Transcript Guerrilla Tactics in Pharmaceutical Innovation and Testing

Guerrilla
Warfare
Guerrilla
Marketing
Guerrilla
Innovation
Guerrilla Tactics in
Pharmaceutical Innovation and Testing
Dr. V. Ravi Chandran
R&D Practitioner
Life Enhancing Technologies, LLC.
Allen, TX
USA
Questions in my mind:
Do I develop
one Molecule
at a time?
Do I develop
all the Drugs
at one shot?
Platform
Technology?
What area
do I apply this
Technology?
Status in the early 2000
Efficacious
Toxic
I wanted to increase the
efficacy and reduce the
toxicity i.e. Increase the
Therapeutic Index
Drugs entering market
Examples
Leading Causes of Death
650,000
559,000
250,000
143,000
Heart Diseases
Cancer
Doctors*
Stroke
131,000
Chronic
Respiratory
Diseases
*JAMA Vol. 284, No.4, July 26, 2000
Guerrilla Tactic – 1 :
Narrow area of attack with maximum impact
Among Heart
Diseases, Heart
Attack is the leading
cause of death in
both men and
women*
*World Health Report 2004. Changing History, WHO 2004 pp 120-124 ISBN 92-4-156265-K
CLASSICAL AGE OLD DRUG
• What is Aspirin?
• Chemically it is Acetyl Salicylic Acid
Guerrilla Tactic – 2 :
Solution is sometimes right before the eyes
Guerrilla Tactic – 3 :
New association among unrelated concepts
Can we therefore develop a
new anti-platelet drug that is
effective, but has minimal or
no side effects?
A drug/chemical
that thins blood is
an effective cardioprotective agent.
Important Conclusion
Question
Guerrilla Tactic – 4 :
Specificity of Approach to New Drug Development
Naturally
Occurring
We will attach a
suitable chemical
group to the existing
drug to eliminate its
toxicity and improve
Therapeutic Index.
Non
Toxic
Chemical Group
Good
Carrier
to Site of
Action
Strategy
Must have
active group
to form
covalent
permanent
bond
Must be
detached &
excreted or
assimilated
Group Selection Criteria
Guerrilla Tactic – 5 : Look Inward
Where do I
Look for solution
To this question?
What is the most
Advanced, compact
Highly energy efficient,
Lean, mean
Fighting machine?
Human
Body
Guerrilla Tactic – 6 : Versatile
L - Threonine
L - Tyrosine
Which
Amino Acids?
Containing
OH group
L – Hydroxy
Proline
L – Serine
Surprising Results in Animal Models
All 3 Amino Acid
Esters are equal
effective
L – Threonine
ester is better
than other two
and Aspirin
None of the 3
Amino Acids
Esters showed
any toxicity in rat
models
Guerrilla Tactic – 7 :
Creativity turns Problems into Opportunities
How to rapidly advance a NCE
without an IND from Lab to Clinical Trials
Guerrilla Tactic – 8 :
Simple Techniques are sometimes most useful
What can be an effective, simple and
reliable technique to measure effectiveness
of anti-platelet drugs in humans
Human Clinical Trials
% INCREASE
PERCENTAGE INCREASE IN CLOTTING TIME 81mg
40
30
20
10
0
30.625
26.25
13.125
PLATROL
PLATROL
BAYER ASA
Percentage increase in clotting time PLATROL vs.. Aspirin (Bayer) at 81mg dose based on 5-day
average increase. The two PLATROL blocks shown above correspond to two separate volunteers
who took the test drug over a period of 5 days. The third volunteer took Bayer Aspirin for 5 days.
As per Figure 2, increase in clotting time for PLATROL occurred on the very first day of drug intake,
and remained higher than Bayer ASA during the subsequent administrations.
Surprise in Metabolism
10000
8000
Platrol
6000
Platrol
4000
Platrol
2000
ASA
0
TIME IN HOURS
16
12
9
7
5
3.
5
ASA
2.
5
0
0.
66
7
1.
