Drug Design: Basic Research, Clinical Trials Flashcards
1
Q
How come death from heart disease is going down in Canada?
A
This death rate is shrinking, because we know the risk factors and we have developed drugs to treat these risk factors
2
Q
What types of clinical trials are we most initiating?
A
25% for cancer
11% for the CNS diseases, (Alzheimer’s and Parkinson’s)
Not easy to come up with a new drug, very few succeed to go to clinical trials
(2016)
3
Q
What types of drugs are people spending money on in Canada?
A
People with chronic disease, inflammatory conditions 12.7% for chronic arthritis
11.7% for diabetes
(arthritis, diabetes)
4
Q
What are 3 main goals for the future?
A
- Personalized therapy (everyone’s different, how much a drug works and the side effects are different, want to know which drug is best for which person)
- Biological Drugs: antibodies, cytokines, cells (things that are developed by biological systems not chemical synthesis)
- New treatments for cancer (understand more the genetic alterations in different types of tumors, what are the specific mutations in each persons specific tumor)
5
Q
Drug discovery, how are drugs found?
A
- From the Lab to the Patient
- Research at the core, on pathology, understanding what’s wrong in the specific disease
- Research in the pharmacology departments in big compagnies
- The pharmaceutical companies spend the most -1/4 on research
- Its harder and harder to find a new drug, need to check new technologies, side effects
- Cost is higher and higher
6
Q
What do newer drugs focus on?
A
Neurology, Oncology and infectious disease
7
Q
What types of drugs are being approved more now?
A
The types of drugs approved are changing, proteins, antibodies, nucleotides
8
Q
Biological drugs: from living organisms/cells (insulin)?
A
Monoclonal antibodies, developed in mice, designed to target a specific component, they are increasing in use
By finding the genetic variability in the cancer we can develop antibodies for it
Inflammatory disease also uses monoclonal antibodies, arthritis
9
Q
What does it take to develop a novel drug?
A
- 2 billion or more for each drug
- 150 researchers
- 14 years, 10 years to get the patents
- Lucky to get one out at the end of all this cost
10
Q
It is hard to get a drug to market?
A
More and more challenging for new drugs, a lot of drugs going into clinical trials for Alzheimer’s have not succeeded
Hepatitis C drugs, many side effect, but one drug worked, and people can be treated and not get liver cancer, only need one of the hundreds to work
11
Q
Why do so many drugs entering clinical trials for Alzheimer’s fail?
A
Alzheimer’s, we don’t know what makes it abnormal, we know what is not normal, but don’t know why
Many drugs got to clinical trials but they were pretty much unsuccessful
So many drugs in the pipeline for Alzheimer’s right now, so much work into this, need to understand more about the pathogenesis
12
Q
New Drugs for Alzheimer’s?
A
An antibody against the amyloid plaques, supposed to stop the plaques from forming
Aducanumab treatment: reduced progression of disease
Approved in the US, not in Canada
Very expensive, small benefit if any based on the drugs already on market
None provide more than a brief, mild benefit
Inhibit acetylcholinesterase (more acetylcholine improve brain activity, doesn’t work for too long)
Inhibit NMDA receptor
Amyloid antibody
But… new drugs this year look more promising
13
Q
Chronic diseases we need to cure or prevent? (3)
A
- Parkinson’s
- Alzheimer’s
- Arthritis
All these require basic research
14
Q
Common killers we need to prevent/cure? (2)
A
- Cancer
- Cardiovascular – MI and stroke
All these require basic research
15
Q
Global concerns? (2)
A
- Emerging infections (covid)
- Pollution
All these require basic research
16
Q
Basic research in the government?
A
Basic research done in universities, funded by CIHR in Canada and the NH in the US
Some of the translational research done in universities too
17
Q
Basic research and industries?
A
Industry does some basic research but focus more on the translational research (take basic and make something workable out of it) and clinical research
18
Q
What are some ways to study the pathogenesis? (3)
A
Look at how cells work
Gene knockout
Develop specific antibodies
19
Q
What are the current drug targets?
A
- Enzymes
- Receptors
- Unknown
- Physicochemical
- Monoclonal AB
- Ion Channels
- Transport proteins
- DNA/RNA, ribosome
Mainly enzymes and receptors, major targets
20
Q
What is the target for AIDS?
A
Enzyme for AIDS is the target,
Most on the surface of the cell but some in the cell, estrogen receptor
21
Q
Reasons for drug failure?
