Rx.3 Cybele Huntington„s: Disease in
a Dish Working Toward a Cure December 10, 2013 Total interviews: 91 Contact: jharness@gmail.com Team: - Julie Harness - Geeta Chauhan - Hildegard Mack - Nick Mordwinkin - Jamieson Sheffield Mentor: Antoun Nabhan

Team Cybele Julie Harness, PhD
Postdoctoral Fellow, UCSF Department of Neurosurgery Stem cell biologist with background in translational research and Huntington’s Disease Hildegard Mack, PhD Postdoctoral Fellow, UCSF Department of Biochemistry Biochemist and cell biologist with background in basic research on aging and age-associated diseases Geeta Chauhan Director Innovation, Alcatel-Lucent CTO New product development, Bell Labs Research Translation, cloud computing, data analytics, multiple startups Nick Mordwinkin, PharmD, PhD Postdoctoral Fellow, Stanford Stem cell biologist with background in next gen seq, drug screening, cell therapy & cardiovascular disease modeling

The Problem: no cure for
Huntington‘s Disease Huntington‘s Disease (HD) at a glance    Deadly dominant genetic neurodegenerative disease affecting all age groups 1 in 10,000 Americans plus their families affected Aberrant gene makes mutant protein, killing Medium Spiny Neurons (MSN) One limitation on HD research/drug discovery   Lack of representative animal models and cell models Impossible to take patient samples since affected cells are inaccessible and residing in the brain Our solution: Create affected cell type in a dish     Idea: reprogram somatic cells into iPSCs and differentiate into MSNs Starting material easily accessible Reprogramming methods established Efficient method to derive MSNs developed by us differentiate Human iPSC MSN

Here is what we
thought….

Cybele’s MSN can add value
in a multitude of ways Tool for Basic Research and Drug Discovery Discovery Preclinical Clinical Development Translational “valley of death” Ph 1 high basic Target Hit throughput research screen Ph 2 Ph 3 high Lead functional First In Proof of NDA Candidate IND content assays Human Concept Investigational New Drug screen New Drug Application Direct Therapeutic Preclinical Phase 1 Phase 2 Phase 3 FDA App & Approval

Original Canvas Ideas

Here is what we did….

Questions to customers Approach: Q:
Cells for in vitro use or direct therapeutic intervention or both? A: Therapeutic is too expensive to finance directly given the small patient population (not attractive to investors). As an in vitro tool, it might be. Product: Q: Is it in vitro cultured cells/platform or data we generate from platform? A: Platform. Academic researchers want to control their own experiment and pharma wants to control compound libraries, experimental details and data. * But they do outsource toxicity regularly. Customer: Q: Academic basic researchers or big pharma? A: Both, but we will focus on them at different stages of development. We also add tox screening companies and CRO‟s as important players. Partnership ecosystem, licensing

Original Canvas Ideas

Cybele Biologics Research Partners: -Lisa
Ellerby at Buck -Bill Horn at USDA ARS -Cyprotex -other researchers/ startups we could generate data and publish with (e.g. Zephyrus) Informal Partners: -FDA – make them aware of cells for preclinical applica ons Strategic Alliances: -CHDI & other distributors such as ATCC, Coriell, CDI Supplier Rela onships: -Lifetech (if we do their reagents) -Whoever we get iPS cells from, maybe Coriell Produc on of the differen ated popula ons Batch release valida on Contac ng CROs, tox companies, pharma etc 1 Enable in vitro research in an indica on with unmet medical need (Hun ngton’s Disease) Fundraising 2 Reduce drug discovery costs by enabling acquisi on of meaningful data earlier in drug discovery pipeline; fail drugs earlier IP for MSN differen a on, freedom to operate 3 Reduce tox screening costs – get meaningful toxicity info early CROs, startup infrastructure, biotech & pharma in bay area -Overhead – space at QB3 or other incubator, regulatory body approvals, costs of filing patent -Cost of raw materials – undifferen ated cells from vendor and CRISPR modifica on -Differen a on of popula ons – hood rental, space at QB3, technician -Batch release costs – verifica on, regulatory body approvals Get: Conference presence Venture arms of pharma Seminars in academia Risk-free trial product Google AdWords Keep: Cust serv/trouble shoot Loyalty program Grow: Custom services Assay Depot/Sci Exchange CRO’s without exper se to differen ate in-house (e.g. System Biosciences) Academics & NPOs working on HD Pharma/biotech companies (e.g. Lifetech) Tox screening companies (e.g. Cyprotex) Distribu on by trusted brand, like Lonza, Lifetech or CDI Nonprofit research orgs like CHDI – recommend product to collaborators Direct sales of cellular popula ons Direct sales of custom differen a on jobs to CROs IPR Licensing (e.g. to CDI)

