Chem 125 Lecture 30 11/17/08

1. Chem 125 Lecture 3011/17/08 This material is for the exclusive use of Chem 125 students at Yale and may not be copied or distributed further. It is not readily understood without reference to notes or the wiki from the lecture.

2. O • • + + • • • • • • • • + + • • + + peroxy acid + H Sulfide  Sulfoxide d-vacant n n * Gives Racemate of Course

3. + + • • • • + + • • Blocking the Proton Pump n H+ * H+ H+ makes *C=N a lower LUMO omeprazole

4. + + + - OH- - H+ - S Enzyme Enzyme • • Blocking the Proton Pump + s* n Pump enzyme is inactivated, slowing flow of HCl to stomach. At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min. (“enteric” coating postpones activation during initial passage through acid stomach)

5. + + + - OH- - H+ + s* - n S Enzyme Enzyme Pump enzyme is tied up. Slows flow of HCl to stomach. • • Should “Chiral Switch” to Single Enantiomer Help Omeprazole? Blocking the Proton Pump ACHIRAL ! At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min. (“enteric” coating postpones activation during initial passage through acid stomach)

6. Should “Chiral Switch” to Single Enantiomer Help Omeprazole? No difference after omeprazole is “activated” by H+ to R-S-O-H (and rendered achiral). Still one enantiomer might be more effective in getting to the key stomach cells that produce acid. Need single enantiomer for laboratory and clinical testing.

7. Chiral Switch 2003 2000 S 2002 1988 RS Proton-Pump Inhibitor Useby Wellmark Members(1.75 M participants in IA/SD)http://www.wellmark.com/health_improvement/reports/ppi/about.htm >15% of Wellmark members >6108 worldwide

8. http://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-carolyn-fitzsimons-nexium.pdfhttp://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-carolyn-fitzsimons-nexium.pdf

9. “Nexium Integrates Clinical, Commercial”Medical Marketing and Media (Dec, 2003)by Mark Tosh …Levine, executive director and develop- ment brand leader, adds the clinical and science proficiency as a research gastroenterologist. …as Levine and his staff put together clinical development plans, such as additional indications or line extensions, they get commercial input at every stage. http://findarticles.com/p/articles/mi_qa5351/is_200312/ai_n21340362

10. purplepill.com

11. http://www.nexium-us.com/moa/moa.asp (for health professionals) Nexium Site PROBLEM: Evaluate whether this series of 7 scenes shows superiority of Nexium.

12. ! From FDA Approved Nexium Labelhttp://www.fda.gov/cder/foi/label/2004/21153slr015_nexium_lbl.pdf (How much would you test?)

13. (RS)-Omeprazole (20 mg) (S)-Omeprazole (20 mg) (S)-Omeprazole (40 mg) 4 the dose of S contained in 20 mg of RS ! Four Clinical Trials 8 Weeks 4 Weeks

14. Nexiumproof.com “If…I told you prescription Nexium heals acid- reflux…damage better, you’d want proof.” NEXIUMPROOF.COM

15. Nexiumproof.com “And now your doctor has that proof.” NEXIUMPROOF.COM

16. Nexiumproof.com “Recent medical studies prove Nexium heals… better than the other leading prescription medicine.” NEXIUMPROOF.COM

17. Nexiumproof.com “No wonder they call Nexium ‘the healing purple pill’.” NEXIUMPROOF.COM

18. Nexiumproof.com “So call your doctor today.” NEXIUMPROOF.COM

19. Nexiumproof.com “because, if left untreated, the damage could get worse.” NEXIUMPROOF.COM

20. Nexiumproof.com NEXIUMPROOF.COM

21. 2CF3 Test

22. Nexiumproof.com “So call your doctor today.” NEXIUMPROOF.COM

23. Perspectives from a Clinician Dianne Duffey M.D., FACS Section of Otolaryngology, Department of Surgery Yale University School of Medicine

24. Disclosure I have no financial interest in any of the drugs or companies discussed I am not a consultant nor on any speakers’ bureaus for any company I will discuss off label or experimental uses of compounds

25. Disclosure • The opinions stated are those of the presenter and are not meant to represent those of the Section of Otolaryngology, Department of Surgery or Yale School of Medicine.

