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LILLY SEROTONIN RECEPTOR ANTAGONISTS FOR MIGRAINE TO ENTER CLINICALS LATER THIS YEAR; PROZAC FOR OBESITY, BULIMIA HAS BEEN AT FDA FOR ONE YEAR

Executive Summary

Lilly has two serotonin receptor antagonists scheduled to begin Phase II trials for migraine by the end of 1989, Lilly Research Laboratories President Mel Perleman, PhD, told New York analysts on May 15. Perleman noted that the "vasoconstrictor effects of serotonin are mediated, at least in part by the activation of 5HT-2 receptors." Lilly has developed a "relatively selective," oral 5HT-receptor antagonist named sergolexole maleate. "Clinical trials of this compound, scheduled to begin later this year, will help us to determine if it prevents migraine," Perleman said. In addition, Perleman reported that Lilly plans to begin clinical trials "later this year" for a selective serotonin 5HT-3 antagonist "which may relieve migraine pain." Commenting on the two serotonin receptor agents for migraine, Perleman noted that "in short, one would be prophylactic -- if a person has a frequently recurring migraine problem . . . they might take it prophylactically on a fairly continuous basis." The 5HT-3 antagonist would be used for treating migraine, he noted, when a patient "does not respond to prophylaxis or starts too late." The two products are further evidence of Lilly's commitment to the serotonin receptor area. The company's serotonin reuptake inhibitor Prozac (fluoxetine) generated over $ 100 mil in its first year of marketing to become the leading antidepressant in the U.S. market, with "more than 30% of antidepressant dollar sales in the U.S.," Lilly Pharmaceutical Division President Eugene Step said. Lilly has reported that it is working to expand Prozac labeling to include such indications as obesity, bulimia, smoking-cessation, obsessive-compulsive disorder, and alcohol abuse. Perleman startled analysts at the meeting with the announcement that supplemental NDAs for obesity and bulimia were filed a year ago. "Those were filed in the first half of last year -- 1988," Perleman reported. Lilly has been tight-lipped about its progress with Prozac outside of the depression area. Lilly is remaining silent on the status of any long-term Prozac studies for weight-loss. Perleman remarked that although the "initial filing was for short term obesity . . . other studies are ongoing." Prozac's effects on weight-loss through appetite control have been documented in studies with non-depressed obese subjects ("The Pink Sheet" Dec. 19, p. 6). In a presentation to analysts in December, Lilly Research VP Leigh Thompson reported on an eight week, placebo-controlled study in 600 non-depressed obese patients that showed that heavier patients lost up to 14 pounds during the treatment period. Thompson also cited a study in 200 diabetes mellitus patients where patients on Prozac lost on average six pounds during the eight week study. Perleman noted that the diabetes mellitus data has been published in a Canadian journal. "The results there were excellent in the sense that not only was there weight loss in type II diabetics, but there was an improved metabolic control," Perleman said. "What that means is that there was a reduced fasting glucose blood level in the subjects taking Prozac. More importantly, [there was] a reduced level of glycohemoglobin HB1-AC, which is a sort of long term measure of glucose control, and about a 20% reduction in the need for oral hypoglycemic agents, as well." On the anti-smoking indication, Perleman said Lilly is "continuing the clinical trials" with Prozac. "The trials that we had do show promise and we have broadened the scope of those trials," the Lilly exec noted. "We are also measuring both those who totally cease and stay off the drug, but we are also interested in those who may not totally stop but may have a substantial reduction in the number of cigarettes smoked per day." He said Lilly is "seeing favorable results in both categories." Prozac is one of nine Lilly products generating over $ 100 mil. in sales. The other eight products are Ceclor (cefaclor), Darvon (propoxyphene HCI), Dobutrex (dobutamine), Humulin (human insulin), Iletin (beef-pig insulin), Keflex (cephalexin), Nebcin (tobramycin), and Vancocin HCI (vancomycin). Lilly's R&D budget of $ 541 mil. in 1988 as a percentage of sales was 13.3% in 1988, compared to 8.6% in 1980. In March, Lilly bought a Cray-2 supercomputer, which the company will use in computer-assisted drug design. Lilly has 50 new compounds currently being evaluated. "Happily, many of these are chronic-care candidates that would be used primarily by office-based physicians," Perleman remarked. In 1980, Lilly had only 25 drug candidates under evaluation and many of those were acute-care hospital products, he noted. One such candidate, quinelorane, a dopamine D2 receptor agonist, is currently in Phase II/III trials for the treatment of sexual dysfunction in both men and women ("The Pink Sheet" Dec. 19, 1988, p. 6). Perleman said the studies are "still in the double-blind phase." He also noted a 5HT-2 receptor antagonist in preclinicals "that also may have potential in sexual dysfunction." In the antibiotic area, Perleman highlighted "a number" of carbacepham compounds. The lead compound in this class, loracarbef, currently in Phase III, "showed excellent activity and biological stability against a broad range of bacteria in preclinical studies," Perleman told the group. (PARAGRAPH)Lilly researchers have also "identified another oral carbacepham candidate that is undergoing early clinical evaluation," Perleman said. Another anti-infective agent cilofungin is in Phase II for treatment of the fungal infection Candida. One area that Lilly is emphasizing is the anticancer area. "Several years ago, [Lilly] made a strategic decision," Perleman said, to "concentrate [its] cancer research on safer, more-effective treatments for patients with solid tumors." Lilly has been investigating compounds with broad-spectrum activity in solid tumors as well as target-specific monoclonal antibodies in a "two-pronged effort." The first approach outlined by Perleman involves three classes of compounds: difluoronucleosides, active against slow-growing carcinomas, in Phase II study; diarylsulfonylureas, active against tumors without inhibiting DNA, RNA, or protein synthesis, in Phase II trials; and GAR transformylase inhibitors which are in Phase II. In conjunction with its biotech partner Hybritech, Lilly is developing "a number of monoclonal antibodies as selective delivery vehicles for antitumor agents," Perleman said. Clinical trials with the first agent from this research, KS1/4-DAVLB, a monoclonal antibody linked with a vinblastine derivative, have been discontinued. "Clinical trials of our second substance of this type, KS1/4-DAVLB hydrazide, just got underway," announced Perleman. Last fall Lilly underwent a major expansion of its sales force to market the emerging new products. For the new sales force, which is Lilly's fourth in the U.S., "we screened 9,000 applications conducted 3,600 interviews, extended 465 offers, and ultimately welcomed 400 excellent new sales representatives to the company," Step told the analysts. Merck, which engaged in a similar expansion last fall, received 28,000 applications from which 480 sales trainees were chosen ("The Pink Sheet" Oct. 31, 1988, T&G-2). Lilly is also expanding its overseas marketing presence. "We have added some 500 sales representatives abroad since 1987," Step observed, "and expanded our marketing-research and marketing-planning organizations outside the U.S. by more than 30%."
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