Here is what we
found….

Universe of Partners Tools &
Platforms Pharma & Biotech Cybele NPOs

Two products to entice licensing/partnering
with cell supply companies and ADMET or pharma  Cryopreserved cell populations for direct sale  Verstile for many downstream applications  New niche product in existing market * ADMET – Absorption Distribution Metabolism Excretion Toxicity  Functional assay: Multi Electrode Array (MEA)  New product in existing market with infrastructure  Ability to determine functional response to compounds over long period of time  Ability to determine relative toxicity of compounds in MSN

We identified several companies interested
in each of our product/service options as partners, customers and/or channels Competitors ATCC Provide reagents Joint development Joint development Velocity System Add to own products Cells for sale as research tool (off-theshelf and custom) Cybele Pfitzer Functional assays based on our cells Co-development / Acquire co-ownership p technology Cyprotex Color code: Channel partner Customer Partner Competitors? Competitors? Drug candidate developed using our cells CDI GSK

Where to focus? Revenue Models
Considered • Drug discovery company: Potentially worth $ billions, but requires >$50M in high-risk investment + significant capabilities added to existing MSN tech • Cells: Relatively easy to advance to market, small revenue stream • Screening services: Longer sales cycle than cells, but can be offered with modest investment on top of that necessary to validate cell products Product offering # of customers Revenue per customer Investment Required and Exit $2000 – 5000 per customer per year ~$100k (Viable) Purified cell products • • • >200 Mostly academic Some pharma research labs in HD Screening projects • • 20-30 Pharma research labs w/ HD interest $100k (pilot projects) to $1M (large-scale screens) ~$250k (Viable) Drug discovery w/ outlicensing of drug candidates • • 10-15 Pharma companies with licensing / acquisition interest in HD Potential for >$1B exit event $50-500M (High-risk)

The market for Cybele as
a tools company (I) General considerations     Niche products in existing markets Our cell product is a „consumable“ Most similar product : neuronal Progenitor. COG = $7, sales price = $1,200 Our cells: COG = $1,500, sales price = $2,200 Top-down analysis     Based on S1 of a similar company, CDI Market for „cells for in vitro drug discovery, toxicity testing and chemical safety” Assumes that HD share of purchases reflects HD share of NIH budget Target market would be entire SAM What about a bottom-up estimate? Target Market = SAM: $8.5 million TAM: $3.5 billion

The market for Cybele as
a tools company (II) Bottom-up analysis  Customer segments considered • Academic reserch labs in the US: ~ 250 • CROs specializing in neuronal cell toxicity: 1 validated   Products offered: Off-the-shelf cells, custom-derived cells, screening service with partner CRO Demand will be highly variable across customers What we can get, based on interviews Type of service What we would need for $1 Million/year Profit per each Sales per year total $500 220 $110,000 Custom cells $10,000 10 $100,000 Screening service $15,000 2 $30,000 Off-the-shelf cells Total Type of service Off-the-shelf cells Profit per each Sales per year $500 2,000 OR Custom cells $240,000 $10,000 100 OR Screening service $15,000 66

Timeline for Cybele as a
tools company 2014 Q1 Q2 2015 Q3 Q4 Q1 Q2 net (revenue-costs), free samples 2016 Q3 Q4 Q1 Q2 net (revenue-costs), trial size sales Q3 Cash Burn (in $1,000) 80 60 40 20 0 -20 Partnerships Products offered Development Milestones -40 -60 Initi alize Beta product Launch Product refinement and assay development product development and upscaling production New product lines Further refinement and upscaling Custom services Cell sales Free samples or sale of trial size Research labs CRO with expertice in ADMET analysis Development of new products Q4

