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Executive Summary

Merck's January launch of the second generation HMG-CoA reductase inhibitor Zocor (simvastatin) will be supported by over 1,200 sales reps under a copromotion agreement with SmithKline Beecham. Zocor, the follow-on compound to Merck's market-leading Mevacor (lovastatin), marketed since 1987, was approved by FDA on Dec. 23. In a same-day press release, Merck announced that it has signed a letter of intent to copromote Zocor in the U.S. with SmithKline Beecham in return for future copromotion rights to an unidentified product. Zocor will be detailed by 700 representatives from Merck's field sales force and 530 reps from SmithKline Beecham. Although the copromotion agreement was hailed as a surprise move from a marketing powerhouse, Merck already has a copromotion arrangement for Zocor in Canada with Glaxo. The late 1990 agreement with Glaxo in Canada is for seven years and gives Merck Frosst copromotion rights to a "major Glaxo product currently under development." The copromotion agreement will mark SmithKline Beecham's first foray into the cholesterol-lowering field. It may also allow Merck to achieve several goals: The differentiation of Zocor from Mevacor with detailing by non-Merck salespeople to a new and broader physician client base may lead to less cannibalization of Mevacor; A larger marketing presence will compete with the recent arrival of Bristol-Myers Squibb's HMG-CoA reductase inhibitor Pravachol (pravastatin) in the cholesterol-lowering drug field ("The Pink Sheet" Nov. 4, p. 3). Bristol-Myers Squibb launched Pravachol in mid-November, following a late October approval, at a 5%-10% discount to Mevacor. Merck is apparently following the same tack with Zocor pricing -- the direct price of the 10 mg dose on a per tablet basis is $1.33, which is equivalent to the direct price for Pravachol. The combined sales force will be able to stress the aspect of cholesterol education. Merck has estimated that 21 mil. Americans have low-density lipoprotein cholesterol levels that may require cholesterol- lowering drug medication. Bristol-Myers Squibb has estimated that there are 60 mil. Americans who, under the National, Heart, Lung & Blood Institute's National Cholesterol Education Program criteria, require further analysis of their elevated LDL levels and that a large percentage of that 60 mil. may require cholesterol-lowering medication. Both companies have noted that so far only the tip of the patient iceberg has been reached by the message of medication for elevated cholesterol: Merck estimates that only 3.5 mil. Americans are currently on drug therapy. Zocor (NDA 19-766) was approved by FDA as "an adjunct to diet for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia (Types IIa and IIb), when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacological measures alone has been inadequate," approved labeling states. FDA gave Zocor a "1C" rating (little or no therapeutic gain over existing therapies). Like Mevacor and Pravachol, Zocor is a once-daily therapy. The recommended starting dose is 5-10 mg/day, with a dosing range of 5-40 mg/day. Unlike lovastatin but like Pravachol, Zocor is recommended to be taken in the evening. Speaking at a Dec. 10 National Pharmacy Cholesterol Council meeting in New Orleans on the treatment of lipid disorders, James McKenney, Medical College of Virginia School of Pharmacy, discussed the comparative convenience of the dosing regimens for lovastatin and pravastatin in a way that appears relevant to simvastatin. The meeting was sponsored in part by Bristol-Myers Squibb. McKenney said the efficacy of Mevacor and Pravachol "would appear to be identical." However, the clinical pharmacist continued, "the dose schedule seems to me to offer some reason for interest here. Lovastatin is recommended for administration at dinner to increase its bioavailability, and that is fine as long as you don't have to add" a cholestyramine resin to the daily medication regiment. "That becomes awful messy to have to take into account the time of the evening dose of resin with your evening dose of lovastatin therapy," McKenney commented. On the other hand, pravastatin "will be able to be administered on an empty stomach at bedtime, which will eliminate" the potential dosing time difficulties. As an HMG-CoA reductase inhibitor in the same family as Mevacor and Pravachol, Zocor also exhibits the possibility of elevated serum transaminase liver enzymes or creatine phosphokinase. The warnings section of labeling notes that "persistent increases (to more than three times the upper limit of normal) in serum transaminase have occurred in at least 1% of patients" who took Zocor in clinical trials. Zocor labeling recommends that liver function tests be performed "before treatment begins, every six weeks for the first three months, every eight weeks during the remainder of the first year, and periodically thereafter," or approximately every six months. Zocor has been marketed outside the U.S. since 1988 and has been prescribed to more than 1 mil. patients in 30 countries. Labeling notes that Zocor has been evaluated for serious adverse reactions in more than 21,000 patients and "is generally well- tolerated." FDA's approval of Zocor was based on a clinical trial data base of 2,432 patients. The mean duration of follow-up to the clinical studies was approximately 18 months. In an Aug. 14, 1991 letter to FDA, Merck committed to nine Phase IV post-marketing actions for Zocor. When Pravachol was approved, Bristol-Myers Squibb also agreed to a similarly detailed battery of eight postmarketing studies in special populations. Merck agreed to: 1) submit in March 1992 the final report of a repeat 104-week rate carcinogenicity study; 2) evaluate fat content of the livers from the low-and mid-dose dogs from the two- year dog study; 3) undertake a male fertility study with a protocol to be submitted "in the near future" for FDA review; 4) evaluate the "possibility of conducting a safety study of gonadal function" in premenopausal women not taking oral contraceptives; 5) complete and report on the Simvastatin Scandinavian Survival Study (4S), the Multicenter Anti-Atheroma Study (MAAS) and the Rotterdam Cardiovascular Risk Intervention Trial (ROCARI); 6) perform pooled analyses of the three trials for total mortality, coronary death, cardiovascular death, non-coronary death, cerebrovascular accident and benign and malignant tumors; 7) pursue with FDA's Division of Biopharmaceutics a "study to better assess bioavailability"; 8) consult with the Division of Metabolism and Endocrine Drug Products about any future plans to study Zocor in children or adolescents; and 9) to "consider the design and implementation of further studies suggested by the agency in our letter dated Aug. 5, 1991." The 4S study of 4,440 patients will determine if Zocor therapy can reduce mortality in patients with ischemic heart disease. The MAAS is looking at the effect of Zocor on the regression of atherosclerotic plaques in 400 patients. The ROCARI study in 9,000 patients with congestive heart disease will see if CHD mortality is decreased on Zocor therapy.

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