1CONFIDENTIAL

THOR-707, an engineered not-alpha IL-2, for the treatment of solid tumors induces strong immunological responses in vivo

Gilles Dufour, PhDDirector, Corporate Development and Clinical Strategy

CSCO Immunotherapy Seminar, Endorsed by AACRMarch 22-23, 2019 • Shanghai, China

2CONFIDENTIAL

Forward-Looking Statements

Statements contained in this presentation regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private SecuritiesLitigation Reform Act of 1995, including statements associated with the expected ability of Synthorx, Inc. (the “Company”) to undertake certain activities and accomplishcertain goals and objectives. These statements include but are not limited to statements regarding the Company’s business strategy, the Company’s plans to develop andcommercialize its product candidates, the safety and efficacy of the Company’s product candidates, the Company’s plans and expected timing with respect to regulatoryfilings and approvals, and the size and growth potential of the markets for the Company’s product candidates. Because such statements are subject to risks anduncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "believes," "anticipates," "plans,""expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are basedupon the Company’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of eventscould differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risksassociated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor ofbuilding a business around such drugs. These and other risks concerning the Company’s development programs and financial position are described in additional detailin the Company’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this presentation speak only as of the date on whichthey were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which theywere made.

The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsementof such products. This presentation discusses product candidates that are under clinical study and which have not yet been approved for marketing by the U.S. Food andDrug Administration. No representation is made as to the safety or effectiveness of these product candidates for the therapeutic use for which such product candidatesare being studied.

3CONFIDENTIAL

IL-2: Background

• Recombinant IL-2 (rIL-2; aldesleukin) is a well known systemic immunostimulatory cytokine that has consistently shown single agent responses and survival benefits across multiple tumor types1,2 thanks to its ability to expand CD8 T cell counts both peripherally and intratumorally

• IL-2’s ability to expand CD8 T cell counts makes it a potential agent for combination with checkpoint inhibitors (e.g., anti-PD1 mAbs) to further promote CD8 responses

• However, rIL-2 is clearly limited by suboptimal pharmacological properties and dose-limiting AEs (vascular leak syndrome (VLS)) that reduce its therapeutic index

1Proleukin Melanoma HCP Website 2Proleukin Renal Cell Carcinoma HCP Website

4CONFIDENTIAL

HIGH DOSEAnti-Tumor Activity

IL-2

LOW DOSENo Anti-Tumor Activity

Suppressionof tumor immune

response

αβγReceptor

αβγReceptor

Suppressionof tumor immune

response

Treg

Treg

Push Beyond

SuppressionPush

to Stimulation

Eosinophil

Toxicityα-receptor mediated innate lymphoid cell release of IL-5 induces eosinophilia

αβγReceptor

Vascular Leak Syndrome (VLS)

HypotensionHypoperfusion

Peripheral EdemaRhabdomyolysis

Pulmonary EdemaImpaired Oxygenation Hepatorenal

Syndrome

Innate Lymphoid

Cells

IL-5

Degranulation

βγReceptor

Stimulationof tumor immune

response

Teff (CD8+)NK cells

Cytolysisvia tumor immune

response

Tumor

IL-2 Biology: Dual Pharmacology Explains Low Therapeutic Index

Blood 2014 124:3572-3576

5CONFIDENTIAL

Site-Specific Bioconjugation

• Installation of a novel amino acid containing a dedicated chemical hook at a specific site

• Designed to bioconjugate moieties such as PEG for improved properties

Specificity

Improved selectivity through altered receptor binding

Polymer-Conjugates

• Increased half-life

• Epitope shielding through covalent PEG attachment via bio-orthogonal chemistry

Novel Amino-Acid EnablesA T

GC

YX

1. doi:10.1038/nature13314. 2. doi:10.1038/nature24659

Novel Amino-Acid Allows Site-specific Pegylation To Create “Not-Alpha” IL-2

6CONFIDENTIAL

Single, stable PEG covalently attached to a novel amino acid installed in the “right” place results in a “not alpha” IL-2 protein

