CRISPR Therapeutics Creating transformative gene-based

Confidential © 2018 CRISPR Therapeutics

CRISPR Therapeutics Creating transformative gene-based medicines for serious diseases

Samarth Kulkarni, PhD

2018 RBC Capital Markets Global

Healthcare Conference

February 22, 2018


Forward-Looking Statements

2

This presentation and other related materials contain forward-looking statements within the meaning of the Private Securities

Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the timing of filing of clinical

trial applications and INDs and timing of commencement of clinical trials, the timing, therapeutic value, development, and

commercial potential of CRISPR/Cas-9 gene editing technologies and therapies, the sufficiency of CRISPR‟s cash resources

and the intellectual property coverage and positions of CRISPR, its licensors and third parties. All statements, other than

statements of historical facts, included or incorporated by reference in this presentation and other related materials, including

statements regarding CRISPR‟s strategy, future operations, future financial position, future revenue, projected costs,

prospects, plans, and objectives of management, are forward-looking statements. The words „„anticipate,‟‟ „„believe,‟‟

„„continue,‟‟ „„could,‟‟ „„estimate,‟‟ „„expect,‟‟ „„intend,‟‟ „„may,‟‟ „„plan,‟‟ „„potential,‟‟ „„predict,‟‟ „„project,‟‟ „„target,‟‟ „„should,‟‟ „„would,‟‟

and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements

contain these identifying words. CRISPR may not actually achieve the plans, intentions, or expectations disclosed in these

forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or

events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a

result of various factors, including: uncertainties regarding the intellectual property protection for CRISPR‟s technology and

intellectual property belonging to third parties; uncertainties inherent in the initiation and completion of preclinical studies for

CRISPR‟s product candidates; availability and timing of results from preclinical studies; whether results from a preclinical trial

will be predictive of future results of the future trials; expectations for regulatory approvals to conduct trials or to market

products; and those risks and uncertainties described under the heading “Risk Factors” in CRISPR‟s most recent annual

report on Form 10-K, and in other filings that CRISPR has made or may make with the U.S. Securities and Exchange

Commission.

In addition, the forward-looking statements included in this presentation and other related materials represent CRISPR‟s

views as of the date of the presentation. CRISPR anticipates that subsequent events and developments will cause its views

to change. However, while CRISPR may elect to update these forward-looking statements at some point in the future,

CRISPR specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as

representing CRISPR‟s views as of any date subsequent to the date of the presentation. Existing and prospective investors

are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are

made.


The CRISPR/Cas9 Revolution

3

A new technology for „editing‟

defective genes has raised hopes for

a future generation of medicines

DISRUPTION DELETION CORRECTION

Specific, efficient, and versatile platform


CRISPR Therapeutics Highlights

4

Strong IP position, experienced leadership, 100+ people, >$250M

cash position as of Q3 2017

STRONG IP & FINANCIAL POSITION

Advancing wholly owned, potentially best-in-class gene-edited

allogeneic CAR-T products toward the clinic

NEXT-GENERATION I/O PLATFORM

50% ownership of Casebia broadens our pipeline and supports our

platform improvement efforts; funded by ~$265M from Bayer

UNIQUE CASEBIA JOINT VENTURE

Pursuing select in vivo indications enabled by in-licensed

technologies, platform improvement, and strategic partners

ADVANCING IN VIVO APPLICATIONS

Rapidly translating revolutionary CRISPR/Cas9 technology into

transformative therapies

LEADING GENE-EDITING COMPANY

Filed first company-sponsored CTA for a CRISPR-based therapeutic;

