Transcript Chem 125 Lecture 10 9/26/07 Preliminary

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.
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Sulfide  Sulfoxide
H O * O
O
O
O
peroxy acid
Gives Racemate of Course
R'
R
S
+
R'
R
+
O
H
••
••
••
R
S••
n
O
••
R'
d-vacant
+
R'
n
+ S +
R
+
O
H
S
O
H
+
Blocking the Proton Pump
OCH 3
OCH 3
N
N
••
+
+
N
S
S
HN
O
N••
OCH3
N
n
••
OCH 3
HN
+
H+
H3CO
omeprazole
*N
H3CO
O
+
S
O H+
HN
H
H+ makes *
H3CO
C=N
a lower LUMO
N
H
S
HN
O
N
H
H 3CO
H
Blocking the Proton Pump
OCH3
OCH3
+
S
HN
N
H3CO
+
- OH-
N
S
S
N
HN
N
Enzyme
Pump enzyme
is inactivated,
slowing flow of
HCl to stomach.
OCH3
-S ••
n
S * H
O
+
N
- H+
+
HN
O
N
Enzyme
H3CO
H
S
H
H 3CO
At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.
(“enteric” coating postpones activation during initial passage through acid stomach)
Should “Chiral Switch” to Single
Blocking the Proton Pump
Enantiomer Help Omeprazole?
OCH3
OCH3
+
S
HN
N
H3CO
+
- OH-
N
S
S
N
HN
N
Enzyme
Pump enzyme
is tied up.
Slows flow of
HCl to stomach.
OCH3
-S ••
n
S * H
O
+
N
- H+
+
HN
O
N
Enzyme
H3CO
H
S
H
ACHIRAL !
H 3CO
At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.
(“enteric” coating postpones activation during initial passage through acid stomach)
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
>6108 worldwide
Chiral
Switch
2003
2000
1988
S
RS
2002
http://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-carolyn-fitzsimons-nexium.pdf
“Nexium Integrates Clinical, Commercial”
Medical Marketing and Media (Dec, 2003)
by Mark Tosh
…Levine, executive director and development 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
purplepill.com
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.
From FDA Approved Nexium Label
http://www.fda.gov/cder/foi/label/2004/21153slr015_nexium_lbl.pdf
(How !much would you test?)
Four
Clinical
Trials
100
95
Esophagitis % Healed
90
85
8 Weeks
80
(RS)-Omeprazole (20 mg)
(S)-Omeprazole (20 mg)
75
(S)-Omeprazole (40 mg)
4 the dose of S
contained in
20 mg of RS !
70
65
60
4 Weeks
Nexiumproof.com
NEXIUMPROOF.COM
“If…I told you prescription Nexium heals acidreflux…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
H
OCH 3
OCH23CF3
N
N
S
N
O
H
N
H3CO
S
N
O
N
H3CO
Perspectives from a Clinician
Dianne Duffey M.D., FACS
Section 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-tomanage 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
Belafsky et al: ENT-Ear, Nose & Throat Journal
Suppl 2,vol 81: September 2002.
Belafsky et al: ENT-Ear, Nose & Throat Journal
Suppl 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 APPROVAL
Prilosec OTC
June 20, 2003
http://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.”
[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
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 NSAIDUlcers
(2004)
associated Gastric
– 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
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?
3) 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?
End of Lecture 30
Nov. 17, 2008
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