From Biology to Biotechnology… The Road Less Travelled…

1. From Biology to Biotechnology… The Road Less Travelled… Cletus J.M.D’Souza Department of Biochemistry University of Mysore

2. A Brief History PROBLEM • "I have an earache" SOLUTION • 2000 BC- Here, eat this root • 1000 AD- That root is heathen, say this prayer • 1850 AD- That prayer is superstition, drink this potion • 1940 AD- That potion is snake oil, swallow this pill • 1985 AD- That pill is ineffective, take this antibiotic • 2000 AD- That antibiotic is artificial , here eat this root

3. How is this relevant to us??? We are only an University Department….

4. You can make a difference… You may have something the world is looking for And you don’t know about it!!!

5. The Road To Discovery… • During the course of your research, you discover many new molecules… • Old molecules with new activities…. • You may even design a molecule for a specific purpose… • Or modify a well known molecule…

6. If your molecule has wonderful biological activities, should it just become one more publication and be lost to mankind…. ????

7. What is a drug?

8. DRUG • A substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication recognized or defined by the U.S. Food, Drug, and Cosmetic Act. • A drug is any chemical or biological substance, synthetic or non-synthetic

9. A drug is a compound which, when injected to an animal produces a Paper !

10. Can a Phytochemical become a drug? • Today there are at least 120 distinct chemical substances derived from plants that are considered important drug and are currently in use in one or more countries in the world

11. Drugs and Medicinal Plants • Some of these drugs are simply a chemical or chemicals extracted from plant materials and put into a capsule, tablet or liquid. • Eg. In Germany a Cynarin drug is manufactured and sold to treat hypertension, liver disorders and highly cholesterol levels.

12. Problem of One Vs Several Chemicals • Drugs usually consist of a single chemical, whereas medicinal plants can contain 400 or more chemicals. • It’s relatively easy to figure out the activity and side effects of a single chemical. • But an extract can have synergistic effects not seen with single chemicals

13. Are only plant products drugs?

14. Is there a quick way to know whether a chemical can become a drug? Bioinformatics….

16. When you look at history of discovery, you may recognize where you are in your path to discovery….

18. O= O= O= CH3C Aspirin

20. Contributions of Biotech • More than 325 million people worldwide have been helped by 160 approved biotech drugs and vaccines • >350 more biotech drugs and vaccines now in clinical trials targeting more than 200 diseases • Biotechnology is responsible for hundreds of diagnostic tests, including HIV tests and home pregnancy tests, DNA fingerprinting…

21. All these were once somebody’s research project… Contribution of Big Pharma companies….. Only about 75 drugs/vaccines

22. How were drugs discovered?

23. How were these drugs discovered? • From traditional knowledge aspirin • Serendipity.. thiozolidine diones • Based on scientific principles antibacterials • Bioinformatics design anticancer

27. How were the drugs developed…?

28. Drug Development Stages • Discovery • Proof of concept • Mechanism • Preclinical • Clinical • Phase I • Phase II • Phase III

29. DNA Microarray Acute Chronic From knowledge of Metabolic pathways In vitro Rodent In vitro Mechanism of action Proof of concept Toxicity IND Discovery Other? Non Rodent In vivo In vivo From Traditional Knowledge

30. Cost Per Stage • Discovery - $.5M • Product Selection - $.5M • Preclinical - $1- 1.5M • Clinical • Phase I - $5-10M • Phase II - $10-20M • Phase III - $30-50M • Product Launch - $5-10M

31. Product Life Cycle

32. Opportunities in Pharma Industry

33. Rule of Thirds in value development in route to commercialization

36. What is the future of Biotech?

37. How to develop a drug to take it to the market? • Identify a potential molecule • Identify a target • Test in vitro and in vivo Decision…. Proceed or discontinue…

38. Preclinical • In vitro studies • In vivo studies-cell culture • Animal studies • Protection of IPR • Application to Govt agencies for permissions…

39. Animal Testing Generally two or more species ( one rodent, one non-rodent). Animal testing is used to measure • how much of a drug is absorbed into the blood, • how it is broken down chemically in the body, • the toxicity of the drug and its metabolites, • how quickly the drug and its metabolites are excreted from the body

40. Short and Long Term Animal Testing • Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance. • Long-term testing in animals ranges in duration from a few weeks to several years. - Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects.

41. Preclinical Studies Acute Toxicity • Objective: To determine Maximum Tolerated Dose (MTD) and No Observable Effect Level (NOEL) • Duration: Typically 14 days after single dose • Animals Required: 2 species (rodent and non-rodent) • Parameters: • Mortality Clinical pathology Gross necropsy Weight change Clinical observations • Points to consider: • Dose selection for repeat dose studies • Choice of Species

42. Preclinical Studies Sub Acute Toxicity • Objective: To determine toxicity after repeated administration of the test material • Duration: 14 – 28 days • Animals Required: 2 species (rodent and non-rodent) • Parameters: • Mortality Clinical pathology  Urinalysis • Histology Weight change Clinical obs • Points to consider: • Dosing regimen – similar to clinical • Recovery period • Duration of clinical trials (Phase I, II, III) • Toxicokinetics • Immunotoxicity

43. Preclinical Studies Subchronic/Chronic Toxicity • Objective: In support of products used to treat chronic conditions • Duration: 30 days to 2 years • Animals Required: 2 species (rodent and non-rodent) • Parameters: • Mortality Clinical pathology • Clinical obs  Behavioral Assessment • Histology Weight change • Points to consider: • Clinical Trials (EU)

44. Preclinical Studies Carcinogenicity • Objective: To evaluate the tumorigenic potential in animals and risk to humans • Duration: 12 months + • Species: Mouse or Rat • Parameters: • Tumor development Clinical pathology • Clinical observations and assessment • Points to consider: • Considerations from: • Pharmacology, Pharmacokinetic or Toxicology (mechanistic in vitro and in vivo) data • Structure-activity relationships • Compound accumulation over long-term use • Continuous use in humans for 6 months +

45. Preclinical Studies Irritation and Sensitization • Objective: To determine the potential of test material to cause irritation and/or sensitization • Duration: Hours to weeks (depends upon test) • Animals Required: 2 species (mice and guinea pigs) • Parameters: observable effects (pruritis, erythema, edema, etc)

46. Preclinical Studies Immunotoxicity • Objective: To determine the potential of a test material to induce an immune response • Duration: Hours to weeks (depends upon test) • Animals Required: 2 species (mice and guinea pigs) • Parameters: observable effects (pruritis, erythema, edema, etc)

47. Preclinical Studies Reprotoxicity/Genotoxicity/Mutagenicity • Objective: To determine the potential of a test to cause one of the above issues • Duration: Weeks to years (depends upon test) • Animals Required:in-vivo and in-vitro tests • Parameters: many

48. We can do up to this stage without difficulty…! • Rethinking experiments • Extending the experiments “Usually” done • Doing the experiments by acceptable protocol • Documenting the results…

49. Next stage is expensive!!!

50. Purpose of a clinical study.. • To determine safety and tolerance n man • Pharmacokinetics (What body does with the drug) • Bioavailability of the drug • Pharmacological profile..