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Executive Summary

Merck's lovastatin approval on Sept. 1 -- just more than nine months after submission of the NDA -- is the drug company's fourth rapid approval in the last two and a half years. The quick FDA review of the high-visibility, anti-cholesterol agent confirms Merck's current standing as one of the most successful firms at preparing and sheparding an NDA through FDA. Merck filed its NDA for the Mevacor brand on Nov. 14, 1986. Lovastatin was approved as a second-line (after diet) therapy for hypercholesterolemia 290 days after submission and approximately six months after review by the FDA's Metabolic & Endocrine Drugs Advisory Committee. Mevacor's review period is the second shortest for a new molecular entity (NME) since the beginning of 1985. FDA set a record clearing Burroughs Wellcome's anti-AIDS drug Retrovir (AZT) in four months, however, any NME approval in less than a year has been a rarity at the agency. Besides lovastatin and AZT, the last NME to do so was LyphoMed's orphan product Pentamidine (isetchionate) in 1984. In addition to Mevacor, other Merck NCEs approved in the two and a half year period from the beginning of 1985 to September 1987 include: Pepcid (famotidine), 16 months; Primaxin (cilastatin/imipenem), 19 months; Noroxin (norfloxacin), 22 months; and Vasotec (enalapril), 27 months. Out of a total seven Merck NCEs approved, only one took FDA longer than longer than 27 months. That product was the hepto-biliary imaging agent Technescan HIDA, which took 78 months. The relative speed with which Merck has cleared its new product applications in the U.S. speaks highly of the company's recent mastery of the "D" side of R&D. The Mevacor application was probably helped by the scientific community's recent high level of interest in cholesterol reduction. Another factor that might have helped the product application along was its review by FDA's Metabolic & Endocrine Drug Division, a group that historically has reviewed NDAs more rapidly than its Cardio-Renal counterpart. Merck's recent, across-the-board ability to get products through FDA without significant delays, however, indicates that the timeliness of the Mevacor approval was more than a one-time achievement. Although the rapid lovastatin approval could also be viewed as a major achievement for FDA -- the drug was approved first in the U.S. -- the agency took a low-key approach to the announcement of the product okay. FDA apparently chose not to get involved in the announcement of the product approval in order to avoid fueling potential patient demand for the drug. The agency has been preparing for Mevacor's arrival most of the summer. FDA public affairs specialists began meeting with Merck representatives early in July to discuss possible public relations approaches to announcing the okay ("The Pink Sheet" July 20, T&G-1). The agency did not attend Merck's Sept. 1 press conference. In a Sept. 1 press release, FDA Commissioner Young's comments on the approval were understated: "The drug may prove a useful addition in the fight against coronary heart disease, our number one cause of death, which kills more than 550,000 Americans a year, more than all forms of cancer combined." Merck introduced the product at a Sept. 1 press conference that included the two Nobel Prize winners whose research led to the product, Michael S. Brown, MD, and Joseph L. Goldstein, MD. However, the company stressed the second-line nature of drug treatment. Referring to diet as "the cornerstone of therapy," Merck emphasized that Mevacor is indicated for those patients whose cholesterol levels put them at risk of developing cardiovascular disease and who do not respond adequately to diet and other non-drug treatments alone. "There is no question that good nutrition is of primary importance in the war against heart disease," Merck Sharp & Dohme Research Labs President Edward Scolinick, MD, said. "That includes eating a prudent low-fat, low-cholesterol diet." Approved labeling calls Mevacor an "adjunct to diet." The indications section of labeling advises doctors before initiating Mevacor therapy to establish that elevated plasma lipids are a primary disorder and are "not due to secondary conditions such as poorly controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease or dysproteinemias." Labeling further suggests that doctors "ideally" determine "that patients for whom treatment with lovastatin is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol." Mevacor should reach pharmacy shelves beginning Sept. 14, Merck said; sales staff launch meetings are scheduled for the week of Sept. 7. A toll-free physician's hot line that provides labeling information is already in operation (1-800-MEVACOR). The product will be supplied in bottles of 60 light blue, octagonal tablets or in unit-dose packages of 100, at a price to pharmacists of $1.25 per 20 mg tablet. Lovastatin is currently being manufactured in the U.S. at Merck plants in Wilson, North Carolina and Elkton, Virginia. The standard starting dose is one 20 mg tab at dinner. For patients with higher than 300 mg/dL serum cholesterol levels (on diet), labeling suggests a starting dose of 40 mg. (two tabs). The maximum daily dose is four tabs. With the number of patients that might potentially benefit from lovastatin therapy in excess of 10 mil., Mevacor is being watched as a major product for Merck