Next Generation Therapies and Related Life Sciences Topics 1 Contents

Next Generation Therapies and related Life Sciences topics 1 Contents

1 Overview of Deloitte’s Next Generation Therapy Practice 3

2 Overview of Next Generation Therapies 8

3 Gene Therapy 19

4 Challenges of Commercializing Gene Therapy 31

5 Gene Editing 35

6 Regenerative Medicine 47

7 Supply Chain/Commercialization 51

8 Appendix 1: Next Generation Therapies Deloitte Case Studies 58

9 Appendix 2: Deloitte’s Life Sciences M&A Opportunities 64

© 2020 Deloitte Global Services Limited Global Life Sciences and Health Care | Practice overview 3 Evolution to Next Generation Therapies We are moving toward an ability to cure and heal rather than merely ameliorating symptoms

Increasing Complexity Regulatory/Reimbursement of Therapeutic Intervention Supply Chain/Commercialization

AI/Bioinformatics

Modify Gene Gene Expression Correction • Antisense • Gene Therapy • RNAi/siRNA with Viral Vectors • Aptamers • Gene Therapy Polyclonal & • Ribozymes with Other Vectors Monoclonal • Exon Skipping • Gene Editing Antibodies (Meganucleases, ZFN, TALENs, CRISPR)

Plasma & Recombinant Regenerative Proteins Medicine • Autologous & Allogenic Cells • Stem Cell Therapy Small Molecules • Mitochondrial Transfer & Infectious • Tissue Engineering Disease Vaccines

Next gen therapies alter the healthcare ecosystem Next Generation Therapies

Translational Medicine at AMC

Biotech Discovery & Outlicensing Internal R&D Ultra Orphan & Accelerated Discovery Pathway Programs BLA/Orphan Indications

New Drug Application (NDA) Value Based Billing & Regulatory Approval Pathway Individual Approvals Prior Authorization & Clinical Protocols Formulary & Tenders Individual Product Production Reimbursement Mechanisms Biological Batch Systems Chemical Synthesis Direct Shipment w/ Manufacturing Process Product COI & COC Specialty & Hospital Pharmacy w/ Batch COI & COC Retail Pharmacy w/Batch Certified & Trained Institutions Distribution Channels COI & COC Clinics & Hospitals Outpatient Therapy Delivery Medical Affairs Led Team Engaging Institution Specialty Sales Forces and P&T Committees Field Sales Force to High Prescribers Multiple Stakeholders through Commercial Focus on-line portals Conferences & Peer Reviewed Articles DTC/DTP Advertising, Long-Term Patient Registry Market Engagement Samples & Coupons EHR & REM/RMPs Rx Data & Adverse Event Reports Real World Evidence Capture

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 5 Revenues of Currently Approved Next Generation Therapies Analysts anticipate a ~$9 Billion market for 48 approved products in the next 6 years

WW Sales of Next Generation Therapies Number of Approved and Total = 48 (USD $MM) Marketed Next Generation Therapies $8,955 9000

$8,335 1,009

8000 889 $7,549 6% $6,742 7000 780

679 $5,676 17% 6000 4,235 3,847 585 5000 3,363 $4,472 2,790 Total =

487 4000 2,152 $3,263 1,509 48 3000 386

867 $1,739 2000 3,599 3,711 3,406 77% 300 3,273 2,939 400 2,476 1000 2,010

1,039 0 2017 2018E 2019E 2020E 2021E 2022E 2023E 2024E

Gene Expression Gene correction Regenerative Medicine

Source: Evaluate Pharma Analyst Consensus Projections; Annual Reports, Product websites and Deloitte Analysis Note: Gendicine and Oncorine are only sold in China with combined sales of USD ~$8 Million in 2017 are not included in revenue projections; Glybera was pulled from the market in 2017 and is not included.

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 6 In the last three years, acquisitions worth over USD $100 Billion have demonstrated the market value of these new technologies

M&A in Next Generation Therapies* Roche** (USD $ Billion) BMS Spark Celgene 5.0 1.0 113.2 74.0 10 Deals These 3 Acquisitions Accounted for more than USD $29.6 Billion

Boehringer ViraTherapeutics PTC Celgene Agilis Takeda Merck Juno Viralytics Novartis Tigenix AveXis Gilead 9.0 .2 .2 Gilead Cell Design Allergan Kite LifeCell 8.7 .6 .4 (Tissue Matrices) 11.0 .2 2.9

Dec-16 Oct-17 Dec-17 Jan-18 Jan-18 Feb-18 Apr-18 Jul-18 Sep-18 Jan-19 Feb-19 Other Total

Source: Company Websites & Press Releases Note:*Only upfront payments represented due to uncertainties about future milestone achievement and sales to generate royalties **Announced February 24, 2019

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 7 In Licensing of Next Generation Therapies The majority of value in licensing deals has been allocated to the back-end

Total Value of Licensing* Major Licensing Deals in the Last 3+ Years (USD $ Millions) (USD $ Millions) Date Upfront Total Buyer Licensee Therapeutic Area Announced Payments Value

Oct-18 J&J Arrowhead RNAi for Hepatitis B $235 $3,700 2015 2,216 Aug-18 Pfizer BioNTech mRNA flu vaccine $120 $425 Cell Therapy for Type 1 Apr-18 Eli Lilly Sigilon $63 $473 diabetes AAV Vectors for GT for Feb-18 Abbvie Voyager $69 $1,119 2016 647 Alzheimer's ZFN for Cancer Drug Feb-18 Gilead Sangamo $150 $3,000 Development Marketing Luxturna in Jan-18 Novartis Spark $105 $170 Europe 2017 1,086 BCMA-targeting CAR-T for Dec-17 J&J Legend $350 -- Multiple Myeloma

May-17 Pfizer Sangamo ZFN for Hemophilia A $70 $545 Baxalta/ Precision Allogenic CAR-T using Arcus Feb-16 $105 $1,700 Shire Bioscience Platform 2018H1 914 Form JV (Casebia) to Dec-15 Bayer CRISPR $ 300 $335 develop CRISPR therapies Merck Mar-15 Intrexon CAR-T with non-viral vector $115 $941 Serono

Total $1,682 $12,408

Source: Alliance for Regenerative Medicine; Company Websites & Press Releases Note: *Only upfront payments represented due to uncertainties about future milestone achievement and product sales to generate royalties © 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 8 Worldwide Growth in Next Generation Therapy Companies On a global basis there has been 15% annual growth over the last 3 years with North America and Europe hosting ~80% of Next Generation companies

2015Q1 580

2018H1 875

Europe & Israel 235 (2018H1) 166 (2015Q1)

North America 466 (2018H1) 302 (2015Q1) Asia 135 (2018H1) 92 (2015Q1)

South America 15 (2018H1) Africa Oceania 8 (2015Q1) 1 (2018H1) 23 (2018H1) (2015Q1) 12 (2015Q1)

