BRISTOL-MYERS SQUIBB LAUNCHING PRAVACHOL IN MID-NOVEMBER AT 5- 10% DISCOUNT TO MEVACOR; SECOND HMG-COA REDUCTASE INHIBITOR APPROVED BY FDA ON OCT. 31

Bristol-Myers Squibb will launch its lipid-lowering drug Pravachol (pravastatin) in mid-November at a direct price discount of 5% and a 10% discount in the price to wholesalers to Merck's competing product Mevacor (lovastatin). Pravachol is priced to wholesalers at $ 1.26 per 10 mg tablet and $ 1.33 per 20 mg tab. According to "Red Book" prices, Mevacor's price to wholesalers is $ 1.40 and $ 1.47 for 10 mg and 20 mg tabs, respectively. BMS' direct price for Pravachol is $ 1.33/10 mg tab and $ 1.40/20 mg tab, putting Pravachol's direct price 5% lower than Mevacor on a per day basis and 10% lower at the price to wholesalers. Pravastatin, licensed from Sankyo, was approved by FDA on Oct. 31 as an "adjunct to diet for the reduction of elevated total and [low density lipoprotein] cholesterol levels in patients with primary hypercholesterolemia (Type IIa and IIb)" who have not responded to a low saturated fat, low cholesterol diet, approved labeling states. Pravachol was designated "1C" (little or no therapeutic gain over existing therapies) by the agency. Labeling notes that in clinical studies, Pravachol was found to be "highly effective in reducing total-C [cholesterol] and LDL- C . . . forms of primary hypercholesterolemia." Therapeutic responses are seen within one week of therapy initiation and a maximum response is "usually seen within four weeks," labeling states. Dosing is once-daily with either 10 mg or 20 mg. Approval was based on six core trials of 1,142 patients given daily doses of pravastatin ranging from 10 mg to 40 mg daily. To date, the worldwide patient experience with pravastatin, both in and out of clinical settings, is in excess of 1 mil. patients, BMS says. Pravachol has been marketed in Italy since 1989 and was launched in France in January. Like Mevacor, Pravachol labeling warns of the possibility of elevated serum transaminase liver enzymes and directs that therapy be discontinued "if ALT or AST values equal or exceed more than three times the upper limit of normal and persist." Labeling also counsels continued liver function tests, with testing conducted before Pravachol therapy is initiated, "every six weeks for the first three months, every eight weeks during the remainder of the first year and periodically thereafter." Labeling suggests the periodic testing should follow a half-yearly schedule. BMS is going up against a well-entrenched first entrant in the HMG-CoA reductase inhibitor class. Mevacor has dominated the lipid-lowering field since its 1987 approval and now has annual sales in excess of $ 1 bil. with approximately 60% of the U.S. market for cholesterol-lowering drug therapies. Warner-Lambert's Lopid (gemfibrozil) also is a player, with 1990 sales in excess of $ 370 mil. BMS has experience in the market, too, with its cholestyramine product Questran. Mevacor's strength and the number of other drug therapies already available notwithstanding, both BMS and Merck maintain that the dollar and market share potential for lipid-lowering drugs remains huge. According to BMS, in the U.S. alone there are an estimated 60 mil. people who fit the National Cholesterol Education Program criteria for the initiation of cholesterol- lowering drug therapy (cholesterol levels greater than 240 mg). Bristol's estimate on the potential drug-treatment segment of the cholesterol market is nearly three times greater than that presented to analysts last November by Merck Chairman Roy Vagelos. At that point, he said data showed only 10% of the eligible patients were being treated with cholesterol-lowering pharmaceuticals, i.e. only 2.4 mil. of the 21 mil. people with hypercholesterolemia requiring treatment as defined by the NCEP. BMS estimates that the current number of patients on lipid- lowering drugs may be much smaller than the Merck figure. Vagelos predicted that while the introduction of Pravachol would eat into Mevacor's market, there was still plenty of room for competitors and expansion ("The Pink Sheet" Nov. 12, p. 8), including Merck's second generation HMG-CoA reductase inhibitor Zocor (simvastatin). Zocor was recommended for approval as a cholesterol-lowering drug by FDA's Endocrinologic & Metabolic Drugs Advisory Committee on March 8 ("The Pink Sheet" March 11, p. 4). BMS says it will meet with FDA in the next several days following the approval to preclear introductory promotional materials for Pravachol. The product has a good safety profile which may be a focal point for promotions. Labeling points out that there was "not a statistically significant" difference between adverse reactions experienced by pravastatin and placebo patients in clinical trials. Another point likely to be stressed in promotions is both the convenience, once daily at bedtime without regard to meals, and the efficacy of nightime dosing. Labeling notes that "once daily administration in the evening appears to be marginally more effective than once daily administration in the morning, perhaps because hepatic cholesterol is synthesized mainly at night." Pharmacokinetic/metabolism studies back this up. Labeling notes that the systemic bioavailability of pravastatin was decreased 60% with evening dosing compared to morning dosing. The lower bioavailability levels "suggest greater hepatic extraction of the drug following evening doses," labeling states. Pravachol was recommended for approval by FDA's Endocrinologic & Metabolic Drugs Advisory Committee on Oct. 23, 1990, one year and nine months after BMS submitted the NDA (19-898) on Jan. 31, 1989. The approval comes 21 months after the NDA submission. The advisory committee recommended that the company conduct a number of Phase IV postmarketing studies in special populations, and BMS committed to most of those studies in a May 23, 1991 letter to FDA, the approval letter states. The company agreed to: 1) design a new larger-scale, placebo- controlled study of 40 mg pravastatin that "will include examination of semen in all patient groups, and will examine urinary gonadotropins"; 2) conduct a study of "gonadal function in premenopausal women not using oral contraceptives." The study will include "multiple baseline determinations, pooled samples, and repeated measurements over time, and allow for smaller sample size and accelerated enrollment"; 3) complete already approved protocols comparing "extra-hepatic tissue effects" of pravastatin compared to other HMG-CoA reductase inhibitors; 4) conduct additional animal studies on long-term effects of HMG-CoA reductase inhibitors "on sterol synthesis" in extrahepatic tissues; 5) perform pooled analyses "from each of the larger placebo-controlled longer-term studies having various coronary endpoints"; 6) report on the major coronary endpoint primary and secondary prevention trials; 7) report to FDA the results of all international trials looking at coronary heart disease endpoints, "regardless" of whether these trials are part of the pravastatin IND; and 8) "work with the Division of Biopharmaceutics to develop an alternate study to assess bioavailability" of pravastatin. Additionally, the approval letter notes, BMS has agreed to conduct the following Phase IV toxicology studies: a three-month dose-ranging study and a two-year carcinogenicity diet study in mice; a three-month dose-ranging gavage study in rats; and bioavailability studies in mice and also perhaps in rats. All the Phase IV studies are currently ongoing as are the six longer-term regression of atherosclerosis and primary and secondary prevention trials, BMS said. The company reported on those trials at the October 1990 advisory committee meeting. The rat and mouse dose- ranging studies are almost complete.