ROCHE U.S. IND FILING FOR 5-FU PRODRUG FOR CHEMOTHERAPY EXPECTED NEXT YEAR; FIRM PLANS TO SCALE BACK WORLDWIDE RESEARCH & DEVELOPMENT SPENDING-TO-SALES RATIO

Roche plans to submit a U.S. IND in 1994 for a 5-FU (fluorouracil) successor that is converted to 5-FU in a three-step process that Roche hopes will make the prodrug more tumor-specific and hence more effective and less toxic. A 5-FUJ prodrug that is already on the market in Japan -- doxifluridine (Furtalon) -- represents an intermediate step between 5-FU and the new prodrug. A poster presented at a Sept. 27-28 presentation for the press on Roche oncology research explains that oral Furtulon "is one of the cytostatics most frequently used for the treatment of patients with breast, colorectal and gastric cancers in Japan." Furtulon is converted to 5-FU by the enzyme PyNPase, which is "preferentially located" in tumors, the poster by Ishitsuka et. al. from Roche's research center in Kamakura, Japan, explains. Because the enzyme is also located in the intestines, "the dose- limiting toxicity of this drug is intestinal toxicity, namely, diarrhea," the poster adds. The new prodrug was designed to be converted to Furtulon in a two-step process through enzymes located in the liver, and in the liver and/or tumors, theoretically avoiding the accumulation of Furtulon in the intestines. In human cancer xenografts in mice, the new prodrug "showed a much higher antitumor activity than 5-FU and Furtulon... particularly in terms of therapeutic indices," the ratio of toxic dose to effective dose. In this model, "the compound showed very potent antimetastatic and anticachectic activities, which are not found with 5-FU and even other cytostatics." In monkeys, the poster adds, "the Furtulon successor gave higher levels of Furtulon in the circulation than Furtulon itself" and intestinal and myelotoxicities "have also been improved." Furtulon was launched in Japan in 1987 and in Korea in 1990 and has also been registered in Italy. The drug is one of Roche's top 10 worldwide in terms of sales: volume is expected to reach $143 mil. (SFr 200 mil.) this year. The Roche research press day, held at corporate headquarters in Basel, Switzerland, included an overview of oncology investigations in which Roche is involved, including the areas of interferon, G-CSF, cancer diagnostics, vitamins and cancer prevention, antisense molecules and retinoids. Roche International R&D President Jurgen Drews, MD, said at the meeting that Roche Pharma expects to lower its R&D expenses as a percentage of sales to about 17%-18% "over the next few years" from the approximate 20% ratio expected this year. Drews characterized the 17%-18% proportion as "characteristic of the leading [research-based pharmaceutical] companies." Right now, he estimated, Roche is "a little bit ahead even of the big spenders in industry but we intend to reduce that." Roche plans to decrease the spending portion not "by cutting activities, by laying off people, but rather by letting research and development grow more slowly, than...revenues grow," Drews explained. Upjohn has a similar plan under which it would reduce the increases in its future R&D spending ("The Pink Sheet" Sept. 27, p. 5). Drews noted that if Genentech, majority-owned by Roche, were included in the R&D/sales figure, the ratio would be about 24%. Genentech's R&D spending-to-sales are "really very high," roughly 50%, Drews estimated.