PCL102 term test 1 (online)

how long is the process to get a drug to the market?

15-20 years

how much is spent per approved drug?

more than one billion dollars

- this includes money spent on mistakes

unmet medical need

a condition whose treatment or diagnosis is not addressed adequately by available therapy

- what we have on the shelves isn't good enough

examples of unmet medical needs?

- mental illness

- cancer

- alzheimer's

- genetic diseases

- combatting drug resistance

number of drugs being tested vs approved drugs

there are thousands of drugs being tested and experimented with, but it is nowhere near the number of drugs approved

new molecular entity (NME)

small molecule chemical drug

biologics license application (BLA)

for biologic drugs like proteins and cell therapies

most common type of drug being approved in 2020

oncology

how long is patent protection?

20 years following filing

generic drugs

- drugs sold by their generic name; not brand name or trade name product

- same chemical, off-patent

- gone through 20 year cycle and everyone else can use the recipe to make it

is a new drug always superior?

overall, only 1 in 10 new drugs offer a SIGNIFICANT therapeutic advantage

what should companies be thinking of when making a new drug? (4)

- medical need (is condition life threatening?)

- availability of current therapy (are patients satisfied with current drug? less frequent dosing? type of dosing?)

- competitor activity (will new therapy be able to compete with current ones? increased selectivity or novel approach?)

- commercial opportunity (getting public exposure)

what is the best dosage for a drug?

to take once a day

attrition of drug development

start with many drug candidates but as go through pipeline, less drugs are being tested

drug pipeline overview

- discovery/preclinical testing

- file IND

- clinical testing (Phase I, II, III)

- file NDA

- FDA approval

- Phase IV

how long does discovery/preclinical testing take?

6.5 years

discovery phase

- choose a disease (aim drug against protein)

- identify drug target (drug binds to disease and inactivates it)

- assay development

- identify lead compound (potential drug candidate)

- modification of the lead compound (optimization)

- identify drug candidate

FDA requirement of discovery phase

- safety in at least two animal species before it gets to humans (exaggerate dosing and chronic exposure 6 months-1 year)

- one rodent, and one non-rodent species

IND (Investigational New Drug)

permission to test drug in humans

how long to get IND looked over by FDA?

about a month

IND components

- composition and source of drug

- manufacturing info

- data from animal studies

- clinical plans and protocols

- names and credentials of physicians conducting trials

clinical trials (Phase I) (how long, how many ppl, purpose)

- 1 month

- 10-20 HEALTHY volunteers

- purpose: safety, tolerance, to see how body processes it and what side effects are (pharmacookinetics), bioavailability in body, pharmacological profile

design of phase 1 clinical trials

dose-escalation

- max dose -> when ppl have too many headaches

measuring in phase 1 clinical trials and where are they done

- hematology (blood characterization)

- biochemical tests of liver and kidney function

- carried out by contract research organizations or major hospitals

clinical trials (phase II) (how long, how many ppl, purpose)

- 3-12 months

- 50-75 patients with disease

- purpose: efficacy -> does drug work? is there improvement on the disease?

design of phase II clinical trials

treatment and control groups

- control groups normally have placebo

other goal of phase II clinical trials

establishing optimal dosage for use in phase 3 trials

clinical trials (Phase III) (how long, how many ppl, purpose)

- 6-12 months

- 100 to 300 patients with disease

- purpose: figure out if there are enough benefits of drug, compare efficacy of new treatment with standard, more statistical significance

design of phase III clinical trials

randomized control

- placebo or established treatment for control group

informed consent

process of understanding what the patient is agreeing to

what does FDA look for approval?

- safety

- evidence of efficacy

- drug has purpose for intended patients

how long does NDA approval take?

6-12 months

how is canada approval different from US

- canada uses TPD instead of FDA

- canada uses NDS instead of NDA

Phase IV clinical trials (how long, people, purpose)

- 3-12 months

- 100-300 people

- purpose: to know for sure that it was a good decision to put drug out (pharmacovigilance)

- no fixed duration

- long term surveillance

pharmacovigilance

monitoring drug safety under actual conditions of use in large numbers of patients

where do reports for phase 4 clinical trials come from?

physicians and pharmacists

phase 4 clinical trials observations

they can pick up on problems with drugs because more ppl are using it now, and pick up on rare adverse reactions

drug approvals over time

drug approvals are declining over time

success rates for clinical trial phases

- phase I -> 70% success rate

- phase II -> 33% success rate

- phase III -> 25-30% success rate

- phase IV -> 70-90% success rate

incidence of cancer statistic (how common)

1/3

death from cancer statistic

1/4

what is cancer

- disease of uncontrolled growth

- includes spreading of malignant tumors into normal tissues and other parts of body

- normal growth control mechanisms are dysregulated

metastatic cancer

- occurs outside of original site

- cancer has traveled to different part of body

dysregulation

- signals to tell cell to grow are always on

- cells don't have stop signal to stop growing

how are cancers organized

- tissue/organ of origin

- mechanism of growth dysregulation (pathway)

how many diseases are in the cancer group?

over 100 diseases

how to treat group with over 100 diseases?

