Fatal fungus.

The year 2007 marks the 10th anniversary of the approval of letrozole (Femara) in the United States, while 2006 marked not only the 10-year milestone of letrozole’s approval in Europe but also the 25th anniversary of Novartis’s (then Ciba-Geigy [1970–1996]) dedication to the aromatase inhibitor (AI) program. It began with the introduction of the first-generation AI aminoglutethimide (Orimeten) in 1981, progressed to the marketing of the steroidal AI formestane (Lentaron), development of the second-generation AI fadrozole (Afema), and finally led to letrozole, the most recent third-generation agent. This long track record in the development of AIs is unique in the pharmaceutical industry. It is quite rare to be involved in the development of a drug that successfully completes the journey from discovery to approval and then advances care in a therapeutic field. The investigators involved in the early development of letrozole had such an opportunity. At Ciba-Geigy (later Novartis), as in other pharmaceutical companies, thousands of compounds would be synthesized each year and, on average, only one or two would reach clinical development. In 1983–1984, the center of excellence for cancer research was transferred from the United States to Basel, Switzerland. As the newly appointed deputy head of the endocrine research department at Ciba-Geigy, I was assigned the AI project because of my previous experience and expertise in endocrine projects with possible oncology indications. As part of the completion of the transfer of all oncology activities to Basel, the last batch of compounds synthesized by Dr. Robert Bowman arrived in Basel from the United States. Unknown to us, the compound that would become known as letrozole was among them. At this point in time, the second-generation AI fadrozole was undergoing clinical testing and was thus our lead compound, with all attention focused on it. The newly arrived compounds were stored in a freezer until an effective and robust in vivo assay was available. In 1986, when such an assay was developed in our labs, these last compounds were finally tested. The results of our early experiments showed that one compound appeared to be different from any of the others we had tested, in that it had a profound effect on the rat uterus. Considering that in those early days, compounds were screened at low mg/kg doses and that aminoglutethimide was active at about 100 mg/kg, we were very surprised to find that even at doses as low as a few hundred lg/kg, the new compound reduced the uterus to a very hair-like fine structure. It was at doses as low as 1 lg/kg that we saw dose-dependency in reducing uterine weight. This made our new compound infinitely more potent than any other AI previously tested. Following this exciting preclinical discovery, and the subsequent preclinical profiling of letrozole as the most potent and selective AI tested, a brainstorming meeting was held to discuss the design of potential future clinical trials. Prof. Henning T. Mouridsen, one of the early investigators, speculated that this compound, now known as letrozole, showed great promise in revolutionizing breast cancer care. The letrozole program benefited tremendously in that it was not developed sequentially but rather dynamically, as a result of many discussions among all members of the letrozole team. Many protocol design meetings were With valuable contributions from Hilary Chaudri Ross, Henning T. Mouridsen, and Patrick Trunet.