CTX001 on track to enter trials in 2018 in hemoglobinopathies

PIONEERING CRISPR IN THE CLINIC


CTX001: β-thalassemia Disruption CTA filed

Q4 2017 Collaboration

CTX001: Sickle cell disease (SCD) Disruption IND filing

1H 2018 Collaboration

Our Portfolio

5

Editing

approach Research IND-enabling Ph I/II Partner Structure

Glycogen storage disease Ia (GSD Ia) Correction Wholly-owned

Duchenne muscular dystrophy (DMD) Disruption Wholly-owned

Correction Severe combined immunodeficiency (SCID) Joint venture

Correction Hurler syndrome (MPS-1) Wholly-owned

Anti-BCMA Allogeneic CAR-T Various Wholly-owned

Cystic fibrosis (CF) Correction License option

Hemophilia Correction Joint venture

CTX101: CD19-positive malignancies Various Wholly-owned IND filing

Q4 2018

Anti-CD70 Allogeneic CAR-T Various Wholly-owned

In vivo: Liver

In vivo: Other organs

Ex vivo: Immuno-oncology

Program

Ex vivo: Hematopoietic


Our Therapeutic Programs

6

Hemoglobinopathies Ex vivo lead candidate in genetically-defined disease

In vivo Enable in vivo applications through platform advancements

Immuno-oncology Expand cell therapy platform with allo CAR-T pipeline


Hemoglobinopathies – Devastating Blood Diseases

7

SICKLE CELL DISEASE (SCD) AND β-

THALASSEMIA Blood disorders caused by

mutations in the β-globin gene

Significant worldwide burden

High morbidity and mortality Heavy burden of patient care

300,000 Annual births in SCD and β-thalassemia, respectively 60,000

Frequent transfusions & hospitalizations

Normal

Cell

Sickle

Cell

β-

thalassemia

Anemia Pain Early death


Our Approach – Upregulating Fetal Hemoglobin

8

1. Powars, et al. Blood 1984; 2. Musallam, et al. Blood 2012

SYMPTOMS ARISE SHORTLY AFTER BIRTH

WHEN HEMOGLOBIN SWITCHES FROM FETAL

TO ADULT

REDUCED RISK OF

EVENTS IN SICKLE CELL

DISEASE1

0

1

2

3

4

5

6

7

8

1 10 100

FETAL HEMOGLOBIN LEVEL (%)

MO

RB

IDIT

Y S

CO

RE

R2 = 0.933

REDUCED

SYMPTOMS IN β-

THALASSEMIA2

3 30

0

1

2

3

4

5

6

7

8

5 10 15 20 25

FETAL HEMOGLOBIN LEVEL (%)

CU

MU

LA

TIV

E R

ISK

Aseptic necrosis

Stroke

Hospitalization

Chest syndrome

Crisis

Meningitis

› Naturally occurring genetic variants cause hereditary persistence of fetal hemoglobin (HPFH),

and lead to reduced symptoms in patients with sickle cell disease and β-thalassemia

› Our gene editing strategy aims to recreate these variants in symptomatic patients — an approach

supported by well-understood genetics


CTX001 Upregulates Fetal Hemoglobin and Engrafts in Mice

9

1. n=6 healthy donors; 2. 16-week engraftment data

CTX001 ENGRAFTS IN VIVO IN MICE2 HIGH EDITING RATES LEAD

TO ROBUST HbF INDUCTION1

HU

MA

N /

TO

TA

L B

ON

E M

AR

RO

W V

IAB

LE

CE

LL

S (

%)

Donor 1 Donor 2 Donor 3

Lead Guide

Control

0

20

40

60

80

100

No reduction in engraftment

of edited cells

Performed at

clinical scale

AL

LE

LIC

ED

ITIN

G (

%)

0

20

40

60

80

100

Hb

F/(

Hb

F+

Hb

A)

PR

OT

EIN

TE

TR

AM

ER

(%)

C o n tr o l C T X 0 0 1

0

10

20

30

40

50

CTX001 Control

0

10

20

30

40

50


0 .0

0 .5

1 .0

1 .5

2 .0

Edited Patient

n=2

Non-carrier

n=4

(γ+

β)/

α G

LO

BIN

mR

NA

RA

TIO

Carrier

n=1

ASYMPTOMATIC SYMPTOMATIC

β

Patient

n=2

γ

β

β β

β-thal: Editing Increases Globin Expression to Carrier Levels

10

GLOBIN mRNA RATIO AFTER GENE EDITING OF β-THAL PATIENT

SAMPLES

EDITING BOOSTS RATIO ABOVE

CARRIER LEVEL (GENERALLY

ASYMPTOMATIC)

β-globin

γ-globin

0.5

1.0

1.5

2.0

0.0


SCD: Bi-Allelic Editing Leads to High HbF Protein Levels

11

1. n=163 single erythroid colonies derived from edited CD34+ cells from healthy donors

B i-Alle lic E d ite d M o n o -Alle lic E d ite d W T /W T

0

10

20

30

40

50

CA

LC

UL

AT

ED

Hb

F/(

Hb

F+

Hb

A)