into the 1990s. If it takes off rapidly, the product could exacerbate Merck's current pleasant challenge of what to do with the large amounts of cash that are building up -- despite a yearly R&D budget of over $530 mil. At the end of 1986, Merck had almost $1 bil. in available cash. One speaker at the introductory press conference explained the potential U.S. patient population. Antonio Gotto, MD, Baylor University estimated that approximately 10% of the U.S. population has high-risk levels of cholestrol, i.e., above 260 mg/dL for persons over 40 and above 240 mg/dL for persons 30-39. Of this 10%, or 24 mil., about half are either children, for which Mevacor is not indicated, or can be treated effectively with diet. Merck noted that the number of individuals in the U.S. with genetically high levels of cholesterol, those who do not respond to diet, is about 400,000. After beginning Mevacor therapy, a patient would most likely continue taking the drug for life, according to the company. Merck Senior Director of Research Studies, Jonathan Tobert, MD, noted that the effects of the drug are fully reversible in four to six weeks. Lovastatin is the first of a new class of cholesterol-lowering drugs that inhibits HMG-CoA reductase, the enzyme that regulates the liver's production of cholesterol. "In clinical studies, the drug reduced total cholesterol by 18-34%, depending on dosage used, and reduced the dangerous low-density lipoprotein cholesterol by 19-39%," FDA said in its release. "Levels of total 'good' cholesterol, the protective high-density lipoproteins, increased by 3-13%." The approved labeling contains two tables showing results of Mevacor versus two existing cholesterol drug treatments, cholestyramine and probucol. A summary of the tables notes that "at all dosage levels tested, Mevacor produced a significantly greater reduction of total plasma cholesterol and total cholesterol HDL cholesterol ratio" when compared to the other two products. The increase in HDL cholesterol was also significantly greater with Mevacor than with probucol, but not cholestyramine. Merck's patent rights to Mevacor are limited essentially to the U.S and Canada, the company noted. However, the firm has worldwide rights to a second generation compound, Zocor (synvinolin), which is about a year behind in development. Merck said it plans to file an NDA for synvinolin by the end of 1987. Squibb is also developing a drug in the HMG-CoA class. Provastatin (formerly called eptastatin) is currently in Phase III study, Squibb said, and an NDA filing is scheduled for the first half of 1988. The effects of lowering cholesterol with Mevacor on cardiovascular morbidity and mortality have not yet been established. For this reason, the National Heart, Lung and Blood Institute has invited Merck and Squibb to participate in and provide financial support for a proposed $60 mil. multi-center study of HMG CoA drugs. Expected to last about 10 years, the study will involve about 5,600 patients. A similar study of Parke-Davis' lipid-lowering agent Lopid (gemfibrozil) recently concluded in Helsinki, Finland. Mevacor's labeling notes that adverse reactions observed in clinical trials "usually were mild and transient." The most commonly reported clinical adverse experiences included rash, headaches and gastrointestinal effects such as nausea, gas, diarrhea, constipation, abdominal pain and heartburn. "It is recommended that liver function tests be performed every four to six weeks during the first 15 months of therapy," labeling states. The company said that the drug was discontinued in about 2% of patients in all studies; about one-third of those because of changes in liver function tests. In addition, Merck noted a high prevalence of lens opacities in patients at the outset of trials. "While new opacities were reported in some patients during the trials, a causal relationship between the drug and these findings could not be established," the firm said. MEVACOR (LOVASTATIN) - INDICATIONS & USAGE [Information exerpted from product labeling] Mevacor is indicated 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 diet and other nonpharmacological measures alone has been inadequate. After establishing that the elevation in plasma lipids represents a primary disorder not due to secondary conditions such as poorly controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease, or dysproteinemias, it should ideally be determined that an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with local triglycerides over 400 mg/dL or with markedly elevated HDL-C values, where non-LDL lipoprotein fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascular risk. In most patients LDL-C may be estimated according to the following equation: LDL-C = Total cholesterol - [0.16 X (triglycerides) + HDL-C] When total triglycerides are greater than 400 mg/dL this equation is less accurate. In such patients, LDL cholesterol may be obtained by ultracentrifugation. Lovastatin has not been studied in patients with Type II hyperlipoproteinemia or with total cholesterol elevations due to elevated intermediate density lipoproteins. The effect of lovastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol on cardiovascular morbidity or mortality has not been established. Mevacor may be useful to reduce elevated LDL cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridemia.

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