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PHRM 847 > L9,10,11 - Drug Discovery > Flashcards

L9,10,11 - Drug Discovery Flashcards

1
Q

How can PGx research used to test correlation?

A

PGx research can test genotype-phenotype association

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2
Q

How can PGx research test causation?

A
  • PGx research can establish the cause-effect relationship between the genetic variation and phenotypic variation
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3
Q

What does a null hypothesis state?

A

No association between any allele and drug resistance

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4
Q

What size of value for X^2 support the null hypothesis?

Null: no association between any allele and drug resistance

A
  • A small value of X^2 supports this

observed N and expected N would be similar

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5
Q

What is the P value for no significant association ?

A

P > 0.1

no presumption against the null hypothesis

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6
Q

What is the P value range for marginal association ?

A

0.05 < P < 0.1

low presumption against null hypothesis

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7
Q

What is the P value for significant association ?

A

P < 0.05

strong presumption against null hypothesis

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8
Q

What is the P value for very significant association ?

A
  • P < 0.01
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9
Q

Does P value measure the strength of an association relationship?

A

No

  • P can be affected by sample size: the bigger the size, the lower the P value, even under the same frequency
  • P can be affected by allele frequency
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10
Q

How can you measure the strength of an association?

A

Odds ratio

  • increased risk for a phenotype by carrying a specific genotype/allele compared to the patients without carrying
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11
Q

How do you calculate odds ratio to measure strength?

A

OR = odds of phenotype in an individual with / odds of phenotype in an individual without

with / without

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12
Q

Calculate the odds ratio for developing drug resistance (persistence) in patients carrying T allele vs patients carrying the C allele:

A

OR = (539/198) / (701/578) = 2.24

  • Patients carrying the T allele will have 2.24 times more chance to develop drug resistance compared to the patients carrying the C allele
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13
Q

Explain how to interpret different odds ratio values:

A
  • OR = 1 –> no association
  • OR > 1 –> increases the risk
  • OR < 1 –> decreases the risk
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14
Q

What does the 95% CI indicate?

A

95% CI is a statistical probability for OR (the standard error of OR)

over 95% of probability that the association is confident

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15
Q

Explain how to interpret 95% Confidence Intervals:

A
  • If the 95% CI is greater than 1, there is a significant risk effect
  • If the 95% CI contains 1, there is no statistical significance
  • If the 95% CI is less than 1, there is a significant protective effect
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16
Q

What is the Bonferroni correction for P values?

A

corrected P = 0.05/N

N = total number of SNPs tested

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17
Q

What value do we use as a corrected GWAS P value?

A

5x10^-8

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18
Q

Do human clinical trials have negative control?

A

No, they often don’t have negative control due to ethical reasons
- they compare to standard of care

19
Q

What is dynamic range?

A

upper limit and lower limit of the data set

20
Q

To have reliable results what is required?

A

large sample size

21
Q

Why do clinical studies often use median ?

A
  • faster
  • patient data may not be normally distributed
22
Q

What kind of mutation did the patients with hypercholesterolemia have?

A

They carry a gain-of-function PCSK9 variants

23
Q

What kind of mutation did the patients with super low LDL have?

A
  • PCSK9 nonsense mutation
  • Y142X
  • C679X
24
Q

What are the impacts of inhibiting PCSK9?

A
  • Inhibiting PCSK9 increases available LDL receptors which allows for more LDL-C to bind –> thus decreasing LDL-C levels