Source: Alliance for Regnerative Medicine Annual Report

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 9 There is a significant opportunity in the China Market in the Next Generation Therapies Space USA and China are the leaders in the development of cell therapies

A representation of clinical trials investigating cell therapies across major markets in the world

Canada Europe Russia 18% 17% 16% 29% USA and China 5% 3% 18% are the leaders in the 40% 1% 36% 17 30 246 development of cell therapies 23% 13% 7% 35% 3% 14% 22% Stem cell & CAR-T therapies represent the largest share of the global cellular therapy market Japan USA 21% 33% USA has the largest number 6% 7% of Stem cell therapies under 1% 24 25% investigation (300+) followed 11% 734 4% 17% by EU (80+) 11% 41% 23% Southeast Asia Australia Middle East 9% 27% 10% 27% 12% 46% 11 15 10% 50 9% 7% 46% 68% 9% 20%

• Stem cells • CAR-T cells • TCR-T cells • NK-T cells • TAA/TSA • TIL • Gamma Delta T Cells

Data as of December 10, 2018 Note: The percentages indicate the proportion of studies for a certain intervention/therapy and the number inside the doughnut hole indicates the grand total of on-going studies registered on Clinicaltrials.gov

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 10 Deloitte’s Experience with Next Generation Therapies Over the last 3 years Deloitte has completed over 20 engagement with clients which span the entire patient journey and industry value chain

Next Generation Therapies Patient Journey

2 Enrollment 4 Treatment 6 Long-term • Confirm • Supportive care Follow Up patient • Community Post-Treatment 1 Referral eligibility 3 Evaluation 5 Physician Evaluation Physician initial • Patient • Patient education Monitoring assessment consent • Genetic eligibility • Observation • Patient registries and referral to • Outpatient/ treatment center inpatient care

Value Chain Element Research & Development Supply Chain Commercial

Representative Projects • Identification of new • Order to Cash • Pricing & Market Access viral vectors acquisition optimization for CAR-T targets for gene therapy • Chain of Identity (COI) • Development of • Risk analysis & mitigation analysis for European stakeholder portal strategy for Phase I launch for launch of CAR-T clinical trials • Supply chain assessment • Customer experience and playbook definition workshops for product launch

Supply Chain/Commercialization Gene AI/Bioinformatics Modify Gene Gene Expression Correction Therapy • Antisense • Gene Therapy • RNAi/siRNA with Viral Vectors • Aptamers • Gene Therapy • Ribozymes with Other Vectors • Exon Skipping • Gene Editing (Meganucleases, ZFN, TALENs, CRISPR)

Regenerative Medicine • Autologous & Allogenic Cells • Stem Cell Therapy • Mitochondrial Transfer • Tissue Engineering

Cell: Building Block of Life Central Dogma of Molecular Biology DNA:DeoxyriboNucleic Acid RNA:RiboNucleic Acid Protein

• There an estimated 37.2 trillion • Carrier of genetic information • Copies genetic information • Building blocks of the structure cells in the human body in the nucleus of the cell from the DNA by binding to and do the work of cells unzipped DNA • Cells are replaced at a • Made of four chemical building • Composed of 23 amino rate of millions per second blocks (nucleotides--ATCG) • Is a single helix made of four acids whose sequence except for few types such which form a double helix nucleotides (AGCU) and ~15 is determined by RNA as the central nervous system, • ~3 billion base pairs Million strands of RNA in a cell • Proteins catalyze chemical lens and oocyte cells which last (A-T, C-G) make up • RNAs shuttle between the reactions which impact DNA, for a lifetime the human genome nucleus and rest of cell RNA and other proteins • Human DNA is tightly • RNA is critical in regulating wound into 23 pairs of protein synthesis and RNA chromosomes & DNA repair • Genes are sequences of DNA ranging from 200 base pairs to 2 million which provide instructions for making proteins • There are between 20,000 and 25,000 human genes of which only 1% are different between individuals

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 13 Gene Therapy Approaches All gene therapies insert engineered DNA/RNA into living cells to make or modify new proteins

Gene Therapy Approaches

In Vivo Ex Vivo

Defective cells are removed from patient

In the body, the genetically altered cells are producing the desired proteins encoded by the therapeutic genes

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 14 Gene Therapy Technology Platforms There are multiple platform technologies which are being utilized

Maturity of Platform Technologies

AAV RNAi CRISPR (adeno associated viruses) (RNA interference) is a natural (Clustered Regularly Interspaced vectors support production pathway involved in regulation of Short Palindromic Repeats) of protein, leading to therapeutic gene expression is a gene editing tool originally effect, without permanently altering discovered as a RNA-based bacterial the patient’s DNA defense mechanism designed to eliminate foreign DNA from invading bacteriophages and plasmids

More Mature Less Mature (Platforms Used with Current Drugs) (Platforms with Drugs in Clinical Trials)

Lentiviral ZFNs vectors are retroviruses used to introduce (Zinc Finger Nucleases) and a functional copy of a gene to the patient’s TALENs extracted hematopoietic stem cells with (Transcription Activator-Like Effector Nucleases) longer term therapeutic effect Gene editing tools to remove a gene or insert a therapeutic gene into the genome in a targeted fashion

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 15 Approved and Marketed Gene Therapies 12 of the 14 products approved across the US, EU and China are still available

In Vivo Ex Vivo

Name Date Name Date (Company) Approved Description (Company) Approved Description Gendicine Oct 2003* Adenovirus with the p53 tumor- Provenge Apr Dendritic cells extracted (Benda Pharma) suppressor gene for head & (Dendreon) 2010*** and viral transfection with neck cancer a recombinant fusion protein Oncorine Nov 2005* Oncolytic recombinant and then reinfused to treat metastatic prostate cancer (Shanghai Sunway adenovirus for nasopharyngeal Biotech) cancer with chemotherapy Strimvelis May Bone Marrow cells are extracted Glybera Nov 2012** AAV1 treatment for lipoprotein (GSK/Orchard) 2016** and transfected with a gamma (uniQure) lipase deficiency retrovirus to treat Adenosine Deaminase Severe Combined Kynamro Jan 2013*** Antisense oligomer which treats Immunodeficiency deficiency (Kastle) homozygous familial (ADA-SCID) hypercholesterolemia Zalmoxis Aug Adjunct treatment for Graft vs Imlygic (Amgen) Nov 2015 HSV-1 Virus to treat melanoma (MolMed) 2016** Host Disease (GvHD) in bone lesions marrow transplants with Exondys 51 Sep 2016*** Anti-sense oligomer for exon “suicide switch”. Retrovirus (Sarepta) skipping to treat Duchenne gene insertion into donor Muscular Dystrorphy (DMD) T- cells infused to patient Spinraza Dec 2016 Anti-sense oligomer for Kymriah Aug 2017 Patient’s T-cells are extracted (Biogen/Ionis) alternate gene splicing for (Novartis) and CAR targeting CD19 Spinal Muscular Atrophy (SMA) inserted using lentivirus for Luxturna Mar 2018 AAV2 treatment for RP caused reinfusion for pALL & DLBCL (Spark) by RP165 gene Yescarta Oct 2017 Patient’s T-cells are extracted Onpattro Aug 2018 RNAi drug to treat adult (Kite/Gilead) and CAR targeting CD19 (Alnylam) hereditary transthyretin inserted using retrovirus for amyloidosis reinfusion for DLBCL

