Precision Biosciences, Inc. · NASDAQ:DTIL
Precision Biosciences — Investor Day (September 2023)
111 slides from Precision Biosciences's investor day presentation, Sep 12, 2023
Slide 1: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements, as may any related presentations, within the meaning of the Private Securities Litigation Reform Act of 1995. The Company intends such forward- looking statements to be covered by the safe harbor provisions for forward
Slide 2: Welcome To Our R&D Day 2023
Welcome To Our R&D Day 2023 September 12, 2023
Slide 3: Today's Overview
Today’s Overview 〉 Precision 2.0 New Identity 〉 ARCUS In Vivo Differentiation & Supporting Preclinical Data 〉 Precision’s Updated Development Plan
Slide 4: Focusing on Our Foundation—In Vivo Gene Editing
Focusing on Our Foundation—In Vivo Gene Editing Precision—from dual to a single platform gene editing company Focused Execution 2023-2025 Ex Vivo CAR T In Vivo Accretive Event Gene Editing Go-Forward Singular Focus In Vivo Gene Editing Pivoting to Our Foundational Strength • ARCUS - wholly owned gen
Slide 5: Current In Vivo Gene Editing Approaches Are Just Scratching the Surface
Current In Vivo Gene Editing Approaches Are Just Scratching the Surface Development today primarily focused on gene knockout in the liver Liver2 ARCUS Breaks Through the Surface Eye Opportunity to go beyond gene Muscle ~7,000-10,000 knockouts in the liver and enable gene monogenic diseases insertion
Slide 6: ARCUS for the More Sophisticated Gene Edit
ARCUS for the More Sophisticated Gene Edit Designed by nature for a multitude of applications versus other gene editing modalities Replace Remove defective and insert functional gene Insertion Insert gene to cause expression Degree of Difficulty ARCUS Remove portion of genome, high Capability To Per
Slide 7: ARCUS Potential to Capture a Significant Portion of the Genetic Medicines Market
ARCUS Potential to Capture a Significant Portion of the Genetic Medicines Market Versus Other Liver-focused Editors The Genetic Medicines Market Opportunity is Substantial Gene Therapy ~$25-$35B Gene Editing market size by 2030 Gene Editing Expected to Disrupt and Continue to Grow the Genetic Medici
Slide 8: What's Important When Gene Editing?
What’s Important When Gene Editing? ON TARGET EDITING EDITING OUTCOMES What happens at the DNA level after a nuclease makes a cut? 〉Specificity: All gene editors need to 〉For gene knockout, the kind of repair doesn’t matter since cut at their specific target site, while any error prone repair can de
Slide 9: Providing Key Framework: On-Target Gene Editing
Providing Key Framework: On-Target Gene Editing Efficiency Percentage of cells that are edited on-target Defined Outcome Random Outcome Distribution of inconsistent edits, Predictable, highly consistent, many of which are not intended or intended = the THERAPEUTIC edit; therapeutic, potentially limi
Slide 10: Providing Key Framework: On-Target Gene Editing
Providing Key Framework: On-Target Gene Editing Efficiency Percentage of cells that are edited on-target Defined Outcome Random Outcome Drivers for Defined Outcome Drivers for Random Outcome Homology-Directed Repair (HDR) Non-Homologous End-Joining (NHEJ) Repair outcomes guided by matching identical
Slide 11: ARCUS is a Sophisticated Editing Tool Designed for Defined Outcomes
ARCUS is a Sophisticated Editing Tool Designed for Defined Outcomes All About The Cut Size Matters Keep It Simple • 3 Prime Overhang Cut • Smallest gene editor (~1500 bp) • Only single component editor that • Small size enables delivery of MORE recognizes and cuts DNA • Drives Homology-Directed Repa
Slide 12: ARCUS Focused on Sophisticated Edits Where Defined Outcomes Are Essential
ARCUS Focused on Sophisticated Edits Where Defined Outcomes Are Essential PROGRAM INDICATION TISSUE TARGET EDIT TYPE / RESEARCH CANDIDATE IND-ENABLING PARTNER DELIVERY SELECTION PBGENE-HBV Chronic hepatitis B Liver HBV Elimination/LNP m3243 primary mitochondrial PBGENE-PMM Muscle PMM Elimination/AAV
Slide 13: Precision Path to Drive Stakeholder Value Through ARCUS Advantages