26. Now, as you’ve heard testified here today: Prilosec fixes symptoms of GERD and Laryngopharyngeal Reflux. • Or does it?

27. All we know is that his symptoms improved: in his body, eating his diet, and living his life.

28. Patient Variables • Are we taking into consideration other factors? • e.g. Diet: does Professor McBride take large amounts of herbal supplements that he didn’t tell us about? • Did he take the prescribed medication on an empty stomach? (i.e.was he compliant?)

29. Clinical Trials • design of a clinical trial • Controlling variables • Statistically sound

30. Biostatistics drive clinical trials design so that if differences are seen, it can be determined “with reasonable certainty” that differences observed are not due to chance

31. Duty - Manufacturer • Are the pharma companies actually designing their studies so that they can make legitimate head-to-head comparisons between competitor compounds?

32. Duty - Physician • evaluate the literature critically • be able to ascertain the validity of research supporting our choices as clinicians.

33. Duty - Patient • Be an educated consumer • Direct to patient (DTP) marketing is ubiquitous • Very effective • www.fda.gov

34. Specialty is Otolaryngology(ENT) • Laryngopharyngeal Reflux (LPR) • Underdiagnosed • Significant source of morbidity and decreased quality of life • Frequently associated with GERD • GERD: Potential for premalignant disease in esophagus, significant public health problem

35. It is estimated that4% to 10% of patients presenting to an otolaryngology practicehave symptoms and/or findings related to LPR. • Laryngopharyngealreflux is increasingly recognized as a probable contributingfactor to nonallergic asthma and many ear, nose, and throatcomplaints. • Studies suggest that acid reflux is present in 50%to 80% of patients with asthma, 10% to 20% of patients withchronic cough, up to 80% of patients with difficult-to-managehoarseness, and 25% to 50% of patients with globus sensation. Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320

36. Reflux • It’s a big problem • Hence, much money to be made

37. LP Reflux • Treatment: PPI, proton pump inhibitors • Reality: PPI are FDA approved http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

38. Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September 2002.

39. Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September 2002.

40. Drug Development • Only 5 in 5,000 compounds entering preclinical testing make it to human testing • 1 in 5 agents in human testing may be safe and effective enough to gain FDA approval www.fda.gov/fdac/special/testtubetopatient/studies.html

41. FDA APPROVALPrilosec OTCJune 20, 2003 http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

42. FDA APPROVAL Prilosec OTC (2003) • “We completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling text.” [omeprazole magnesium delayed-release tablets, 20mg] [for the treatment of frequent heartburn] http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

43. FDA APPROVALNexium • Esomeprazole magnesium (Nexium) • 1) Healing erosive esophagitis; 2) Maintenance of healing of erosive esophagitis; and 3) Treatment of symptomatic gastroesophageal reflux disease (2001) • Approved for the Risk Reduction of NSAID- associated Gastric Ulcers(2004) • Treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome(2006) http://www.fda.gov/cder/foi/nda/2001/21154_Nexium_Approv.pdf

44. FDA APPROVAL CLINICAL TRIALS

45. Clinical Trials - drug studies in humans • Phase I • Phase II • Phase III • Phase IV http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

46. Clinical Trials - drug studies in humans • Phase I • Healthy volunteers • Endpoint: side effects • Determines metabolism and excretion of drug • N=20-80 • Phase II • Phase III • Phase IV http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

47. Endpoints • AE - Adverse event, a side effect • SAE - Serious adverse event; resulted in damage to patient, hospitalization, surgery etc. • Reported to the FDA during trials

48. Clinical Trials - drug studies in humans • Phase I • Phase II • Effectiveness • Preliminary data: effectiveness of drug for a particular disease or condition • Comparison to placebo or to a different drug • Safety and short-term adverse effects studied • N=dozens - 300 • Phase III • Phase IV http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

49. Clinical Trials - drug studies in humans • Phase I • Phase II • Phase III • Safety and effectiveness • Study different populations; different dosages; combination with other drugs • N=several hundred - 3,000 • Phase IV http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

50. Clinical Trials - drug studies in humans • Phase I • Phase II • Phase III • Phase IV • Postmarketing study commitments • Studies required of or agreed to by a sponsor • Conducted after FDA approval received • Gathering additional information about product’s safety, efficacy or optimal use http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html