*Only approved in China **Only Approved in the EU ***Only Approved in the US Notes: Kynamro was withdrawn from US in May 2018 before Kastle Therapeutics bankruptcy; Glyberra was withdrawn from the EU in October 2017 Sources: EvaluatePharma and company websites

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 16 Approved In Vivo Gene Therapies Sales Currently approved and on-market in vivo gene therapies have ~ USD $1B in sales and are projected to be a ~USD $4B market

WW Sales of In Vivo Gene Therapy Drugs Name Approval (USD $MM) $4,027 (Developer) Date Description $3,934 $3,825 Spinraza Dec 2016 Gene splicing $3,634 (Biogen/Ionis) antisense for SMA

$3,191

Exondys 51 Sep 2016 Exon skipping 2,060 2,071 (Sarepta) antisense for DMD $2,682 2,098

2,185

$2,121 Imlygic Nov 2015 HSV-1 Virus to treat 2,120 (Amgen) melanoma lesions

1,931 594 599 615 Onpattro Aug 2018 RNAi drug to treat 1,692 168 $1,087 (Alnylam) adult hereditary 579 157 146 transthyretin amyloidosis 498 135 884 929 1056 787 400 116 Luxturna Mar 2018 AAV2 treatment for 589 (Spark) RP caused by RP165 98 300 352 gene 166 155 8… 48 87 105 146 179 178 149 2017 2018E 2019E 2020E 2021E 2022E 2023E 2024E

Notes: Glybera (Uniqure) was pulled from the market in 2016 so is not included; Gendicine and Oncorine are only sold in China with combined sales of USD ~$8 Million in 2017 are not included in analysis Source: Evaluate Pharma for Consensus Equity Analyst Projections; company websites

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 17 Approved Ex Vivo Gene Therapies Sales Current approved and on-market ex vivo gene therapies have ~USD $350 million in sales with projections to achieve ~USD $3.9 billion

Sales of Ex Vivo Gene Therapy Drugs Name Approval (Developer) Date Description (USD $MM) $3,917 Yescarta Oct 2017 Patient’s T-cells are $3,511 (Kite/Gilead) extracted and CAR targeting CD19 inserted using retrovirus for $3,038 reinfusion for DLBCL Kymriah Aug 2017 Patient’s T-cells are 2308 (Novartis) extracted and CAR $2,509 targeting CD19 2059 inserted using lentivirus for 1743 $1,931 reinfusion for pALL & DLBCL 1371 Zalmoxis Aug 2016 Retrovirus gene (MolMed) insertion into donor $1,324 983 T- cells infused to patient for GvHD 1,000 in BMT 590 878 $762 764 Provenge Apr 2010 Dendritic cells 645 (Dendreon) extracted and viral 486 283 304 66 transfection with a $352 38 57 84 17 28 recombinant fusion 2 10 544 protein. Cells 420 445 465 493 518 325 393 reinfused to treat metastatic prostate 2017 2018E 2019E 2020E 2021E 2022E 2023E 2024E cancer

Notes: Strimvelis transferred to Orchard Therapeutics on June 2018 and had sales of $3.2MM in 2017 and $2MM in 2018. Future sales are uncertain and have not been included Source: Evaluate Pharma for Consensus Equity Analyst Projections; company websites

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 18 Future of Gene Therapies Expectations are for ~40 new gene therapies to be approved in the U.S. alone

539 Preclinical

17%

142 Phase 1 By 2022 45%

Jan 2017 39 products Gene Therapy +/- 4 Pipeline in US & EU 34% 213 Phase 2

Oncology Orphan Ultra Orphan Other TA 31 Phase 3

7 In Review/Approved

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 19 I don’t know if their [MIT] estimates [~40 approved gene therapy drugs by 2022] are right or wrong. But I know that directionally, these predictions are correct. Just this past year we saw the first three approvals of gene therapies: two cell-based gene therapies for blood cancers, and a directly administered gene therapy to address a form of hereditary retinal dystrophy. The promise is very much becoming a reality. These recent product approvals represent just the tip of the iceberg.

Scott Gottlieb FDA Commissioner Bio 2018, June 7, 2018

© 2020 Deloitte Global Services Limited Global Life Sciences and Health Care | Practice overview 20 CAR-T & TCR Approaches for Gene Therapy The most mature approaches either target surface tumor antigens (CAR-T) or attack internal tumor cancer proteins as they migrate to the surface (TCR)

Chimeric Antigen T-Cell Receptor T-Cell Receptors (CAR-T) (TCR)

New Types of Immune Cells using CAR Approach • Tumor Infiltrating Lymphocytes (CAR-TIL) • Gamma Delta T-Cells (CAR-γδ) • Natural Killer T-Cells (CAR-NKT) • Cytostatic T-Cells (CAR-CTL) • Natural Killer Cells (CAR-NK) • Cytokine Induced Killer Cells (CAR-CIK) • T-cell Receptor Fusion Complex (TRUK)

Source: National Cancer Institute; Wells Fargo Securities Conference, Nov. 2017

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 21 Proliferation of CAR-T/TCR Candidates in Development Of the ~200 drugs in development, 13 are projected to generate an additional USD $5B+ above Kymriah and Yescarta revenues by 2024

Projected Sales of CAR-T/TCR Drugs (USD $MM) 8,560

6,654

5252

4,663 3717

3,183 2156

1,000 1167 878 1,870 764 401 645 941 486 2,059 2,308 1,743 304 1,371 983 590

2019E 2020E 2021E 2022E 2023E 2024E

New Entrants Kymriah Yescarta

Source: EvaluatePharma Consensus Forecasts; Wells Fargo Securities Conference, Nov. 2017

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 22 Gene Therapy in the Context of Immuno-Oncology Gene therapy will continue to be a complementary approach to monoclonal antibody based checkpoint inhibitors

Blocking T-Cell • Yervoy (CTLA-4) Checkpoint Pathways • Opdivo (PD-1) Targets: CTLA-4, PD-1, PD-L1/2 • Keytruda (PD-1) PD-1 Tumor PD-L1/2 • Tecentriq (PD-L1) Anti–CTLA-4, T Cell Anti-PD-1 Cell CD80/86 CTLA-4 • Bavencio (PD-L1) T-cell inactivation • Arzerra (CD-20) T-cell activation • Imfinzi (PD-L1) • Campath (CD-52) • Rituxan (CD-20)

