L9 BioCurate Flashcards
Drug Discovery and Development - Stages
See onenote
- Idea
- Novel MoA (Mechanism of Action)
- Target
- Lead Discovery
- Preclinical
- IND (Investigational New Drug)
- Clinical Trials (1,2,3)
- Registration
Basic Research (Pre-Discovery) - Steps 1-3
see onenote
Contribute to understanding of disease and identify potential drug targets
Drug Discovery and Development
see onenote
- lead discovery
- preclinical
- IND
- clinical trials
IND
Investigational New Drug application
- submit all preclinical results and detailed clinical trial plans for FDA approval
Lead Discovery
Create novel molecule (or select existing start point) then optimise to maximise efficacy and achieve clear IP position
Ideally generate lead and back-up drug candidates
Preclinical
Analyse new drug for efficacy and safety using lab and animal models
Clinical trials
Safety and efficacy in 3 phases, usually beginning in healthy volunteers, then moving into larger groups of patients
Who does the different stages of Drug Discovery and Development?
See onenote
Basic research - government, academia, research institutions and companies
drug discovery and development
- biotech companies, research division of pharmaceutical companies, government-industry collaborations
- pharmaceutical companies (Big Pharma Venture Capital)
Venoclax Example
See onenote
Idea - 1988
Approved - 2017
Took 29 years from idea to FDA approval
Financing Drug Discovery and Development
see onenote
estimated cost >$1 billion
Principal investors in drug development differ at each stage:
- basic discovery research: government, uni, philanthropic organisations
- late-stage development: pharmaceutical companies, VCs
between these two: must prove efficacy and safety of a proposed new drug
- funding gap occurs = “valley of death”, translation gap
Why do we call it the Valley of Death?
see onenote slides
- drug discovery and associated IP protection are not well supported by public-sector funding of medical research in Australia
- many target-hypotheses fail to achieve proof-of-concept (PoC) in animal models (or patients)
- drug discovery activities often prevent or delay publication
BUT big pharma of VC groups will not fill the gap
- success rate for converting basic science into useful therapies is low, creating deterrent to investment
Projects effectively hold no commercial value until drug candidate demonstrates PoC in an animal model
- only then can VCs value a program
Existing government bridges
see onenote
- biomedical translation fund
- entrepreneur’s program
- global innovation linkages program
- therapeutic innovation Australia
ETC…
National Health and Medical Research Council (NH&MRC) funding, 2018
See onenote slides
More than 80% of all applications are not funded
Australian Research Council
see onenote
- more than 80% ARC applications failed, those that were successful only received 65-68% of the requested funds
Go to the market BUT…
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- public offering
- becomes publicly traded company
BUT…
- biotech companies have a low success rate
BioCurate - The Opportunity
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- Australia’s top two biomedical uni, UoM and Monash both located in Melbourne
High research output…but limited patent output…minimal VC funding …limited pharma R+D spending
BioCurate - Facts
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- founded and owned by UoM and Monash, supported by Victorian Govt
- 10 years guaranteed initial funding (A$80M)
- designed to bring industry know-how, experience, and management expertise to the academic sector
- independent, self sustaining
- building a pipeline of project opportunities with validated reproducible biological results
BioCurate’s Operating Model
See onenote diagram
Uni => BioCurate => Out-license to Pharma or spin-out then out-license to pharma
BioCurate - Going National
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A$22.3m Biomedical Translation Bridge (BTB) grant under Medical Research Future Fund (MRFF)
- fund and nurture early stage health and medical research ventures
MTPConnect umbrella
- BioCurate
- UniQuest
- Medical Devices Partnering Program (MDPP)
BioCurate - the first 12 months
- independent offices and systems established
- board and management in place
- project review process established: 80, 23, 12
80 = review new project opportunities
23 = short list
15 = approved projects
12 = active projects
BioCurate - Project Review Process
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Different to traditional government funding, biocurate has ongoing Industry and Scientific Advisory Group reviews to ensure milestones are met
Assessing Projects
- what is the product?
- market feasibility?
- how is it differentiated from existing treatments?
- IP - no potential for new IP or IP too old
- is there a defined clinical pathway
- is there a clear regulatory pathway
- what gaps exist in the data?
