Drug discovery and development in Neuroscience

Question 1

What kind of conditions are meant when we talk about CNS disorders?

Answer 1

• Neurological / neurodegenerative disorders
• psychiatric disorders
• substance use disorders

Question 2

What are the major trends in terms of costs for treating CNS disorders? describe the price of disease, direct and indirect costs.

Answer 2

Price of disease = cost per patient * n
direct costs = diagnosis, treatment, medicine, hospital care
indirect costs = rehabilitation, day care, years lost to disease (YLD)

psychiatric disorders have high price of disease!

Question 3

What trends in drug discovery and development in neuroscience have been important over the last 50 years?

Answer 3

In general, patients cost less over time, but number of patients increase.

In the beginning of the 1900s, hospitalization increased due to increasing interest and diagnosis of mental health (Freud and those guys). In the middle of the 20th century, we saw a development of tricyclic antidepressants and antipsychotics, both resulting in a decrease in hospitalizations.

Question 4

What is meant by a screenable target?

Answer 4

A target that can be effectively and efficiently tested in laboratory setting to identify drug candidates. Depends on:

-accessibility -> drug can reach target
- measurable activity -> drug - target interaction can be identified
- biological relevance

Question 5

What is high throughput screening?

Answer 5

It describes methods used to quickly conduct millions of chemical, genetic or pharmacological tests. It includes automation (AI) and parallel processing.

Question 6

What are examples of current drug target in the CNS?

Answer 6

Transporters -> SSRIs, SNRIs, NRIs, NDRIs, DAT blockers such as amphetamine, dexamphetamine and methylphenidate

Receptors -> D2 antagonists / partial agonists

Ion-channels -> TCA that also target voltage-gated sodium channels or pain killers that target α2δ subunit of voltage-sensitive calcium channels

Enzymes -> MAO / COMPT inhibitors

RNA -> gene technologies such as CRISPR

Question 7

What are important criteria before INDA A(investigational new drug application)?

Answer 7

• indication of preclinical efficacy based on in vitro or in vivo studies
• safety profile consisting out of toxicology studies, understanding of pharmacokinetics, ADME properties and assurance that drug can be produced with high quality

Question 8

What are important criteria before NDA (new drug application)?

Answer 8

• clinical efficacy demonstrating the effectiveness of drug in the target population
• including long-term effects and risk/benefit analysis

Question 9

What is an unmet medical need?

Answer 9

A condition or symptom whose treatment or diagnosis is not addressed adequately by available therapy.

Question 10

Describe the phases in drug development

Answer 10

Phase I: goal is to assess safety, tolerability, pharmacokinetic and pharmacodynamics. Involves 20-100 healthy volunteers.
- mesure max tolerated dose
- biomarker changes
- measure ADME

Phase II: goal is to evaluate efficacy, determine optimal dosing. Involves 100-300 patients.
- measure reduction in symptoms severity
- measure dose response

Phase III: goal is to confirm efficacy and monitor long-term use. Involves large-scale studies (1000-3000) with diverse populations
- Compare with current consistent treatment (ethical) or placebo

Question 11

What kind of studies are required to bring a novel drug to the market?

Answer 11

-discovery: theoretical -> define target and mechanism
- preclinical: in vitro / in vivo -> drug must be safe and have biological effect (proof of concept)
- clinical: drug must be safe and beneficial compared to exciting treatment
- Additional, phase IV -> special population studies

Question 12

What is FDA (US) and EMA (Europe) guideline?

Answer 12

FDA (food and drug administration) or EMA (European medicines agency) guidelines are official recommendations and regulatory requirements for drug development, approval and post-market surveillance.

Question 13

What criteria that could be met to make a drug successful?

Answer 13

Clinical criteria (efficiacy and safety)
Regulatory criteria
Market criteria (unmet need, cost-effective)

Question 14

What is meant by a translational gap in drug development?

Answer 14

The gap highlights difficulties in predicting human responses based on preclinical data, usually becuase animals are chosen to be as normal as possible but the average population has high individual differences.

Remember α7 subtype.

Question 15

Consider validity in animal models

Answer 15

• Construct validity: how well is the model made?
• Face validity: How does the model look in the human disease?
• Predictive validity: How well does the model predict treatment outcomes and efficacy?

Question 16

What is ADME?

