1. For copyright notice see final page of this file
Chemistry 125: Lecture 30 Esomeprazole as an Example of Drug Testing and Usage
The chemical mode of action of omeprazole is expected to be insensitive to its stereochemistry, making clinical trials of the proposed virtues of a chiral switch crucial. Design of the clinical trials is discussed in the context of marketing. Otolaryngologist Dr. Dianne Duffey provides a clinician’s perspective on the testing and marketing of pharmaceuticals, on the FDA approval process, on the clinical trial system, on off-label uses, and on individual and institutional responsibility for evaluating pharmaceuticals.
Synchronize when the speaker finishes saying “…talking about configuration - about handedness.” Synchrony can be adjusted by using the pause(||) and run(>) controls.
For copyright notice see final page of this file

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

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

4. Blocking the Proton Pump
Enzyme
- OH- + S
- H+ + + + s* •
Enzyme - 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. Blocking the Proton Pump
Should “Chiral Switch” to Single Enantiomer Help Omeprazole?
Blocking the Proton Pump
- H+ n s* •
Enzyme - +
- OH-
Pump enzyme
is tied up.
Slows flow of HCl to stomach. S +
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. Proton-Pump Inhibitor Use by Wellmark Members (1
Proton-Pump Inhibitor Use by Wellmark Members (1.75 M participants in IA/SD)
>15% of Wellmark members
>6108 worldwide
Chiral
Switch
2003
2000 RS S
2002
1988

8. http://www. astrazeneca

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.

10. purplepill.com

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

12. (How much would you test?)
From FDA Approved Nexium Label !
(How much would you test?)

13. Four Clinical Trials 8 Weeks 4 Weeks (RS)-Omeprazole (20 mg)
4 the dose of S
contained in mg of RS !
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 2003 budget from NYTimes, Oct 12, 2004
2005 Forbes 8 May 2006
NEXIUMPROOF.COM

21. Test
2CF3

22. Perspectives from a Clinician
I can remember sitting in organic chemistry at the University of North Carolina and fuming about the need to learn how to make paint…….when all I wanted to do was treat patients.
I hope you realize how fortunate you are to have the insights and relevant applications provided by Professor McBride. It’s certainly my honor to be able to participate and share with you some of my observations and dilemmas experienced as a clinician.
Dianne Duffey M.D., FACS
Section of Otolaryngology, Department of Surgery
Yale University School of Medicine

23. 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
This slide gets longer and longer as we move forward in the current economic climate. Also, medical institutions are becoming much more aware and guarded about conflict of interest on the part of their faculty and medical providers. Even the appearance of COI will increase gastric acid production in institutional administrators.

24. 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.

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

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

27. 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?)

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

29. 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

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

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

32. Duty - Patient Be an educated consumer
Direct to patient (DTP) marketing is ubiquitous
Very effective

33. 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

34. 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, % 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:

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

36. LP Reflux Treatment: PPI, proton pump inhibitors
Reality: PPI are FDA approved

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

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

39. 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

40. FDA APPROVAL Prilosec OTC June 20, 2003

41. 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]

42. 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)

43. FDA APPROVAL
CLINICAL TRIALS

44. Clinical Trials - drug studies in humans
Phase I
Phase II
Phase III
Phase IV

45. 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

46. 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

47. 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

48. 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

49. 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

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

51. 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

52. 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”

53. 20mg esomeprazole (p<0.05) or 40mg esomeprazole (p<0.001) over
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)
EO 40mg
O 20mg (n = 576, 572)

54. How are we able to use these drugs for LPR?
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:

55. “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).

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

57. MARKETING

59. 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: /456006a

60. Student Questions for Dr. Duffey
1) Who controls the number of warnings in TV drug commercials?
2) Considering the recent case of Vioxx, do you think clinical
trials should be longer?
If off-label uses can’t be advertised, how do doctors learn about them?
4) Do physicians take advantage of side-effects for off-label usage?

61. End of Lecture 30 Nov. 17, 2008
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