A
multiple control pathways interact
Human cells are complex, many interactions, need to unravel all the components which takes a lot of time and effort
22
Q
Genomics and developing drugs?
A
Understanding the genome
What’s in it
Slowly getting to know the genetic abnormalities in specific diseases
Develop gene therapy to replace defective one in the cell
23
Q
Cystic Fibrosis research?
A
Know the genetic abnormalities on it
Deliver a specific gene in the airways of an infected person
Make very thick mucus get an obstruction
Still being studied
Trials not successful
24
Q
November 16th, 2023
Britain approves the world’s first gene therapy?
A
CRISPR-based treatment for sickle-cell disease and thalassemia
First successful gene therapy
Clinical trials all completed, works
Sickle cell disease, not normally shaped RBC, don’t transport O2 well, can vary in intensity
Thalassemia much worse, monthly transfusions, serious problems
Gene therapy, able to replace the malfunctioning gene with the CRISPR gene, (know exactly what gene is malfunctioning)
25
Patient profile?
By finding the differences between people we can find the disease mechanism
Understand the pathogenesis also
26
Measuring the gene expression?
- Response to stimuli: environmental changes (like drugs or disease) often cause changes in expression
- Disease markers and drug targets: changes in expression associated with disease can be diagnostic markers and/or suggest novel pharmaceutical approaches
27
Microarray technology?
Understand changes in DNA
Can label DNA and read it
28
Want to develop drugs to find a target ligand?
Develop different drugs to interact with the active site of the enzyme, need to develop many drugs to find one that binds with a high affinity and specificity
29
Combinatory chemistry?
Preclinical testing some compounds are good
Go back to library and find the similarities with the good ones
Find a lead compound then, make more of the lead to find the best
Combine the various parts of the molecule all at one, get a mixture of products and can test what parts work better
Make many compounds, pick a few that are very good
30
Robotics: High throughput screening?
Need a way to test all the compounds efficiently
Chemical synthesis, robot testing everything
Mass screening
Invitro studies – random high-volume screening and combinatorial chemistry (go through thousands of compounds)
31
High throughput screening looks at what, how many?
Robotics and bioinformatics: 20,000 compounds/day
Look for agonists or antagonists of the target
32
What are the test systems for high throughput screening?
Test system: mammalian cells, microbes, human hepatocytes, microsomes, synthetic membranes
(the things used to test the compounds in the system are varied)
33
Two general types of high throughput screens?
Cell-free: ligand receptor interactions
Cell-based: multiple targets (living cells, what drugs interact)
34
How to detect through quantification?
Fluorescence, luminescence, enzymatic, radioactive, immunological labels
35
What 4 basic elements does HTS require?
- Suitable compound libraries
- Assay method configured for automation (can’t test one at a time, need thousands to be tested)
- Robotics workstation
- Computerized system capable of handling the data
36
Conducting a reporter gene assay?
To detect target gene expression, luciferase linked to a specific gene, went it binds the gene it gives off luminescence
37
Subcellular fractions, in testing systems?
Look at target proteins, look for drugs that bind it, a mixture with different drugs, isolate the protein see what bound to it, run through mass spectroscopy, and get the structure of the drug
38
Can use living systems as test systems?
classic one is zebra fish
Can label the vasculature of the zebrafish and also label the young vasculature of the young zebrafish, angiogenesis, the formation of new blood vessels
Can label anything and see if it’s altered by a drug
Can initiate cancer in zebrafish and then test for something that will prevent the progression or improve the tumor
You would screen the zebrafish before you use the drug in rat/mouse or humans
Use juvenile, to be stuck in the wells and test what will have an impact in tumor growth
39
What can HTS NOT evaluate?
- Bioavailability (need to do this in a live animal)
- Pharmacokinetics
- Toxicity
- Mutagenicity (it could cause cancer)
- Specificity (what are the side effects)
40
Look at yeast living system?
Label the DNA repair gene with Jellyfish fluorescent protein
Expose yeast to mutagens that might cause cancer if DNA repair gene activated it will fluoresce
41
What is chemotaxis and metastasis?
Cancer cells spread, motile, into circulation = metastasis
Chemotaxis, cells pull other cells into the area
Can test if they will cause movement
42
Can create better candidates continuously?
