SEARLE UNDER MONSANTO: SYNTHELABO JOINT VENTURE HAS FOUR DRUGS IN CLINICAL TRIALS AND ONE NDA FILED; SEARLE MAINTAINING BIG R&D BUDGET (OVER 25% OF SALES)

Executive Summary

Lorex, Searle's six-year-old joint venture with the French firm Synthelabo, currently has four compounds in advanced clinical development and an NDA pending at the FDA, Searle noted in a recently issued report profiling company R&D activities. The Lorex compounds include three central nervous system agents -- the hypnotic zolpidem, currently in Phase III, and two Phase II compounds, the antidepressant fengabine and alpidem, an anxiolytic/anticonvulsant -- as well as a cardioselective beta blocker/diuretic combo product, Kerlidex, also in Phase III. Searle filed an NDA for the single agent, Kerlone (betaxolol), in 1986. An ophthalmic formulation of the beta blocker, Betoptic, was approved for treatment of glaucoma in 1985 and is marketed in the U.S. by Nestle subsidiary Alcon. The Searle report identifies 11 compounds in six therapeutic areas that have reached the clinical stage of development. Monsanto's financial support of Searle R&D is also evident. In 1986, a year in which Searle reported an operating loss in excess of $100 mil., the firm spent 27% of sales, or $177 mil., on R&D. Cardiovascular research is proceeding along biotechnology and conventional drug development lines. Searle Central Research, in collaboration with Washington University and Monsanto, is developing atrial natriuretic factor, now in Phase II. "Atrial peptides produced through biotechnology should prove useful in the treatment of renal shutdown caused by trauma, abdominal surgery or immuno-suppressant therapy," the report states. "Molecular modifications of naturally occurring peptides could be useful in treating edema and hypertensive disorders." A second biotech project between Monsanto and Invitron focuses on a second generation TPA product. According to a recent Invitron prospectus, Searle is now considering which among the several TPA molecules that have been cloned and expressed it wants to develop. Searle said it hopes to have its second generation thrombolytic in the clinic "in the very near future." Another cardiovascular in human testing is the cholesterol-lowering agent SC-40230, which the company claims has a mechanism of action different from either Merck's recently approved lipid-lowering drug Mevacor (lovastatin) or Squibb's pravastatin. Further back in the Searle pipeline are the anti-arrhythmic SC-40230 and the renin inhibitor SC-32796. Both are in preclinicals. Besides the three Lorex central nervous system agents, a fourth compound, milacemide, has also reached the clinical phase. Milacemide, which increases glycine levels in the brain, is being studied for depression as well as for epileptic seizures. In addition, the report notes two analgesics that have not yet made it to the clinic -- SC-39566, a long-acting non-opiate with potential oral activity and SC-42867, a prostaglandin with greater specificity than prostaglandin synthesis inhibitors. Searle's ulcer prostaglandin drug, Cytotec (misoprostill), is still awaiting approval in both the U.S. and Japan. The NDA, filed in May 1984, is now over three years old at FDA. The product is marketed in 17 countries. In the meantime, Searle has a second prostaglandin compound, enisoprost, in Phase II trials. According to the company, the drug is more potent and has a longer duration than Cytotec, properties that could result in a once-daily dosing schedule. "To supplement the flow of new products through the Searle pipeline and support the company's ambitious growth objectives, Searle has embarked on an aggressive licensing and acquisition program," the report states. "We created during 1986 a corporate function reporting directly to the chief executive to direct the company's licensing and commercial development efforts. We consider this function so vital that it has been assigned its own separate clinical development group." In mid-1986, Searle hired a Pfizer clinical research exec, R.L. Goode as senior VP-product licensing. Verapamil Hypertension Indication Boosts Calan New Rxs 115% In First Half of 1987 The firm's licensing activity is most visible in the anti-infective area, where an agreement covering a quinolone antibiotic with Hokuriku Seiyaku of Japan was reached in May. The drug, SC-47111, "has been studied in over 2,000 patients and clinical trials will begin in 25 more countries starting in 1987," the report notes. Searle, which has the product in Phase II in the U.S., has exclusive worldwide marketing rights outside Japan, Korea, Taiwan and some Eastern European countries. The product could be launched as early as 1988, the firm said. In the anticancer area, the company's lead compound is the antineoplastic agent Polima (carbetimer), currently in Phase II. A low molecular weight polymer which exhibits anti-tumor activity in animal models, carbetimer has shown low toxicity in clinical testing to date, according to the firm. Finally, Searle has focused its work in the anti-inflammatory area on the elastase inhibitor compound SC-39026. The Phase I compound "may be the first anti-arthritic that truly acts on the disease itself," the company said. Searle's stated 10-year goal is to quadruple sales, from $665 mil. in 1986 to over $2.5 bil. by the mid 1990s, an increase that would move the company from its current 34th ranking in the pharmaceutical industry into the top 10. The company has targeted at least one new product introduction every year. During 1987, Searle's calcium channel blocker Calan (verapamil) was the first drug in its class to be approved for mild to moderate hypertension. The new indication carries three years of market exclusivity from generic ANDA approvals. Searle shares the exclusivity with Knoll, the original NDA holder for verapamil. In addition, Calan SR, a sustained release version, was approved for once-a-day dosing at the same time ("The Pink Sheet" Dec. 22, 1986, p. 4). "New prescriptions for our calcium antagonist Calan and Calan SR increased 115% in the first half of 1987 over the same period a year earlier," Searle said. Chart omitted.