Clinical trials and drug discovery

Question 1

What happens in basic research stage of drug development?

Answer 1

Target selection and lead finding

Question 2

What is lead finding?

Answer 2

When the target is identified and the lead compounds are found

Question 3

What happens in lead finding?

Answer 3

Cloning of target and then put into assay which will be tested with thousands of compounds in a companies library

Question 4

Properties taken into account then selecting a lead molecule?

Answer 4

Lead molecule optimisation- improve target specificity, improve potency, pharmaceutical and pharmacokinetic properties, reduced safety liabilities

Question 5

What happens in lead optimisation?

Answer 5

A broader range of assays are completed on different test systems, measure the activity and time course of compounds in vivo and check for unwanted effects in animals, evidence of genotoxicity and usually for oral absorption
Then a short list of lead molecules are optimised - ranked

Question 6

What in vitro assays undergo in lead optimisation?

Answer 6

In vitro mutagenicity, clastogenicity and specific cardiac arrhythmia.
Also assays to screen for interference with bile salt export pump which may affect liver injury are more common now

Question 7

What do in vitro mutagenicity test do?

Answer 7

Multiple strains of Salmonella engineered to be histidine deficient, those bacteria that are mutated back to have histidine are Ames positive- so may be carcinogenic

Question 8

What do in vitro clastogenicity assays do?

Answer 8

Looks at gene mutations, chromosome aberration or breakage, and chromosome loss or gain

Question 9

What, other than assays, are used in lead optimisation studies?

Answer 9

Overexpressed KO mouse - to obtain information on the intended target
Exploratory studies

Question 10

What are exploratory studies for?

Answer 10

Identify unwanted toxicities evident after repeat administration for short duration as well as to identify putative toxicities based on a known cause of concern

Question 11

What are benefits of exploratory studies?

Answer 11

Provide data to move the best candidate forward, allow to test for a specific cause of concern and can also provide data to help understand both on and off target toxicity

Question 12

What is the difference between on and off target toxicity?

Answer 12

On- exaggerated and adverse pharmacological effects at the target of interest
Off- Refers to adverse effects as a result of modulation of the target

Question 13

Goals of non clinical safety evaluations

Answer 13

Toxicity, toxicokinetics, max non toxic dose/ min effective dose, dose selection for first in human, identification of specific monitoring requirements

Question 14

Aim of preclinical development

Answer 14

To satisfy all the requirements that have to be met before a new compound is deemed ready to be tested for the first time on humans

Question 15

What is meant by good laboratory practice?

Answer 15

Formal operating code which aims to eliminate human error as far as possible in preclinical development

Question 16

Why is GLP important in drug development?

Answer 16

To ensure reliability of the data submitted to the regulatory authority and labs are regularly monitor for compliance with the GLP
Applies to the non- clinical studies for the safety of man, animals and environment

Question 17

What happens in preclinical development?

Answer 17

General toxicology- clinical pathology and pathology, Small molecules toxicology, safety pharmacology- undesirable effects on physiological functions e.g. CVS,CNS and respiratory
Genetic toxicology - in vitro and in vivo tests designed to detect compounds that induce genetic damage
Pharmacokinetics- drug metabolism

Question 18

What are the similarities between small molecules and biopharmaceuticals?

Answer 18

Safety pharmacology, 1,3,6 month studies, developmental toxicology

Question 19

What does small molecule pre clinical development have which biopharmaceutical do not?

Answer 19

14C ADME, max tolerated dose, t half short, toxic metabolites, Pk/PD correlation, genotoxicity, carcinogenicity

Question 20

What do biopharmaceuticals pre clinical development have that small molecules don’t?

Answer 20

Tissue binding study, x target of saturation, t half long, immunogenicity, no PK/PD

Question 21

What are different immunotherapies and how are they used to treat cancer?

Answer 21

Checkpoint inhibitors- natural brake on immune system so T cells attack tumours
CAR T cell Therapy (Chimeric Antigen Receptor)- genetically engineer a patients own immune cells to make a new protein
Cancer vaccine- train your body to protect itself against own damaged or abnormal cells