Precision Path to Drive Stakeholder Value Through ARCUS Advantages 1 2 Drive Organic Development Establish Premium Partnerships Focus on Eliminations, Excisions and Insertions Work with leading Big Pharma/Biotech to drive differentiated programs forward Lead Current PBGENE-DMD PBGENE-HBV PBGENE-PMM
Slide 14: The ARCUS Advantages: A Deeper Dive
The ARCUS Advantages: A Deeper Dive Jeff Smith, PhD, Co-Founder Chief Research Officer
Slide 15: The Dream
The Dream Precision was born 14
Slide 16: The Dream
The Dream Simple, Efficient, Safe Defined Outcomes 15
Slide 17: Bringing the Dream to Reality with Creation of ARCUS
Bringing the Dream to Reality with Creation of ARCUS • ARCUS is derived from the homing endonuclease I-CreI found in green algae ARCUS • Evolved in nature to safely edit a genome and add function ― CRISPR-based editing tools engineered from enzymes evolved to knockout DNA only Only gene editing plat
Slide 18: Defined Outcomes Accomplished Through ARCUS Advantages
The Cut Defined Outcomes Accomplished Through The Size ARCUS Advantages The Simplicity 17
Slide 19: Defined Outcomes Are More Desirable than Random Outcomes
Defined Outcomes Are More Desirable than Random Outcomes: More therapeutic edits and fewer unknown safety risks On target DNA Cut Highly consistent, Defined Outcomes - HDR Distribution of Random Outcomes - NHEJ Small Deletion More Therapeutic Edits Fewer Therapeutic Edits Big Deletion Fewer Random R
Slide 20: It's All About The Cut
It’s All About The Cut ARCUS’s 3 prime, 4 base pair cut drives Defined Outcomes DNA replication direction 3’ overhang DNA replication direction This unique cut drives high efficiency repair by HDR OR “Perfect” Re-ligation leading to Defined Outcomes Gene editing tools utilizing NHEJ produce more “ra
Slide 21: The ARCUS Cut is Uniquely Designed to Drive Defined Outcomes
The ARCUS Cut is Uniquely Designed to Drive Defined Outcomes ARCUS cut leads to HDR or “Perfect” Re-ligation Cas9 CCGTATGCAATTA GCTAGGTCG Blunt cut GGCATACGTTAAT CGATCCGTA induces NHEJ The ARCUS Cut TALEN/ZFN Generates a DNA replication direction CCGTATGCA ATTAGCTAGGTCG 3’ overhang Staggered cut req
Slide 22: ARCUS Cut Drives HDR and Starts Closer to the Defined Outcome
ARCUS Cut Drives HDR and Starts Closer to the Defined Outcome 1 In nature DNA Competitors strands can break start here Lower efficiency, higher chance 2 Need Exonuclease to for random events create an overhang 3 Broken DNA in HDR ready-state with 3’ ARCUS starts here overhang Designed to avoid added
Slide 23: "The Proof" That It's All About The Cut
Gene Insertion Experiments “The Proof” That It’s • ARCUS inserted with greater efficiency than CRISPR/Cas9 All About The Cut • 3’ overhang cut is critical for HDR 22
Slide 24: ARCUS Inserted with 17x Higher Efficiency than CRISPR
ARCUS Inserted with 17x Higher Efficiency than CRISPR A true head-to-head comparison ARCUS vs CRISPR insertions 40% 36% 32% 28% Head-to-head comparison at same site, Insertion Efficiency % 24% 17x same dose, with same DNA template. 20% higher 16% 12% ARCUS was More Efficient 8% 4% 0% Mock DNA Templa
Slide 25: 3' Overhangs Promoted Insertion Through HDR
3’ Overhangs Promoted Insertion Through HDR Chewing off the 3' overhangs impacts insertion efficiency Impact of 3’ overhangs made by ARCUS 60% 50% 49% • TREX1 removes 3’ overhangs of ARCUS Insertion Efficiency % 40% Loss of • TREX1 generates CRISPR-like blunt cuts 30% 3’ overhangs • Blunt cut ablate
Slide 26: The Cut Drives Defined Outcomes
The Cut Drives Defined Outcomes ARCUS generates a 3’ overhang cut 3’ overhang cut enables Homology-Directed Repair (HDR) 3’ overhang cut with complementary overhangs in ready-state for “Perfect” Re-ligation Higher HDR and “Perfect” Re-ligation result in higher rate of Defined Outcomes More Defined O
Slide 27: Defined Outcomes Accomplished Through ARCUS Advantages
The Cut Defined Outcomes Accomplished Through The Size ARCUS Advantages The Simplicity
Slide 28: Size Matters for Where You Can Deliver
Size Matters for Where You Can Deliver ARCUS can use different delivery vehicles to target diverse tissue types ARCUS LNP AAV Liver Eye Muscle CNS Other 27
Slide 29: Size Matters for Where You Can Deliver
