syntex and start my own the last remaining problem, the aroma- lecular acrobatics.” Our scientific repu- sentence started or sum up a grandiose English scientists, A. J. P. Martin and a few months after that conference I company. tization of androstadiendione, and tation allowed us to attract the best idea. At the end, no one remembered R. L. M. Synge, called paper chromatog- was working with George for Syntex in I decided to call the company were producing estrone. During this talent. But all this was not in line with who the originator was. Yet the discus- raphy, which was used for the analysis Mexico. ALZA, after my name. I wanted to time, a former president of Mexico vis- the operation of a small-sized chemical sions were so forceful, the decibel level of amino acids. My question was, could Syntex won the cortisone race. One show my full commitment to this new reason for the firm’s success was its Chemical Heritage Chemical Heritage ited us and on observing our process producer of steroid intermediates. so high, that on occasions with our chil- I modify this technology for the field of controlled-release concept. I founded Chemical Heritage remarked wittily: “So, in goes Adam, Prices fell and other steroid manufac- dren watching, Edith came running steroids, which are not water soluble? ability to produce very large quantities ALZA Corporation in 1968. Syntex out comes Eve!” turers became competitive. down the staircase in our home, looking Soon after I had started my studies of raw materials at very low cost. Up- retained a 25% ownership in ALZA, john, in collaboration with Syntex, then Continued on page 12 at Rochester, Walter Bloor decided to Continued on page 13 10 11 23-2 CHF 2005 9/8/05 2:45 PM Page 12

The Early Days of Syntex Life after Syntex Continued from page 10 Continued from page 11

for survivors, only to find us roaring tivity proved to be convincing. Eventu- Joshua Lederberg and Carl Djerassi, ship, we encouraged reasonable risk which became the pioneer in controlled wide range of drug-delivery technolo- with laughter. ally among others, Syntex-ICI, Syntex- and represented what would become taking. Another distinguishing charac- drug delivery, and in fact I am proud gies. Looking back to the early days of We were the brilliant amateurs with Recordati, and Syntex-Astra products the driving force behind the future teristic, perhaps unique at that time, of to say that I was the inventor of the this technology, I am amazed at how a “can do anything” attitude. We were were launched. boom in . the Syntex organizational model was controlled-release technology. large the current size of the market is like stem cells (though then none of us The year 1961 marked the start of This discipline-based, rather than ther- that researchers could spend up to 20% After many years of hard work, and how much it promises to grow, and really knew the concept). We could dif- the inevitable changes Syntex was to apeutically structured, organizational of their time on personal projects (a ALZA became profitable in 1981. It also at how many drug-delivery tech- ferentiate into anything we desired. undergo. model led to a wide-ranging approach forerunner of today’s Google concept!). was acquired by Johnson & Johnson in nologies and patents now exist. Even Production, finance, sales, marketing— It began with the decision to begin to identifying target drugs. This enabled creative scientists to pur- 2000 and contributed $700 million in today, controlled-release technologies all held no fear for us. moving the company to the United In 1968, Alex came to us with the sue projects outside of the mainstream sales to Johnson & Johnson that same are being used in new fields such as The source of all these activities States to become an important factor in idea of a new venture dedicated to his research dictated by senior manage- year. consumer products and agriculture. had to be our chemists. We rapidly the domestic and world market. We all novel concepts on drug delivery, and ment. Looking back, the stories of ALZA Since ALZA, I have been blessed turned the risk-taking volunteers into accepted Djerassi’s idea of Palo Alto as eventually the decision was made to Offering job security was high on and Syntex are so different. At Syntex with the opportunity to start many executives. This movement resulted in a a desirable site because of its closeness launch such a company outside of Syn- our list. In the eyes of the business everything went on smoothly, we had other companies. Some of these tech- healthy effect on our research. Talented to Stanford University and other major tex. Thus, to the regret of his many community, Syntex was perceived as a products the market needed, the com- nologies stemmed from my own ideas, youngsters moved up rapidly, allowing academic centers, and also because no friends, after 17 years he ended his bril- “nice” company, and we consistently pany had sales, and financing was not a but in large part they resulted from the new ideas to blossom and preventing major pharmaceutical company was liant career with us to take up new made the list of best companies to problem. At ALZA it was the opposite. collaboration of a large number of very our research from becoming stale. located on the West Coast. After painful challenges. work for. I am often approached by for- The concept of controlled drug delivery capable scientists with whom I have had soul-searching, Alex accepted the chal- The growth of our business was mer employees of Syntex who speak was very hard to sell, our first two the fortune to be associated. The com- Expansion lenge of launching the start-up (Carl meteoric, ever expanding domestically fondly of the good old times at our products did not make the numbers we panies are too numerous to list them Profits from sales of our bulk steroid was already at Stanford), excited by the and internationally. company and the caring family spirit had planned, and at one point the fi- all, but we have developed many novel products, now on a much larger scale, possibility of laying the foundations of characteristic of our corporate culture. nancial situation of ALZA was seriously technologies, for example, computa- still provided our basic income. Yet in a new major, international pharmaceu- Retirement—and I feel particularly gratified that even compromised. It took a lot of effort tional chemistry and combinatorial 1958 we started a pharmaceutical com- tical company. I remained