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week 12 part 2 Flashcards

1
Q

What are examples of several diseases that lead to dementia?

A
  1. Parkinson’s
  2. Frontotemporal dementia
  3. Alzheimer’s disease
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2
Q

How many people in the UK are coping with Dementia at the moment?

A

About 850,000 people

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3
Q

How many patient’s suffer from Alzheimers?

A

About 500,000 people

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4
Q

What carries the biggest burden?

A

Alzheimer’s

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5
Q

What is Dementia?

A

Ageing demographics

Numbers are going to increase

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6
Q

What is the cost to the economy?

A

About 24 billion a year

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7
Q

What are the rapidly developing countries?

A
  1. Mexico
  2. Indonesia
    Young population at the moment but going to age significantly
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8
Q

What is the consequence of getting older?

A

The cost of looking after people start to accelerate

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9
Q

Who first described Alzheimer’s disease?

A

Alois Alzheimer’s

1906

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10
Q

How long did it take for any kind of treatment to come about?

A

50-60 years

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11
Q

What was the first cholinesterase inhibitor?

A

Tacrine
Patented in 1986
Approved a decade later in 1993

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12
Q

What is the gold standard for Alzheimer’s disease?

A

Donepezil

Best of the cholinesterase inhibitors

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13
Q

What is Donepezil?

A
  1. Once a day drug
  2. With dementia people: it is easy to forget
  3. It is a systematic treatment
  4. Still the mainstay of treatment
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14
Q

What was another drug that came into the market for Alzheimer’s but was not useful?

A

Mematine

2002

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15
Q

What is the cost for drug development?

A
  1. $5.6 billion for AD treatment
  2. $2.8 billion for industry average
  3. $790 million for cancer treatment
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16
Q

What does phase III of the 2018 AD pipeline have?

A
  1. 26 agents
  2. 17 DMTs
  3. 1 cognitive enhancing agent
  4. 8 drugs for behavioural symptoms
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17
Q

What was found among DMTs?

A
  1. 14 addressed amyloid target
  2. one involved a tau-related target
  3. one involved neuroprotection
  4. one had metabolic MOA
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18
Q

What does DMTs include?

A

6 immunotherapies

All addressing amyloid

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19
Q

Of the drugs with amyloid agents?

A

There were 5 Beta-site amyloid precursor
protein cleavage enzyme inhibitors
six immunotherapies
Three antiaggregation agents

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20
Q

What does preclinical mean?

A
  1. Early drug discovery
  2. Work done in the lab/placement
  3. Trying to stain for a gene that is going up or down in the disease tissue
  4. it is at 1.65 billion
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21
Q

What is phase I studies?

A
  1. Safety studies
  2. Drug-interaction studies
  3. It is at 1.19 billion
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22
Q

What is phase II studies?

A
  1. Checking the safety and care in the patient

2. It is at 1.04 billion

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23
Q

What does phase III equal?

A

Amount of all the preclinical work

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24
Q

What is critical in drug discovery?

A
  1. Target validation

2. Choosing the target so it goes through all the preclinical failures into the clinical stage

25
Q

What does each colour associate each target with?

A

A hypothetical mechanism

26
Q

What are the blue tombstone?

A

All the phase III and phase II encircling those one or 2 (cholinesterase inhibitors and mematine) drugs that made it through clinic

27
Q

What seems to be failing in drug development for AD?

A

The breakthrough of proof of efficacy in the clinical trial

28
Q

What happened over the last 10-15 years?

A

Companies have been pulling out of neurological or CNS research
but particularly in the area of Dementia and Alzheimers

29
Q

What is a really vibrant charity funding sector?

A

Alzheimer’s Research UK Defeat Dementia

30
Q

What does Alzheimer’s Research UK fund?

A

More research into Alzheimer’s disease than any other charity

31
Q

Why was Defeat Dementia Campaign set up?

A

Try and invest 100 million over 5 year period

32
Q

Where did the Defeat Dementia Campaign leverage lots of funds from?

A

Various initiatives:

  1. Dementia consortium
  2. Drug Discovery Alliance
  3. Dementia Discovery Fund
  4. UK Demential Research Institute
33
Q

What is the role of Dementia discovery fund?

