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History of Statins Scott M History of Statins Scott M. Grundy, MD, PhD University of Texas Southwestern Medical Center Dallas, Texas COI: Consultant: Merck, Janssen Akira Endo discovered Compactin in 1977 Penicillium citrinum Pen-51, the fungus that produces compactin Kaneko , Endo, et al. Eur J Biochem. 1978: 87: 313-321. Hypolipidemic effects of compactin in dogs. Tsujita, Endo, et al. Atherosclerosis 1979: 21:307-313 Akira Yamamoto's patient with familial hypercholesterolemia first received compactin in 1978. Effect of Compactin in a Patient with Heterozygous Familial Hypercholesterolemia Yamamoto et al. Atherosclerosis 1980; 35: 259-266 Compactin Treatment in Heterozygous Familial Hypercholesterolemia Mabuchi et al. NEJM 1981: 305: 478-482 Discovery of Lovastatin • At the end of the 1970s other pharmaceutical companies to begin searching for another statin. • In July 1976, Merck Research Laboratories, signed a confidentiality agreement with Sankyo and obtained samples of compactin and confidential experimental data. • Under the direction of Alfred Albert, Merck set out to find its own statins . • In February 1979 Albert isolated a statin very similar to compactin, called mevinolin (lovastatin) Alfred W. Albert Discontinuation of Compactin Development • In August 1980 Sankyo discontinued the clinical development of compactin. • The drug apparently caused lymphoma in dogs when given in high doses Suspension of Development of Lovastatin • In April 1980, Merck began preliminary clinical studies of lovastatin • But after 5 months, in September 1980, they discontinued the clinical trials because of rumors that compactin caused cancers in dogs. • For this reason Merck halted studies on lovastatin. Early FDA Involvement • Following Merck's decision to terminate clinical trials, FDA became actively involved in maintaining interest in the development of the statins. • Dr. Sol Sobel at FDA took key decisions to keep statins alive Dr. Sol Sobel’s Crucial Decision • In July 1982, Merck made lovastatin available, under an arrangement approved by the FDA to Roger Illingsworth of Oregon Health Sciences University and Scott Grundy and David Billheimer of the University of Texas Southwestern Medical Center. • Although Merck did not have an IND at the time, IND's were granted to Illingworth and Grundy under a process that included Merck's agreement to allow FDA to provide the researchers access to the Drug Master File. Discovery of the LDL Receptor Michael Brown Brown and Goldstein 1978 Joseph Goldstein Effects of Lovastatin on LDL Levels and Clearance LDL-C FCR mg/dL − + − + Lovastatin Lovastatin Bilheimer, Grundy, Brown, Goldstein 1983 Roy Vagelos’s Crucial Decision • In March 1984, Merck submitted an IND for lovastatin. • Thereafter, the new drug application for lovastatin was approved only nine months after its submission to FDA • This was one of the shortest approval times for a new drug Roy Vagelos application up to that time. Roy Vagelos’s Crucial Decision • The decision to approve cholesterol lowering agents for marketing at this time was based on the surrogate of lowering LDL cholesterol (not on cardiovascular endpoints). • This surrogate was a key component in shortening the review time for lovastatin, and Roy Vagelos the drug was released for marketing in 1987. Scandinavian Simvastatin Survival Study Secondary Prevention 2,223 Placebo 2,221 Simvastatin Terje R. Pedersen 4S Trial Main Results P S Simvastatin better Placebo Total mortality 256 182 better CHD mortality 189 111 Major CHD event 622 431 Any CHD event 927 708 Any atheroscl. event 1,023 796 CABG or PTCA 383 252 0 0.2 0.4 0.6 0.8 1.0 1.2 Relative Risk (95% Confidence Intervals) ScandinavianScandinavian SimvastatinSimvastatin Survival Survival Study Group.Study Lancet Group.. 1994;344:1383 Lancet. 1994;344:1383–1389 –1389 II.1 Major Primary Prevention Statin Trials AFCAPS ASCOT CARDS JUPITER Lova Atorva Atorva Rosuva 20 mg 10 mg 10 mg 20 mg 10 20 % 30 in CHD 40 −36% −37% −37% 50 −44% 60 Statin Safety • Cataracts • Liver disease • Memory loss and confusion • Myalgias ~10% • Myopathy (rare) • Diabetes (9%?) • Peripheral neuropathy (very rare) Statin Costs • 2000 $3.00 per day • 2012 $0.25 to 0.50 per day Potential of Statin Usage • Currently, about 40 million patients worldwide (including about 20 million in the United States) are being treated with statins. • This figure is dwarfed by the number of individuals who might benefit from the drugs. • The World Health Organization suggests that about 200 million individuals worldwide have heart disease, stroke, or diabetes. • This suggests that statins are underused. Horton JD, Goldstein JL, Brown MS. J Clin Invest. 2002; 109:1125-31. Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS; Cell Metab. 2008 Dec;8(6):512-21 Cholesterol Homeostasis LDL LDL-R Bile Acetate Cholesterol Acids Potential Add-on Drugs to Statins LDL PCSK9 Statins Inhibitor Bile Acetate Cholesterol Acids Ezetimibe Bile Acid Resins History of Statins • Biochemistry/molecular biology • Drug discovery • In vitro testing • Animal testing • Human testing (phases I, II, III) • FDA registration • Phase IV testing • Acceptance by medical community and public Public Government Industry Practice Academic .
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