Potentiating Immune-Cell Promoting T-cell Costimulatory Effector Function Receptor Signaling Targets: IDO, TGF-β Targets:

Antibody binding CSF1, OX-40, CD19, CD137/4-1BB, GITR recruits T cells (ADCC) FcγR Immuno-Oncology CD3 CD19/CD33 Tumor T Cell Immune Tumor Immune (I-O) Approaches Cell Cell Cell Cell Antibody construct Bringing effector and target cells into proximity

Adoptive T cell Isolate T cells Improving the Function Targets: CD19 of Innate Immune Cells • Kymriah Reverse engineering T cells Targets: NK, Macrophage, Dendritic Cells to recognize tumor cells • Provenge (CD19) Reinfuse IL-2 Receptor (Dendritic Tumor Tumor T Cell CAR T Cell CART Cell Cells) • Yescarta Cell (CD19) Target Antigen Antigen specific T cell activation and tumor cell killing

Source: Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities

© 2020 Deloitte Global Services Limited Global Life Sciences and Health Care | Practice overview 24 Lessons Learned from Gene Therapy Commercialization Early gene therapy products struggled with product uptake

Gene Therapy Products Launched (Bubble size is Cost of Course of Therapy in USD $000’s) Lessons Learned

• The total cost of care matters; not just the drug price for Yescarta determining reimbursement (2017) $373 7500 • Establishing treatment networks requires balancing patient reach Luxturna vs. cost to serve (2017) $850 6000 Kymriah • Being prepared to offer value 600 (2017), $475 based pricing (e.g. rebates, Glybera performance guarantees, long (2012) payment terms) is essential at $1,200 first launch Strimvelis (2016) $700 • Identifying and capturing the potential patient pools

Estimated Estimated Target Patient Population 25 for ultra orphan indications 15 requires working with healthcare 0 50 100 150 200 250 providers and hospitals Estimated Revenue 1 year After Launch (USD $ Millions)

US EU

Source: Company Press Releases

Medical/Hospital Commercial • Rare genetic diseases require a testing • Uncertainty about IP ownership for CRISPR infrastructure to identify patients • Obtaining reimbursement • Long-term patient follow-up and registry for high cost of therapy maintenance (10-15 years) • Logistics/Supply Chain Issues for autologous therapies • As CRISPR brings down the cost of discovering new therapies--will this lead to a flood of similar therapeutic solutions

Technical/Scientific Ethical/Moral • Off-target edits • Potential religious issues with altering • Immunogenicity human genetics • Delivering the gene editing machinery to the • Should there be a uniform patient informed cell nucleus consent process regardless of where the therapy is developed? • Ensuring genetic changes continue for new generations of cells • Going beyond treating diseases to selecting for specific human traits • Addressing diseases which are the result of multiple genes

Supply Chain/Commercialization Gene AI/Bioinformatics Modify Gene Gene Expression Correction Editing • Antisense • Gene Therapy • RNAi/siRNA with Viral Vectors • Aptamers • Gene Therapy • Ribozymes with Other Vectors • Exon Skipping • Gene Editing (Meganucleases, ZFN, TALENs, CRISPR)

Regenerative Medicine • Autologous & Allogenic Cells • Stem Cell Therapy • Mitochondrial Transfer • Tissue Engineering

Cas9 protein was discovered in bacteria to combat viruses and By swapping out different gRNAs, The Cas9 protein breaks uses guide RNA (gRNA) to identify researchers can target specific both strands of DNA at viral DNA targets to disable regions of DNA to modify the specific target point

Repair/ Replace a Gene

Silence a Gene

Source: Adopted from Bloomberg BusinessWeek Kolker, R. (2016), “How Jennifer Doudna’s/Feng Zhang’s gene editing technique will change the world” Accessed at: https://www.bloomberg.com/features/2016-how-crispr- will-change-the-world/

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 28 Alternatives to CRISPR-Cas9 for Gene Editing TALENs, Zinc Finger Nucleases, Meganucleases and Homologous Recombination are all alternatives to CRISPR-Cas9

1989 1996 2003 2010 2012 Homologous Meganucleases Zinc Finger Transcription Activator- Clustered Regularly Interspaced Recombination Nucleases Like Effector Nucleases Short Palindromic Repeats (ZFNs) (TALENs) nucleases (CRISPR)

Homologous Recombination Nuclease Based Gene Editing

Adeno- associated virus (AAV)

Source: BCG, Homology Medicines Website,

Common Single Mutation Disorders Description Thalassaemia Absence and/or errors in gene responsible for production of haemoglobin, an oxygen carrying protein present in the red blood cells

Sickle cell anemia Genetic mutation which causes the entire blood cell to change shape under stressed conditions

Haemophilia A hereditary bleeding disorder with partial or total lack of an essential blood clotting factor. It results in excessive bleeding and often spontaneous internal Over 10 bleeding in 1000

Cystic Fibrosis A genetic disorder that affects the respiratory, digestive and reproductive births (1%) systems involving the production of abnormally thick mucus linings in the lungs and can lead to fatal lung infections. The disease can also result in have at various obstructions of the pancreas, hindering digestion. least one

Tay Sachs Disease A fatal genetic disorder in which harmful quantities of a fatty substance called of these Ganglioside GM2 accumulate in the nerve cells in the brain. It is caused by a conditions decrease in the functioning of the Hexosaminidase A enzyme

Fragile X syndrome A genetic mutation which varies considerably in severity among patients. Fragile X syndrome is the most common cause of inherited mental retardation.

Huntington's Disease A degenerative brain disorder, which affects the ability to walk, talk, think, and reason. This disease begins between ages 30-45, and every individual with the gene for the disease will eventually develop the disease

Source: WHO Genomic Resource Center

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 30 Publicly Traded Gene Editing Companies Market capitalization far outpaces revenue and all companies are unprofitable

$0 $10 $20 $30 $40 $0 Homology Medicine (FIXX), 0.7 ($25) Sangamo Therapeutics (SGMO), 1.6

($50) Precision Biosciences (Private), 0.2

($75)

Editas Medical (EDIT), 1.6 Intellia Therapeutics CRISPR Therapeutics ($100) (NTLA), 1.0 AG (CRSP), 2.5

($125) Cellectis SA (CLLS), 1.2 2017 Net Income (USD Net(USD Income $MM) 2017

($150) 2017 Revenue (USD $MM)

Homologous Recombination IP Meganucleases IP Zinc Fingers IP TALENs IP CRISPR IP

Source: Company 10-K reports; Company Press Releases; Market Capitalization calculated as of 12 May 2018