A

Help small new company to get going

34
Q

What is Alzheimer’s Research UK Drug Discovery Alliance?

A

Combine academic excellence with drug discovery expertise to discover new therapeutic approaches for dementia

35
Q

What is the mission for Drug Discovery institute?

A

Work with academic researchers to accelerate the translation of basic science into drug discovery

36
Q

What are target areas for ODDI?

A
  1. Proteostasis
  2. Neuroinflammation
  3. Synaptic health
37
Q

What is Proteostasis?

A
  1. Parkinson’s disease
  2. Lysosomal dysfunction
  3. Phenotypic screens DUB
38
Q

What is Neuroinflammation?

A
  1. Genetic Hits (TREM2, PLCG2, complement)

2. Microglial genes DUBS

39
Q

What is synaptic health?

A
  1. Tech Dev
  2. Wnt pathway
  3. Trophic support
  4. GEFs
40
Q

What are common problems with targets?

A
  1. They are not molecularly defined
  2. Not Druggable
  3. Too promiscious and essential
  4. We know nothing about them (dark proteome)
41
Q

What does alleles appear to track with?

42
Q

What is human genetics and target validation used for?

A

Genetic studies for 40-50,000 even 100,000 patients

Start to pick up risk variants that have small effects

43
Q

What has been changed in Alzheimer’s tissue?

A

Morphology of microglia

Changes earlier on in the animal model

44
Q

What is one of the earliest changes in cellular biology?

A

Changes in the inflammatory status

45
Q

What does Target Evaluation Grid look at?

A
  1. Tractability
  2. Developability
  3. Efficacy
46
Q

Tractability

A
  1. known protein structures/druggable pckets
  2. Viable in vitro assays and screening plan
  3. In vivo PD assays (ex vivo measures)
  4. Best point in pathway/mode of action to intervene
  5. Known expression in normal vs. disease tissue
47
Q

Developability

A
  1. No safety flags? KO? CNS vs periphery
  2. Chemical starting points; novel IP space
  3. First Time in Human endpoint
  4. Defined target population
  5. Defined regulatory runway to show approaching the target is safe
48
Q

Efficacy

A
  1. Confirmed GWAS risk gene
  2. Disease association changes
  3. Known blocks e.g. siRNA/agonism
  4. Lower order models
  5. proof-of-principle data (mouse etc.)
49
Q

What does target evaluator analyse?

A

Data that is available in the same way for all of the targets and spits out this vector plots/spider plots
you can see how you can compare with eac other more easily

50
Q

What is a recent risk factor from a G1 study for AD?

51
Q

What do you have to be wen you validate target?

A
  1. Very rational

2. Quantitative

52
Q

What is target tractability?

A
  1. Carry out assay
  2. Help chemistry identify new molecules against it
  3. Making proteins
  4. Assay development and validation
53
Q

What is NLRP3 inflammasome

A 
The NLRP3 inflammasome is
activated by many and
diverse stimuli.
• NLRP3 variants are
associated with both
increased and protective risk
for LOAD (Tan MS. et al., J.
Neuroimmunol., 2013).
• NLRP3-deficiency in the
APP/PS1 mouse decreased
neuroinflammation and
protected from spatial
memory loss
54
Q

Inflammasome phenotypic screen

A

Assay validated, simplified, in HTS
format, paradigm streamlined for
robotics
• Aim to screen 80K set (Janssen)

55
Q

Screening using bespoke compound libraries

A

• Libraries: MIDAS diversity set (10K), kinase PKIS, epigenetic, Ubiquigent.
• Hit annotation.
• Hits follow up – resynthesis, full dose response, IL1β release, other
cytokines, protection from pyroptosis, selectivity vs other inflammasomes,
microglial assays in human cells.

56
Q

What is competitive landscape?

A

1.CRID3 (MCC-950, CP-456773)
IC50 < 10 nM

  1. Nodthera (2 patents)
  2. IFM therapeutics (5 patents)
  3. Inflazome (2 patents)
57
Q

What is In Vivo PK?

A
  1. Bioavailability
  2. CNS penetration
  3. Dose-limited exposure
  4. Metabolite qualification
58
Q

What should compound exposure match?

A 
concentrations
required for effect in vitro
AND
be well below
exposures that cause
toxicity

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