Lecture 18 - cancer drug discovery Flashcards
what is the average cost of bringing a drug to the market?
1.3 billion dollars
how is target discovery initiated if a pathway is known?
This is the first step where a potential drug target is chosen, usually a protein, based on what is known about its involvement in the pathogenesis of certain diseases.
Usually, a protein or gene associated with a disease, is identified. For e.g., HER2 is over expressed in subtypes of breast cancer; FLT3 is mutated and overactive in acute myeloid leukaemia – so these could be a targets for new treatments.
how does discovery and screening work of targets?
potential drug are screened to asses if there are any candidates that can interact with the identified target through high throughout screening HTS or high contact screening HCT.
examples could be libraries of small molecules, MABs and antibody drug conjugates
Antibodies can also be designed specifically to target a particular protein
computational models and computational chemistry are employed to predict how a potential drug will interact with its target and optimise its structure for maximum effectiveness.
describe preclinical testing
once a promising drug candidate has been identified, it undergoes preclinical testing.
this involves ;laboratory studies: including target or drug chemistry, drug formulation, in vitro cell assay to see f the drug has the desired effect
animal models; assess ADME, toxicity as well as drug efficacy
what is the clinical development stage?
once drug proved to be sae and effective in preclinical studies, moves to clinical trial stage, where testing drug s in humans starting with small trials into larger studies that assess both safety and effectiveness.
drugs often fail because cell lines a lab and mice are not very representative of how a drug will behave in a person with a tumour.
what is phase 3 trial?
The time between the discovery/scientific research on a drug and marketing authorisation is known as the Valley of Death.
phase 3 trials are crucial for registering a drug. this involves coamprign drugs to the placebo - usually for disease which have no treatment. or to standards of care or active competitors - want eh drug to be superior for best treatment
if the drug has positive results, then submit application to FDA or EMA for marketing authorisation
what is attrition in drug development ?
attrition rate is high failure rates associated with drug development.
most drugs fail in clinical trials debut o lack of efficacy and safety. safety issues become more apparent in phase 3 trials
what is the marketing authorisation stage?
when drug under gone clinical trials to show it is safe and effective, the Pharma company can submit marketing authorisation application to the appropriate authorities.
drug cannot be sold unless it has been authorised by the national regulatory authority or centralised process for the specific country it is sold it eg;
- US food and drug administration - NDA
- EMA
- MHRA
what are patents?
Patents grant Pharma companies’ exclusive rights to prevent others from making, using, selling, or importing a product or process. This protects the Pharma company and allows them a monopoly in the market for their new drug
However, patents only last a set period of time (usually ~20 years) – but it can take 10+ years to go through drug development. So, Pharma companies have limited time to make back the R&D costs.
Once a drug comes off patent, other Pharma companies can make generic versions of the drug at a much lower price.
what is drug repositioning ?
repositions drug is when a drug that is already approved for one condition can run trials in different conditions with similar mechanisms of pathogenesis. for example, HER2 is expressed in various tumour cells and use trastuzumab as treatment, trastuzumab can also be sued in HER2 + cancers.
how was thalidomide repositioned.
thalidomide prescribed for morn gin sickness but thalidomide is teratogenic.
repurposed for treatment of systemic lupus erythematous, leprosy and multiple myeloma. being investigated as antiagngiogenic in tumours
how is sildenafil repurposed?
sildenafil can inhibit PDE5 for treating angina, PDE5.
PDE5 is involved in breaking down cGMP (a smooth muscle relaxer). By preventing cGMP breakdown through inhibiting PDE5, this would allow blood vessels to dilate. Dilation of the coronary arteries would treat angina
In phase 3 trials it did not have the desired cardiovascular effects. But it had one unexpected side effect… unusually strong and persistent erections
what is a cat haring agreement?
Cost sharing agreements can help make drugs more affordable/accessible to patients. These are legal agreements where a Pharma company may offset some of the drug costs if the healthcare providers agree to collect additional data for them i.e., phase 4 post-registration safety and efficacy information. (Some clinical trials may only run for a number of years, but some drug related toxicities may take longer to develop so phase 4 data is very valuable – helps detect adverse events and saves the Pharma company from potential liabilities
Why are drugs so expensive?
dug companies may have 10-20 potential drug in their pipeline costing costs of money. of these drugs various will fail at stages.
So for the few drugs that make it through- these need to be of high cost
To allow the Pharma company to cover all the costs of drugs that have failed
so what for very few drugs make it to the clinic?
cancer druga are very expensive:
Drugs are used in combination as many cancers incurable- thus the new drug doesn’t replace the old drug on the market just used as well as in some cancers- less revenue/drugs
The seriousness of cancer often means a willingness to pay the market price even for a modest improvement- very politically emotive!
With personalised medicines this will become even more expensive as smaller groups of patients will be the “ market” for new drugs
