1. Chem 125 Lecture 30 11/17/08 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 n + + + Sulfide  Sulfoxide peroxy acid + + H + Gives Racemate of Course ** n d-vacant

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

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

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

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. Proton-Pump Inhibitor Use by Wellmark Members (1.75 M participants in IA/SD) http://www.wellmark.com/health_improvement/reports/ppi/about.htm http://www.wellmark.com/health_improvement/reports/ppi/about.htm >15% of Wellmark members >6  10 8 worldwide 1988 2002 2003 2000 Chiral Switch RS S

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

9. …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 “Nexium Integrates Clinical, Commercial” Medical Marketing and Media (Dec, 2003) by Mark Tosh

10. purplepill.com

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

12. From FDA Approved Nexium Label http://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) Four Clinical Trials 4 Weeks 8 Weeks 4  the dose of S contained in 20 mg of RS !

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

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

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

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

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

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

20. Nexiumproof.com NEXIUMPROOF.COM

21. Test 2 CF 3

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

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 that 4% to 10% of patients presenting to an otolaryngology practice have symptoms and/or findings related to LPR. Laryngopharyngeal reflux is increasingly recognized as a probable contributing factor to nonallergic asthma and many ear, nose, and throat complaints. Studies suggest that acid reflux is present in 50% to 80% of patients with asthma, 10% to 20% of patients with chronic cough, up to 80% of patients with difficult-to- manage hoarseness, 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 APPROVAL Prilosec OTC June 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.” http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf [omeprazole magnesium delayed-release tablets, 20mg] [for the treatment of frequent heartburn]

43. FDA APPROVAL Nexium 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

51. Clinical Trials - drug studies in humans Phase 0 Phase I Phase II Phase III Phase IV Clin Cancer Res 2008; 14(12), 2008

52. Clinical Trials - drug studies in humans Phase 0 –Exploratory, first-in-human trials –A.k.a. microdosing studies –Designed to speed up development of promising agents –Establishes very early on whether agent behaves in human subjects differently that expected from preclinical studies –Single, subtherapeutic dose of drug, small number patients (n=10-15) –Not targeting efficacy (dose too low for therapeutic effect) –No potential benefit to patient –Endpoint: pharmacodynamic and/or pharmacokinetic response –Interrogate and refine a target or biomarker assay for drug effect –Expected effects at nontoxic doses and over short exposure durations (e.g. <7days) Clin Cancer Res 2008; 14(12), 2008

53. Reflux Studies Sustained resolution (>7days) of heartburn in patients with erosive esophagitis –No statistically significant difference between esomeprazole 20mg (n=620) and omeprazole 20mg (n=626) –Chose omeprazole 20mg dose because it’s “the approved dose for this indication” http://www.fda.gov/cder/foi/label/2007/021153s027s028,021689s008s011lbl.pdf

54. However, healing of erosive esophagitis was statistically significantly better for 20mg esomeprazole (p<0.05) or 40mg esomeprazole (p<0.001) over 20mg omeprazole (n = 656, 654, 650) Another study: no difference EO 20mg O 20mg (n = 588, 588) Another study: statistically significantly better for EO 40mg (p<0.001) over O 20mg (n = 1216, 1209) Another study: no difference EO 40mg O 20mg (n = 576, 572) http://www.fda.gov/cder/foi/label/2007/021153s027s028,021689s008s011lbl.pdf

55. Approximately 20% to 43% of patients with LPR experience heartburn, and 18% have esophagitis. How are we able to use these drugs for LPR? Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320

56. “Off-label” Use of Marketed Drugs “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rational and on sound medical evidence, and to maintain records of the product’s use and effects. Use of a marketed product in this manner when the intent is the “practice of medicine” does not require the submission of an IND [Investigational New Drug] application, IDE [Investigational Device Exception] or review by an Institutional Review Board (IRB). http://www.fda.gov/OC/OHRT/IRBS/offlabel.html

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

58. MARKETING

60. Meanwhile, research investment in oncology has been growing steadily across the industry. Some view Indiana- based Eli Lilly's recent $6.5-billion bid for the biotechnology firm ImClone as a sign of increased demand for cancer drug candidates. Health-care insurance plans, too, have traditionally been more willing to pay high premiums for cancer therapies although there are signs that this attitude may be changing. And the pharmaceutical industry has recently embraced the drive towards genetically targeted, individual treatments in oncology a concept that once made companies cringe because it reduced the market for a given drug. That, says Conover, was before the industry realized that patients would pay tens of thousands of dollars for an expensive new drug. "All of a sudden," he says, "'market limiting' is OK. ” Industry is shifting attention to Oncology (cancer), Immunology (e.g. rheumatoid arthritis), Neurology (Alzheimer ’ s) Nature News, Published online 4 November 2008 | Nature | doi:10.1038/456006a

61. End of Lecture 30 Nov. 17, 2008