Genome Editing6c5a46c7-5b71-40ab-afe3-f723ed4… · (whole genome sequencing, definition and identification of genetic risk factors) – Intervention - CRISPR is about to possibly

Confidential© 2018 CRISPR Therapeutics

Genome EditingWhat will the Future bring?

Swiss Re, October 2018

Rodger Novak, MD

President, Director & Chair of the Board CRISPR Therapeutics AG


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 Gene Editing is Precise and Highly Efficient

4

https://www.youtube.com/watch?v=UKbrwPL3wXE

https://www.youtube.com/watch?v=UKbrwPL3wXE


CRISPR Publications Between 2012 and 2017

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› Fully democratized technology – academia as driver of innovation

› Reasons are ease of use, versatility, preciseness and low costs


Human Therapeutics - Two Principles Apply to Gene Editing

Ex-vivo and in-vivo applications

6

IN VIVO – REQUIRES DELIVERY EX VIVO - USES ELECTROPORATION


Adressable Disease Areas, Benefits and Challenges

7

Benefits

Challenges

Hematology

Neurodegenerativ

e Diseases

Immuno-Oncology

Cardiology

Ophtalmology

Autoimmune

› Causative treatment of severe diseases of all

organ systems

› Monogenic and polygenic diseases

› Ease of use as driver of innovation –

including unraveling complex disease

biologies

› Early stage of pharmaceutical development

› Ex vivo therapies most amenable – however,

primarily cost intense cell therapies

› Systemic use – in vivo – target organ

specificity (delivery) and pharmacology


Somatic vs Germline Mutations

8

Somatic Mutation Germline Mutation

Nonheritable

Mutation in specific organ

tissue or tumor

› Mutations occur in nongermline

tissues

› Cannot be inherited by offspring

› Mutations in egg or sperm

› Can be inherited

› Cause of familial genetic disorders

Mutation in

egg or sperm

All cells

affected in

offspring

Inheritable


Anti-BCMA Allogeneic CAR-T Various

CTX001: β-thalassemia Disruption Clinical trial approvals in

multiple EU countries

CTX001: Sickle cell disease (SCD) Disruption

CRISPR Therapeutics Portfolio (Selection)

9

Editing

approach Research IND-enabling Ph I/II

Glycogen storage disease Ia (GSD Ia) Correction

Duchenne muscular dystrophy (DMD) Disruption

CorrectionSevere combined immunodeficiency (SCID)

Cystic fibrosis (CF) Correction

Hemophilia Correction

CTX101: CD19-positive malignancies Various IND/CTA filings Q4

2018

Anti-CD70 Allogeneic CAR-T Various

In vivo: Various Organ Systems – monogenetic and complex multigenetic origin

Ex vivo: Immuno-oncology – complex multigenetic

Program

Ex vivo: Hematopoietic – mostly monogenetic

Comments

Clinical trial approvals in

multiple EU countries plus

USA

IND/CTA filings Q2

2019

IND/CTA filings

Q42019

Ex vivo: Regenerative medicine (autoimmune) – complex

multigenetic approach

Diabetes mellitus Type I Various


Two Key Components Drive Transformation of Health Care

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• Democratization of gene editing technology

(CRISPR)

• Dramatic drop in genome sequencing costs

• Much improved understanding of human biology

• ……

• Modest treatment effects require huge pivotal

trials – tremendous economic risk of failure

• Limited consideration of variable human

genetics with suboptimal or variable

outcomes

• Often treatment of symptoms – not causative

• …..

Enabling & Affordable

Breakthrough

Technology(ies) Available

Exhaustion of

“One Pill Fits All“

Model

Personalized Medicine


Significant Drop in Cost for Human Genome Sequencing

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› DNA sequencing costs are dropping by 37% per year – current cost US$ 1000/genome

to less than US$ 100 within the next 4 to 5 years

› Data value so far limited since most mutations could not be treated, lack of biological

understanding and context, a weak link that might be addressed by CRISPR


Autologous CAR-T is Transformative, But has Limitations

12

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


Power of CRISPR Gene-Editing - Allogeneic CD19 CAR-T

13

CRISPR enables an allogeneic approach that

remedies issues with autologous CAR-T

CTX101 – 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


Changing Clinical Trial Paradigm

14

If done properly, potential to expand a phase I/II trial into a registrational trial,

as well as to additional genotype and age cohorts, if supported by safety and

efficacy

Sites

Highly specialized sites needed to

access target patient population

& provide optimal medical care

Reduced number of

available patients incl.

