Intellia Therapeutics is a biotechnology company focused on developing gene editing treatments using CRISPR/Cas9 technology. They have over 100 employees and are located in Cambridge, Massachusetts. Their initial focus is on delivering CRISPR to the liver to treat diseases like transthyretin amyloidosis, alpha-1 antitrypsin deficiency, and hepatitis B. They are also exploring delivering CRISPR to other tissues and cells, both in vivo and ex vivo, to treat diseases like hemoglobinopathies and cancer. They face technical, regulatory, and public perception challenges in developing these novel genetic medicines.

1. EURORDIS Meeting
Sean Burns, MD
Medical Director
November 4, 2016

2. Our Mission: To develop potentially curative gene editing
treatments that positively transform the lives of people living
with severe and life-threatening diseases
• Opened labs early 2015, and became a public company in May, 2016
• Located in Cambridge, Massachusetts
• Currently ~100 employees; more than 2-fold growth over past year
• Human therapeutics rights to foundational CRISPR/Cas9 intellectual
property from University of California and University of Vienna
• Collaborations
– Novartis – focus on CAR T Cells & Hematopoietic Stem Cells
– Regeneron – focus on the liver
Intellia Therapeutics Overview
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3. • Nuclease remains constant across targets
• Guide RNA sequence varies, specifying the location to be cut
Cas9: “Programmable molecular scalpel”
Target Sequence
Guide Sequence PAM
tracrRNA + crRNA
Cas9
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CRISPR Enables Surgery on Unhealthy Genes

4. CRISPR Can Target Genetic Diseases at their
Source within the DNA Sequence
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TTR (Amyloidosis) SERPINA1 (AATD) Many IEMs
Error prone repair results in frame
shift and loss of expression
Correction of a single
amino acid mutation
Insertion of a
large gene cassette
Example: Example: Example:
Jiang et al. 2015 Science 348: 1477

5. Gene Therapy
• Healthy copies of a gene inserted into
a cell with a faulty version
• Typically delivered using a virus, with
permanent expression desired
• “Transgene(s)” insert randomly into
genome or persists as episomes
• Gene expression is usually constant
and higher than normal
Gene Editing
• Faulty gene is corrected/changed in place
• Delivered by viral or non-viral means, with
transient expression but permanent
changes
• Specific site within genome is targeted
• Gene expression remains normal and
dynamic, as usual control elements are
preserved
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Comparing Gene Therapy and Gene Editing

6. INITIAL FOCUS
• Liver Diseases
(LNP Delivery)
ADDITIONAL EXPLORATION
• Eye
• Muscle
• CNS
• CAR T oncology
• HSC
• Non CAR T oncology
• Autoimmune and
inflammatory
EX VIVO IN VIVO
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Delivery of CRISPR is Tailored to the Application

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Liver (primarily)
Large
Low
Transient
Straightforward
Lipid Nanoparticle
(LNP)
Adeno-Associated Virus
(AAV)
Varies by serotype
Smaller
Potentially high
Long term
More challenging
Tropism
Capacity
Immunogenicity
Duration
Manufacturing
at scale
Leading In Vivo Delivery Options

8. 0%
10%
20%
30%
40%
50%
60%
70%
Vehicle 0.1 0.5 2.0
Median%Editing
Dose (mg/kg)
0%
50%
100%
Vehicle 0.1 0.5 2.0
Median%ControlSerumLevels
Dose (mg/kg)
175%
200%
Editing in a dish Editing in living mice Serum TTR levels in mice
Single administration in mice Tested 9 days after administrationMouse liver cells treat with LNP
0%
10%
20%
30%
40%
50%
60%
70%
80%
C 0.04 0.1 0.4 1.1 3.4 10 31
%Editing
Cargo concentration (nM)
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Case Example: Knocking Out TTR Gene in
Mice Using LNP-mediated Delivery

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Our Pipeline of Sentinel Indications
Programs
Type of
Edit
Delivery
In Vivo
Transthyretin Amyloidosis (ATTR) Knockout LNP to Liver
Alpha-1 Antitrypsin Deficiency (AATD)
Knockout
Repair
LNP to Liver
Hepatitis B Virus (HBV) Knockout LNP to Liver
Inborn Errors of Metabolism (IEMs)
Knockout
Repair
Insertion
LNP to Liver
Ex Vivo
Hematopoietic
Stem Cells (HSCs)
Knockout
Repair
Insertion
Electroporation
CAR T Cells
Knockout
Insertion
Electroporation

10. Technical
• How do we effectively delivery to
the desired tissues + cells?
• Can we achieve sufficient editing
at the intended genetic target to
have the desired biological
effect?
• Can we achieve a high degree of
specificity with our edits to
minimize off-target risk?
• How do we assess and manage
any potential immunogenicity?
Regulatory
• How should we assess safety and
efficacy of this new therapeutic
modality?
• What pre-clinical animal studies
are feasible, if target sequences
are species-specific?
• How can we design trials for
personalized genetic medicines in
ultra rare patient populations?
• Will there be patients left to treat
after the trial is completed, given
that the therapy is permanent?
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Challenges to be Addressed

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Public Perception Challenges
C.R.I.S.P.R.
“Jennifer Lopez Sets
Futuristic Bio-Terror
Drama at NBC…the
thriller explores the next
generation of terror: DNA
hacking.”
(Oct 18, 2016)

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Because the potential impact on patients’ lives is enormous
We Are Working Hard to Solve These Challenges