in Mexico, Thoughts on Management today many of my former coworkers and hard work to perfect the technol- chemistry; gene shuffling; biomarkers, pany in Mexico based on novel topical but was in daily phone contact with In 1982, strictly adhering to the rules I and colleagues, who found their way ogy and to demonstrate the benefits of including nano bar codes, and much and systemic steroids. Our first big hit Palo Alto, and every month went for a established, I relinquished my executive into new business ventures, embraced the drug-delivery concept. more. I am also proud that many ALZA was Synalar. This topical corticoid for week to the West Coast. positions, but continued on the board many of these ideas—and my manage- Among the many technologies we alumni have branched out as I did and treatment of psoriasis later became the Slowly the era of gifted amateurs of directors with the title of founding ment philosophy lives on. developed at ALZA were the transder- created their own companies. first product of our U.S. venture. In- yielded to outstanding professionals. A chairman. The value of our company rose as- mal patch, oral osmotic delivery (Oros), My most recent endeavor, Alexza novative research collaborations with host of new talent entered the picture. I also became chairman of the tronomically. After a large number of and liposomal delivery (Stealth). Our MDC, is worth special mention. During large pharmaceutical firms provided In all activities, scientific or business, newly created board of science. This stock splits, at its maximum an original pharmaceutical products include Pro- the late 1990s, I did some research on another source of income. Apart from the motto was excellence. move sent a forceful message to em- investment of $2 per share was worth cardia XL, Duragesic, Nicoderm, Glu- addiction and became very interested in becoming eventual providers of the so- ployees and the outside world about $16,750. In 1994, Syntex was acquired cotrol XL, and Ditropan XL. The the cigarette as a potential drug-delivery called active ingredients, we showed The Mature Company the importance of research for our by Roche Holdings for $5.3 billion. company currently has more than 900 device. After further research I learned great foresight in retaining the right to One of the early important decisions company. The board enabled brilliant In closing, I want to share with you active patents and about 1,200 patents that after a single puff nicotine gets into market under our own label. Nobody we had to face was whether we should scientists, such as E. J. Corey and my favorite quote by Anatole France, pending. the brain in approximately 15 seconds. thought of us as becoming a competi- stick to steroids or expand additionally Michael Bishop, not only to provide which has always inspired me: “To ac- The success of the controlled drug- The question I had was, can existing tor in the pharmaceutical market. into the field of organic medicinal their invaluable scientific input into complish great things, we must not delivery technology can be seen by the drugs be delivered via a similar device? Alex and I were traveling the world, chemistry. After heated discussions my Syntex’s search for new medicines but only act, but also dream, not only plan, size of the market and the number of We know now the answer is yes. writing new collaboration and license point of view prevailed, and we opted also to pursue their love of science but also believe.” companies and products that use the I founded Alexza in 2000 to explore agreements. Our biggest coup was to for an ambitious plan: to enter the vast within a . Copyright 2005 George Rosenkranz the idea of delivering existing create a worldwide distribution of our and for us new world of nonsteroidal Over the years, my management drugs via a rapid-onset-of-action new compounds practically overnight drug research. The consequences were philosophy began to jell, a corporate device. We began with a short and without a cent of investment. This monumental, as we had to deal with culture to develop. To quote one of my list of existing medications and novel approach consisted of selecting as fundamental aspects of biology, phar- own speeches, I observed that “people soon discovered that a large per- a partner one of the top five drug firms macology, and toxicology—all areas tend to be most productive, creative, Summer 2005 Summer centage of these can be 2005 Summer in a European country. We proposed to where we lacked experience. and innovative when they work in an volatilized. We now have a large provide them with the active ingredi- This decision ultimately led to the atmosphere of joy, mutual trust, and library of existing drugs and an ents, not for a fixed price and royalty, discovery, development, and commer- respect. Intellectual honesty, quality, ever-increasing number of 23:2 but for 30% of the net sales price. We cialization of our first blockbuster, the and striving for excellence are the key.” patents. Alexza has developed 23:2 would have no say in the pricing. The nonsteroid anti-inflammatory drug Our research philosophy was George Rosenkranz and Alejandro Zaffaroni very interesting technologies and label would bear the Syntex name naproxen. “patent and publish,” as we understood with their awards. Photo by Steven Begleiter. is well advanced in developing jointly with theirs. They would have A few years later, important organi- the profound need of scientists for peer new medications. right of first refusal for our future zational changes were made. Institutes recognition and provided them with a For their lifetime achievements in Syntex Thus both the first company and elsewhere, George Rosenkranz and products. But again, we retained our were created along disciplinary lines. collegial, quasi-academic atmosphere. I started on my own and my lat- Chemical Heritage Chemical Heritage Alejandro Zaffaroni were both awarded the Chemical Heritage right for marketing under our own la- In fact one of the first institutes estab- This was in stark contrast to the pre- est company are in the drug- vailing emphasis on secrecy of our Chemists’ Club Winthrop-Sears Award at bel. This arrangement was unheard of lished in Palo Alto was that for molecu- CHF in 2004. These articles are based on delivery field. in those days, but our research produc- lar biology, under the leadership of competitors. To foster entrepreneur- their speeches of acceptance for the awards. 12 13