ARCUS 1500 bp SaCas9 4200 bp AAV Genome Capacity ~4700 bp Size Matters for Cas12a 4900 bp Where You Can Deliver: ARCUS ARCUS is the Smallest Gene SpCas9 Editing Tool in Development 5100 bp Base Editor (ABEmax) 5800 bp – 6500 bp Prime Editor (PEmax) 7200 bp Sizes include editor and expression machine
Slide 30: Size Matters for Going Beyond the Liver
Size Matters for Going Beyond the Liver ARCUS has demonstrated editing in a breadth of diverse tissue types Indication Organ Delivery Animal model edited Hepatitis B + undisclosed Liver LNP / AAV NHP / Mouse Duchenne Muscular Dystrophy Muscle AAV NHP / Mouse Undisclosed CNS TBD NHP* / Mouse Sickle C
Slide 31: Size Matters for What You Can Deliver: Two Nucleases in One AAV
ARCUS 1500 bp SaCas9 4200 bp AAV Genome Capacity ~4700 bp Size Matters for ARCUS Cas12a 4900 bp What You Can Deliver: Small ARCUS Size Allows SpCas9 Two Nucleases in One AAV 5100 bp ARCUS for Gene Excision Base Editor (ABEmax) 5800 bp – 6500 bp Prime Editor (PEmax) 7200 bp Sizes include editor and e
Slide 32: Size Matters for What You Can Deliver: DNA Template in a Single AAV
ARCUS 1500 bp SaCas9 4200 bp AAV Genome Capacity ~4700 bp Size Matters for ARCUS Cas12a 4900 bp What You Can Deliver: Allowing Delivery with a SpCas9 DNA Template in a Single AAV DNA Template 5100 bp for Gene Insertion Base Editor (ABEmax) 5800 bp – 6500 bp Prime Editor (PEmax) 7200 bp Sizes include
Slide 33: Defined Outcomes Accomplished Through ARCUS Advantages
The Cut Defined Outcomes Accomplished Through The Size ARCUS Advantages The Simplicity 32
Slide 34: Simplicity: ARCUS is the Only Single Component Editor
Simplicity: ARCUS is the Only Single Component Editor ARCUS Single protein with a DNA recognition motif and catalytic 1 activity all in one; no guide RNA required Editing outcome not dependent on simultaneous delivery of multiple components leading to higher efficiency Single component requires less
Slide 35: Simplicity: Multiple Components in Separate Delivery Vehicles Results in Lower Efficiency
Simplicity: Simultaneous Delivery of Multiple Components in Separate Delivery Vehicles Results in Lower Efficiency CRISPR Base Editor Prime Editor 1 Cas9 2 1 dCas9 or Cas9n 2 1 Cas9n 2 pegRNA 3 deaminase Reverse 3 transcriptase 34
Slide 36: Simplicity: Fewer Components Results in Higher Efficiency
Simplicity: Fewer Components to Deliver Results In Higher Efficiency and Defined Outcomes at a Lower AAV Dose ARCUS + DNA Template gRNA + DNA Template CRISPR/Cas Nuclear DNA Nuclear DNA 35
Slide 37: Simplicity: ARCUS Can Go Where Few Other Gene Editors Can Follow
Simplicity: ARCUS Can Go Where Few Other Gene Editors Can Follow ARCUS CRISPR Base ARCUS + gRNA Prime + gRNA + gRNA Mitochondria 36
Slide 38: ARCUS Versus Other Gene Editors in Development
ARCUS Versus Other Gene Editors in Development ARCUS CRISPR Base Editor Prime Editor Cut Result 3 prime overhang Blunt end cut Variable1 Variable1 Large insertions HDR NHEJ / DNA capture Not Applicable Not Applicable Cut Large excisions Perfect re-ligation NHEJ Not Applicable Not Applicable Kilobase
Slide 39: Highest Probability of Defined Outcomes
• 3’ Overhang Stimulates HDR • Supports “Perfect” Re-ligation The Cut • Designed for High Efficiency, Highly Therapeutic Gene Edit • Smallest Gene Editor The Size • Enables ARCUS + Additional Payload Highest Probability In One Delivery of Defined Outcomes • Delivery to More Tissues Across Body • Sin
Slide 40: The Cut (Insertion)
The Cut (Insertion) Cassie Gorsuch, Ph.D. Vice President, Gene Therapy Discovery
Slide 41: Gene Insertion Efficiency and Outcomes are Context-Dependent
Gene Insertion Efficiency and Outcomes are Context-Dependent 1 2 3 4 Dividing cells Non-dividing, primary Dividing cells in vivo Non-dividing cells in vivo in culture cells in culture (infant/child) (adults) Increasing Level of Evidence & Difficulty 40
Slide 42: ARCUS Inserted with High Efficiency in Dividing Cells in Culture
ARCUS Inserted with High Efficiency in Dividing Cells in Culture High Efficiency Gene Insertion Mechanism of Repair 1 100 75.9% 75 Gene Insertion (%) 50 92% Dividing cells HDR 25 in culture 0 0 0.2 Mock DNA Template DNA Template + Alone ARCUS Data on file 41
Slide 43: ARCUS Inserts Efficiently in Both Copies of Target Gene