The market for Cybele as
a drug discovery company General considerations      Use own cells for Drug discovery for HD, Risk mitigated due to use of hPSC Result in refine cell products, new product lines HD in NA + EY > 60,000 Onset age: 30-50 yr, 10% < 20yr, 10% > 55yr OrphanDrug status, Tax breaks, FDA fee waiver, funding... Top-down analysis      Drug Development cost ~ $100 Million Price range $50k/patient/year $250k/patient/year Target 50% market penetration Low End Target Market = $1.5B High End Target Market= $7.5B TAM: $3 Billion SAM $2.4 Billion Target Market = $1.5B

Drug Discovery Business Model •
• • • • • Skill Sets/ Capabilities: Medicinal Chemistry, HTS, PKPD, Pharmacology Use Partners and CROs Exit by Phase 2a Burn Rate ~ $1-1.5 Million / month Phase 1 ~ 50 patients, Phase 2 ~ 100 patients, Phase 3 100-400 patients Role Model Company: Evotec Biological Insight Timeline Cost Key Partners Lead Optimization 12-18 months 18 months $10-40 Mil NCATS Assay, NCATS TRND Screen, Chemistry groups Preclinical Phase1-2a 1 yr 2-3 yrs $5 Mil $15 Mil NCATS BrIDGS Phase 3 to Launch $40 Mil Velocity Pharmaceuticals, CROs, Big Pharma

Cybele on the Investment Readiness
Scale IRL1 present new data to top five customers review development plan data points final definition of pre-clinical and clinical path “proof of relevance” criteria/data/stages/quality timeline to preclinical data and clinical data points rough cost to each data point value of program at each data point non-dilutive money sources engaged strengths/weakness compared to competition probability and go/no go criteria at each stage discussions with all pharma/large biotech identify strategic need/fit at company level present independent data specific pre-clinical and clinical path/data needed internal experts engaged KOL discussions Multiple pre-clinical and clinical paths identified Independent data confirming base technology works define clinical problem the technology solves define early data customers consider gating define best partners (like CROs) for outsourcing quick check on IP external experts identified best outsourcing for this project additional immediate data opportunities IRL2 IRL3 IRL4 IRL5 X X X X X X X X X X X X X X X X X

Here is what we will
do next….

Next Steps 1 Complete patent
application. 2 Continue “bottom-up” market size analysis for cell product 1 Get back to the lab and create the data our interview partners would like to see 2 Focus on licensing partners!

Immediate Next Steps: How much
will they cost? Cell population Total Cost ~ $10,000 Disease in a dish Running Total Cost ~ $40,000 Functional Assay Running Total Cost ~ $100,000 • Acquire new undifferentated iPS line • CRISPR modify lines to contain varying repeats + control • Repeat differentiation and QC in incubator lab Interested Parties: Academic labs • Provide batch to Buck Institute for independent validation/collaboration on their phenotypic paper • Refine protocol final stages for screening compatibility • Quantify pathology in CRISPR-modified iPS differentiated cells • Metabolism, cell adhesion, electrophysiology, survival Interested Parties: • Run HTS at Stanford HTBC – show cells are viable for HTS • Generate MEA array platform for high content ephys screening Interested Parties: Contact: jharness@gmail.com

Big Thanks • Teachers, Course
Advisors, Mentors • Karl Handelsman, Antoun Nabhan • Customers and Industry KOLs who took time to do the interviews and explain us things • UCSF, QB3, Stanford, UC Berkeley for making the Entrepreneurship resources available • US Govt has many programs for small businesses, NIH is investing greatly for Life Sciences Research Translation • Lots of people ready to help. All you have to do is ask, and if one shows passion and great drive people ready to line up and make your vision a reality.