- can't use a single drug

- try to design drugs to re-gain control of dysregulated mechanisms

how do control mechanism get dysregulated?

mutations in disease

- can lead to dysfunction in proteins

growth of cancer

- starts in single cell

- cell keeps growing and dividing

- gets in blood and travels to new location and continues growing and dividing

benign tumor

- not cancer

- cells grow locally and don't spread

malignant tumor

- cancer

- cells invade neighboring tissue and travels in bloodstream

direct of heritability statistic

1/20

- so pretty low

how is most cancer formed

genetic change in own lifetime

hallmarks of cancer (6)

- signal is always on to grow and divide

- signal to stop is broken

- cancer moves to different part of body

- immortal, doesn't die easily

- angiogenesis

- resisting cell death

angiogenesis

formation of new blood vessels that are called by tumors

proto-oncogene

healthy gene in body that tells cell to grow when they need to

- turns to oncogene in cancer

oncogene

gene that tells cell to keep growing out of control

- cell growth/division is accelerated

external signals and oncogenes

- in normal cell growth, cells only grow in response to external signals

- in cancer, cell don't listen to external signals and grow with or without them

types of oncogenes that could be affected (4)

enzyme, vesicle transport, carrier protein, assembly

tumor supressor genes

- mutation in tumor supressor gene means it never turns off cell division

- they normally stop cell overgrowthmo

breast cancer susceptibility genes

- most are tumor supressor genes

- BCRA1 and BCRA2

BCRA gene test

blood test that see if there are mutations in BCRA1 or BCRA2

inherited mutations

mutations present in egg or sperm that form child

acquired mutations

- acquired in life some time later

- starts in one cell and then is passed on by division

- not passed onto next generation

- most cancers caused by acquired mutations

chemotherapy

- race to kill cancer cells

- cytotoxic (cell-killing) and interfere with DNA replication

- not cancer specific, for most cancers

side effects of chemotherapy

kill any quickly dividing cells, so it can kill rapidly dividing normal cells (hair cells, bone marrow, etc)

- bc cytotoxic

challenges of discovering drugs to treat cancer (3)

1. targeted therapy

2. changes in cancer genome and remission

3. druggable proteins

4. cancer and the immune system

targeted therapy

target proteins that are only in cancer cells, or that are far more abundant in cancer cells than normal cells

what is involved in targeted therapy

- biopsy to detect disease prior to symptoms

- matching correct drug to correct protein in unique tumor

biopsy (what and goal)

- it is a sample of genome

- goal is identify sequence changes in DNA in the tumor vs patient's normal cells

- use microscopes, proteomic profile and genomic profile

Challenge 2: changes in cancer genome

bc cancer changes rapidly because the cells are dividing a lot (evolves over time)

- can possibly resist drugs

Challenge 3: druggable protein

- does target protein have pocket on surface that can strongly bind to drug molecule

- if it has that pocket, then protein is druggable

- only minority of human proteins are druggable

Challenge 4: leveraging body's immune system to treat cancer

sometimes immune system can get rid of cancer, but other times cancer can escape immune system

where are target identification and target validation in the pipeline?

drug discovery

drug target

molecule involved in the disease that the drug should target to stop the disease

aspirin and COX

aspirin is drug that targets COX to stop pain

- COX is protein that makes you feel pain

- COX is drug target

Taxol (what is it and target protein)

- anticancer drug

- target protein is tubulin

pancreatic lipase

target protein for weight loss drug

carazolol

drug that targets the beta adrenergic receptor and blocks it

saquinavir

drug that helps treat/prevent HIV

- inhibits HIV protease

SARS-CoV2

- main protease of COVID

- spike protein on it binds to ACE II receptor

why can't we target polysaccharides, lipids, or nucleic acids

- toxicity

- low specificity

- hard to find potent compounds

pharmacology

science and study of drugs

pharmacokinetics

what the body does to the drug

pharmacodynamics

what the drug does to the body

receptor

- molecule that drug binds to produce effect

- involved in cellular communication

- mostly cell surface proteins (or in cell)

ligand

bind to receptors

signal transduction

1. extracellular signaling molecule activates cell surface receptor

2. receptor signals to intracellular molecules and cell responds

effector proteins

second messenger inside cell

agonist

binds and triggers receptors normal effect or enhanced

antagonist

blocks receptors

enzymes

- have substrate that binds

- induced fit

types of enzymes to target

pathogen enzymes, bacteria enzymes, virus enzymes, human enzymes

penicillin

targets bacteria enzymes

HIV drugs (protease, reverse transcriptase)

target virus enzymes

viagra

targets human enzyme, phosphodiesterase (inhibits it)

how do we identify a drug target?

- data mining

- genome wide association studies

- profiling mRNA/protein

- familial studies for inherited diseases

why use genomes to identify targets?

genomes have a lower complexity than proteins

how much of our genetic code is the same?

- 99.6%

- 0.4% is what makes us unique and can make us have different diseases

genomics

study of structure of genome, how genes interact and genomic variation among individuals

- mapping genes, sequencing DNA