Test and test, optimizer, test again to get a clinical trial drug
By modifying a lot might find a better more specific drug
43
What does the new drug Ibrutinib do?
blocks enzyme overexpressed in B cell malignancies: approved in 2014
Treats chronic lymphocytic Leukemia, can live normal life with few side effects, targets specific enzyme that is overexpresses
44
New drug for heart disease, block the enzyme that lowers LDL receptors?
More LDL receptors, less cholesterol build up
PCSK9: blocks cholesterol removal by the liver, so inhibit it more cholesterol broken down
Statins stop cholesterol formation also helps
45
What is biosimulation?
Biosimulation: computer-aided mathematical simulation of biological processes and systems
- Increasingly used to predict drug effects (positive and negatives)
46
What is hybridoma technology?
Method of producing large amounts of identical antibodies or monoclonal antibodies
47
What are different types of antibodies?
- Chimeric antibodies (mouse variable region + human constant regions)
- Primatized antibodies (chimeric with primate-derived variable regions)
- Humanized antibodies (all human except antigen recognition site)
- Transgenic mouse antibodies: fully humanized antibody
48
What is a monoclonal antibody?
Clones of just one antibody, bind only one antigen
49
Monoclonal antibody successes in 3 areas?
Autoimmune disorders
Cancer
Osteoporosis
50
Monoclonal antibody successes in autoimmune disorders?
Autoimmune disorders
- Crohn’s disease, Rheumatoid arthritis
51
Monoclonal antibody successes in cancer?
Cancer
- B cell malignancies, breast cancer
Monoclonal antibodies targeting a HER2 protein overexpressing cell, gets rid of tumor cells
52
Monoclonal antibody successes in osteoporosis?
Osteoporosis
- Antibody agonist osteoclasts, prevent osteoclasts, prevent bone breakdown
53
What does adalimumab do?
Tumor Necrosis Factor inhibition for autoimmune disease
54
Preclinical Evaluation?
Use all the techniques, needs to go through an animal before being tested in humans
Test for toxicity and side effects
55
What is the classical animal used in animal testing?
Classical animal used is rats
Transgenic knockout mice
Other animals used but 92% is rodents
56
What can be learnt in a rat model?
Detailed mechanism of action in rats
Can learn the pharmacokinetics in a rat model
57
What is the AMES test?
a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
58
Steps to developing a drug?
Find a target:
- A naturally occurring molecule to be enhanced or inhibited
Find a lead:
- A “drug like” molecule that interacts specifically with the target
Optimize:
- Find a compound in the same family as the lead that is specific and effective enough to be a drug
ADMET:
- Absorption, Distribution, Metabolism, Excretion, and Toxicity
59
What type of vaccines are the 4 approved in North America?
4 new vaccines (2 mRNA and 2 viral vector)
60
Clinical trials in humans are essential to answer the 3 fundamental questions regarding a drug?
1. Is it safe
2. Is it effective
3. How does it compare to other drugs
61
What is preclinical research used to test?
Preclinical research in test systems and other species can eliminate some ineffective or toxic compounds,
62
What can only human studies test?
Variability,
but only by testing in humans can the variability between species, and the variability within humans, be understood.
63
How long do clinical trials take, what can effect the time?
Clinical trials take years, depending on the mechanism of action and the disorder being studied, and they are most expensive stage of the drug development process
64
The drug development process in Canada? (4)
- Preclinical research
- 3 stages of clinical trials
- Review by Health Canada
- Post marketing phase (phase 4)
Drugs are more highly monitored before they can be sold but they are constantly monitored after they are put on the market for rare side effects
65
Why does a drug have to be tested on humans before being put on the market?
Lab rats have the same pharmacodynamics and pharmacokinetics, but humans have a diverse pharmacokinetics and pharmacodynamics from one person to the next. Therefor it is necessary to analyze these variations in human clinical trials
66
Clinical trials is the stage?
Clinical trials are the most expensive stage of drug development and the stage where most drugs fail.
67
What do Health Canada and the FDA do?
- Monitor clinical trials and post marketing
- They can recall products on the market if they deam them not safe
- Recalled monster drinks, skin lightening cream
68
Phase 1 clinical trials test for what?
Safety, dose, pharmacokinetics
69
Phase 1 clinical trials, who is monitored?
Dozens of healthy volunteers (paid, go in to be monitored)
20-80 people
70
How are Phase 1 clinical trials caried out?
- Give a low dose, monitor then increase the dose to find the appropriate dose, and safety
71
Phase 2 clinical trials test for what?
Effectiveness and side effects vs placebo, pharmacokinetic variants
72
Phase 2 clinical trials, who is monitored?