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 31 Venture Capital Investment in Gene Editing Companies In the last five years ~USD $1.4 Billion invested in gene editing start-ups

Venture Capital Investment in Gene Editing Companies Human Therapeutic Gene Editing (USD $Millions) 4 2 1 Founding to IPO Acquisitions Joint Ventures Total=$1,382 MM in timeframe

$607 Gene Editing Companies with VC Investment

Agenovir (VIR) Homology Medicine (IPO)

Arbor Bioscience Intellia Therapeutics (IPO)

Caribou Biosciences Locus Bioscience $365 Casebia Therapeutics (JV) Logic Biotherapeutics $273 CRISPR Therapeutics AG (IPO) Poseida Therapeutics

CureVac Gmbh Precision Bioscience

Editas Medicine (IPO) Synthego $86 $52 Egenesis Universal Cells (AZ)

Exonics 2013 2014 2015 2016 2017

Source: Includes only equity investment in private companies. Excludes IPO funding, outlicensing revenue, royalties, sponsored research, government grants and debt financing . Data compiled from Crunchbase.com. Accessed on 16 May 2018 at https://www.crunchbase.com/

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 32 Current Clinical Trials Utilizing Gene Editing Technologies China dominates for CRISPR trials but the U.S. and Europe are the most preferred destinations for the majority of gene editing patients

Trials Patients Trials Patients U.S. and Western Europe 18 675 Peoples Republic of China 13 451 Crispr 3 65 Crispr 10.5 361 Talens 5 478 Talens 1.5 70 ZFN 10 132 ZFN 1 20

Crispr Crispr ALL 20 Sickle Cell Disease 7 B-cell Leukemia 80 Multiple Myeloma 58 HIV-1 5 Zinc Fingers B-cell Leukemia 80 Hemophilia B 12 Gastric Cancer 20 HIV 79 Esophogeal Cancer 21 MPS I 7 Talens Zinc Fingers Bladder Cancer 20 MPS II 9 BPDCN 20 HPV 20 Lung Cancer 15 β-thalassemia 9 ALL 240 Talens Prostate Cancer 20 ALL 210 AML 156 HPV 40 Kidney Cancer 20 Cervical Cancer 30 Cervical Cancer 30

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 33 Clinical Trials Utilizing Gene Editing Technology The next few years will continue the growth of products reaching human clinical trials

IND NDA/BLA Market Discovery Preclinical Phase 1 Phase 2 Phase 3 Filing Filing Sales

2018-2019

Company Compound Indication Milestone Timing Collaborators

CTX001 β-thalassemia (Europe) Phase 1/2 2018Q1 Vertex

CRISPR Therapeutics AG CTX001 Sickle Cell Disease IND Filing 2018H1 Vertex

CTX101 CD-19 Cancers IND Filing YE2018

Regeneron Intellia Therapeutics ATTR Liver Disease (transthyretin amyloidosis) IND Filing YE2018 Pharmaceuticals

Editas Medicine EDIT-101 Ophthalmology - Leber congenital amaurosis IND Filing 2018H1

Homology Medicines sHMI-102 Metabolic--Adult Phenylketonuria (PKU) IND Filing YE2018

Pediatric metabolic disease methylmalonic Logic Biotherapeutics LB-001 IND Filing YE2018 acidemia (MMA) Sangamo Bioverativ/Sanofi BIVV003 Sickle Cell Disease IND Filing May-18 Therapeutics Allogenic B-Cell Acute lymphoblastic leukemia Cellectis UCART22 IND Filing May-18 (B-ALL) with CD-22

Homologous Recombination Zinc Fingers TALENs CRISPR On average drugs which enter Phase 1 take 5-8 years to reach FDA approval but gene editing drugs with accelerated approvals are moving faster Source: Company Websites

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 34 Diagnostic Applications of Gene Editing New Cas proteins have opened the door to create highly sensitive assays for viral infectious diseases

Viruses Baltimore Virus Classification New CAS Protein

Double stranded DNA viruses 1 (e.g. Adenoviruses, Herpesviruses, Poxviruses) New Cas Protein (Cpf1/Cas12a) Single stranded DNA viruses (Sense) Discovered in bacterium (e.g. Parvoviruses) 2 Francisella novicida which allows editing of both double Double Stranded RNA Virus strand DNA targets and single 3 (e.g. Reoviruses) strand DNA

Single Stranded RNA Virus (sense) 4 (e.g. Picornaviruses, Togaviruses)

Single Stranded RNA Virus (antisense) New Cas Protein 5 (e.g. Rhabdoviruses) (Cas13) Discovered in Prevotella sp. Single Stranded RNA-RT Viruses with DNA intermediate and can be programmed 6 (e.g. Retroviruses) to bind to a target RNA for a specific cut and then Double Stranded DNA-RT Viruses with RNA intermediate continues cutting multiple RNA 7 (e.g. Hepadnaviruses)

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 35 Diagnostic Proofs of Concept using Gene Editing Academics have shown success using gene editing for Dx applications

Initial Academic Dx Techniques Technique Description Proof of Concepts

DETECTR DETECTR demonstrated ability to detect (DNA Endonuclease Targeted HPV16 and HPV18 which cause 70% of CRISPR Trans Reporter) cervical cancer. Out of 25 human developed by Howard Hughes samples from UCSF for HPV16, DETECTR Medical Institute and UC Berkeley made the right call for all of the samples. leverages Cas12a ability to target For HPV18, DETECTR got it right for 23 of double stranded viruses and then 25 samples cut a synthetic single stranded DNA which links to a fluorescent marker

SHERLOCK SHERLOCK demonstrated ability to (Specific High-Sensitivity distinguish multiple related viruses Enzymatic Reporter UnLOCKing) (Zika, dengue, West Nile, & yellow fever) developed by MIT/Broad Institute from one another. The method had which uses Cas13 and synthetic RNA high sensitivity (attomolar level—two armed with reporter beacons to molecules in 1018) and requires no identify presence of target with high specialized equipment which results in a sensitivity and specificity low Cost of reagents (USD 0.61 per test). Reagents can be lyophilized making them cold chain independent

Source: Chen JS et al. “CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity” Science 15 Feb 2018; Myrhvold C et al. “Field-deployable viral diagnostics using CRISPR-Cas13” Science 27 Apr 2018: Vol. 360, Issue 6387, pp. 444-448

Supply Chain/Commercialization

AI/Bioinformatics

Modify Gene Gene Expression Correction • Antisense • Gene Therapy • RNAi/siRNA with Viral Vectors • Aptamers • Gene Therapy Regenerative • Ribozymes with Other Vectors • Exon Skipping • Gene Editing (Meganucleases, ZFN, Medicine TALENs, CRISPR) Regenerative Medicine • Autologous & Allogenic Cells • Stem Cell Therapy • Mitochondrial Transfer • Tissue Engineering

