De-risking preclinical assets with early human insights recent advances in human tissue and disease models

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1 De-risking preclinical assets with early human insights recent advances in human tissue and disease models Christopher Boyer, Executive Director, Bio-Link South Parade, Blackburn VIC 3130 Australia

2 Bio-Link o Professional business development and corporate advisory services o Focused on facilitating commercial partnerships in the biopharma, diagnostics, nutraceuticals and medical devices industries o Privately owned, Sydney and Melbourne offices, multi-disciplinary team of 10 employees o Australian and international clients include biotech and medical device companies and medical research institutions

3 Commercialisation services Consulting and Technology Analysis Strategic reviews, competitive landscapes, IP, development plans Proactive Business Development Focused on identifying, engaging with, and closing deals with strategic partners on optimum terms Scouting Targeted scouting and triage of partnering and in-licensing opportunities Project Management Coordination of commercially focused R&D, collaborations Sourcing of Funding Facilitating access to funding: grants (e.g., EP, NHMRC, NIH, SBIR, MJFF, NIH TRND), high net worth investors, venture capital

4 Biotech: one of the best returns... Type of investment Average return/year Risk Property 8% Medium Shares 8% Medium Bonds 6% Low Savings 2.8% Very low Biotech Equity 25% High and one of the highest risks Source: Canstar Investment, AUS, 2018, Forbes:The Biotech Venture Capital Math Problem

5 3 main business models in biotech Aussie Biotech - Seller- Sell for $ Pharma - Buyer- 2 nd type: Medium-sized Pharma Buy cheap, opportunistic 6-20 assets Early mid. stage Clinical stage Sells to Big Pharma e.g. Morphosys, Mallinckrodt, Pierre Fabre, Molnlycke 1 st type: Small biotech Early stage 1-3 assets Little cash Tries to sell ASAP Sell for $$$ 3 rd type: Big Pharma Major buyers Lots of cash Many assets Late stage assets Bring to market

6 Looking for best return on investment Aussie Biotech - Seller- Where you want to sell Earliest Pharma buys Pharma - Buyer- Lead Optimisation In vivo PD ADME/ TOX IND-enabling Phase 1 Phase 2-3 NDA approval/ Market RISK VALUE

7 Aussie Biotech - Seller- Typical chat with Pharma Hey Pharma, we have great in vivo data, massive indication, wanna license? Pharma - Buyer- Interesting, cool approach, right up our alley and we re totally prepared to jump in early. What about tox? Doesn t seem to hurt the mice. ADME / Tox package? Come on, mate we can t afford that Hmmn, pity just a bit too risky

8 Unto the valley of death?

9 New options emerging Aussie Biotech - Seller- In vivo data Small animal model Scenario 1: ADME/TOX Large animal model Cost: $1M Time: 9-12 months Pharma - Buyer- Phase I Human data Scenario 2: TOX/Efficacy Artificial human model Pharma - Buyer- Cost: $30K 100K Time: 1-3 months

10 Let s try that again Aussie Biotech - Seller- Hmmn, pity just a bit too risky OK, let s take baby steps. Pharma - Buyer- What do you have in mind? Simulated human tox studies Humanised 3D models I m listening Option & eval. $40K, 2 months. You pay Could work, can we see proposal? Now we re talking

11 Traditional preclinical disease models fail to accurately inform the potential efficacy [and toxicity] of compounds transitioning into Phase I, especially those with novel mechanisms of action - PAREXEL

12 How to de-risk preclinical investment Show that a drug candidate will likely translate to humans before testing it in humans o Safety/toxicity o Efficacy o Termination of deficient projects/compounds (?)

13 Humanised 3D cultures - The paradigm shift Technologies o Spheroids o Organoids o Organs on a chip o Bio-hybrid systems o Disease modeling Benefits o Robust and reproducible o Detailed target validation o Early translation to human physiology o Strong IRB support to replace, reduce & refine (3Rs) o Rapid and cost-effective o Scalability - Low to High throughput

14 Example: Humanised 3D model of Alzheimer s Disease Validation in AD animal model 1mm Model of CNS Model of Alzheimer s (AD) Drug screening Papadimitriou et. al; Developmental Cell 2018

15 Human ipsc derived NSPCs: DAPI / GFAP / B3 Tubulin

16 Example: Humanised 3D model of Alzheimer s Disease Validation in AD animal model 1mm Model of CNS Model of Alzheimer s (AD) Drug screening Papadimitriou et. al; Developmental Cell 2018

17 Companies investing in early human insights 3D cell culture market to reach USD $4.7 bn in 2022 (Allied Research) Big Pharmas Novartis J&J Merck Roche Sanofi GSK Takeda CROs offering 3D humanised assays Charles River Evotec StemoniX Ocello Organovo Creative BioLabs InSphero

18 CROs servicing the market Company Service offerings Clients and deals Evotec Charles River Laboratories Organovo High-content screening Target validation & identification Target discovery Hit ID 3D tissues for screening therapeutics 3D bioprinter Celgene: $45M upfront; Sanofi: 3M upfront; 300M milestones Bayer: 14M upfront; 300M milestones Academics Biotech/pharma Government/foundations NIH: US$1.7M L'Oréal Yale

19 Alternative approaches for early human insights Toxicity and efficacy screening in o Human heart tissue o Human DRG tissue o Provides insights in aged cells In vivo drug screening in o Hollow fiber model o Multiple human xenografts o Mouse PK/PD Toxicity and efficacy screening in o Bioprinted human tissues o Measures liver metabolism/toxicity o Measures excretion from kidneys

20 What if.? In vivo data Small animal model Scenario 1: ADME/TOX Large animal model * Scenario 2: TOX/Efficacy Artificial human model Phase I Human data * 66% failure rate Animals poor predictors of human physiology - Chocolate is toxic to dogs - Paracetamol is toxic to cats - Mice don t develop Alzheimer s

21 Christopher Boyer, Executive Director South Parade, Blackburn VIC 3130 Australia