Drug Discovery Fundamentals I

Question 1

What factors can contribute to the development of neurodegenerative disease?

Answer 1

Genetic risk factors, environment, lifestyle, illness and surgery.

Question 2

What is the aim of new therapeutic drugs?

Answer 2

To alter the course of the disease and ideally reverse the damage (instead of just symptomatic relief).

Question 3

What is Alzheimer’s disease (AD)?

Answer 3

A chronic, progressive neurodegenerative disorder with symptoms including memory loss, confusion and personality change.

Question 4

What pathology is seen in AD?

Answer 4

1. Neurofibrillary tangles - tau
2. Senile plaques - amyloid-beta

Question 5

What is the average lifespan for an individual with AD?

Answer 5

There is an average lifespan of 4-8 years from diagnosis.
Individuals who experience symptoms earlier in life are more likely to have a more rapid rate of decline.

Question 6

What are some challenges in developing therapeutics for AD?

Answer 6

1. The majority of cases are sporadic with no significant genetic component.
2. There are many different factors which contribute to development of the disease.
3. The pathology of AD begins in the brain around 10-20 years before symptoms start to show.
4. Many mutations which are known to increase the risk of AD are also in other organs so cannot be targeted without affecting their function.
5. There a few useful biomarkers for AD.

Question 7

What current treatments are available for AD?

Answer 7

1. Cholinesterase inhibitors - such as donepezil, galantamine and rivastigmine. They target cholinergic dysfunction by preventing the breakdown of ACh and potentiating cholinergic synapses.
2. Memantine - an NMDA glutamate receptor blocker.
3. Other symptomatic therapies for specific symptoms such as sleep, depression and pain.

Question 8

What emerging treatments are there for AD?

Answer 8

Lecanemab - approved for use in the UK but not funded. A monoclonal antibody which targets amyloid-beta clearance.

(Aducanumab was withdrawn from the market and donanemab is awaiting approval).

Question 9

What is lecanemab and how does it work?

Answer 9

It is an MAb IV infusion which targets and removes amyloid-beta from the brain, leading to a modest slowing of cognitive decline.

Question 10

What are some issues surrounding the use of lecanemab?

Answer 10

1. There is a large burden to the patient, carer and clinical setting as it has to be administered through an IV every 2 weeks.
2. It has only been approved for those with early AD (including MCI and mild dementia).
3. Prior to administration, patients must have confirmation of elevated amyloid-beta in the brain (PET scan).
4. There is a risk of ARIA - inflammation and bleeding in the brain.

Question 11

What components make up a good drug?

Answer 11

1. Activity - how well it binds to a target and generates the desired response.
2. Solubility - how well it can be absorbed if taken orally.
3. Oral bioavailability - how much of it reaches the appropriate tissue in the active form.
4. Half-life - how long it stays in its active form in the body.
5. Metabolic prolife - whether it (or any byproducts) produces any toxic side effects.

Question 12

What are the 3 pillars of drug development?

Answer 12

1. The drug needs to be at the site of action over the desired time period (pharmacokinetics).
2. The drug needs to bind to its target (pharmacodynamics).
3. The drug needs to elicit the desired pharmacological or physiological effect (biomarkers).

Question 13

What are the 5Rs in drug discovery?

Answer 13

1. Right target
2. Right tissue
3. Right safety
4. Right patients
5. Right commercial potential

Question 14

What are the aims of drug discovery?

Answer 14

To confirm the drug target and validate if and how drugs can modulate it.