ARCUS Inserts Efficiently in Both Copies of Target Gene Resulting in High Functional Impact - Dividing Cells in Culture ARCUS inserts in both alleles* Bi-allelic editing results in high 1 functional impact 60 Therapeutic Gene Induction (%) 51.4% 50 40 37.1% 91% 30 Dividing cells Bi-allelic 20 in cul
Slide 44: ARCUS Can Drive Efficient HDR in Both Dividing and Non-Dividing Cells
ARCUS Can Drive Efficient HDR in Both Dividing and Non-Dividing Cells… …Previously Thought to be Nearly Impossible for Gene Editing “However, traditional HDR "By the late 1980's, dogma “Inability to correct genes has very low efficiency in most in the field of DNA repair in non-dividing cells human
Slide 45: ARCUS Inserts Efficiently in Non-Dividing Cells in Culture
ARCUS Inserts Efficiently in Non-Dividing Cells - in Culture High Efficiency Gene Insertion Mechanism of Repair 2 40 28.6% 30 Gene Insertion (%) 20 57% Nondividing HDR 10 primary cells in culture 0 0% Mock DNA Template + ARCUS ARCUS Ability to Insert by HDR in Non-Dividing Cells is Attributable to t
Slide 46: ARCUS Inserts with High Efficiency in Infant Nonhuman Primates
ARCUS Inserts with High Efficiency in Infant Nonhuman Primates; Sustained Effect Demonstrated at 12 months 3 Dividing cells High Efficiency Gene Insertion Day 84 Day 365 25 in vivo 19.9 NHP #1 NHP #1 15.3 20 Gene Insertion (%) 15 NHP #2 NHP #2 10 + 5 ARCUS DNA Template AAV AAV 0 1e13 vg/kg 3e13 vg/k
Slide 47: ARCUS Inserts with High Efficiency in Adult Nonhuman Primates
ARCUS Inserts with High Efficiency in Adult Nonhuman Primates Previously Thought to be Unachievable 4 Nondividing High Efficiency Gene Insertion cells in vivo 50 44.6 40.6 Gene Insertion (%) 40 >3x 30 insertion efficiency of CRISPR-based 20 approach* + 10 ARCUS DNA Template 0 0 0 0.1 LNP AAV 0 1.75
Slide 48: ARCUS is Ideal for Therapeutic Gene Insertion
ARCUS is Ideal for Therapeutic Gene Insertion High efficiency insertion rates High HDR observed Designed to Increase Therapeutic Effect Biallelic editing demonstrated Breadth in Level of Evidence Demonstrating Insertion in Dividing and Non-Dividing Cells In Vitro and In vivo 47
Slide 49: Gene Insertion Pipeline
Gene Insertion Pipeline PROGRAM INDICATION TISSUE TARGET COMPLEX EDIT TYPE PARTNER Sickle cell disease/ PBGENE-NVS HSCs — Insertion Beta thalassemia PBGENE-LLY2 Undisclosed Liver — Insertion Ornithine transcarbamylase iECURE-OTC Liver OTC Insertion deficiency 48
Slide 50: Reasons to Believe in Precision's Gene Insertion Approaches
Reasons to Believe in Precision’s Gene Insertion Approaches High efficiency gene insertion in dividing and non-dividing cells in vitro and in non-human primates (NHP) In NHP study 1-year follow-up biopsies demonstrate durability with gene insertion YEAR efficiency of 20%, well above the expected thr
Slide 51: Size (Excision)
Size (Excision) Cassie Gorsuch, PhD Vice President, Gene Therapy Discovery
Slide 52: Size Matters: Only ARCUS Packages Two Nucleases in a Single AAV
Size Matters ARCUS ARCUS Only ARCUS is small enough to package two different nucleases in a single AAV AAV Genome Capacity (~ 4700 bp) ARCUS P ARCUS nuclease P ARCUS nuclease 1 P ARCUS nuclease 2 CRISPR/Cas U P SaCas9 U P AsCas12a/Cpf1 U P SpCas9 Prime Editing U P ABE SpCas9 Nickase (Adenine Base Ed
Slide 53: ARCUS Nucleases Excise Mutations and Restore Function in DMD
ARCUS Nucleases Excise Mutations and Restore Function in DMD ARCUS 1 ARCUS 2 Exon 44 Exon 56 Exon 57 Two complementary ARCUS nucleases Exons 45-55 delivered in a single AAV are used to excise a mutation “hot spot” in Exons 45-55 responsible for ~50% of DMD cases Exon 44 Exon 56 Exon 57 Exons 45-55 d
Slide 54: ARCUS-Edited Dystrophin Preserves Majority of Protein Domains
ARCUS-Edited Dystrophin Preserves Majority of Protein Domains With the Goal of Improving Function Normal ABD R1-R3 R4-R19 R20-R24 CR CT Dystrophin ELEVIDYS (Sarepta) Recently approved product ABD R1-R3 R24 CR ARCUS ABD R1-R3 R4-R17.5 R22.5-R24 CR CT Edited Dystrophin ABD: actin binding domain, R: ro
Slide 55: "The Proof" That Size Matters in DMD
• ARCUS can be delivered to muscle tissues “The Proof” That • Two ARCUS nucleases fit into a single AAV Size Matters in DMD • ARCUS compatible 3’ overhangs enable “Perfect” Re-ligation 54
Slide 56: In Vivo Functional POC Study Design