Appendix

Cybele
Business Model Canvas Progression

Cybele Biologics – Original Pre
Course Canvas Immediate: -People to help protect IP (lawyers etc.) -Non-profits and advocacy groups like HDSA for the cause of finding cure for a specific genetic disorder Long term: People to invest/help fundraise/advise/strate gize Govt; Research Universities (IRBs) Patient Advocates, Support Groups / Fund Raisers -Production of differentiated cellular product -Repeatable process, efficient delivery of cellular lines, batch release QC -Analytics tools for creation/ testing / validation -Scientists creating new cellular lines, -Intellectual Property on the diff cell lines creation process Immediate: -Differentiated cell populations – human cellular model for HD and other genetic disorders -Drug discovery platform and tools -Research conferences (like CHDI) -Lunchtime seminars @ universities -Newsletters -Direct outreach -Social media (LinkedIn) Reliable steady supply Long term: -Cellular transplantation therapies -Future custom lines for personalized genomics -Consent forms for acquisition of new materials -Internet -Direct Sales -Partner w/trusted brand and sell co-labeled product through them -StemBANCC -Regional Support Groups (eg HDSA) Immediate: -Drug Discovery Researchers -Pharma Companies -Basic researchers -iPSC Scientists Long term: -Patients -Medical Centers -Physicians -CMS – what health insurance co‟s will reimburse Ideal Customer now: Doing drug discovery for HD & other neurodegenerative disorders requires a stead supply of the HD Cellular Model for testing Attracting top scientists for creation of new cellular systems Immediate: -Sales of cellular models Long term: -Cell-based therapy -Drug treatment mitigating/eliminating disease Analytics + Simulation models to speed up creation of new lines IPR Licensing Production of the Cellular lines – equipment, verification, regulatory body approvals

Cybele Biologics-Canvas version II (Week
1 Canvas) Immediate: -People to help protect IP (lawyers etc.) -Nn-profits and advocacy groups like HDSA for the cause of finding cure for a specific genetic disorder Long term: People to invest/help fundraise/advise/strategi ze Govt; Research Universities (IRBs) Patient Advocates, Support Groups / Fund Raisers -Production of differentiated cellular product -Repeatable process, efficient delivery of cellular lines, batch release QC -Analytics tools for creation/ testing / validation -Scientists creating new cellular lines, -Intellectual Property on the diff cell lines creation process -Consent forms for acquisition of new materials An appropriate and affordable cellular model system for basic research on HD. An appropriate and in large quantities deliverable cellular system for drug discovery. A direct therapeutic agent in transplantation therapies. MVP needs to be - Highly pure - Batch-to-batch homogeneity - QC criteria tbd - Producible in large quantities -Research conferences (like CHDI) -Lunchtime seminars @ universities -Newsletters -Direct outreach -Social media (LinkedIn) -Internet -Direct Sales -Partner w/trusted brand and sell co-labeled product through them -StemBANCC -Regional Support Groups (eg HDSA) Academic/Industry researchers interested in basic HD biology. Drug discovery companies with a focus on HD or neurodegenerative diseases (may be interested in expanding to HD). Companies developing cell-based therapies (no matter for which disease, may be interested in expanding to HD) HD Patients, their physicians, medical centers, CMS (what health insurance co’s will reimburse) Attracting top scientists for creation of new cellular systems Immediate: -Sales of cellular models Long term: -Cell-based therapy -Drug treatment mitigating/eliminating disease Analytics + Simulation models to speed up creation of new lines IPR Licensing Production of the Cellular lines – equipment, verification, regulatory body approvals