(%)

Unedited Mono-Allelic Bi-Allelic

8% of cells1

unedited

16% of cells1

mono-allelically

edited

76% of cells1

bi-allelically

edited

ESTIMATED HbF EXPRESSION AT THE CELLULAR

LEVEL

Inc

rea

sin

g b

en

efi

t

50

0

40

30

20

10


Pioneering CRISPR Clinical Trial

12

Potential to expand into a registrational trial, as well as to additional

genotype and age cohorts, if supported by safety and efficacy

CTX001-111

A single arm Phase 1/2 study to assess the safety and efficacy of

CTX001 in patients with β-thalassemia

Sites

Sites with extensive

transplant experience in

E.U. countries with

significant disease burden

Up to 30 adult

transfusion-dependent

patients

Patients Endpoints

HbF levels and transfusion

requirements are clinically

relevant and easily

measurable


Autologous CAR-T is Transformative, but has Limitations

13

Patient-to-patient variability

Costly, complicated manufacturing

Patients progress or die while

waiting

Commercial challenges of bespoke

therapy

. . . But there are still significant

limitations to autologous CAR-T

CAR-T has generated tremendous

excitement . . .

The first-ever treatment that

genetically alters a patient‟s own

cells to fight cancer, a milestone

that is expected to transform

treatment in the coming years


Our Approach: Gene-Edited Allogeneic CD19 CAR-T

14

CRISPR enables an allogeneic approach that

remedies issues with autologous CAR-T

CTX101 – our initial immuno-oncology

product candidate

Consistent healthy-donor

lymphocytes

Low COGs and simpler

manufacturing

Product available immediately

Off-the-shelf product – broader

access

MHC I

knock-out

TCR

knock-out

Anti-CD19

CAR

Multiplex

editing in

one step

TCRα

locus

CAR

β2M

locus


Equal or Better Editing Rates Achieved After Tech Transfer

15

Process development and manufacturing initiated for CTX101 –

commencing IND-enabling studies

TC

R-

B2M

-

CA

R+

0

2 0

4 0

6 0

8 0

1 0 0

Ed

itin

g (

%)

EDITING RATES ACROSS MULTIPLE DONORS E

DIT

ING

(%

)

100

80

60

20

0

40

TCR- MHC I- CAR+

In-house

At CMO


CTX101 Eliminates CD19-Expressing Tumor Cells In Vitro

16

0 2 4 6 8

0

2 0

4 0

6 0

8 0

1 0 0

CTX101 COMPARES FAVORABLY

TO LENTIVIRAL “AUTOLOGOUS”

CAR-T

Ratio T cells:Nalm6

0 8

CE

LL

LY

SIS

(%

)

100

80

60

20

0

40

6 4 2

CTX101 (TCR- β2M-

CAR+)

Both produced using the

same donor T cell material

n=2 independent

experiments

Lentiviral Anti-CD19


Numerous Opportunities Beyond CTX101

17

Make rapid entry using

validated tumor targets

Healthy-donor allo approach in

well-validated tumor targets

CD19, BCMA

Expand into solid with novel

targets and advanced

editing

Precise edits to make CAR-T

effective in solid tumors

CD70, resistance to tumor

microenvironment

Unlock the full

potential of CRISPR

Multiplex editing to enable

more complex products

Switches, neoantigens,

bispecifics

Collaborations with Neon and MGH

to identify and exploit new targets


Gene-Edited Allo CAR-T Targeting CD70

18

1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

› >85% CAR+

using a

proprietary

single chain

made in-house

› >99% TCR

knock-out

even before

purification

TU

MO

R V

OL

UM

E (

mm

3)

DAYS

No treatment n=8 mice

CAR-T n=4 mice

SUBCUTANEOUS A498 RENAL CELL CARCINOMA

MODEL COMPLETELY ELIMINATED

CAR-T dosed

10 32 30 28 26 24 22 20 18 16 14 12

0

140

120

100

80

60

40

20


NON-VIRAL VIRAL

Delivering CRISPR/Cas9 to Unlock In Vivo Applications

19

Adeno-Associated Virus (AAV)

Lipid Nanoparticles (LNPs)

Messenger RNA (mRNA)