In Vivo Functional POC Study Design Objective: Assess muscle function in a humanized, Readouts: murine model of DMD 〉Excision of Exons 45-55 Muscle 〉Dystrophin restoration Test Article: 〉Force frequency 〉BaseScope for editing in Pax7+ cells A single AAV with 2 early generation ARCUS nucleases, expre
Slide 57: ARCUS Excision Results in "Perfect" Re-ligation
Due to the Cut, ARCUS Excision Results in “Perfect” Re-ligation Quadricep Defined Outcome 25 14.6 20 Excision(%) Genome repair via direct re-ligation 15 Exon 44 Exon 56 Exon 57 72% 10 Perfect Re-ligation 5 0.0 0 Untreated Treated 56
Slide 58: Edited Dystrophin Protein Variant Expressed in Target Tissues
Edited Dystrophin Protein Variant Expressed in Target Tissues Quadricep Calf 20 13.0 8 Dystrophin restoration (%) Dystrophin restoration (%) 4.0 15 6 10 4 Truncated dystrophin protein 5 2 produced from splice edited mRNA 0.0 0.0 0 0 Treated Untreated Treated Untreated ABD R1-R3 R4-R17.5 R22.5-R24 CR
Slide 59: Maximum Force Output in ARCUS-Treated Mice was Significantly Improved
Maximum Force Output in ARCUS-Treated Mice was Significantly Improved 350 *# 300 *# *# 250 ARCUS-treated mice achieved *# Force (mN) 200 150 *# 86 Output Levels % Maximum Force 100 *# Treated (hDMDdel52/mdx) #1 compared to non-diseased, *# *# Untreated (hDMDdel52/mdx) #2 Healthy Control (hDMD/mdx) #
Slide 60: ARCUS Ability to Edit Muscle Satellite Stem Cells
ARCUS Ability to Edit Muscle Satellite Stem Cells Suggests Maintained Muscle Function Over Time We observed evidence of the edited dystrophin mRNA transcript in PAX7+ cells, a marker for muscle satellite stem cells Pax7+ Edited DMD 44-56 mRNA 40X ASGCT 2023, Owens, “ARCUS-Mediated Excision of the ‘H
Slide 61: Reasons to Believe in Precision-Prevail Approach for DMD
Reasons to Believe in Precision-Prevail Approach for DMD Small size of ARCUS enables delivery of two nucleases in a single AAV to excise hot-spot region of dystrophin and the unique cut yields complementary 3’ overhangs and for “Perfect” Re-ligation Edited Dystrophin protein variant expressed across
Slide 62: Simplicity
Simplicity Cassie Gorsuch, PhD Vice President, Gene Therapy Discovery
Slide 63: Simplicity: ARCUS is the Only Single Component Editor
Simplicity: ARCUS is the Only Single Component Editor ARCUS Single protein with a DNA recognition motif and catalytic 1 activity all in one; no guide RNA required Editing outcome not dependent on simultaneous delivery of multiple components leading to higher efficiency Single component requires less
Slide 64: Hepatitis B Virus (HBV): Precision's Program PBGENE-HBV
Hepatitis B Virus (HBV) Precision’s Program: PBGENE-HBV
Slide 65: HBV Currently Lacks a Curative Treatment
HBV Currently Lacks a Curative Treatment Hepatitis B is a leading cause of morbidity in the US and death globally, with no current curative options > 300 million An estimated 15% to 40% of patients cHBV infections globally > 1,000,000 cHBV infections in the US with HBV infections may develop complic
Slide 66: The Quest for a Functional Cure Through HBV Elimination
The Quest for a Functional Cure Through HBV Elimination Strategy Sustained Undetectable Circulating HBV Surface Functional Cure = Antigen (HBsAg) and HBV DNA After a Finite Course of Treatment. “Ability to achieve functional cure today is extremely limited… Gene editing therapies would enhance the p
Slide 67: Hepatitis B Viral Lifecycle
Hepatitis B Viral Lifecycle HBV DNA HBsAg Hepatocyte cccDNA HBV RNAs Host DNA Integrated HBV DNA 66 Nucleus
Slide 68: ARCUS Approach for a Functional Cure
ARCUS Approach for a Functional Cure ARCUS eliminates cccDNA and inactivates integrated HBV to drive durable antigen loss HBV DNA HBsAg HBV-infected Hepatocyte cccDNA HBV RNAs Integrated HBV DNA 67 Nucleus
Slide 69: ARCUS Approach for a Functional Cure
ARCUS Approach for a Functional Cure ARCUS eliminates cccDNA and inactivates integrated HBV to drive durable antigen loss HBV DNA HBsAg HBV-infected Hepatocyte cccDNA HBV RNAs Integrated HBV DNA 68 Nucleus
Slide 70: ARCUS Approach for a Functional Cure
ARCUS Approach for a Functional Cure ARCUS eliminates cccDNA and inactivates integrated HBV to drive durable antigen loss Elimination of cccDNA HBsAg and inactivation of integrated DNA reduces HBV DNA HBV RNA, HBV DNA, and HBsAg potentially leading to a functional cure HBV-infected Hepatocyte cccDNA