LaunchPad Centr al Ke y
Par tne r s Ke y Activitie s la wye rs (IP p ro t e ct io n , p ro d u ct ma n u fa ct u rin g d ra ft in g lice n sin g a g re e me n t s) fu n d in g a g e n cie s/fo u n d a t io n s wit h a n in t e re st in su p p o rt in g Week 3 Canvas Value Pr op o sitio ns Cu sto m e r Re lation sh ip s h ig h p u rit y ce ll p o p u la t io n Ge t : p re se n t a t io n s a t  CRO 's n e e d in g t o fo r t h e ra p e u t ic co n fe re n ce s (t a lk, p o st e r, s u b co n t r a ct t o g e t t ra n sp la n t s ve n d o r e xh ib it io n ) r e lia b le , h ig h p u r it y (R& D fo r n e w p ro t o co ls h ig h p u rit y ce ll Ge t : se min a rs a t a n d ce ll lin e s) p o p u la t io n s fo r u n ive rsit ie s/re se a rch co mp a n ie s wa n t in g t o Hu n t in g t o n 's Dise a se in st it ú t io n s co mme rcia lize p ro d u ct q u a lit y co n t ro l p ro d u ct d e ve lo p me n t HD re se a rch cu st o me r su p p o rt e st a b lish e d ce ll p o p u la t io n s ma rke t in g re se a rch b io p h a rma /b io t e ch Ke y Re so u r ce s Hu n t in g t o n 's Dise a se Ge t : a d s in ma jo r scie n t ific h ig h p u rit y ce ll p o p u la t io n s fo r t o t h e ir cu st o me rs, Hu n t in g t o n 's Dise a se d ist rib u t io n ch a n n e ls) t h e ra p e u t ic e va lu a t io n Hu n t in g t o n 's d ise a se d ire ct sa le s (o rd e r via o u r co mp a n ie s d e ve lo p in g sh ip p in g t o cu st o me r) re se a rch e rs in a ca d mia p ro d u ct fo r fre e in re t u rn re se a rch e rs e xp lo rin g h o me p a g e , e xp re ss g ra n t $ a n d in d u st ry (p ro vid e t h e ra p ie s jo u rn a ls ls Ch an nea n d o n t h e se co mp a n y (t o g e t a cce ss la b sp a ce Cu stom e r Se gm e n ts Hu n t in g t o n 's Dise a se a d viso ry b o a rd t h e ra p e u t ics co -la b e lin g wit h t ru st e d IP b ra n d (o rd e r a n d Cu st o me r Ad vo ca cy g ro u p s like CHDI, HDSA d o in g b a sic re se a rch o n we b p a g e /n e t wo rk) To p Re se a rch Scie n t ist s Co mp a n ie s/In st it u t io n s d ist rib u t io n via t h e ir fo r fe e d b a ck) o t h e r Ne u ro d e g e n e ra t ive d ise a se s like Pa rkin so n 's Co st Str uctu r e Re ve nu e Stre Co mme rce Su p p ly Ch a in e am s re n t fo r la b sp a ce d ire ct sa le s e q u ip me n t p u rch a se s lice n sin g fe e s fo r re g u la t o ry a p p ro va ls, IP-la wye rs re a g e n t co st s sa la rie s ma rke t in g ca mp a ig n s Li c e n se d fr o m b u si n e ssm o d e l g e n e r a t i o n .c o m u n d e r a Cr e a t i ve Co m m o n s At t r i b u t i o n -S h a r e Al i ke 3 .0 Un p o r t e d Li c e n se

Week 4 Canvas

Week 5 Canvas Keep: Loyalty
perks Grow: Custom services

Week 6 Canvas

Cybele Biologics -- Week 7
Canvas - Discussion KOL‟s HDSA CHDI CIRM QB3, SparkMed NCATS CDI Lifetech Cyprotex Production of the differentiated Cellular lines High purity pop. of Repeatable mature MSN process, efficient delivery of cellular lines, High purity pop. of committed MSN Analytics tools for creation/ progenitors testing / validation of cellular lines Well-char. Pop. of MSN Athena Health -ins co can influence pharma to use our cells FDA - influences pharma to use our cells for tox/whatever Stanford hospital Whoever Dr Layzer put as contacts Physiologically relevant cell population of MSN Get: Conference presence Venture arms of pharma Seminars in academia Risk-free trial product Keep: Cust serv/trouble shoot Loyalty program Grow: Custom services Well-char. populations of other human cells Scientists creating new cellular lines, Intellectual Property on the diff cell lines creation process Assay Depot/Sci Exchange Cells w/native genotype of known poly-Q length Academics & NPOs working on HD Pharma Companies Tox screening companies Distribution by trusted brand, like Lonza Reduction in drug discovery costs CRO‟s without expertise to differentiate in-house Nonprofit research orgs like CHDI – recommend product to collaborators Reduction in tox screening costs Production of the Cellular lines – equipment, verification, regulatory body approvals Attracting top scientists for creation of new cellular systems Analytics + Simulation models to speed up creation of new lines Direct sales of cellular populations Direct sales of custom differentiation jobs to CROs IPR Licensing

