Guerrilla Warfare

Guerrilla Marketing

Guerrilla Innovation

Guerrilla Tactics in Pharmaceutical Innovation and Testing

Dr. V. Ravi ChandranR&D Practitioner

Life Enhancing Technologies, LLC.Allen, TX

USA

Do I develop one Molecule

at a time?

Questions in my mind:

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

Drugs entering market

Examples

I wanted to increase the efficacy and reduce the

toxicity i.e. Increase the Therapeutic Index

Leading Causes of Death650,000

559,000

250,000

143,000 131,000

Heart Diseases Cancer Doctors* Stroke ChronicRespiratory

Diseases

*JAMA Vol. 284, No.4, July 26, 2000

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

Guerrilla Tactic – 1 : Narrow area of attack with maximum impact

• What is Aspirin?• Chemically it is Acetyl Salicylic Acid

CLASSICAL AGE OLD DRUG

Guerrilla Tactic – 2 : Solution is sometimes right before the eyes

Guerrilla Tactic – 3 : New association among unrelated concepts

A drug/chemical that thins blood is an effective cardio-protective agent.

Can we therefore develop a new anti-platelet drug that is effective, but has minimal or

no side effects?

Important Conclusion Question

Guerrilla Tactic – 4 : Specificity of Approach to New Drug Development

We will attach a suitable chemical

group to the existing drug to

eliminate its toxicity and improve

Therapeutic Index.

NaturallyOccurring

Chemical Group

NonToxic

Good Carrier

to Site of Action

Must be detached & excreted or assimilated

Must have active group

to form covalent

permanent bond

Strategy Group Selection Criteria

Guerrilla Tactic – 5 : Look Inward

Where do ILook for solutionTo this question?

What is the mostAdvanced, compact

Highly energy efficient,Lean, mean

Fighting machine? Human Body

Guerrilla Tactic – 6 : Versatile

Which Amino Acids?

ContainingOH group

L - Threonine

L - Tyrosine

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 AspirinNone 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

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.

PERCENTAGE INCREASE IN CLOTTING TIME - 81mg

26.2513.125

30.625

010203040

PLATROL PLATROL BAYER ASA

% IN

CR

EASE

Surprise in Metabolism

SALICYLIC ACID CONCENTRATION IN PLASMA ng/ml

020004000

60008000

10000

00.6

67 1.5 2.5 3.5 5 7 9 12 16

TIME IN HOURS

SA IN

PLA

SMA

ng/m

l

Platrol

Platrol

Platrol

ASA

ASA

Platrol

Surprise in blood profile

ASA Concentration in Blood ng/ml

0

200

400

600

800

1000

1 3 5 7 9 11 13 15

Hours after administration

ASA

in b

lood

ng/

ml Time

Platrol

Platrol

Platrol

ASA

ASA

Platrol

CONCLUSIONS

Acetyl group is responsible for Anti-Platelet

Activity of Aspirin

L-Threonine ester of Aspirin is a good carrier of

Acetyl Group

Salicylic Acid is also a good carrier of

Acetyl group

Are we finally getting closer to finding a “super”

Aspirin?

Are there better carriers of

Acetyl Group than Salicylic

Acid?

Let us go back and take one more look at Aspirin and Salicylic Acid.

Guerrilla Tactic – 9 : Capitalize on what others totally missed

Is there a naturally occurring molecule (that is essential to

the human body) comes very close to our requirements

Guerrilla Tactic – 10 : Nature has the Answer

Yes!

Acetylate L-Tyrosine and

test it for anti-platelet activity.

Make acetyl ester of all other naturally

occurring OH containing Amino

Acids.

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)

0.00

5.00

10.0015.00

20.00

25.00

30.00

0 1 1.301 1.3979 1.699 2

Log Dose (mg/kg)

Clo

tting

tim

e (m

in)

4 Hours AceTyro

24 Hours AceTyro

4 Hours AceSer

HUMAN TRIALS

OAT and OAS Effect on Human Blood Clotting Time

5

5.5

6

6.5

7

7.5

8

8.5

9

0 10 20 30 40 50 60

Time (Hrs)

Clot

ting

Tim

e (m

in)

Vol 1, 1000 mg (OAT)

Vol 2, 350 mg (OAT)

Vol 3, 1000 mg (OAT)

Vol 4, 750 mg (OAS)

Dramatic results with Acetylated Amino Acids!

Both at 81 and 325 mg dose, Bayer

Aspirin increased clotting time only

by 13%

O Acetyl Tyrosine increased

clotting time by more than 50%

and it was sustained after

24 hrs

O Acetyl Serine increased

clotting time by 23%

Advantages of Acetylated Amino Acids1. Non-toxic2. All metabolites are natural to human body3. All 4 AA are good carriers of acetyl group4. Mechanism of action is identical to Aspirin5. No Toxicity whatsoever6. All AAA are nutritional supplements7. Require no FDA approval to test 8. No NDA needed for marketing 9. Ideally suited for long term therapy

Guerrilla Tactic – 11 : Synergy

Now, how about Acetylated Dipeptides

Will they have any Anti –

platelet activity?

SynthesizedO,O-Diacetyl Serine-Serine

O,O-Diacetyl Serine-TyrosineO,O-Diacetyl Serine-Threonine

Human TrialDose 600 mg of O,O-Diacetyl Seryl Serine

H uman C lotting T ime

3

4

5

6

7

8

0 50 100 150 200 250

T im e (Hrs)

Clo

tting

Tim

e (m

in)

OO-DiS erine

1. Rapid increase in clotting time (up to 87.5%)2. Sustained increase in clotting time (37.5%) up to 8 days!3. Is it as good as dissolving clot like TPA? Or it can replace

Aspirin in sudden heart attack? Likely so.4. Non Toxic5. No Side effects or adverse reactions6. Qualifies as nutritional supplement, hence requires no IND

or NDA to test in human subjects7. Qualifies for matter of composition patent, as it is novel, and

patentable.

Salient Features of Di-Acetylated Dipeptide

Life Enhancing

Technologies

Summary

9000 molecules in 3 years

Largest Drug Pipeline in the

World

Numerous Patents

covering 80% of the market

Creative processes and

Guerrilla tactics

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, non-toxic, safe and

effective cardio-protective agent

S(-)Ketorolac- L-Threonine Ester, a superior pain killer

of narcotic strength, but with

no addiction potential

KeraKlear optic drops for dry

eyes …

Truly Life Enhancing!

Thank You