Slide 71: Hepatitis B – ARCUS is Differentiated Versus Other Approaches
Hepatitis B – ARCUS is Differentiated Versus Other Approaches ENTRY INHIBITORS HBV DNA HBsAg Hepatocyte NUCLEOS(T)IDE ANALOGS CAPSID ASSEMBLY MODULATORS NUCLEIC ACID POLYMER THERAPY cccDNA HBV RNAs ANTISENSE ARCUS OLIGONUCLEOTIDES Host DNA SMALL INTERFERING RNA Integrated HBV DNA 70 Nucleus
Slide 72: ARCUS Recognizes a Highly Conserved Sequence in cccDNA
Selecting Target Site: ARCUS Recognizes a Highly Conserved Sequence in cccDNA Target site conserved in 92% ARCUS of isolates Target Site across genotypes1,2 Core S PreS1 X PreS2 1. Gorsuch CL, et al. Mol Ther. 2022;30(suppl 9):2909-2922. 2. Image source adapted from: Tu T, et al. Viruses. 2021;13(2)
Slide 73: ARCUS Recognizes a Highly Conserved Sequence in Integrated HBV DNA
Selecting Target Site: ARCUS Recognizes a Highly Conserved Sequence in Integrated HBV DNA ARCUS Targeted region is present in Target Site the vast majority of integrations1 Core S PreS1 X PreS2 1. van Buuren, N, et al. JHEP Rep. 4.4 (2022): 100449. Published 2022 Feb 12. doi:10.1016/j.jhepr.2022.100
Slide 74: ARCUS Approach to Eliminate cccDNA and Inactivate Integrated HBV
ARCUS Approach to Eliminate cccDNA and Inactivate Integrated HBV to Drive Durable Antigen Loss with Goal of Functional Cure Therapeutic Outcomes 1 Elimination by exonuclease ARCUS DNA break HBV DNA and HBsAg loss occurs “Indel” via DNA repair HBV cccDNA HBV cccDNA HBV DNA and HBsAg loss 2 DNA break
Slide 75: "The Proof" HBV Program
• ARCUS designed to eliminate cccDNA and “The Proof” inactivate integrated HBV DNA • POC demonstrated both in vitro and in novel HBV Program animal models • mRNA improvements to achieve efficiencies needed for HBV 74
Slide 76: ARCUS Eliminated cccDNA in HBV-infected Primary Human Hepatocytes
ARCUS Eliminated cccDNA in HBV-infected Primary Human Hepatocytes ARCUS 85% 29% Elimination by Remaining cccDNA exonuclease HBV cccDNA has indels ~90% Total cccDNA editing efficiency Gorsuch et al, 2022. Molecular Therapy 75
Slide 77: ARCUS Dual Mechanism Drives Desired Therapeutic Outcomes
ARCUS Dual Mechanism Drives Desired Therapeutic Outcomes cccDNA elimination and integrated HBV inactivation led to sustained HBsAg loss ARCUS ARCUS Integrated HBV DNA HBV cccDNA 90% 87% editing efficiency editing efficiency Therapeutic Outcome Therapeutic Outcome 80% 77% 80% sustained loss sustained
Slide 78: HBV Episomal In Vivo Model
HBV Episomal In Vivo Model ao Ad “un 77
Slide 79: ARCUS Inactivated Viral DNA and Durably Reduced HBsAg By 96%
Step 1: ARCUS Inactivated Viral DNA and Durably Reduced HBsAg By 96% Editing Efficiency Therapeutic Outcome 30000 ARCUS Dosed 25000 HBsAg (% of control) 40% 86% 20000 96% reduction indels in reduction in viral copy remaining 15000 in secreted number viral DNA HBsAg 10000 5000 0 1 2 3 4 5 6 7 Control
Slide 80: ARCUS Eliminated and Inactivated >80% Total Viral DNA
Step 2: ARCUS Eliminated and Inactivated >80% Total Viral DNA Editing Efficiency Through Viral Elimination Editing Efficiency Through Indels 35 100 30 23.4 44% 80 44% indels in remaining AAV Copies/Diploid Cell 25 indels viral in DNA remaining AAV % Indels 60 20 66% Of reduction in remaining 15 vira
Slide 81: Enhancing HBV Efficacy via mRNA Optimization
Enhancing HBV Efficacy via mRNA Optimization ARCUS Protein Expression in Mice 10000 ARCUS Protein (ng/g tissue) 8000 6000 mRNA Sequence Optimization 8x 4000 increase 2000 0 Current ARCUS mRNA Future ARCUS mRNA 80
Slide 82: Reasons to Believe in Precision's Approach for HBV
Target CTA/IND Reasons to Believe in Precision’s Approach for HBV 2024 ARCUS is only approach for HBV targeting both elimination of cccDNA and inactivation of integrated HBV DNA 80% reduction in HBV DNA and 96% reduction in HBsAg after a finite course of treatment in preclinical animal models Precis
Slide 83: HBV Expert Discussion
HBV Expert Discussion Alan List, MD Mark Sulkowski, MD Chief Medical Officer Chief, Division of Infectious Diseases Precision BioSciences, Inc. John Hopkins University School of Medicine 82
Slide 84: Primary Mitochondrial Myopathy
