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