5
SA IN PLASMA ng/ml
SALICYLIC ACID CONCENTRATION IN PLASMA
ng/ml
Platrol
Surprise in blood profile
ASA Concentration in Blood ng/ml
Time
800
Platrol
600
Platrol
Platrol
400
ASA
200
ASA
Platrol
15
13
11
9
7
5
3
0
1
ASA in blood ng/ml
1000
Hours after administration
CONCLUSIONS
L-Threonine ester
of Aspirin is a
good carrier of
Acetyl Group
Salicylic Acid is also
a good carrier of
Acetyl group
Acetyl group is
responsible for
Anti-Platelet
Activity of Aspirin
Are we finally
getting closer to
finding a “super”
Aspirin?
Are there better
carriers of
Acetyl Group
than Salicylic
Acid?
Guerrilla Tactic – 9 :
Capitalize on what others totally missed
Let us go back and take one more
look at Aspirin and Salicylic Acid.
Guerrilla Tactic – 10 :
Nature has the Answer
Is there a naturally
occurring molecule
(that is essential to
the human body)
comes very close to
our requirements
Yes!
Make acetyl ester
of all other
naturally
occurring OH
containing Amino
Acids.
Acetylate LTyrosine and
test it for antiplatelet activity.
Anti-platelet Activity of Acetylated naturally occurring
OH containing Amino Acids
Rat Whole Blood Clotting Time (min)
Doses: Vehicle, 10, 20, 50 and 100 mg/kg
Clotting time (4 & 24 hours)
Clotting time (min)
30.00
25.00
20.00
4 Hours AceTyro
15.00
24 Hours AceTyro
10.00
4 Hours AceSer
5.00
0.00
0
1
1.301 1.3979
Log Dose (mg/kg)
1.699
2
HUMAN TRIALS
OAT and OAS Effect on Human Blood Clotting Time
9
Clotting Time (min)
8.5
8
Vol 1, 1000 mg (OAT)
7.5
Vol 2, 350 mg (OAT)
7
Vol 3, 1000 mg (OAT)
6.5
Vol 4, 750 mg (OAS)
6
5.5
5
0
10
20
30
Time (Hrs)
40
50
60
Dramatic results with Acetylated Amino Acids!
Both at 81 and 325
mg dose, Bayer
Aspirin increased
clotting time only
by 13%
O Acetyl Serine
increased
clotting time by
23%
O Acetyl
Tyrosine
increased
clotting time by
more than 50%
and it was
sustained after
24 hrs
1.
2.
3.
4.
5.
6.
7.
8.
9.
Advantages of Acetylated Amino Acids
Non-toxic
All metabolites are natural to human body
All 4 AA are good carriers of acetyl group
Mechanism of action is identical to Aspirin
No Toxicity whatsoever
All AAA are nutritional supplements
Require no FDA approval to test
No NDA needed for marketing
Ideally suited for long term therapy
Guerrilla Tactic – 11 : Synergy
Now, how about
Acetylated
Dipeptides
Will they have
any Anti –
platelet activity?
Synthesized
O,O-Diacetyl Serine-Serine
O,O-Diacetyl Serine-Tyrosine
O,O-Diacetyl Serine-Threonine
Human Trial
Dose 600 mg of O,O-Diacetyl Seryl Serine
H u man C lo ttin g T ime
C lotting Time (min)
8
7
6
5
OOD iS erine
4
3
0
50
100
150
T im e (Hrs)
200
250
Salient Features of Di-Acetylated Dipeptide
1.
2.
3.
4.
5.
6.
7.
Rapid increase in clotting time (up to 87.5%)
Sustained increase in clotting time (37.5%) up to 8 days!
Is it as good as dissolving clot like TPA? Or it can replace
Aspirin in sudden heart attack? Likely so.
Non Toxic
No Side effects or adverse reactions
Qualifies as nutritional supplement, hence requires no IND
or NDA to test in human subjects
Qualifies for matter of composition patent, as it is novel, and
patentable.
Life
Enhancing
Technologies
Summary
Largest Drug
Pipeline in the
World
9000 molecules
in 3 years
Creative
processes and
Guerrilla tactics
Numerous
Patents
covering 80% of
the market
Better
Alternatives
for 6 out of
top 10 – $ 41
Bill in sales
Better
Alternatives
for 68 out of
top 200 –
$ 120 Bill in
sales
Be on the lookout for
AAA – Once a day
capsules, nontoxic, safe and
effective cardioprotective agent
S(-)Ketorolac- LThreonine Ester, a
superior pain killer
of narcotic
strength, but with
no addiction
potential
KeraKlear optic
drops for dry
eyes …
Truly Life
Enhancing!
Thank You