Guerrilla Warfare Guerrilla Marketing Guerrilla Innovation.
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Guerrilla WarfareGuerrilla Marketing
*After I graduated from the University of Florida, I worked as a senior scientist at Sterling Drug Company. This company is know for one major OTC product at that time, Bayer Aspirin. This was acquired from Bayer Drug Company of Germany during first world war, under the enemy properties acquisition act. I didnt last in that company for more than 1 year, as I realized I was not fit to work in large corporations. Many of my ideas were rejected, and I didnt care for corporate politics. Then I went to start and run my own businesses in USA, most important of those would be American Generics, a generic drug company, and Signature Pharmaceuticals, a state of the art liquid manufacturing unit. I successful ran those companies and sold sold them to Ranbaxy USA in early 2000. After this I starting to wonder what I would do with myself. Earlier I developed certain concept at Sterling Drug Company. When I went back and checked with some scientists at Sterling and on in the literature, I found nothing. All my ideas were abandoned by Sterling Drug Company. Now I need to come up with a modification of what I learned at Sterling and see if it can be applied. I also realized it has to be some sort of platform technology so that I can develop as many new drugs as possible in a short span of time. I also noted that when other scientists developed all those drugs, increase in efficacy always resulted in increase in toxicity as well. Most important examples were the NSAID research led to the development of super aspirins, such as celebrex and vioxx. Therefore can I develop a technique that will improve efficacy and reduce toxicity? Basically high therapeutic index drugs.Yes, in fact I did develop all these 2000 drugs and tested significant number of them. So how come a single scientist with no large company backup can develop so many drugs? I used well know guerrilla tactics and we will go through some of them.
Now the next part of the slide: Patents.
Guerrilla Tactics in Pharmaceutical Innovation and Testing
Dr. V. Ravi ChandranR&D PractitionerLife Enhancing Technologies, LLC.Allen, TXUSA
*Thank you very much for providing me an opportunity to present some of my scientific work today. Please feel free to interrupt me anytime during this presentation with any questions. Now, Let me begin my presentation with posing certain questions.
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
EfficaciousToxicDrugs entering marketExamples
I wanted to increase the efficacy and reduce the toxicity i.e. Increase the Therapeutic Index
*There was one thing that was common during the past several decades of new drug development. Scientists were consistently able to increase the efficacy of the drugs, but when it came to toxicity, they didnt have much luck. Increase efficacy always resulted in increased toxicity. Even the drugs that were just entering the market, such as Lipitor and Plavix, had significant side effects. As I was pondering this question in early 2000 I attended the American Pharmaceutical Association Conference. In this conference a well know guerrilla was the keynote speaker. Let us bring in this Guerilla.
Leading Causes of Death
*JAMA Vol. 284, No.4, July 26, 2000
*It is clear from this slide, if I had to have a significant impact, I should concentrate on heart diseases. So among the heart diseases, which is major cause of death?
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-KGuerrilla Tactic 1 : Narrow area of attack with maximum impact
*What is heart attack? Heart attack is triggered when parts of heart does not receive enough blood due to blocking of blood flow. The blood flow to heart is either reduced or completely blocked by the formation of atherosclerotic plaques on the walls of the arteries. What is atherosclerotic plaque? It is a collection of white blood cells such as platelets and lipids like cholesterol which combine together and themselves to the arterial walls.Why do they do it?Due to improper diet, high in fats, lack of exercise, age, certain medications, blood pressure, diabetes etc.How do you prevent this? Proper diet, exercise, Limone Gene, Red Wine etc.You can also take Aspirin.What does aspirin do? It increases clotting time of blood.How does it increase clotting time? By preventing aggregation of platelets and preventing the formation of atherosclerotic plaques and by thinning the blood. How does it do this? IN order to examine this, let us take a look at aspirin.
What is Aspirin?Chemically it is Acetyl Salicylic Acid
CLASSICAL AGE OLD DRUG
*When aspirin is taken orally, it gets absorbed in the duodenum and reached portal vein. This is where it comes into contact with circulating platelets. Aspirin enters platelets and then it undergoes enzymatic reaction with COX-1 enzyme.
Guerrilla Tactic 2 : Solution is sometimes right before the eyes
*Define what is COX-1 large peptide etc, - Serine at 530 position. Etc.According to FDA, any drug that increases clotting time, is an effective cardio protective agent, and can be classified as a prophylactic agent to prevent heart attacks. All anti-platelet drugs can increase clotting time.By using high school logic, I arrived at the conclusion, that all anti-platelet drugs are effective in preventing myocardial infarction.Let us therefore reinforce this conclusion in the next slide.
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 ConclusionQuestion
*This brings up important question. Do I develop a new molecule, or make modifications to an existing molecule. What is the well know molecule that is proven? Aspirin. But there are numerous problems with Aspirin, most important being GI toxicity. Now even if I cant improve the efficacy, can I just be able to decrease its toxicity? Any decrease in toxicity will improve therapeutic index. Therefore now I need a strategy, that is explained in the next slide.
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.NaturallyOccurringChemical GroupNonToxicGood Carrierto Site of ActionMust be detached & excreted or assimilatedMust have active group to form covalent permanent bondStrategyGroup Selection Criteria
Guerrilla Tactic 5 : Look Inward
Where do ILook for solutionTo this question?What is the mostAdvanced, compactHighly energy efficient,Lean, meanFighting machine?Human Body
*Human body contains lots of biochemicals, fats, lipids, carbohydrates, minerals, vitamins, coenzymes, hormones etc. Out of all these, the most useful chemicals are generally amino acids. All amino acids occurring in the human body, including those made by the human body are stereo-specific, of the L-variety. They contain generally an acid group and a basic group. They are essential components of human biochemistry, basic building blocks of all types of proteins, enzymes and various hormones, completely non-toxic and easily assimilated into the body or metabolized and excreted. So I decided to take a careful and intense look at the amino acids. The next question, is which amino acid as posed in the next slide.
Guerrilla Tactic 6 : Versatile
Which Amino Acids?ContainingOH groupL - ThreonineL - TyrosineL Hydroxy ProlineL Serine
*In order to react aspirin with an amino acid, we need only those amino acids that contain OH group to form esters. Let us check out the results we got from the animal studies conducted in the next slide.
Surprising Results in Animal Models
All 3 Amino Acid Esters are equal effectiveL Threonine ester is better than other two and AspirinNone of the 3 Amino Acids Esters showed any toxicity in rat models
*When compared to aspirin, which produced severe lesions, ulcer, bleeding and anatomical signs of gastric irritation, our AA esters didnt show any GI toxicity at the highest dose. We decided to advance L-Threonine to human trials.
Guerrilla Tactic 7 : Creativity turns Problems into Opportunities How to rapidly advance a NCE without an IND from Lab to Clinical Trials
*Once we decided to advance our compounds to human trials, we wanted to know if we can speed up the process. I want to take these drugs straight to human trials from the lab. I felt that proof of concept study is best conducted in human subjects. Can we therefore conduct human trials in USA without an IND for a NCE?There is a provision in the US laws that if the new drug is manufactured in a given state, then clinical trials can be conducted in the same state without filing IND with the US FDA. There is just one condition that has to be met. An authorized institutional review board must approve the testing protocol.The IRB that we chose agreed to test these drugs in the human after they were convinced that there is really no harm to any subject can occur as the drugs we are trying to test are just amino acid esters, and they have proven their efficacy and toxicity in animal models. This was a significant breakthrough and we were able to conduct several human trials quickly without filing IND.
Guerrilla Tactic 8 : Simple Techniques are s