© 2020 Deloitte Global Services Limited Global Life Sciences and Health Care | Practice overview 37 Technologies Underpinning Regenerative Medicine Regenerative medicine relies upon the ability to grow new cells to replace damaged ones Development of Stems Cells Embryonic Stem Cells at 5 days; can renew themselves indefinitely

Endoderm Pluripotent Stem Cells Induced Pluripotent Stem Cells (iPSCs) are reprogrammed adult stem cells found throughout the body (bone marrow, skin, Totipotent Mesoderm cord blood, fat, Embyonic Pluripotent lung, neurons, Stem Cells Stem Cells mammaries, and baby teeth) which can be Able to turned back differentiate into any type of cell in into pluripotent the body. Found in cells and make blastocysts during new types of cells very early embryo development Ectoderm 1-5 days Pluripotent Stem Cells

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 38 Geographic Spread of Regenerative Therapies The majority of unique approved products have been in Asia

Markets Where Currently Marketed Regenerative Medicine Products Initially Approved (N=37)

• Spherox • Vergenix-STR EU • ReNovoCell • Holoclar 7 • ReGenerCell • Alofisel • Vergenix-FG

South U.S. Korea • Ossron • Cupistem 18 9 • Hyalograft 3D • Cellgram-AMI

• Epicel • Transcyte • Holoderm • Cartistem India • Kaloderm • Neuronata-R • MACI (Carticel) • Apligraf 18 • Omnigraft • Dermagraft • Queencell • Gintuit • Cardiocel • Stempeucel • Vascucel • HPC Cord Blood* Japan • HeartSheet • Aurix 2 • Temcell

Note: *Due to FDA regulation Cord Blood Products are required to have a BLA filed by each processing site. There are 8 approved BLAs for Cord Blood in the U.S.

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 39 Cost of Approved Regenerative Therapies Regenerative therapies have a significant range in costs

Cost per Therapy Category Product Name Description (USD) Wound Care Apligraf Skin substitute with a dermal layer of human cells (fibroblasts) in a bovine type I collagen and cornified epidermal layer of human keratinocytes. $1500 - $2500 Indicated for the treatment of chronic venous leg ulcers and diabetic foot ulcers Dermagraft Dermal substitute made from human cells (fibroblasts), placed on a $1700 dissolvable mesh material and used in wound closure of diabetic foot ulcers Epicel Permanent skin replacement grown from autologous keratinocytes which $6000 - $10,000 are co-cultured with irradiated murine cells to form cultured epidermal per 1% of autografts (CEA). Indicated for treatment of deep dermal or full thickness body surface burns Cartilage MACI Autologous cellularized scaffold indicated for the repair of single or multiple Replacement (Carticel) symptomatic, full-thickness cartilage defects of the knee with or without $15,000 - $35,000 bone involvement Cartistem Allogeneic human umbilical cord blood-derived mesenchymal stem cells indicated for the treatment of knee cartilage defects such as traumatic $19,000 - $21,000 articular cartilage, degenerative arthritis and rheumatoid arthritis. Spherox Spheroids of human autologous chondrocytes for use in cartilage defects $9,500 - $12,000 per treatment Heart HeartSheet Skeletal myoblast sheets for treating heart failure made by culturing Conditions skeletal myoblasts contained in patients thigh muscle tissue and then $122,000 transplanting the sheets onto the surface of the patient’s heart. Cellgram-AMI Autologous bone marrow-derived mesenchymal stem cell injection for $19,000 treatment of acute myocardial infarction per treatment

Opthalmology Holoclor Autologous cultures of limbal stem cells which regenerates a functional $100,000 corneal epithelium allowing recovery of visual acuity. Indicated for the treatment of moderate to severe ocular burns IV Cell Temcell Allogeneic mesenchymal stem cell for the treatment of acute radiation Therapy (Prochymal) injury, chronic obstructive pulmonary disease, Crohn’s disease, graft- $170,000 - $200,000 versus-host disease, Type I diabetes and myocardial infarction Sources:www.bioinformant.com © 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 40 Supply Chain/ Commercialization

Regulatory/Reimbursement

Supply Chain/Commercialization

AI/Bioinformatics

Modify Gene Gene Expression Correction • Antisense • Gene Therapy • RNAi/siRNA with Viral Vectors • Aptamers • Gene Therapy • Ribozymes with Other Vectors • Exon Skipping • Gene Editing (Meganucleases, ZFN, TALENs, CRISPR)

Regenerative Medicine • Autologous & Allogenic Cells • Stem Cell Therapy • Mitochondrial Transfer • Tissue Engineering NextGen therapies are of two types – gene and cell therapies

NextGen Therapy Approaches

Gene Therapy* Cell Therapy**

Allogenic Autologous

One healthy One patient donor

One tissue One tissue source source

Master cell bank

Several One batch batches cell of cell product product

Treatment Treatment of of several one patient patients

PCV

Examples of Examples manufactures

*Source: Research Gate publication (link) **Source: Apceth MSC platform (link)

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 42 There is a step change increase in the complexity to manufacture and deliver of cell & gene therapies The patient is a both a supplier of raw material and “bioreactor” for effective delivery of cell and gene therapy Monitoring / long-term follow-up Product receipt and infusion

Drug product shipment

Cell processing and manufacture

Cell shipment to manufacturing site

Cell collection

Patient enrollment and scheduling Supply Chain and Manufacturing are

Site selection stretched to include multiple stakeholders and activation including patients and clinicians

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 43 Cell and Gene therapy supply chain is enabled by specialized services from raw input suppliers and global CDMOs

Raw Input Suppliers CDMOs

Drug Product Day 0 Processing Vectors

Equipment (e.g., centrifuge, flowctyometer) Raw materials (e.g., reagents, media)

Vector Manufacture Day 0 Processing Drug Product Manufacture

Proprietary technology Process Execution Process Development • Vector design • Cell characterization, cell selection/enrichment • Cell culture and transduction • Assay development and validation • Critical control point analysis • Process validation • Cell line and medium optimization • Process analysis laboratory • COI/COC management

GMP Manufacturing Product Storage and Logistics GMP Manufacturing • Process optimization and scale-up • Cold/Cryo storage • GMP-certified manufacturing • Stability testing • COI/COC management • Clean rooms and GMP suites • Formulation and lyophilization • Robust supply chain and courier network • Clinical-grade manufacturing • Aseptic fill and finish • Sterile fill/finish

Storage and distribution Regulatory Compliance Quality Control • Product storage • Registration with regional regulatory bodies • In-Process QA & QC • Distribution network • Periodic audits and manufacturing facility • Final product release & stability testing certification • Periodic staff training program

Product Storage and Logistics • Cryogenic storage • Temperature controlled packaging for shipping • COI/COC management

Regulatory Compliance • Registration with regional regulatory bodies • Periodic audits and manufacturing facility certification • Periodic staff training program

