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Biotechnology in Practice > L9 BioCurate > Flashcards

L9 BioCurate Flashcards

1
Q

Drug Discovery and Development - Stages

A

See onenote

  1. Idea
  2. Novel MoA (Mechanism of Action)
  3. Target
  4. Lead Discovery
  5. Preclinical
  6. IND (Investigational New Drug)
  7. Clinical Trials (1,2,3)
  8. Registration
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2
Q

Basic Research (Pre-Discovery) - Steps 1-3

A

see onenote

Contribute to understanding of disease and identify potential drug targets

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3
Q

Drug Discovery and Development

A

see onenote

  1. lead discovery
  2. preclinical
  3. IND
  4. clinical trials
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4
Q

IND

A

Investigational New Drug application

- submit all preclinical results and detailed clinical trial plans for FDA approval

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5
Q

Lead Discovery

A

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

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6
Q

Preclinical

A

Analyse new drug for efficacy and safety using lab and animal models

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7
Q

Clinical trials

A

Safety and efficacy in 3 phases, usually beginning in healthy volunteers, then moving into larger groups of patients

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8
Q

Who does the different stages of Drug Discovery and Development?

A

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)
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9
Q

Venoclax Example

A

See onenote

Idea - 1988
Approved - 2017

Took 29 years from idea to FDA approval

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10
Q

Financing Drug Discovery and Development

A

see onenote

estimated cost >$1 billion

Principal investors in drug development differ at each stage:

  1. basic discovery research: government, uni, philanthropic organisations
  2. 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

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11
Q

Why do we call it the Valley of Death?

A

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

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12
Q

Existing government bridges

A

see onenote

  1. biomedical translation fund
  2. entrepreneur’s program
  3. global innovation linkages program
  4. therapeutic innovation Australia
    ETC…
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13
Q

National Health and Medical Research Council (NH&MRC) funding, 2018

A

See onenote slides

More than 80% of all applications are not funded

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14
Q

Australian Research Council

A

see onenote

  • more than 80% ARC applications failed, those that were successful only received 65-68% of the requested funds
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15
Q

Go to the market BUT…

A

see onenote slides

  • public offering
  • becomes publicly traded company

BUT…
- biotech companies have a low success rate

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16
Q

BioCurate - The Opportunity

A

see onenote slides

  • 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

17
Q

BioCurate - Facts

A

see onenote

  • 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
18
Q

BioCurate’s Operating Model

A

See onenote diagram

Uni => BioCurate => Out-license to Pharma or spin-out then out-license to pharma

19
Q

BioCurate - Going National

A

see onenote

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)
20
Q

BioCurate - the first 12 months

A
  • 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
21
Q

BioCurate - Project Review Process

A

see onenote diagram

Different to traditional government funding, biocurate has ongoing Industry and Scientific Advisory Group reviews to ensure milestones are met

22
Q

Assessing Projects

A
  1. what is the product?
  2. market feasibility?
  3. how is it differentiated from existing treatments?
  4. IP - no potential for new IP or IP too old
  5. is there a defined clinical pathway
  6. is there a clear regulatory pathway
  7. what gaps exist in the data?
23
Q

Curation and Catalysis

A
  1. manage risk/reward risk taking
  2. benefits of scale to cut cost and time
  3. technology aggregation to enhance competitive reach
  4. focus on unmet need, rigorous science, commercial potential and customer needs
  5. connect “islands of expertise”
  6. advance critical knowledge at the organisational level
  7. protect IP
24
Q

Early Phase Drug Discovery

A

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

25
Q

The drug development funnel

A

see onenote diagram

For every 10,000 compounds, only 1 will make it to an FDA approved drug

26
Q

Requirements for early phase drug discovery

A
  1. biomarkers
  2. PK/PD relationship (dose concentration/concentration-effect)
  3. Exposure
  4. Dose-reponse
  5. Cmax vs AUC (maximum conc. vs conc. over time)
27
Q

Biomarkers

A

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
28
Q

Biomarkers in drug development

A

see onenote slides

  1. conventional approach
    - measures performance of novel therapies using clinical outcomes such as mortality or disease progression
  2. 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

29
Q

Improving Drug Development

A

see onenote

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
30
Q

PK/PD

A

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

31
Q

Effective PK/PD design, analysis and interpretation help to:

A

see onenote

  • understand drug’s MoA
  • elucidate relationship between dose and effect
  • improve translation of findings from preclinical to clinical
32
Q

Drug exposure and dose-response

A

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

33
Q

XC50 (IC50 or EC50)

A

see onenote slides

IC50 = conc. of an inhibitor where the response if reduced by 50%

EC50 = conc. of a drug that gives half-maximal response (E - effective)

34
Q

Cmax vs AUC

A

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

35
Q

Cmax

A

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

36
Q

AUC

A

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.
37
Q

Statistical significance

A

see onenote

Wrong interpretations
- around half mistakenly assume non-significance means no effect

38
Q

Critical issues for drug development

A
  • rigorous, reproducible data
  • IP strategy
  • “differentiation”
  • international competition
  • back-up program
  • data required to proceed into the clinic

Biotechnology in Practice (25 decks)

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