Primary Mitochondrial Myopathy Wendy Shoop, PhD Research Leader – Mitochondrial Programs
Slide 85: Simplicity: ARCUS Can Go Where Few Other Gene Editors Can Follow
Simplicity: ARCUS Can Go Where Few Other Gene Editors Can Follow ARCUS CRISPR Base ARCUS + gRNA Prime + gRNA + gRNA Mitochondria 84
Slide 86: Primary Mitochondrial Myopathy Currently Lacks a Curative Treatment
Primary Mitochondrial Myopathy (PMM) Currently Lacks a Curative Treatment Mitochondrial diseases (MDs) Primary mitochondrial myopathies (PMM) are the most common are genetically defined disorders leading to defects in hereditary metabolic energy production predominantly affecting skeletal muscle dis
Slide 87: Multi-Copy Mitochondrial DNA is Critical for Mitochondrial Function
Multi-Copy Mitochondrial DNA (mtDNA) is Critical for Mitochondrial Function Essential for energy production Mitochondrial DNA (mtDNA) Human Cell Mitochondria 86
Slide 88: The mtDNA is Prone to Mutation, Leading to Mitochondrial Disease
The mtDNA is Prone to Mutation, Leading to Mitochondrial Disease m.1555A>G. m.14709T>C. m.1624C>T m.14484T>C, m.14459G>A m.14487T>C m.3243A>G m.13513G>A m.3460G>A. m.4300A>G. 4,977 bp deletions m.11777C>A, m.11778G>A m.5545C>T. m.10158T>C, m.10191T>C, m.10197G>A m.8993T>G/C, m.79176T>G/C m.7445A>G,
Slide 89: PBGENE-PMM Distinguishes a Single Base Difference at m.3243
PBGENE-PMM Distinguishes a Single Base Difference at m.3243 • Mutation Prevalence of 1/5001 m.3243 associated PMM m.3243A>G • ~36% of Mitochondrial Diseases are driven by estimated at ~14k patients in the US alone3 m.3243A>G2 Mutant mtDNA sequence 5’-C A G G G C C C G G T A A T C G C A T A A A-3’ 5’
Slide 90: mtDNA Mutations Are Commonly Heteroplasmic
mtDNA Mutations Are Commonly Heteroplasmic Situation where two or more mtDNA variants exist in same mitochondria Clinically asymptomatic Clinically symptomatic 40% mutant 60% mutant 70% mutant 80% mutant Biochemical threshold Mutant mtDNA Wild-type mtDNA mtDNA, mitochondrial DNA. 89
Slide 91: Key Differences Between Editing Nuclear DNA and Mitochondrial DNA
Key Differences Between Editing Nuclear DNA and Mitochondrial DNA Nuclear DNA mtDNA • Most cells contain one nucleus • Each cell contains many mitochondria • Nuclear DNA is diploid • mtDNA is polyploid (hundreds to thousands of (two copies per cell) copies per cell) • Mechanisms exist to repair DSBs
Slide 92: mitoARCUS Therapeutic Approach to Shift Heteroplasmy
mitoARCUS Therapeutic Approach to Shift Heteroplasmy Cytoplasm mitoARCUS MTS ARCUS mito-targeting polyA sequence WT MTS ARCUS mtDNA Mitochondrial matrix mutant ARCUS mtDNA mtDNA, mitochondrial deoxyribonucleic acid; MTS, mitochondrial targeting sequence; WT, wild-type. 91
Slide 93: mitoARCUS Localizes Exclusively to Mitochondria
mitoARCUS Localizes Exclusively to Mitochondria ARCUS fused to a mitoARCUS Mitochondria Mitochondrial Targeting Sequence (MTS) localized to mitochondria in vitro Nucleus Merged Images MTS, mitochondrial targeting sequence. Shoop, et al. ESGCT MIT. Poster 422. 92
Slide 94: "The Proof" PMM Program
• Single component nature of ARCUS allows specific “The Proof” editing of mutant mtDNA with no off-target editing • ARCUS-induced heteroplasmy shift resulted in PMM Program respiratory improvement in edited cells • POC of in vivo mtDNA editing with mitoARCUS 93
Slide 95: PBGENE-PMM Shifts Heteroplasmy
PBGENE-PMM Shifts Heteroplasmy On target efficacy 120% Relative mtDNA copy number 100% 80% 60% 40% 20% 0% Control PBGENE-PMM mutant mtDNA WT mtDNA mtDNA, mitochondrial DNA; WT, wild-type. 94
Slide 96: PBGENE-PMM Specifically Eliminated Mutant but Not Wildtype mtDNA
PBGENE-PMM Specifically Eliminated Mutant but Not Wildtype mtDNA On target efficacy Mitochondrial off target specificity 120% 14 Relative mtDNA copy number 12 100% 10 mtDNA copy number 80% 8 60% 3x higher dose 6 40% 4 20% 2 0 0% 0 20 40 60 80 Control PBGENE-PMM Hours post nuclease treatment mutant m
Slide 97: PBGENE-PMM Designed Not to Cut Nuclear DNA
PBGENE-PMM Designed Not to Cut Nuclear DNA On target efficacy Nuclear off target specificity 120% 1.0% Relative mtDNA copy number 100% 0.8% 80% 0.6% 20x higher dose % indels 60% 0.4% 40% Limit of Detection (LOD) 20% 0.2% 0% 0.0% Control PBGENE-PMM Offsite 1 2 3 4 5 6 7 8 9 10 11 12 13 14 mutant mtDN
