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LISINOPRIL APPROVAL IS EXPECTED BY YEAR END FOLLOWING "APPROVABLE" NOTICE IN LATE OCTOBER, VIGELOS TELLS ANALYSTS; INITIAL USE IS IN HYPERTENSION

Executive Summary

The second-generation ACE inhibitor lisinopril (Merck's Prinivil and Stuart's Zestril) is "approvable" for use in treating hypertension, Merck's Chairman and Chief Exec Roy Vagelos, MD, told Boston securities analysts Nov. 12. "Having just received an 'approvable' latter from the FDA, we expect Prinivil to be approved for treatment of high blood pressure by year end," Vagelos said. "We hope that approval for use in congestive heart failure will be obtained in the near future." Merck said that it was notified of lisinopril's approvable status in an Oct. 30 letter from FDA. A December approval for lisinopril would mark yet another quick trip for Merck through the FDA drug review process. Lisinopril's NDA for both hypertension and congestive heart failure indications was filed with FDA in April 1986. A December approval would put the ACE inhibitor's review at 20 months -- or about ten months shorter than the current average review time for new chemical entity approvals. Recently, FDA Commissioner Young referred to Merck as "the gold standard in putting together NDAs." Getting FDA approval for its anticholesterol agent, Mevacor, took Merck only nine months. If approved in December, lisinopril would be the fourth Merck drug to be approved in 20 months or less over the last three years. Lisinopril would be Merck's eighth new chemical entity approved over the three year time-span. Lisinopril is the subject of a cross co-licensing agreement with ICI that also includes co-marketing of the ICI-developed aldose reductase inhibitor ponalrestat (ICI's Statil). Vagelos said that ponalrestat clinical studies "are continuing." During the fall, Merck and ICI have been running "coming soon" name recognition ads for their respective brands of lisinopril -- Prinivil and Zestril -- setting up a marketing showdown between two companies with strong positions in the cardiovascular area. Merck's background of important new cardiovascular introductions began with Hyrodiuril (hydrochlorothiazide), and includes Aldomet (methyldopa), Moduretic (amiloride/hydrochlorothiazide), and Vasotec (enalapril). ICI Pharmaceutical is the developer of propranolol, which it has marketed outside the U.S., and currently has the top selling beta blocker brand in the U.S., Tenormin (atenolol). Vagelos also noted that Prinzide (lisinopril/hydrochlorothiazide) is currently pending at FDA. ICI also has marketing rights to the combination product. Contributing to lisinopril's quick review was FDA's decision not to seek an advisory committee recommendation for the hypertension claim. However, in a review of lisinopril's congestive heart failure claim last month, FDA's Cardio-Renal Drugs Advisory Committee recommended that FDA wait for results from a Merck study just getting underway before approving the claim ("The Pink Sheet" Oct. 19, P. 13). Merck is seeking approval of lisinopril in Class II-IV congestive heart failure patients. The FDA advisory committee looked favorably on Merck's other ACE inhibitor, Vasotec. The panel unanimously recommended approval of the first generation ACE inhibitor for Class II-IV congestive heart failure patients. The committee recommendation represents an expansion on congestive heart failure labeling currently held by Squibb's Capoten (captopril). The advisory committee had been scheduled to discuss an expanded congestive heart failure claim for Capoten at the Oct. 13 advisory committee meeting, but because of time constraints did not consider the issue. Squibb has indicated that approval for the new claim will not require advisory committee consideration. Merck is predicting that Vasotec will be approved for use in congestive heart failure "early in 1988" with a claim for "reduction of mortality in severe cases." Vagelos said that Merck is also studying Vasotec as "first line therapy for congestive heart failure and for use in hypertensive patients with diabetes or kidney problems." Vasotec sales in 1987 "will be more than double" 1986 sales, Vagelos reported. Based on analysts' estimates of Vasotec 1986 sales, worldwide sales of the ACE inhibitor could top $500 mil. this year. "In the U.S.," Vagelos commented, Vasotec "is now prescribed for high blood pressure more often than Capoten." He maintained that Vasotec is also outperforming Capoten in the treatment of hypertension in Italy, Holland, Scandinavia and Australia. "We expect it will soon be true in Japan," Vagelos added. Merck has yet another antihypertensive emerging from the pipeline in the U.S. Vagelos reported that Merck plans to file an NDA for the calcium channel blocker Splendil for hypertension "early in 1988." Licensed from Astra under a 1982 agreement, Splendil has "completed U.S. clinical trials," Vagelos said. He indicated that Marck would seek a once-a-day dosage for the calcium channel blocker. Merck is improving its "depth chart" in the gastrointestinal area with another compound licensed from Astra. Vagelos reported that Merck plans to file an NDA for the anti-ulcer agent Losec (omeprazole) in December. Vagelos indicated that a key niche indication for Losec in the crowded antiulcer field could be in "healing the lesions of gastroesophageal reflux disease." Commenting on the ongoing launch of Mevacor, Vagelos said the anticholesterol agent "has exceeded our expectations so far." Mevacor was approved by FDA on Aug. 31 and introduced the week of Sept. 14. "There are already indications that the market for cholesterol-lowering drugs is expanding, and that 30% of new Rxs in this expanded market are going to Mevacor," Vagelos noted. "We plan to introduce Mevacor abroad as soon as possible in the relatively few countries where we have patent rights." In his speech to the analysts, Vagelos highlighted the role of public education in expanding the anticholesterol market. "Despite widespread public attention to the threat of cholesterol," Vagelos remarked, "extensive communication efforts by Merck and national health authorities will be required to achieve sound management of the problem across the broad groups who are at risk and to assure an appropriate role for this new therapy." Vagelos also explained the company's pricing for Mevacor. "For a potentially life-saving advance in therapy," Vagelos stated, "we feel that the price that Merck receives is very fair: $1.25 for the 20 mg daily dose taken by most patients." Vagelos contended that other available anticholesterol agents, taken at their maximum dosage in order to mimic Mevacor's cholesterol-lowering efficacy, "would cost the patient more than Mevacor." Merck is currently studying both Mevacor and the company's other HMG CoA inhibitor Zocor to determine the drugs' ability "to stop or reverse the build-up of cholesterol plaque on artery walls." Vagelos said that Merck also plans to do studies with mortality and morbidity studies with Zocor in patients with pre-existing cardiovascular disease. An NDA for Zocor for cholesterol reduction was submitted to FDA in October. Vagelos said that Zocor "is similar to Mevacor, but more potent and with a longer duration of action," Unlike with Mevacor, Merck has worldwide exclusion patent rights to Zocor.

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