UPJOHN LAZAROID HEAD TRAUMA TREATMENT IND START-UP EXPECTED THIS MONTH; FAST-TRACK PURSUIT OF LAZAROIDS STEMS FROM UPJOHN's SLOW R&D RECORD

Upjohn's lead lazaroid for head trauma is poised to begin a fast-track/Treatment IND development project later this month. After only three years of active R&D, the first lazaroid compound has moved into FDA's expedited review program. Phase I studies on U74006-F through a 2 mg/kg dose showed "no toxicity, no problems with the compound," Upjohn Corporate VP for Pharmaceutical Research J. R. Mitchell, MD, PhD, told financial analysts at Prudential-Bache Capital Funding's annual health care conference Oct. 11. "The tentative protocol is there" for Phase II trials under an expedited review plan with FDA, Mitchell reported. Upjohn "is anticipating starting this by the end of the month." "Following right behind" the head trauma work, Mitchell added, "we have submitted" a Treatment IND request "and are waiting to hear from FDA on subarachnoid hemorrhage." According to the expedited approval plan developed by FDA in the fall of 1988, the agency will identify significant potential products for life-threatening diseases early in the product development stage and try to work out with the sponsor an expanded Phase II efficacy trial which, if successful, can be used by itself to support an early approval of the product. FDA described the expedited review plan as working in conjunction with Treatment IND studies. Upjohn says that the first two lazaroid indications will be studied under Treatment INDs. The lazaroids fit the description of fast-track drugs very well. They are aimed at situations that are clearly life-threatening and where death is likely to come within a short period after the event. Because there are no effective current treatments for head injuries, it would be difficult to replicate a successful initial Phase II trial for ethical reasons ("The Pink Sheet," Oct. 24, 1988, p. 3). Mitchell characterized the FDA participation in the expedited drug review as a relationship with "colleagues" who "are joining us under the commissioner's new regulation in helping to develop this compound." Upjohn's aggressive development schedule for the lazaroid family of neuroprotective compounds is evidence of the company's effort to retool its drug R&D effort to highlight drug development skills as well as research leads. Upjohn is well aware of the backlash from its prostaglandin research commitment and its image as a firm constantly working on, but often not finding commercial use for, breakthrough categories of products. Mitchell, in fact, openly referred to the company's long pursuit of prostaglandins and its effect on the company's research resources. Noting that in 1980, "almost half" of Upjohn R&D was devoted to prostaglandins, Mitchell commented: "While the company felt good about the excellent return on its investment in basic research, we were really not at all pleased at where it found itself in terms of peer companies in drug development rates." After commissioning a study of industry development times, Upjohn found that it was taking almost 50% longer to bring products to market than "peer companies." The peer company average, Mitchell reported, was "something in the range of 6.8 years," while "Upjohn was considerably slower than this" at about nine years, Mitchell said. The R&D development study was performed for Upjohn two years ago by the Strategic Management Consultant Group. As a result of its view of a development lag at Upjohn, the company has undertaken a major overhaul of its R&D structure and personnel. Mitchell pointed out: "Over the last 18 months to two years, the company has replaced its leadership in discovery research, in clinical investigations, in pharmacy research and formulation, in biotechnology and in drug safety." Mitchell himself is part of the revamped structure. The former director for experimental therapeutics at Baylor College of Medicine, Mitchell joined Upjohn in March, succeeding long-time R&D vet Jacob Stucki. The company also has recently brought Udo Axen back from Japan as VP for discovery research. Upjohn also has "created a very active acquisitions unit, both on the licensing side, but particularly from an R&D side, to have a quick 'hit team' that can respond in a quick two-week to four-week timeframe to any opportunities as well as creating opportunities themselves." The firm's collaboration with New York City-based Procept on soluble CD4 for AIDS and the CD4/T-cell exotoxin combo, CD4-PE40, is a recent example of the firm's new-found drug development vigor, Mitchell maintained. Upjohn licensed the exotoxin-linked CD4 from NIH in the spring ("The Pink Sheet" May 29, T&G-12). The lazaroids are at the head of the effort to revive Upjohn's development skills. Use of the compounds for spinal cord injury is also under study as a means of preventing the rippling effect of secondary cell damage from trauma. Clinicals in that area are upcoming. The compounds also have shown promise in animals in myocardial infarction and reperfusion injuries, Mitchell noted. Contrasting the lazaroids to the prostaglandins, Mitchell said the new compounds "work extraordinarily well" in animal models. He claimed that the lazaroid compounds are "spectacularly effective in all animal models in which the disease process has reactive oxygen lipid peroxidation, lymphocytes and inflammation involved." Mitchell noted that the lazaroids are "not panaceas" and they work on a single area of injury "but that area that we stumbled into is now a major focus of research throughout research academe -- and that is the area of oxygen radicals inflammation response." Upjohn has lined up five centers for the head trauma study: the University of Cincinnati, University of California at San Francisco, University of California at San Diego, University of Virginia and University of Texas at Galveston. Study sites for the subarachnoid hemorrhage indication are "still under discussion," an Upjohn spokesperson said. The company expects to have 100-200 patients initially for each trial. The lazaroid Treatment IND is one of 11 INDS Upjohn plans to file in the next nine months. Other upcoming INDs from products in Upjohn's accelerated development program include the firm's E. coli-produced soluble CD4, scheduled for a December filing for the treatment of stable AIDS. Also projected for first quarter 1990 INDs is an anticonvulsant "more potent than phenytoin in animals," according to Mitchell. The drug is being developed in conjunction with NIH. Upjohn also is working on three "sequence specific" anti-tumor compounds, all of which will be in Phase I/II "within the next three to six months," Mitchell commented. The fundamental change in R&D focus also led Upjohn to expand its worldwide approach to drug development. The company now thinks and works globally in moving a drug through the pipeline, Mitchell said. The firm's European development efforts are headquartered in Crawley, England. Upjohn also has European research centers in Sweden, the U.K., France and West Germany, and additionally has committed itself to "high risk exploratory research" in academe not aimed at developing drugs; its first agreement is with John Reed at the University of Glasgow. Upjohn is close to approval on a second generation injectable cephalosporin licensed from Japan. Zefazone (cefmetazole sodium) reached "approvable" status at FDA in mid-August. Licensed from Sankyo, the product is designed for a broad range of infections in the genitourinary system, skin and soft tissues, and abdominal and respiratory tracts. A computer-assisted NDA for the product was filed in December 1987.