Curation and Catalysis
- manage risk/reward risk taking
- benefits of scale to cut cost and time
- technology aggregation to enhance competitive reach
- focus on unmet need, rigorous science, commercial potential and customer needs
- connect “islands of expertise”
- advance critical knowledge at the organisational level
- protect IP
Early Phase Drug Discovery
see onenote slides
Major objective of early drug discovery development is to select promising compounds and to identify potentially safe and effective doses and dosing regiments
a. basic science research and target identification
b. target pharmacology and biomarker development
c. lead identification
The drug development funnel
see onenote diagram
For every 10,000 compounds, only 1 will make it to an FDA approved drug
Requirements for early phase drug discovery
- biomarkers
- PK/PD relationship (dose concentration/concentration-effect)
- Exposure
- Dose-reponse
- Cmax vs AUC (maximum conc. vs conc. over time)
Biomarkers
see onenote slides
A measurable and quantifiable biological parameter that serves an an indicator of a particular physiological state
- in medical context, detection of a biomarker indicates particular disease state or response to therapeutic intervention
Biomarkers in Health care
- blood pressure
- blood glucose
Research
- tumour markers in cancer research
- interleukins in inflammation research
Biomarkers in drug development
see onenote slides
- conventional approach
- measures performance of novel therapies using clinical outcomes such as mortality or disease progression - biomarker-driven approach
- can sometimes predict drug efficacy more quickly than conventional clinical endpoints
- potential to accelerate product development in certain disease areas
- monitor safety of a therapy
- determine if a treatment is having the desired effect on the body
- predict patients who might respond better to a drug from a safety or efficacy perspective
- potentially enable time and cost savings in clinical trials
Biomarkers used in many stages of drug development
Improving Drug Development
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Biomarkers can:
- monitor safety of a therapy
- determine if a treatment is having the desired effect on the body
- predict patients who might respond better to a drug from a safety or efficacy perspective
- potentially enable time and cost savings in clinical trials
PK/PD
see onenote
PK - pharmacokinetics = pharmalogical analysis of therapeutics administered to a living organism
- fate of a drug from time of delivery to the body until the time of complete elimination from the body
- the study of how an organism affects a drug
PD - pharmacodynamics = study of the biochemical and physiological effects of a pharmaceutical drug
- PD places particular emphasis on dose-response relationship (relationship between drug conc. and effect)
- study of how a drug affects an organism
Integration of PK/PD studies in early development helps with compound selection and guides creation of an efficient clinical development strategy
Effective PK/PD design, analysis and interpretation help to:
see onenote
- understand drug’s MoA
- elucidate relationship between dose and effect
- improve translation of findings from preclinical to clinical
Drug exposure and dose-response
Must be able to relate in vitro IC50 to in vivo effects
- measure exposure to determine if sufficient levels of drug achieved in vivo:
- in blood
- in organs/tissue
Also need PD assay to prove target engagement and effect
Essential for interpretation of both efficacy and toxicity
XC50 (IC50 or EC50)
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IC50 = conc. of an inhibitor where the response if reduced by 50%
EC50 = conc. of a drug that gives half-maximal response (E - effective)
Cmax vs AUC
see onenote
Must understand:
- if response is driven by max conc. achieved (Cmax - highest conc. of drug in blood) or for the duration of “target-coverage” (AUC - area under the curve, overall drug exposure)
- if there is a clear dose-response relationship
Critical to understanding desired drug characteristics
Cmax
Cmax - highest serum conc. seen for a drug after a single dose
For an oral drug Cmax is dependent on the rate of drug absorption and its disposition profile e.g. different formulations of the same drug could lead to different Cmax
Short term side effects most likely at or near Cmax
AUC
Area under the curve
- represents total drug exposure over time
- useful in monitoring drugs with a narrow therapeutic index (i.e. levels of drug required for therapeutic effect are not very much higher than levels at which side effects may occur)
- used to determine whether alternative methods of drug delivery at an equivalent dose (e.g. injection vs tablet) release the same dose of drug to the body
- bioavailability = fraction of drug absorbed systematically and therefore available to produce a biological effect. This is often measured by quantifying AUC.
Statistical significance
see onenote
Wrong interpretations
- around half mistakenly assume non-significance means no effect
Critical issues for drug development
- rigorous, reproducible data
- IP strategy
- “differentiation”
- international competition
- back-up program
- data required to proceed into the clinic