Answer 16

Adsorption - Distribution - Metabolism - Excretion, part of pharmacokinetics (what the body does to the drug)

• Adsorption: how the drug gets into the bloodstream
• Distribution: how the drug is transported from the bloodstream to the target (BBB )
• Metabolism: how to drug is broken down.
  
  • phase I: oxidation, reduction, solubility
• phase II: conjugate reactions which ffurther increase water solubility to enhance secretion
• Excretion: the process by which drugs are eliminated from the body

Question 17

What preclinical ADME criteria are important to fulfil in order to bring leads further in development?

Answer 17

• Proper adsorption with high bioavailability
• Distribution to the right places in the body (crossing BBB)
• Ensure a long half-life, the drug shouldnt be metabolised too fast
• In terms of excretion, ensure good clearance rates to prevent toxicity

Question 18

Define a biomarker

Answer 18

A measurable indicator of a biological process, condition or disease state. An example in neuroscience are reduced BDNF levels, increased cortisol for depression and tissue damage and amyloid beta or tau for AD.

Question 19

How would biomarkers contribute to supporting the validity of animal models?

Answer 19

Biomarkers that are relevant in both animals and humans provide a translational link, which enhances the model’s construct validity.

Question 20

What types of biomarkers do we have?

Answer 20

• a pharacodynamic / response biomarker: used to show that a biological response has occurred after drug engagement
• a predictive biomarker: used to identify individuals that are likely to respond to a drug
• a monitoring biomarker: measured repeatedly for assessing status of a disease during drug exposure

Question 21

What kind of data would you consider important before bringing the drug candidate to patients?

Answer 21

Preclinical stage:
- mechanistic evidence
- efficacy
- ADME
- pharmacokinetics including half-life, peak concentration
- toxicity
- pharmacodynamics -> drug-dose response curves and be aware of U-shaped or M-shaped curves

Question 22

How would you consider safety?

Answer 22

Consider acute and chronic toxicological effects; what is the lethal dose, what are some long-term effets, do off-target effects occur in vital orgrans?

What is the therapeutic window?

Question 23

What kind of preclinical data (proof) could help designing phase II trials?

Answer 23

The “Cross-species translational toolbox” suggests different “proof” that we should give attention to:

1.a: Proof of Distribution (evidence that the drug reaches the target organ) – mechanistic target engagement
1.b: Proof of Occupancy (evidence that the drug interacts with relevant target in vivo) – mechanistic target engagement

2. Proof of Mechanism (evidence for direct mechanistic pharmacodynamic effect in relevant compartment in vivo) – mechanistic target engagement
3. Proof of Principle (Evidence for pharmacological effect on cellular function (e.g. circuit) or pathophysiology in an integrated system in vivo) – disease relevant pharmacodynamic marker
4. Proof of Concept (Evidence for pharmacological effect on symptoms in relevant biological or disease system in vivo) – disease relevant pharmacodynamic marker

Question 24

What is a target product profile and why is it important for a development project?

Answer 24

A target product profile (TTP)/label, is a strategic document outlining the desired attributes of a drug candidate. It is important to the value of the product, as it ensures that all members and stakeholders are aligned and that there’s transparency.

Question 25

What is described in a TPP?

Answer 25

The indication of the drug, the mechanism of action, the dosing regimen, the efficacy (endpoints) , the safety profile, the side effects, the formulation (administration form), the patient population and developmental milestones.

Question 26

What is a phase II study and what kind of results are essential?

Answer 26

Phase II: goal is to evaluate efficacy, determine optimal dosing. Involves 100-300 patients.
- measure reduction in symptoms severity
- measure dose response
- of course also safety

The important readouts include optimal dosing and efficacy measures (primary endpoint) such as better scores on psychological tests or amyloid beta reductions.

Question 27

Describe the strategies in early drug screening

Answer 27

• target driven: looking for a substance to match a target
• Disease driven: looking for a target which could be linked to a disease

Target must be indentified and validated before screening the target must be ‘druggable’

Question 28

Give examples on how novel molecules can be screened.

Answer 28

High throughput screening (HTS): automations and robotics
- Virtual screening
- fluoresence-based assays
- radioligandbinding assays

Question 29

What criteria would you think are important for selecting hits

Answer 29

A new drug should be better than the other ones already available.

Must have higher potency (less of the drug needed), efficacy (better outcomes), selectivity (less side-effects), longer half-life (less frequent intake), lower production costs (more availability), safer.