DRUG DISCOVERY

Question 1

What are the stages of development of a new drug?

Answer 1

1. Basic Research and Drug Discovery
2. Pre clinical development/research
3. Phase 1 Clinical Development
4. Phase 2 Clinical Development
5. Phase 3 Clinical Development
6. Regulatory Review
7. Continuous Review

Question 2

What happens during Basic Research and Drug Discovery?

Answer 2

Research is found in universities and research centres to find a target selection ie usually a POI that can be targetted in disease for example.
Once we have a target we must find an array of drugs whether it be antibody, chemical or other. Theses are called leads. Leads are found using libraries of millions of drugs against the receptor assays running.
Moving forwards, the aim is to decrease the number of candidate compounds in testing. This is done by using exploratory preliminary toxicology and safety experiments.

Question 3

How long typically does Basic Research and Target Selection take?

Answer 3

Approximately 3-6 years.

Question 4

How does lead finding usually take place after a drug target has been derived from research?

Answer 4

The usual approach involves cloning of the target protein-normally the human form. An assay system must then be developed, allowing the functional activity of the target protein to be measured. This could be a cell-free enzyme assay, a membrane-based binding assay or a cellular response assay.

Question 5

What tests are usually done with the POI and the lead?

Answer 5

This could be a cell-free enzyme assay, a membrane-based binding assay or a cellular response assay.

Question 6

What is the purpose of lead optimisation.

Answer 6

Many of the drugs screened in the libraries may be a ‘fit’ for the target. However, we must identify those, dependent on their properties, that are suitable for further development.
The goal of lead optimization is to rank-order this shorter list of candidate molecules and select the top candidate with the best profile that would then move into more formal nonclinical drug development.

Question 7

Preliminary toxicology and regulatory safety studies can be carried out during phase 1 and phase 2 of drug development. What kinds of tests do these involve?

Answer 7

Prior to initiation of animal toxicology experiments usually that take place in Phase 2 pre clinical development, other liabilities are often assessed in silico and in vitro.
In vitro screening assays detect mutagenicity and specific cardiac arrhythmia biomarkers such as hERG channel binding and inhibition.
Variations of the Ames test are often used to detect compounds that are mutagens.
If these pass, then administration to in vivo testing will be allowed.
Exploratory safety such as off target binding profile, preliminary CV and CNS safety test are also carried out. These include: ECG, whole body plethysmography and Irwin Activity Screens.

Question 8

What are the aims of preclinical development?

Answer 8

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

Question 9

What are the kinds of testing that take place during pre clinical development for submission for Clinical Trials?

Answer 9

Regulatory toxicology:
- haematology/kidney/liver/coagulation/organ toxicity

Regulatory safety:
-
CVS/CNS/respiratroy
Non clinical safety evaluations: 
-
 toxicity/reversibility/toxicokinetics/ max and min dosage/dosage selection for first human/specific monitoring requirements/ADME studies in animals

Question 10

Clinical Development goes through distinct stages, describe these stages.

Answer 10

Phase 1 studies are performed on a small group of healthy volunteers and their aim is to check for signs of any potential dangerous effects. Eg. CV, resp,hepatic,renal
We are also testing for the tolerability and the pharmacokinetic (ADME) properties.
Phase 2 studies are performed on a group of patients and are designed to test for efficacy in a clinical situation.
Phase 3 trials are the definitive double blind, randomised trials used on thousands of patients, aimed at comparing the new drug with already existing drugs.
Phase 4 studies are comprised of post marketting surveillance aiming to detect long term and rare side effects.
Over these trials, there will be testing for carcinogenicity, reproductive and juvenile toxicity, immunotoxicity and repeat dose toxicity.

Question 11

What are biopharmaceuticals?

Answer 11

Therapeutic agents produced by biotechnology rather than conventional synthetic chemistry.

Question 12

How is testing biopharmaceuticals different to small molecule drugs?

Answer 12

Testing is very similar, however biopharmaceuticals run into fewer toxicological problem, rather their problemed area is relating to production, quality control and drug delivery.

Question 13

What comes under biologics as a category?

Answer 13

Antibody based therapy
Vaccines
RNAi
CAR-T
Gene therapy

Question 14

What are the differences in immunotoxicology between small molecule drugs and biologics?

Answer 14

Small molecule drugs:
- we have clear indicators of standard toxicology eg haematological change, weight change, histopatholgy.
In biologics - thorough understanding required due to potential cytokine storm

Question 15

What do checkpoint inhibitors do?

Answer 15

They release a natural break on your immune system so T cells can recognise and attack tumours.

Question 16

What is CAR-T?

Answer 16

Chimeric Antigen Receptor Therapy is an approach of engineering the immune cells to make a new protein that is capable of fighting cancer.

Question 17

What is the role of cancer vaccines?

Answer 17

To train your body to protect itself against its own damaged or abnormal cells - including that of cancer cells.

Question 18

Blocking CTLA-4 on T cell surface causes what?

Answer 18

Cancer to vanish.

Question 19

What is the function of PD1?

Answer 19

Tamps down the immune system.

Question 20

What is the function of PDL1?

Answer 20

It protects cancers from T cells.

Question 21

What kind of drug is Ipilimumab and how does it work?

Answer 21

It is a checkpoint inhibitor.
By blocking CTLA-4 on the surface of T cells, it allows the T cell to recognise cancer as a foreign body. Upon recognition, T cells can then proliferate to attack the cancer.

Question 22

PDL1 is found on the surface of specific cancer cells. What does Pembrolizumab do?

Answer 22

Pembrolizumab is another checkpoint inhibitor. Usually, PDL1 on the surface of specific cancer cells binds with PD1 on T cells so that the T Cell does not recognise the cancer. Pembrolizumab blocks the PDL1, therefore it cannot bind with the T cell. The T cell will recognise the cancer as a foreign body and proliferate to begin to attack it.

Question 23

Explain how CAR-T works?

Answer 23

By extracting blood from a patient, we can extract their CD3 and T Cells. By transfecting the T Cells with the PO by use of CRISPR and Cas9, we can put back into the subject.