DD- Future approaches

Question 1

Issues in drug development

Answer 1

Sustainability (increasing costs)

Risk aversion

Question 2

What is pharmacogenomics

Answer 2

Drug development for small groups of population

Based on individual genomic factors which contribute to drug response

Question 3

HER-2 overexpression example of pharmacogenomics

Answer 3

O/E 20% breast, and in gastric ca patients

Clinical trials for Trastuzumab

Question 4

Advantages of pharmacogenomics

Answer 4

Efficient, potent disease targetting
Improved safety profile
Better dosing ability
Earlier screening implementations
Reduced costs
-Less ADRs and failures, shorter duration treatment

Question 5

Issues in pharmacogenomics

Answer 5

Target validation
Higher development costs (~30% higher)
Ethics of marking disorders

Question 6

Target validation issues in pharmacogenomics

Answer 6

Are polymorphisms consistent
Does the gene product produce a functional protein
Is the gene expressed for the entirety of the disease progression

Question 7

What is biopharmaceuticals- examples

Answer 7

Genetically modified proteins (large molecule drugs) used therapeutically

Vaccines, recombinant proteins, blood/tissue products, synthetic peptides, gene/cell therapy, monoclonal antibodies

Question 8

Properties of biopharmaceuticals

Answer 8

Species-specific* (issues with dev?)
Long acting
Parenteral administration
Eliminated by degradation/ catabolism
Relatively unstable (heat-sensitive, contamination)
Cannot cross the BBB

Question 9

Generations of biopharmaceuticals

Answer 9

1st gen (artificial human proteins prepped by transfection)
2nd gen (Proteins GM'd pre transfection to improve efficacy)
3rd gen (Novel proteins with specific target functions)

Question 10

Monoclonal antibodies-features

Answer 10

Immunoglobulins used to recognise a specific antigen
Targetting immune, inflammatory, oncological disease

1st gen (murine antibodies; induced HAMA response- toxicity)

2nd gen (chimeric 67% or humanised 100%)
- have improved efficacy due to affinity maturation (b ell cloning w/reduced chance of immune response)

ADCs (mAbs bound to small molecule drugs via biodegradable covalent links to improve targetting)
- Increased tolerability and lower toxicity

Question 11

Monoclonal antibody examples

Answer 11

Secukinumab for Ankylosing spondylitis
IL-17a mAb which is key inflammatory mediator in AS
RCT: reduced clinical/biological features of AS, well tolerated

Question 12

Issue with preclinical mAb testing

Answer 12

Species specific effects- primates most effective
-Repro tox not feasible (abortions, long gestation)

Alternative: GM mice with surrogate antibodies
-Can support chronic/repro tox

Long time to generate; species cross reactivity may still not prove safety- cytokine storm

Question 13

Advantages of biopharmaceuticals

Answer 13

Less unexpected toxicity
Quicker discovery process (no screening/lead optomisation)
Reduced infection risk
Less need for routine gentox

Question 14

Disadvantages of biopharmaceuticals

Answer 14

Expensive (complex purification process)
Not orally active
Short plasma t1/2
Don’t cross BBB

Question 15

Biotechnology example

Answer 15

Implantable Drug Delivery Devices for metastatic cancer pain
-Pain occurs in 67% patients
RCT of IDDD showed 20% reduction in pain score and QoL for treatment group
Issues with terminal patients

Question 16

Pharmacogenomic example schizophrenia

Answer 16

Gene polymorphisms identified for variability in Dopamine D2/3 receptor response
-14 novel gene markers identified based on pharmacodynamic mouse assays of efficacy
PDE7B identified to be related to risperidone response

Question 17

Potential approaches for improving DD

Answer 17

Reducing cycle times
Enhance the hit rate
Increase links with academia