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DDD x > week 12 part 2 > Flashcards

week 12 part 2 Flashcards

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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?

Study These Flashcards
A
  1. Target validation

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

25
What does each colour associate each target with?
A hypothetical mechanism
26
What are the blue tombstone?
All the phase III and phase II encircling those one or 2 (cholinesterase inhibitors and mematine) drugs that made it through clinic
27
What seems to be failing in drug development for AD?
The breakthrough of proof of efficacy in the clinical trial
28
What happened over the last 10-15 years?
Companies have been pulling out of neurological or CNS research but particularly in the area of Dementia and Alzheimers
29
What is a really vibrant charity funding sector?
Alzheimer's Research UK Defeat Dementia
30
What does Alzheimer's Research UK fund?
More research into Alzheimer's disease than any other charity
31
Why was Defeat Dementia Campaign set up?
Try and invest 100 million over 5 year period
32
Where did the Defeat Dementia Campaign leverage lots of funds from?
Various initiatives: 1. Dementia consortium 2. Drug Discovery Alliance 3. Dementia Discovery Fund 4. UK Demential Research Institute
33
What is the role of Dementia discovery fund?
Help small new company to get going
34
What is Alzheimer's Research UK Drug Discovery Alliance?
Combine academic excellence with drug discovery expertise to discover new therapeutic approaches for dementia
35
What is the mission for Drug Discovery institute?
Work with academic researchers to accelerate the translation of basic science into drug discovery
36
What are target areas for ODDI?
1. Proteostasis 2. Neuroinflammation 3. Synaptic health
37
What is Proteostasis?
1. Parkinson's disease 2. Lysosomal dysfunction 3. Phenotypic screens DUB
38
What is Neuroinflammation?
1. Genetic Hits (TREM2, PLCG2, complement) | 2. Microglial genes DUBS
39
What is synaptic health?
1. Tech Dev 2. Wnt pathway 3. Trophic support 4. GEFs
40
What are common problems with targets?
1. They are not molecularly defined 2. Not Druggable 3. Too promiscious and essential 4. We know nothing about them (dark proteome)
41
What does alleles appear to track with?
Disease
42
What is human genetics and target validation used for?
Genetic studies for 40-50,000 even 100,000 patients | Start to pick up risk variants that have small effects
43
What has been changed in Alzheimer's tissue?
Morphology of microglia | Changes earlier on in the animal model
44
What is one of the earliest changes in cellular biology?
Changes in the inflammatory status
45
What does Target Evaluation Grid look at?
1. Tractability 2. Developability 3. Efficacy
46
Tractability
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
Developability
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
Efficacy
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
What does target evaluator analyse?
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
What is a recent risk factor from a G1 study for AD?
1. GAL3ST4
51
What do you have to be wen you validate target?
1. Very rational | 2. Quantitative
52
What is target tractability?
1. Carry out assay 2. Help chemistry identify new molecules against it 3. Making proteins 4. Assay development and validation
53
What is NLRP3 inflammasome
``` 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
Inflammasome phenotypic screen
Assay validated, simplified, in HTS format, paradigm streamlined for robotics • Aim to screen 80K set (Janssen)
55
Screening using bespoke compound libraries
• 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
What is competitive landscape?
1.CRID3 (MCC-950, CP-456773) IC50 < 10 nM 2. Nodthera (2 patents) 3. IFM therapeutics (5 patents) 4. Inflazome (2 patents)
57
What is In Vivo PK?
1. Bioavailability 2. CNS penetration 3. Dose-limited exposure 4. Metabolite qualification
58
What should compound exposure match?
``` concentrations required for effect in vitro AND be well below exposures that cause toxicity ```

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