THOR-707: “Not alpha” IL-2 Structural Design and Receptor Binding Properties

PEG-IL-2 Synthorin Properties Receptor Binding Properties

IL-2 binds to the IL-2 receptor αβγ complex at high affinity because of the α chain

Targeted pegylation of THOR-707 at the novel amino acid blocks αchain binding

IL-2 Receptor αChain

IL-2 Receptor ß Chain

7CONFIDENTIAL

Compared to aldesleukin, THOR-707 shows a strong preference for expanding tumor-fighting lymphocytes vs. eosinophils responsible for VLS

Pre and Post Aldesleukin InducedLymphocyte Expansion1

1. Meyers FJ, et al. Clin Pharmacol Ther. 1991;49:307.

• Aldesleukin dosing limited in people (37 mcg/kg) and NHP by VLS (25 mcg/kg and higher)

• No signs of VLS in NHP with THOR-707 up to 1,000 mcg/kg

THOR-707 Single Dose Leukocyte SubpopulationsHigh Lymphocytes, No Eosinophils

0

Days-1 2 4 6 8 10 12 14 16 18 20

White blood cellsLymphocytesEosinophils

10

20

30

40

Ce

ll C

ou

nts

x 1

03/µ

LDose

0

10

20

30

40

Pre Treatment Post Treatment

Ce

ll C

ou

nts

x 1

03/µ

L

Lymphocytes

Eosinophils

THOR-707THOR-707 Increases Lymphocyte Expansion in Non Human Primates (NHP) without Increasing Eosinophils

8CONFIDENTIAL

THOR-70760% Ki-67 in CD8+ Teff Cells Is Associated With Maximal Expansion and Can Be Achieved With THOR-707 Without VLS in NHPs

Peripheral CD8+ T CellsActivation and Proliferation

Peripheral CD8+ T Cells pSTAT5 Expression

Ki67 is a closer PD marker to monitor cell proliferation compared to pSTAT5 in CD8+ T cells.

Peripheral CD8+ T Cells Ki67 Expression

pre-d

ose

0.5h

post

dose

pre-d

ose

0.5h

post

dose

pre-d

ose

0.5h

post

dose

pre-d

ose

0.5h

post

dose

pre-d

ose

0.5h

post

dose

0

20

40

60

80

100

pS

TA

T5

+%

in

CD

8+

T c

ells

vehicle

30 mcg/kg

300 mcg/kg

100 mcg/kg

1000 mcg/kg

9CONFIDENTIAL

THOR-707CD8+ Teff Expansion and Proliferation in Tumors Following a Single Dose looks similar to Immune Checkpoint Inhibitors

Select Immune Checkpoint Inhibitors THOR-707

Following 3 Doses IV of CPIs

CD

8+

in T

eff

–%

of

TIL

80

40

60

20

0Untreated Fvax 𝛂CTLA-4 𝛂PD-1 𝛂PD-L1 𝛂PD-1 +

𝛂CTLA-4 Da

y 0

Da

y 1

Da

y 2

Da

y 3

Da

y 5

Da

y 7

Da

y 1

0

0

2 0

4 0

6 0

CD

8+

% in

C

D3

+T

V e h i c l e

3 m g / k g

P r e - d o s e

* * * * * *

Single dose of THOR-707

CD

8+

% in

CD

3+

T

60

0Day 0 Day 1 Day 2 Day 3 Day 5 Day 7 Day 10

40

20

Predose

Predose

3 mg/kg

THOR-707 levels of CD8+ tumor infiltration are comparable to those observed for select immune checkpoint inhibitor mAbs (e.g, CTLA-4, PD-1, PD-L1, and combinations of them) in mouse melanoma tumor model1

1. PNAS Vol 107 No. 9, pages 4275-4280 (02 Mar 2010)

10CONFIDENTIAL

THOR-707THOR-707 Is Efficacious as Single Agent and When Combined with mPD-1 Antibody