Cybele Biologics -- Week 7
Canvas Research Partners: -Lisa Ellerby at Buck -Bill Horn at USDA ARS -Cyprotex -other researchers/ startups we could generate data and publish with (e.g. Zephyrus) Informal Partners: -FDA – make them aware of cells for preclinical applica ons Strategic Alliances: -CHDI & other distributors such as ATCC, Coriell, CDI Supplier Rela onships: -Lifetech (if we do their reagents) -Whoever we get iPS cells from, maybe Coriell Produc on of the differen ated Cellular lines Repeatable process, efficient delivery of cellular lines, Analy cs tools for crea on/ tes ng / valida on of cellular lines Scien sts crea ng new cellular lines, 1 Enable in vitro research in an indica on with unmet medical need (Hun ngton’s Disease) 2 Reduce drug discovery costs by enabling acquisi on of meaningful data earlier in drug discovery pipeline; fail drugs earlier 3 Reduce tox screening costs – get meaningful toxicity info early Intellectual Property on the diff ell lines crea on process Produc on of the Cellular lines – equipment, verifica on, regulatory body approvals A rac ng top scien sts for crea on of new cellular systems Analy cs + Simula on models to speed up crea on of new lines Get: Conference presence Venture arms of pharma Seminars in academia Risk-free trial product Google AdWords Keep: Cust serv/trouble shoot Loyalty program Grow: Custom services Assay Depot/Sci Exchange CRO’s without exper se to differen ate in-house (e.g. System Biosciences) Academics & NPOs working on HD Pharma/biotech companies (e.g. Lifetech) Tox screening companies (e.g. Cyprotex) Distribu on by trusted brand, like Lonza, Lifetech or CDI Nonprofit research orgs like CHDI – recommend product to collaborators Direct sales of cellular popula ons Direct sales of custom differen a on jobs to CROs IPR Licensing (e.g. to CDI)

Cybele Biologics -- Week 8
Canvas Research Partners: -Lisa Ellerby at Buck -Bill Horn at USDA ARS -Cyprotex -other researchers/ startups we could generate data and publish with (e.g. Zephyrus) Informal Partners: -FDA – make them aware of cells for preclinical applica ons Strategic Alliances: -CHDI & other distributors such as ATCC, Coriell, CDI Supplier Rela onships: -Lifetech (if we do their reagents) -Whoever we get iPS cells from, maybe Coriell Produc on of the differen ated popula ons Batch release valida on Contac ng CROs, tox companies, pharma etc 1 Enable in vitro research in an indica on with unmet medical need (Hun ngton’s Disease) Fundraising 2 Reduce drug discovery costs by enabling acquisi on of meaningful data earlier in drug discovery pipeline; fail drugs earlier IP for MSN differen a on, freedom to operate 3 Reduce tox screening costs – get meaningful toxicity info early CROs, startup infrastructure, biotech & pharma in bay area -Overhead – space at QB3 or other incubator, regulatory body approvals, costs of filing patent -Cost of raw materials – undifferen ated cells from vendor and CRISPR modifica on -Differen a on of popula ons – hood rental, space at QB3, technician -Batch release costs – verifica on, regulatory body approvals Get: Conference presence Venture arms of pharma Seminars in academia Risk-free trial product Google AdWords Keep: Cust serv/trouble shoot Loyalty program Grow: Custom services Assay Depot/Sci Exchange CRO’s without exper se to differen ate in-house (e.g. System Biosciences) Academics & NPOs working on HD Pharma/biotech companies (e.g. Lifetech) Tox screening companies (e.g. Cyprotex) Distribu on by trusted brand, like Lonza, Lifetech or CDI Nonprofit research orgs like CHDI – recommend product to collaborators Direct sales of cellular popula ons Direct sales of custom differen a on jobs to CROs IPR Licensing (e.g. to CDI)