Chem 125 Lecture 3011/17/08

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+

SRR'

O

••

O

n +++

Sulfide Sulfoxide

SRR'

••

••

OO

OH

peroxy acid

OO••

SRR'

OH

+SR

R'

OH+

••

H+

SRR'

O

••

Gives Racemate of Course

*

nd-vacant

N

SOHN

N

OCH3

H3CO

••

••

Blocking the Proton Pump

H+

N

SOHN

N

OCH3

H3CO

H

••

+

H+

N

SOHN

N

OCH3

H3CO

H

+N

SOHN

N

OCH3

H3CO

H

H

+

+n

*

H+ makes *C=N a lower LUMOomeprazol

e

n

Blocking the Proton Pump

N

SO

HN

N

OCH3

H3CO

H- H+

+N

SOHN

N

OCH3

H3CO

H

H

+

+S••

Enzyme

-

At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.

*

(“enteric” coating postpones activation during initial passage through acid stomach)

Pump enzymeis

inactivated,

slowing flow of HCl to stomach.

N

SS

HN

N

OCH3

H3CO

Enzyme

- OH-+

S

Blocking the Proton Pump

N

SO

HN

N

OCH3

H3CO

H

+

At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.

ACHIRAL !

(“enteric” coating postpones activation during initial passage through acid stomach)

Should “Chiral Switch” to Single Enantiomer

Help Omeprazole?

- H+

n*

S••

Enzyme

-

N

SOHN

N

OCH3

H3CO

H

H

+

+N

SS

HN

N

OCH3

H3CO

Enzyme

- OH-+

Pump enzymeis tied up. Slows flow of HCl to stomach.

S

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.

Proton-Pump Inhibitor Use

by Wellmark Members(1.75 M participants in

IA/SD)http://www.wellmark.com/health_improvement/reports/ppi/about.htm>15% of Wellmark members

>6108 worldwide

19882002

2003

2000

ChiralSwitch

RS

S

http://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-

carolyn-fitzsimons-nexium.pdf

…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

purplepill.com

Nexium Site

http://www.nexium-us.com/moa/moa.asp (for health professionals)

PROBLEM: Evaluate whether this series of 7 scenes shows superiority of Nexium.

From FDA Approved Nexium Labelhttp://www.fda.gov/cder/foi/label/2004/21153slr015_

nexium_lbl.pdf

!(How much would you test?)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed

(RS)-Omeprazole (20 mg)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed

(S)-Omeprazole (20 mg)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed (S)-Omeprazole (40 mg)

Four Clinic

al Trials

4 Weeks

8 Weeks

4 the dose of S

contained in 20 mg of RS !

Nexiumproof.com

NEXIUMPROOF.COM

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

Nexiumproof.com

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

Nexiumproof.com

NEXIUMPROOF.COM

“Recent medical studies prove Nexium heals…better than the other leading prescription medicine.”

Nexiumproof.com

NEXIUMPROOF.COM

“No wonder they call Nexium ‘the healing purple pill’.”

Nexiumproof.com

NEXIUMPROOF.COM“So call your doctor today.”

Nexiumproof.com

NEXIUMPROOF.COM

“because, if left untreated,the damage could get worse.”

Nexiumproof.com

NEXIUMPROOF.COM

Test

N

SON

N

OCH3

H3CO

H

N

SON

N

OCH3

H3CO

H

2CF3

Nexiumproof.com

NEXIUMPROOF.COM“So call your doctor today.”

Perspectives from a Clinician

Dianne Duffey M.D., FACSSection of Otolaryngology, Department of Surgery

Yale University School of Medicine

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

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.

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

• Or does it?

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

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?)

Clinical Trials

• design of a clinical trial– Controlling variables– Statistically sound

• 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

Duty - Manufacturer

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

Duty - Physician

• evaluate the literature critically

• be able to ascertain the validity of research supporting our choices as clinicians.

Duty - Patient

• Be an educated consumer

• Direct to patient (DTP) marketing is ubiquitous

• Very effective

• www.fda.gov

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

• 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

Reflux

• It’s a big problem

• Hence, much money to be made

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

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

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

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

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

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

FDA APPROVALPrilosec OTC

June 20, 2003http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

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]

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

FDA APPROVAL

CLINICAL TRIALS

Clinical Trials - drug studies in humans

• Phase I

• Phase II

• Phase III

• Phase IV

http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

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

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

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

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

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

Clinical Trials - drug studies in humans

• Phase 0

• Phase I

• Phase II

• Phase III

• Phase IV

Clin Cancer Res 2008; 14(12), 2008

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

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

• 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

• 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

“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

Duty - Physician

• evaluate the literature critically

• be able to ascertain the validity of research supporting our choices as clinicians.

MARKETING

• 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

End of Lecture 30Nov. 17, 2008