12 Drug Discovery and Development

Question 1

Classical drug discovery process

Answer 1

1. Study molecules - examine effects on disease
2. Isolate active components
3. Determine structure and resynthesise
4. Prove biological activity of the active principle
5. Chemically modify structure

Question 2

Modern day discovery process

Answer 2

1. Understand biology of disease
2. Identify molecular target to alter the biology
3. Develop drug that acts on target
4. Test the hypothesis that drug wil have clinical effects

Question 3

Drug design issues

Answer 3

Expensive and high-risk buisness / 10-15 years to develop (patent are 20 years) / high attrition rate (1 in 10 drugs that start clinical phases will make it to market)

Question 4

Drug design - why do most drugs not make it to the market

Answer 4

40-50% lack clinical efficacy

30% unmanageable toxicity

10-15% poor drug like properties

10% lack of commercial needs and poor strategic planning

Question 5

Drug regulation process (4)

Answer 5

1. Each drug must be safe and efficacious and manufactured to high quality standards
2. Efficacy must be proven across ethnicities as well as across different age group (depending on targets)
3. Each drug must pass regulatory review by the specific governing body from each individual market territory (UK = MHRA / EU = EMA / USA = FDA)
4. Approved drugs must appeal to floral markets across different healthcare systems and distribution systems

Question 6

Stage 1 - name

Answer 6

Drug discovery

Question 7

Drug discovery - description

Answer 7

Selecting therapeutic areas to invest in is driven by therapeutic need / prevalence of disease / likelihood of success

Question 8

Drug discovery (stage1) - steps

Answer 8

First step in modern day drug discovery is target identification

Three cornerstones for target selection - link to human disease / link to pathway and mechanism of action / link to chemical modality —> requires extensive knowledge and fundamentals of biological mechanisms driving disease progression

Lead identification - once targets identified, now research put into identifying suitable chemicals to interact with target

High throughput screening (HTS) - screening of the entire chemical compound library against the drug target (usually over 100k)

In-silico ‘virtual’ screening - selecting from the chemical compound library, smaller subsets of chemicals with potential activity at the target protein in a computational model

Question 9

Drug discovery (additional considerations)

Answer 9

Additional considerations - technical feasibility / research and development costs / commercial considerations - competition and market share

Question 10

Stage 2 - name

Answer 10

Preclinical development

Question 11

Preclinical development - description

Answer 11

In vivo and invitro testing

Build a profile of the efficacy and safety of a drug candidate and potential liabilities that can be monitored in the clinic —> informed regulatory bodies decision to progress to FIH trial

Pharmacodynamic and Pharmacokinetic testing - dose ranging

Toxicology testing to inform the safety profile of lead compound

Question 12

Stage 3 - name

Answer 12

Clinical development

Question 13

Clinical development - description

Answer 13

Phase 1 - healthy volunteers (very low starting dose - PK/PD - safety, tolerability, dose ranging studies)

Phase 2 - cohort of patients with target disease (establish efficacy and dose repsonse relationship safety)

Phase 3 - large cohort of patients with target disease (large scale safety and efficacy studies)

Question 14

Stage 4 - name

Answer 14

Pharmacovigilance

Question 15

Pharmacovigilance - description

Answer 15

Each drug demonstrate safety and efficacy in the intended patient population

Benefits must outweigh the risks

Strict regulatory standard govern the conduct of pre-clinical, clinical trials, manufacturing)

Long term population monotoring to see adverse effects in wider population