A New Statin Drug A Brief History of

A New Statin Drug: A Brief History of My Career Bonny Ortolano, Ph. D. Genome Pharmaceuticals Cambridge, Massachusetts

My Educational Background • B. S. in Chemistry from Temple University, 1982 • Ph. D. in Biochemistry from Bryn Mawr College, 1987 • Postdoctoral Research, Cornell University, Ithaca, NY, 1987 -1989

My Professional Background • Joined Genome Pharmaceuticals, 1989, as Research Scientist • Promoted to Research Team Leader, 1994 • Promoted to Senior Scientist in 2001 • Supervised development of a new statin drug

Research and Development Organization at Genome

Statin Drugs • Class of cholesterollowering drugs • Inhibitors of HMGCo. A reductase, an enzyme • Enzyme catalyzes rate-limiting step in sterol biosynthesis • Cholesterol is a sterol • Example statins – – – Lovastatin Pravastatin Simvastatin Atorvastatin Fluvastatin Cerivastatin

HMG-Co. A Reductase • Target enzyme of statin drugs 2 steps • Enzyme is key catalyst in HMG-Co. A synthesizing cholesterol HMG-Co. A Reductase • Catalyzes conversion of Mevalonate HMG-Co to mevalonate • Statin drugs block enzyme, 10 steps inhibits production of cholesterol Acetyl Co. A Cholesterol

Example Statin: Lipitor • Generic name: atorvastatin • Our drug is similar, but more effective in diabetics • Patent pending

Effectiveness of Lipitor

Getting a Drug to Market • • • Scientists design and synthesize drug Test drug in vitro (in test tube) Get pre-approval of FDA for clinical trials Perform placebo-controlled dose-response study on hypercholesterolemia patients Submit results to FDA Get preliminary approval Test on wider group Get final approval from FDA Design delivery system, packaging, etc. Market drug through physicians

Reality of Drug Development • Initial development and testing – 6 years – $1. 5 million • Clinical testing and FDA approval – 6 years and – $6 million • Development and marketing – 1 year – $2 million

My Career • • Exciting and challenging Meet lots of bright people Financial rewards Satisfaction in developing new pharmaceuticals