Single Agent, Day 17 Combo, Day 17

*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001

0

1 0 0 0

2 0 0 0

3 0 0 0

4 0 0 0

T re a tm e n t g ro u p s Q W x 3 IV

Tu

mo

r V

olu

me

(m

m3)

SE

M

* * * p < = 0 .0 0 1

Ve

hic

le

1 m

g/k

g

3 m

g/k

g

6 m

g/k

g

9 m

g/k

g

* * *

* * *

* * *

Treatment group QW x 3 IV

Vehicle 1 mg/kg 3 mg/kg 6 mg/kg 9 mg/kg

2000

1000

4000

3000

Tum

or

Vo

lum

e (

mm

3)

±SE

M

0

Durable regressions observed in THOR-707 + anti mPD-1 treated mice with four mice tumor free on day 49 following THOR-707 withdrawal on Day 14 and anti-PD-1 withdrawal on Day 17

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

1 4 0 0

1 6 0 0

D a y s

Me

an

tu

mo

r V

olu

me

(m

m3

S

EM

)

T H O R - 7 0 7 d o s i n g d a y

a n t i P D - 1 d o s i n g d a y

400

1600

800

0

1200

200

1400

600

1000

0 5 10 15 20 25 30 35 40 45 50 55

DaysTHOR-707 dosing dayAnti PD-1 dosing day

Mea

n T

um

or

Vo

lum

e (m

m3)

±SE

M

0

1 0 0 0

2 0 0 0

3 0 0 0

4 0 0 0

5 0 0 0

T re a tm e n t g ro u p s

Tu

mo

r V

olu

me

(m

m3

)

SE

M

v e h ic le (Q W x 3 , iv ) +

is o ty p e c o n tro l (1 0 m g /k g , B IW x 3 , ip )

T H O R -7 0 7 (6 m g /k g - Q W x 3 , iv )

a n t i P D -1 (1 0 m g /k g - B IW x 3 , ip )

T H O R -7 0 7 (6 m g /k g - Q W x 3 , iv ) +

a n t i P D -1 (1 0 m g /k g , B IW x 3 , ip )

* *

* * *

* p < = 0 .0 5

* * p < = 0 .0 1

* * * p < = 0 .0 0 1

*

Treatment group0

2000

1000

5000

3000

Tum

or

Vo

lum

e (

mm

3)

±SE

M

4000

Vehicle (QW x 3 IV) + isotype control (10 mg/kg, BIW x 3 IP)

THOR-707 (6 mg/kg, QW x 3 IV)

Anti PD-1 (10 mg/kg, BIW x 3 IP)

THOR-707 (6 mg/kg, QW x 3 IV) +Anti PD-1 (10 mg/kg, BIW x 3 IP)

0

11CONFIDENTIAL

• We applied our Expanded Genetic Alphabet platform technology to the design and production of THOR-707, a site-specifically pegylated IL-2 with a not-alpha IL-2R engagement profile

• THOR-707 induces the activation of both pSTAT5 and the molecular marker of proliferation Ki67, which is temporally correlated with the expansion of CD8+ T cells

• In NHP THOR-707 elicits maximal expansion of peripheral CD8+ T at 100 mcg/kg. There are no observations of VLS in those animals up to the maximal tested level of 1,000 mcg/kg

• The ability of THOR-707 to induce the expansion of CD8+ T cells results in anti-tumor effects both as single agent as well as in combination with an anti-PD1 mAb.

• THOR-707 IND submission is planned for 2Q19 with initiation of a Phase I/II clinical studies thereafter

Conclusions

12CONFIDENTIAL

The Synthorx Team

• Ingrid B. Joseph• Lina Ma• Jerod L. Ptacin• Carolina E. Caffaro• Hans R. Aerni• Kristine M. San Jose• Michael J. Pena• Robert W. Herman

• Yelena Pavlova• David B. Chen• Ken Bragstad• Shukuan Li• Jasmine Nguyen• Laura K. Shawver• Lilia K. Koriazova• Marcos E. Milla