› Improved tissue

specificity

› Reduced

immunogenicity

› Self-inactivation

› Increased potency

› Expansion beyond liver

delivery

› Improved tolerability

› Controlled duration of

expression

› Tissue specificity

› Increased potency


Potent Liver Editing Using Proprietary LNP Technology

20

SIGNIFICANT DECREASE IN SERUM C3 LEVELS AFTER EDITING IN VIVO

Editing and serum protein quantified in five mice following intravenous LNP dose

P B S O p tim iz e d

L N P

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

No

rm

ali

ze

d C

3 S

eru

m L

ev

els

P B S O p tim iz e d

L N P

0

2 0

4 0

6 0

8 0

1 0 0

Ed

itin

g (

%)

~80% editing in mouse livers and 87% reduction in serum C3 protein using

just 1 mg/kg total RNA: ~3X higher potency than other published data

87%

reductio

n

ED

ITIN

G (

%)

100

80

60

20

0

40

PBS Optimized

LNP N

OR

MA

LIZ

ED

C3 S

ER

UM

LE

VE

LS

120

80

60

20

0

40

PBS Optimized

LNP

100


Optimizing the CRISPR/Cas9 Platform

21

NUCLEASE

ENGINEERING

Enhance CRISPR/Cas9 system

through protein engineering

GUIDE RNA OPTIMIZATION

Identify optimal guide RNA formats

and sequences for therapeutic editing

STEM CELL ENGINEERING

Expand applications of gene-edited

stem cells to treat disease

ADVANCED EDITING

Improve efficiency of gene

correction and multiplexing

PLATFORM

ENHANCEMENT


Fifty-Percent Ownership of Casebia Therapeutics

22

THERAPEUTIC

FOCUS AREAS Hematology Ophthalmology

CRISPR has full access

at no cost to all new IP for use within the field of

human therapeutics

Joint research on

platform technology

– protein engineering,

delivery, etc.

IP

Committed IP for select indications

Committed $370M $265M to Casebia and

$105M to CRISPR

50%

ownership

50%

ownership

Cardiology


Foundational Intellectual Property Landscape

23

BROAD

INSTITUTE

Patent Filings

Strategic Investors

>$3B Partners & Total Deal Size

>$3B <$2B

Human Therapeutics Licensees

via

EMMANUELLE

CHARPENTIER

UC

BERKELEY /

U. VIENNA

Foundational IP estate Broad IP estate

› Direct license to foundational IP covering all human therapeutic fields; term through 2033

› Four large pharma partnerships indicate strength of the Charpentier / Berkeley foundational IP estate

› Access to Vilnius IP estate through invention management agreement


Strong US and Global Foundational IP Position

24

UC-CRISPR granted foundational

patents, including use in eukaryotes

Next steps

› Advancing applications

globally in ~80 jurisdictions

worldwide based on arguments

developed in Europe

UNITED STATES First-to-invent

UC-CRISPR appealing interference decision

in Federal Appeals Court

Next steps

› Appeal expected to

take <12 months

› Multiple patent

applications moving

forward in parallel –

both narrow and

broad claims

EUROPE AND GLOBAL First-to-file

› 3 patents granted between E.U.

and U.K. include single-guide

RNA & uses in all settings

› Patents of broad

scope granted in

China, Australia,

New Zealand,

Singapore,

Mexico

› Appeal ongoing to overturn Feb 2017 PTAB

decision to end the first interference on

technical grounds


MIKE TOMSICEK, MBA Chief Financial Officer

Chief Financial Officer, Abiomed

Experienced Management Team

25

LAWRENCE KLEIN, PHD Head of Business Development & Strategy

Associate Partner, McKinsey & Company

KALA SUBRAMANIAN, PHD SVP, Strategic Development & Operations

Global Head of Program Management, Novartis

SAM KULKARNI, PHD Chief Executive Officer

Partner, McKinsey & Company

RODGER NOVAK, MD President & Chairman

Head of Anti-Infectives R&D, Sanofi

TONY HO, MD Head of Research & Development

Head of Oncology Innovation, AstraZeneca

TYLER DYLAN-HYDE, PHD Chief Legal Officer

Partner, Morrison & Foerster

JIM KASINGER, JD General Counsel & Corporate Secretary

General Counsel, Moderna

Confidential

CRISPR Therapeutics

www.crisprtx.com

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CRISPR Therapeutics Creating transformative gene-based