PCSK9 inhibitor is monoclonal antibody

25
Explain the algorithm for managing LDL-C cholesterol:
1. Optimize statin therapy 2. If LDL-C is greater than 70 mg/dL, **add ezetimibe** 3. If LDL-C is still greater then 70, add other lipid-lowering therapy | LDL-C target is < 50 mg/dL for high ASCVD risk patients
26
What is ICER?
incremental cost-effectiveness ratio
27
How is ICER calculated? | incremental cost-effectiveness ratio
ICER = (Cost2 - Cost1) / (QALY2 - QALY1)
28
What is QALY?
quality-adjusted life-year
29
Explain this chart:
- 0 --> no effect on the qaulity - If you can increase by 2.5, that's very good - If it is list price (red line) even insurance won't pay - Crossing the top dotted line indicates it's a reasonable deal - crossing the bottom line indicates its a very good deal
30
What is discounted cash flow?
- method used to estimate the value of an investment based on its expected future cash flows - takes into account that **future money is always less than current money** | 10% discount rate is often assumed
31
What are key points to consider for drug value evaluation?
- does it offer a new advantage (better route, fewer side effects) - How does it fit in treatment plans? - What data should trials show for approval? - What data should trials show for commercial success? - How should it be priced so payers will buy it?
32
What problems are associated with non-cancer drug development?
- trials may be very long and require thousands of patients - safety profile needs to be excellent - alternative endpoint may not be accepted (CV: needs to lower mortality) - may only get approved for narrow populations - competes with many existing widely used drugs - biologics may be significantly more expensive than small molecules and payers may not want to pay
33
What are the drugs of the future beyond small molecules and antibodies?
- RNA interference - mRNA medicine - monoclonal antibody and antibody-drug conjugate (ADC) - gene therapy - CRISPR-mediated gene-editing and mutation repair - stem cell (iPSCs) therapy
34
Explain RNA interference (antisense oligonucleotides (ASO)) drugs:
- blocking the mRNA directly to reduce the protein being made from that particular mRNA - halts the process of creating a disease-causing protein - Onpattro (patisiran) - an RNAi drug for people with hereditary transthyretin-mediated amyloidosis (rare and deadly)
35
Explain mRNA medicine:
- introduce exogenous mRNA into the body so cells can make proteins based on the introduced mRNA - COVID-19 vaccine
36
Explain monoclonal antibodies and antibody-drug conjugates (ADCs):
- A type of Y shape protein that specifically binds to its target (target protein) to block the function of that target protein OR help to recognize a specific group of cells (cancer cells) that express the target protein - PD1 and PD-L1 drugs are common mabs
37
Explain gene therapy drugs:
- virus as a vehicle to deliver gene - FDA-approved adeno-associated virus (AAV) drug **Luxturna** to treat a rare form of inherited vision loss
38
Explain CRISPR-mediated gene-editing and mutation-repair: | just give an example
- a trial of an experimental CRISPR-Cas9 therapy for the blood disorder B-thalassemia has been launched
39
Explain stem cell (iPSCs) therapy:
- most are still being developed - has the potential to generate many cell types in the body to replaced damaged tissue
40
What are the 4 steps in mRNA medicine?
1. scientists generated an mRNA sequence that codes for the virus spike protein 2. the RNA sequence, a blueprint for making the spike, is swathed in a lipid coating for delivery 3. Once it arrives, cells read the information in the mRNA sequence to produce millions of copies of the spike protein 4. the protein fragments spur the immune system to produce antibodies that can protect when a real virus enters the body ------- - making the exogenous mRNA stable is key - finding the right coating to deliver them into the cell is critical
41
Explain the process of gene therapy with adeno-associated virus (AAV):
1. Transgene is packaged into AAV vectors 2. Through a one-time IV infusion, AAVs carrying the transgene target the **liver** 3. In the liver, AAV vectors deliver transgene to the nucleus of liver cells to enable production of therapeutic protein
42
What kind of drug is zolgensma?
- Gene therapy with AAV - biologic drug consisting of AAV9 capsids that contain a SMN1 transgene along with synthetic promoters - indication: tx of peds pts <2 yrs with spinal muscular atrophy (SMA) with bi-allelic mutations in the SMN1 gene | this drug increases SMN1 to increase survival of motor neurons
43
How does the CRISPR/Cas9 DNA editing technique work?
1. A cell is transfected with an enzyme complex containing: guide molecule, healthy DNA copy, and DNA-cutting enzyme 2. A specially designed synthetic guide molecule finds the target DNA strand 3. An enzyme cuts off the target DNA strand 4. the defective DNA strand is replaced with healthy copy
44
What does CRISPR stand for?
Clustered Regularly Interspaced Short Palindromic Repeats

PHRM 847 (8 decks)

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