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

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 Death *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 Changing History, WHO 2004 pp ISBN 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. Naturally Occurring Chemical Group Non Toxic 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 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 Which Amino Acids? Containing OH 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 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 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

Surprise in blood profile

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

HUMAN TRIALS

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 Acids 1.Non-toxic 2.All metabolites are natural to human body 3.All 4 AA are good carriers of acetyl group 4.Mechanism of action is identical to Aspirin 5.No Toxicity whatsoever 6.All AAA are nutritional supplements 7.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? 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

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 Toxic 5.No Side effects or adverse reactions 6.Qualifies as nutritional supplement, hence requires no IND or NDA to test in human subjects 7.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