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 45 Manufacturing and process development for cell and gene therapies is growing rapidly . . . making the CDMO market a hot target for roll-ups & acquisitions

Sustained growth driven by new approvals

• FDA expects 200 cell & gene therapy IND applications each year by 2020 and 15 - 20 approvals each year by 2025

• A key distinction of cell & gene therapies is that they are being granted accelerated approvals with smaller clinical trials resulting in therapies entering the market with the completion of only Phase I/II

Manufacturing capacity crunch is resulting in a backlog for CDMOs Emergence of new players and capabilities in the market • There is a wide gap between the market demand and the supply capacity on the end of vector and cell manufacturers • Existing players are expanding their services and making huge investments to develop specialized capabilities • Current wait time averages more than 15 months for CMOs to start cell and gene therapy projects1 • In addition to cell therapy capabilities, many facilities provide APIs, vector manufacturing and other biologics production services Short-shelf life and highly-coordinated distribution network increases complexity

• Novel cell and gene therapies require advanced capabilities in decentralized locations for a faster turnaround of Consolidations and partnerships among industry players therapeutic product, including cell scheduling and planning, manufacturing capacity collaboration and • Two of the largest M&A deals ever in the CDMO industry timely transport were seen in 2017 – 2018:

• Establishment and maintenance of chain of identity and • Lonza’s acquisition of Capsugel for $5.5B chain of custody in a regulatory-compliant manner requires robust systems and processing, and trained personnel • Thermo Fisher’s takeover of Patheon for $7.2B

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 46 There has been a surge in M&A activity with many cell therapy manufacturers investing to bolster their market presence Recent deals from the European market illustrate the pace of activity

Net Transaction # Buyer Target Overall Capacity Capabilities Employee # Value 1 Novartis CELLforCURE SASU 3600m2 CMO & manufacturing CMO capabilities 2300 N/A International AG facility Distribution services

Other capabilities 2 Hitachi Chemical Apceth Biopharma GmbH 2 GMP/BSL2 production CMO capabilities 36 $86.7 M Advanced Therapeutics facilities incl. 600 m2 Solutions, LLC cleanroom area Product tech platforms 3 Orgenesis Inc. Hemogenyx-Cell SA N/A Product tech platforms 12 N/A 4 Roche Holding AG Tusk Therapeutics Ltd N/A Product tech platforms 25 $745 M 5 The Invus Group, BioNTech AG GMP facility CMO capabilities 850 N/A LLC (10 independent cleanroom suites) Product tech platforms 6 Thermo Fisher (CN) Patheon N.V. 22 facilities not incl. CMO capabilities 9000 $7.2 B Luxembourg S.a.r.l corporate offices Product tech platforms

Distribution services 7 JSR Corporation; KBI Biopharma Inc. 4 facilities CMO capabilities 600+ $100 M CMIC Holding Product tech platforms

Other capabilities 8 Catalent Pharma Cook Pharmica LLC 2 GMP production facilities CMO capabilities 750 $950 M Solutions, Inc. Product tech platforms

Distribution services

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 47 There are many cell and gene therapy CDMOs across the globe with a concentration in the US and UK Several CDMOs offer a range of services across the cell and gene therapy value chain

ILLUSTRATIVE: ESTONIA Representative footprint, not exhaustive • Cellin Technologies CANADA UNITED KINGDOM FINLAND • C3i • Cobra Biologics • Finvector • CCRM • The Clinical Trial Company • Advent Bioservices Ltd GERMANY • Catapult Cell & Gene Therapy • Cellex Cell Professionals • Cellular Therapeutics Ltd. • Angel Biotechnology PLC • Oxford Biomedica • Apceth Biopharm (Hitachi) • Roslin Cell Therapies • CARAT (CARs for Advanced Therapies) NETHERLANDS • BioNTech (Invus) • Batavia • Fraunhofer Gesellschaft SOUTH KOREA • Esperite SWITZERLAND • CureCell • Lonza • Lonza Netherlands B.V ITALY ISRAEL JAPAN USA BELGIUM • Anemocyte • Aldevron • Atvio • AGC Asahi Glass • Eurogentec • Molmed • VGXI Inc • Medinet Co. Ltd. • MasTHerCell • MassBiologics CHINA FRANCE • Niko CeLL innovation Co. • Paragon Bioservices (Catalent) • WuXi • Takara Bio • Novasep • Brammer Bio (Thermo Fisher) AppTec SPAIN • Yposkesi • KBI Biopharma (JSR Corporation; CMIC Holding) • 3P SINGAPORE • Bio Elpida • Gravitas Biomanufacturing Biopharmaceuticals • CryxGen • CELLforCURE • Cognate Bioservices • Praxis (Novartis) • FUJIFILM Cellular Dynamics Pharmaceutical • Hitachi Chemical Advanced Therapeutics • Histocell SL Solutions, LLC AUSTRALIA • Cell Therapies Pty Ltd • Q-Gen Cell Therapeutics

Vector Day 0 processing Drug product

Companies that provide more than one of the above services

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 48 Specialized manufacturing equipment in cell and gene therapies is distinct from other biologics manufacturing

Activity Equipment required Illustrative vendor(s)

Apheresis wash Cell separation system Biosafe, GE Healthcare and cell separation (e.g., Sepax)

Cell selection or Cell separator Miltenyi Biotec, Thermo Fisher Scientific enrichment (e.g., CliniMACs, Dynamag)

Cell thawing Incubators or dry thawers Thermo Fisher Scientific (e.g., CytoTherm)

Transduction Centrifuge for spinoculation Biosafe, Thermo Fisher Scientific (e.g., Sepax devices)

Cell expansion Bioreactor, CO2 incubator, static culture bags (e.g., GE Healthcare Xuri, Wave bioreactor)

Cell harvest Centrifuge and de-beading device (e.g., CliniMACS, Miltenyi Biotec, Thermo Fisher Scientific Dynamag)

Cell cryopreservation Controlled rate freezer GE Healthcare (e.g., VIA freeze)

Cell characterization Flow cytometer, cell counter, viability analyzer (e.g., BD Biosciences, Thermo Fisher Scientific FACSCalibur, Cellometer K2)

In addition to such equipment, cell manufacturing also requires a number of reagents (e.g., growth media) and consumables (e.g., cell bags)