- Hundreds of patient volunteers (100-300)
- Continuously monitored
73
How are phase 2 clinical trials carried out?
- Compared to a placebo (or current drug taken) group to see if the drug has less side effects
- The drug needs to improve to drugs already on the market to be approved
- Document side effects (some go away quickly others stay around longer)
- Expand pharmacokinetic studies (genetic polymorphisms, determine toxicity)
(not always compared to a placebo)
74
Phase 3 clinical trials test for what?
Verify effectiveness and side effects with longer use vs placebo
75
Phase 3 clinical trials who is monitored?
- Thousands of patients (1,000-3,000)
76
How are phase 3 clinical trials carried out?
- Can use parallel or a variety of crossover designs.
- Control for lifestyle, compliance, and monitor effect when treatment is stopped.
- Monitor adverse reactions for long term use
- Double blind/randomized studies
77
How long can clinical trials take?
Can take 6-7 years, and only 1 in 5 drugs will succeed
78
What is the main reason for failure in clinical trials?
Lack of efficacy is the main reason for failure, due to the pathogenesis being unclear
79
What is a crossover design?
Crossover design (one group taking placebo, the other taking the drug and at one point they switch)
80
What is the data compared to?
To interpret the data, the beneficial and side effects are compared to the placebo and nocebo responses.
81
What can effect the level of placebo effect?
A mild to strong placebo response can occur in about 1/3 of participants
Psychosocial effects when taking the drug can influence the placebo effect (level of pain relief doubled when the doctor cam to check on the patient)
82
What is New Drug Approval?
NDA review Health Canada (New Drug Application review)
If the trial is successful, a file will be submitted to the relevant government agencies, requesting new drug approval
83
What approaches are used to review the safety data in a NDA? (4)
- Characterize exposure database
- Identify drug-related adverse events
- Estimate risk (or rate) of those adverse events
- Identify risk factors for those adverse events
(this process can be long too)
84
What is done after the NDA is accepted?
The drug must be given a trade name
The manufacturing facilities will prepare for mass production
85
What factors influence manufacturing?
- Want a drug to be administered orally (preferably)
- Need sterile conditions
- Each pill needs to have the exact same amount of active ingredient
86
Behavioral conditioning?
Associate the pill with pain relief
When taking the pill with no active ingredient in it there will still be some pain relief
87
Diabetes prevention trial (4000 patients) Patient compliance on results?
- Placebo
- Drug B potential therapeutic
- Drug A current therapy
- Intensive lifestyle modifications (some people are not willing/able to changer their lifestyle)
- Patient compliance has a huge effect on the outcome
- Taking the drug at the right time and all the time reduces the risk a lot
After monitoring for 5 years there is a big difference between the people taking the drug and the placebo group
88
Both drugs A and B got rid of the Ulcer, but more ulcers came back using drug A. This is showing what?
The importance of post monitoring
89
The importance of post monitoring, ovarian cancer example?
Ovarian cancer drug: tumor went away but almost always came back, some of the cancer cells were resistant and the patient died
90
What are pharmacogenomics?
The application of genomic concepts and technologies to the study of drug activity and metabolism, including gene expression, or inactivation, and Single Nucleotide Polymorphism association studies
91
What is toxicogenomic?
Initial emphasis may be to avoid adverse reactions rather than screen for responders
What are the problems we face, can we fix them before they happen
Screen drugs for every P450 enzyme it could induce/block, minimize some problems
92
What is Reclast?
A drug used in a 3 year study for osteoporosis, approved in 2007, 1 dose injection per year. Can prevent people at risk of osteoporosis and fractures from getting them
93
What are the major problems concerning drugs failing during clinical trials?
Pathogenesis is still unclear
The cost to develop new drugs gets more and more expensive, the easy drugs are already discovered
94
What does Phase 4 (post-marketing monitor for?
Drug on the market, new side effects, safety, efficacy
95
Warnings added to drugs already on the market?
Continual surveillance to detect rare reactions, further optimize use.
Drugs with low bioavailability due to extensive metabolism by CYP3A4 may need warnings to avoid grapefruit. Rare but serious side effects may require a special warning.
96
Rare side effects detected in phase 4?
Uncommon adverse drug interactions occur in 1:1,000 cases, need to study 3,000 cases to find the one rare case, or even test 100,000 people before finding anything (aspirin side effect in children)
97
Who monitors drugs during Phase 4 post marketing?