different genotypes

Patients Endpoints

Clinical endpoints incl. selection

of proper surrogate

pharmacological markers of

particular relevance


Foundational Intellectual Property Landscape

15

BROAD

INSTITUTE

Patent Filings

Strategic Investors

>$3BPartners & 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


Major Developments Using CRISPR Technology SinceInception 2013

16

Chinese scientists report first time successful use of CRISPR to edit targetgenes in twin monkey embryos (germline)

January 2014

October 2018

CRISPR Therapeutics announces approval of CTA in beta-thalassemiain several European countries (somatic)

June 2018

October 2016

Chinese scientists report editing of fertilized eggs (non-viable) to gene editbeta-thalassemia (germline)

April 2015

Chinese scientists administer CRISPR modified cells into a patient suffering

from aggressive lung cancer (somatic)

Scientist in Oregon report successful editing of human embryos with cardiacdisease (germline)

August 2017

October 2018China - use of base editing in human embryos to correct a mutation causing

Marfan Syndrome (germline)

China - healthy mice are born to same sex parents using CRISPR

technology (germline)


The US and the UK Quickly Change Position on GermlineEditing

17

› 2015 - immediately following first reports of embryonic gene-editing in China, an

international summit convened by the US National Academy of Sciences (NAS) concluded

that actually trying to produce a human pregnancy from such modified germlines was

“irresponsible”.

› 2017 - a report from the NAS and the National Academy of Medicine stated that clinical

trials for editing out heritable diseases could be permitted in the future, but only for

serious conditions under stringent oversight.

› 2018 - United Kingdom’s Nuffield Council on Bioethics stated that heritable genome editing

could be “ethically acceptable in some circumstances.”

› 2018 - a Pew Research Council study released at the end of July found that 72 percent of

Americans think changing an unborn baby’s DNA to treat a serious disease would be an

appropriate use of gene-editing technology.

http://nuffieldbioethics.org/project/genome-editing-human-reproduction


Impact on Insurers?

18

› Thorough prenatal diagnostics possible and affordable

› Value of diagnostic tests will increase significantly,

including whole genome sequencing

› Germline editing would offer prevention of deleterious

diseases

› Significant reduction of morbidity and mortality a must for

genome medicines – highly dependent on disease

indication

› E.g. I/O applications with potential for population-wide

impact

› Some genetic diseases with first time option for causative

treatment› Major increase in cost to be expected – personalized

medicines, cell therapies, and orphan indications as large

cost drivers

› Change in reimbursement strategy – value-based pricing

due to higher sticker prize with post-commercialization

monitoring

Prevention / (Prenatal) Diagnostics

Morbidity / Mortality

Costs / Reimbursment$


Concluding Thoughts

19

› The question is not if, but when will personalized or precision medicine have its full impact

on our healthcare system

› Gene editing, particularly CRISPR/Cas9, will be at the forefront in fueling this rapid change

in medicine – two aspects are important

– Diagnosis - CRISPR is the perfect tool to better understand complex disease biology, putting

genomic analysis and with that disease risk assessment in a significantly more valuble context

(whole genome sequencing, definition and identification of genetic risk factors)

– Intervention - CRISPR is about to possibly become the missing link between genomic diagnostic

and potential cure – currently only somatic editing, but possibly germline editing in the future

› Insurers will/can consider this development in an effort to better define patient risk profiles

in the context of life insurances or critical illness insurance

› Major ethical considerations to be considered in the context of germline editing – different

countries with different legislation – but also risk assessment definitions for individual

clients

Confidential

CRISPR Therapeutics

www.crisprtx.com

Confidential

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Genome Editing6c5a46c7-5b71-40ab-afe3-f723ed4… · (whole genome sequencing, definition and identification of genetic risk factors) – Intervention - CRISPR is about to possibly

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