Slide 98: PBGENE-PMM Improved Mitochondrial Function
PBGENE-PMM Improved Mitochondrial Function On target efficacy Impact on energy production 120% 4 Relative mtDNA copy number 3.5 100% OCR (pmol O2/min/1000 cells) 3 80% 2.5 60% 2 1.5 40% 1 20% 0.5 0% 0 Control PBGENE-PMM Control PBGENE-PMM mutant mtDNA WT mtDNA mtDNA, mitochondrial DNA; WT, wild-type
Slide 99: mitoARCUS Shifted Heteroplasmy in In Vivo Mouse Model
mitoARCUS Shifted Heteroplasmy in In Vivo Mouse Model Heart Tibialis Anterior Quad Calf Kidney Liver Spleen 20 0 % Change mutant mtDNA -20 (normalized to brain) -40 -60 -80 -100 -120 Control mitoARCUS mtDNA, mitochondrial DNA. Zekonyte U, et al. Nat Commun. 2021. 2021;12(1):3210. 98
Slide 100: PBGENE-PMM Strategy
PBGENE-PMM Strategy Attributes of PBGENE-PMM Construct Delivery Tissue-Specific Subcellular Specificity Expression Localization Single-vector AAV Muscle-specific promoter MTS traffics mitoARCUS PBGENE-PMM specifically delivery drives gradual limits nuclease expression nuclease to mitochondria cuts m
Slide 101: Reasons to Believe in Precision's Approach to Treat PMM
Target CTA/IND Reasons to Believe in Precision’s Approach to Treat PMM 2025 Simplicity of ARCUS single component editor enables targeting mutant mitochondrial DNA whereas other guide RNA-based editors cannot Opportunity for a one-time, potentially curative treatment for adult patients who today are
Slide 102: Mitochondrial expert discussion
Mitochondrial expert discussion Alan List, MD Carlos T. Moraes, PhD Michio Hirano, M.D. Chief Medical Officer Esther Lichtenstein Professor of Neurology Chief, Division of Neuromuscular Disorders; Precision BioSciences, Inc. University of Miami Miller School of Medicine New York-Presbyterian/Columbi
Slide 103: Concluding Remarks
Concluding Remarks Michael Amoroso President & Chief Executive Officer
Slide 104: More Defined Outcomes Accomplished Through ARCUS
• 3’ Overhang Stimulates HDR The Cut • Supports Perfect Re-ligation • Designed for High Efficiency, Highly Therapeutic Gene Edit More Defined • Smallest Gene Editor Outcomes • Enables ARCUS + Additional Payload The Size Accomplished In One Delivery • Delivery to More Tissues Across Body Through ARCU
Slide 105: Next Steps: Precision to Drive Stakeholder Value Through ARCUS
Next Steps: Precision to Drive Stakeholder Value Through ARCUS Drive Organic Development in Sophisticated Edits Focus on Insertions, Excisions and Eliminations Lead PBGENE-HBV PBGENE-PMM Partnered programs (Elimination) (Elimination) Programs 2023 Positive INTERACT FDA 2023 Final Clinical Candidate
Slide 106: Thank you
Thank you
Slide 107: Appendix
Appendix un
Slide 108: Glossary of Terms
Glossary of Terms AAV Insertion On-Target Effect Adeno Associated Virus, common viral delivery Insert gene to cause expression Expected and desired alterations to the genome vehicle for gene therapy as a result of actions on intended genomic sites Knockout Defined Outcome Cause scar in gene to stop
Slide 109: Hemoglobinopathies are a Major World Health Problem
Hemoglobinopathies are a Major World Health Problem Sickle Cell Disease Affects the structure/function of Sickle Cell ~1,000 children hemoglobin, reducing the ability of Disease Affects in Africa are born with red blood cells to transport oxygen >300,000 SCD every day and • Acute sickle cell pain cr
Slide 110: Ornithine Transcarbamylase (OTC) Deficiency is a Severe, Ultra Rare Genetic Condition
Ornithine Transcarbamylase (OTC) Deficiency is a Severe, Ultra Rare Genetic Condition with Extremely High Unmet Medical Needs OTC Deficiency (OTCD) Neonatal onset has been associated with • Results from genetic defect in a liver enzyme driving detoxification of ammonia. mortality rates • Patients wi
Slide 111: Duchenne Muscular Dystrophy Currently Lacks a Curative Treatment
Duchenne Muscular Dystrophy Currently Lacks a Curative Treatment On average, children lose their ability to walk by age 12 Mutation on the X chromosome interferes with dystrophin protein production, which is needed to form and maintain healthy muscle Affects approximately 1 in 3,500 live male births
Precision BioSciences — Investor Day (September 2023) on 6ix