Cell and gene therapies CDMOs are grappling with being oversubscribed

Manufacturing • There is a wide gap between the market demand and the supply capacity on the end of vector and cell manufacturers capacity crunch • Current wait time averages more than 15 months for CMOs 1 is resulting in to start cell and gene therapy projects1 a backlog for • There is a general lack of industry or institutional knowledge about CDMOs how, when, or where companies would want to establish commercial manufacturing operations of products currently in development, thereby making forecasting a major challenge Short-shelf life and • The supply chain network requires close coordination between multiple stakeholders across organizations and geographies for cell highly-coordinated scheduling and planning, manufacturing capacity collaboration and 2 distribution network timely transport of cellular products increases complexity • Establishment and maintenance of chain of identify and chain of custody during the entire manufacturing process in a regulatory-compliant manner requires robust systems, processing and trained personnel Communication • CDMOs have expressed frustrations over the lack of consistent and frequent communication with client companies and information • Collection and sharing of manufacturing data between entities requires 3 flow between establishment of customized communication portals, and training of CDMO entities is yet personnel for its optimal usage to be streamlined • Navigating the complexities in the financial and product supply chain between the various entities requires establishment of a robust model within the organizations

Supply Chain/Commercialization

AI/Bioinformatics

Regenerative Medicine • Autologous & Allogenic Cells • Stem Cell Therapy • Mitochondrial Transfer • Tissue Engineering

© 2020 Deloitte Global Services Limited Global Life Sciences and Health Care | Practice overview 51 Explosion of Data in Healthcare Healthcare like many other sectors of the economy is grappling with the profusion of data and evidence

Clinical Social Devices GWAS

Clinical Trials Tele Health

Regulatory

ACO Networks Publications

Operational Payors Patient CRM

Evidence Financial

PBM Sensors Modeling insights Communities

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 52 Decoding the Human Genome adds Exponentially to Healthcare Data The Human Genome Project jumpstarted DNA sequencing which provides one of the most insightful but dense data sets available in healthcare

Genome Sequencing Overview Data Storage Requirements for Whole Genome Sequencing

1 Petabyte=1x1015 Bytes (2 Petabytes=all U.S research libraries) Storage Requirements for a Single Genome: • 4 MB for an abbreviated version (Powerpoint file) • 100 GB for a complete version (Laptop Hard Drive)

Source: National Human Genome Research Initiative (NHGRI); Mike Orcutt “Bases to Bytes” MIT Technology Review, April 25, 2012

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 53 Genome Sequencing Cost Declining, Use Growing Exponentially Sequencing entire populations driven by cost declines and sequencing capacity availability

Cost of Whole Genome Sequencing ($) and Genomes Completed

100,000,000 $95,263,072 $19,934,346 Consumer DNA Tests 1,030,000 $11,455,315 7,800,000 10,000,000 $70,175,437 895,000 Over 12MM 1,875,000 $16,180,224 $752,080 Tests Ordered $53,751,684 345,000 1,000,000 $8,927,342 $108,065 144,689 Over 1 $31,125 Millions 100,000 500,000 Genomes Sequenced 10,000 $5,985 $4,905 $2,257

$5,550 1,000 $10,497 Cost of Testing $1,363 $1,121 has Declined Faster than 100 Genomes Sequenced Moore’s Law

2004 2013 2001 2002 2003 2005 2006 2007 2008 2009 2010 2011 2012 2014 2015 2016 2017 2018E

Sources: Deloitte Analysis; GenBank and Whole Genome Shotgun Statistics from NCBI; International Society of Genetic Genealogy; Antonio Regalado, 2017 was the year consumer DNA testing blew up” MIT Technology Review, February 12, 2018; illumine Website, Broad Institute; Nature “Genomes by the Thousands” October 28. 2010

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 54 Data is Behind Delivering Effective Patient Care Healthcare is increasingly becoming a data industry and delivering better patient outcomes requires new capabilities in data mining and analytics

Levels of Data Involved in Patient Care Strategic Implications

Molecular pathways • Current focus on genomics will expand • Solution implications include agility to integrate Genome data, model new data and reference sets, and capture clinical associations and annotations Gene Expression • Increased use of advanced analytics to enable Epigenome clinically interpretable and actionable insights with implications on resource planning and Metabolome information governance

Phenotypic Data (EHR) • Stewardship of the Data still unclear. Diversity of business models will increase around Microbiome controlled data collaboration as new layers of data come online Currently, genomic and phenotypic data are the most widely integrated into clinical care delivery.

Developing the necessary data and analytics infrastructure through direct investment, commercial solutions, and strategic partnerships has become a new source of competitive advantage

Source: http://www.nap.edu/catalog/13284/toward-precision-medicine-building-a-knowledge-network-for-biomedical-research

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 55 Challenges in Using Data in Healthcare Turning data into clinical insights which impacts clinical outcomes is complex

• Create reports & dashboards • Finding appropriate sources of data with insight potential and • Select visualization tools Report (e.g. Qlik, Spotfire, Tableau) Identify clinical annotation (e.g. EHR, claims, social media, imaging, • Develop external interfaces clinical trials, genomic) and policies with external collaborators • Obtain permission to utilize data • Navigate national data privacy requirements Insight

• Select analytic tools • Handle structured and (e.g. SAS, R, MATLAB) Ingest unstructured data • Establish standard workflows • Obtain storage capacity and toolkits and determine modality • Determine level of self-service Integrate (e.g. public cloud, private and experimentation allowed cloud, private servers)

• Determine data architecture & ontology • Create data governance framework • Develop data cleansing approaches • Develop data curation standards

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 56 Deloitte Involvement in Data Transformation Efforts Deloitte has been intimately involved in the digitization of biology and healthcare across all sectors

4 provider PM models Novel trial design (NCI MATCH, I-SPY2) Roche acquires Apple Health TCGA at AACR 2011 Shift in Oncology standard of care Flatiron for $1.9B App in iOS 11.3 Crizotinib Approval Kymriah Approval

2011-2013 2014 2015 2016 2017 2018

PM Business Mayo Moffitt Cases PM PM Provider Strategies Implement PM Inova Geisinger City of Hope UKHC Sustainability IUSM VCU

Amgen TRIP Celgene Platform

RWE RWE Networks Informatics RWE Patient RWE POCs RWE COEs Pharma Strategies Engagement Patient ML/AI/POCs Numerous Celgene Services pharma launches iKU Numerous Novartis pharma

Deloitte / Vineti Partnership CAR-T

Other Life Aggregators: MTB Vendors Aggregators: Aggregators: Liquid Sciences Strategies Emerge Supply Demand Biopsy

M2Gen Value Based Contracting Crohn’s & Colitis ORIEN: Foundation Medicine COH, Illumina Huntsman, M2Gen CINJ

In case of any questions, please feel free to reach out to:

Philip Pfrang Advisory, Partner [email protected]

© 2020. For information, contact Deloitte Touche Tohmatsu Limited. Global Life Sciences and Healthcare 58 Deloitte refers to one or more of Deloitte Touche Tohmatsu Limited, a UK private company limited by guarantee (“DTTL”), its network of member firms, and their related entities. DTTL and each of its member firms are legally separate and independent entities. DTTL (also referred to as “Deloitte Global”) does not provide services to clients. Please see www.deloitte.com/about for a more detailed description of DTTL and its member firms.

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