Drugs are monitored by doctors and pharmacists
98
What are black box warnings for?
Can cause serious side effects if taken with other drugs, drug not taken off the market though
99
Phase 4 clinical trials can give a better picture of what?
The dose response curve
100
When is the dose altered?
In pediatric pharmacology and in older people, their ability to metabolize drugs is decreased
Will not be given to pregnant women for fear of teratogenic effects
101
What are 3 Special situations regarding clinical trials?
- Shorter duration for potentially fatal disease
- Fast track for urgent need
- Financial assistance for orphan drugs
102
What are orphan drugs?
Orphan drugs:
- For situations where not many people have the problem
- Government subsidies
- Companies lose profit, but good for humankind
103
What are the most frequent drug target diseases?
cancer, neurology, infections
104
What are the targets for current trials?
monoclonal antibodies, hormones, cytokines, cells
105
What is a checkpoint protein?
checkpoint proteins of cancer cells block T-cell attack
106
What do checkpoint inhibitors do?
Inhibitors of CTLA-4 on the T-cell and PD-1 on the T-cell or its ligand on the cancer cell can free the T-cell to attack the tumor.
107
What does the checkpoint inhibitor Pembrolizumab do?
o Pembrolizumab targets PD1-1 and has been a breakthrough in therapy for some forms of lung cancer and a variety of malignancies.
108
What does the checkpoint inhibitor Ipilimumab do?
o Combination of ipilimumab (blocks CTLA-4) and PD-1 blocker (Pembrolizumab) has revolutionized therapy for melanoma
109
What is Herceptin used to do?
Herceptin: monoclonal antibody that blocks excessive growth factor (HER2) receptors on breast cancer cells
110
How are radioisotopes and chemotherapeutic drugs delivered directly to a tumor?
Using antibodies, minimizing systemic toxicity
111
What can radioactive antibodies be used to do?
To label tumor cells
To detect metastasis
To deliver effective therapy in prostate Cancer(radioactive compound attached to the antibody, to target and destroy cancer cells) actinium-225 lutetium177 (target tumor cells, target prostate-specific membrane antigen)
112
Monoclonal antibodies against CGRPs (calcitonin Gene-Related Peptide)?
Have greatly decreased the frequency of migraine headaches in a significant fraction of patients
113
What are 3 ways to block CGRPs?
- Receptor blocking Monoclonal antibody
- CGRP-grabbing monoclonal antibody
- Receptor blocking drug
4 antibodies developed all worked to prevent migraines better than placebo
114
What does ibrutinib block to treat lymphocytic leukemia?
It blocks an enzyme (BTK) that is necessary for the survival of malignant B cells,
More effective than chemotherapy, less side effects oral administration
115
What are PCSK9 inhibitors?
They are monoclonal antibodies that block the enzyme that binds the LDL receptor in the liver and targets it for destruction.
More LDL receptors means more removal of LDL from circulation.
this can slow the development of myocardial infarcts, atherosclerosis, and stroke
116
What is Sofobuvir/Sovaldi?
A drug that blocks a key enzyme needed for RNA replication. It can cure Hepatitis C which is a major cause of liver failure
117
What is the target of vaccines against Covid-19?
Target is the spike protein that binds to the ACE2 receptor to gain entry into cells
118
mRNA vaccines?
They provide the mRNA to code for the spike protein, antibodies will be made for the spike protein
119
Adenoviral vector vaccines?
Deliver a gene for the spike protein, so the body can make antibodies against it
120
Tumor cell vaccine?
1. Patient draws blood
2. In the lab, tumor antigen is linked to a cytokine
3. Complex binds to dendritic cell precursor
4. Complex is taken in by the dendritic cell precursor
5. Dendritic cell matures and is infused back into patient
6. Dendritic cell displays tumor antigen and activates T cells
7. T cells attack cancer cells
121
New vaccine for RSV (Respiratory Syncytial Virus) in 2023
(Beyfortus) nirsevimab
RSV Occurs in children under 2 years old, Thousands of children hospitalized from this almost ¼ of all hospitalizations result in a transfer to intensive care
122
What are proteomics?
Individual therapy
123
The future will involve?
- Many improvements in methods of drug administration,
- Genetic analysis to predict responders and outliers for specific drugs
- Intracellular drug targets
- Improved ability to cross the blood brain barrier, etc. (target the CNS)
- Avoid injection, (deliver through mouth, patch, lungs)
