Synthorx 8-K Regulation FD Disclosure

Exhibit 99.1

  THOR-707: Using Synthetic Biology to Reprogram the Therapeutic Activity ofInterleukin-2(IL-2) Marcos E. Milla; Jerod L. Ptacin; Carolina E. Caffaro; Hans R. Aerni; Lina Ma; Laura K. Shawver; Lilia K. Koriazova; Ingrid B. Joseph Synthorx Inc. Research & Development, La Jolla, CA  

BACKGROUND Recombinantinterleukin-2(rIL-2 or aldesleukin) is an approved immunotherapy in melanoma and renal cell carcinoma based on complete durable remissions. The anti-neoplastic properties ofIL-2 are mediated by interactions with theIL-2 receptor beta-gamma chain complex(IL-2R), which leads to expansion and differentiation into T effector and T memory cells directed against the tumor. But the widespread use ofrIL-2 is limited by interaction with the high affinityIL-2 receptor alpha chain(IL-2R) on regulatory CD4+ T cells (Tregs), which leads to immunosuppression, and on type 2 innate lymphoid cells residing in the vascular endothelium, which leads to eosinophilic recruitment and activation, resulting in the often-severe complication of vascular leak syndrome (VLS). ArIL-2 biased towardIL-2 affinity with noIL-2R interaction could address these needs.IL-2 Has A Low Therapeutic Index Due to Its Dual Pharmacology at the High Affinity and Intermediate Affinity Receptor Forms Novel Amino Acids Encoded By Our New DNA Base Pair Enable Precise Bioconjugation of BiologicsTHOR-707:IL-2 IO SynthorinPEG-IL-2 Synthorin PropertiesTHOR-707’s Key Differentiations Single, stable PEG covalently attached to the novel amino acid installed at the “right” place:not-alphaIL-2 proteinIL-2 binds to the receptor form with high affinity because of chain Targeted pegylation ofTHOR-707 at the novel amino acid blocks chain engagementTHOR-707’s Key Differentiations Improved Selectivity—Reduced CD4+ Treg bias with retained activity at CD8+ T and NK cells Increased Therapeutic Index—At least 10 in preclinicalnon-human primate (NHP) studies Ease of Use—Expected Q2W dosing or less frequent Reduced Risk of Immunogenicity—Covalent attachment of stable PEG shields new amino acid; pegylation site devoid ofMHC-II anchors

RESULTS A Single Dose ofTHOR-707 Increases Intra-tumoral T Cell Fraction and TCR Diversity in MouseCT-26 tumors TCR sequencing was performed on infiltrating T cells via immunoSEQ™ (Adaptive Biotechnologies) By Day 8, tumors from mice dosed with 6 mg/kg ofTHOR-707, alone or in combination with 10 mg/kg BIW of mouseanti-PD-1, showed significantly lower TCR repertoire clonality (higher clonal diversity)Post-hoc Dunn’s test at Day 8 demonstrates that theTHOR-707 andTHOR-707 +anti-PD-1 treatment groups show lower clonality compared to either vehicle oranti-PD-1 alone (PKW= 0.0047) TCR sequencing also demonstrates thatTHOR-707 elevates TIL fraction alone or in combo with CPI TheTHOR-707 induced increase in T cell clonal diversity is also observable in blood (Day 8) TIL clonality vs T cell fraction, Day 8 Peripheral T cell clonality, Day 8THOR-707 Reprograms theCT-26 Tumor Microenvironment for High Teff Activity,IFN-g Induction and Checkpoint Ligand Expression Key Findings: Induction of multiple markers ofIL-2 response and T cell activation, including theIL-2 receptor chains, CD28,4-1BB and CD40 Elevated expression of the checkpoint inhibitory receptorsPD-1 and CTLA4, and thePD-1 ligandsPD-L1 andPD-L2 Induction of genes reporting onIFN-g signaling pathways Methodology:CT-26 tumor samples were profiled via mRNAseq (Omniseq) and analyzed by GeneCentric to identify cell and molecular signatures of lymphocyte infiltration and activation Nomenclature shown for human ortholog genesTHOR-707 Is Efficacious as a Single Agent and When Combined With aPD-1 Inhibitor in theCT-26 Mouse Tumor ModelTHOR-707 Single Agent Study, Day 17 Combination Study Overall Survival (n=14)CT-26 colon tumor-bearing Balb/c mice were treated withTHOR-707 (1, 3 or 6 mg/kg QWx3) alone,anti-PD-1 (10 mg/kg, BIW x 3) alone, or the combination ofTHOR-707 at 6 mg/kg withanti-PD-1THOR-707 showed dose-dependent single agent antitumor activity. In combination withanti-PD1, 5/14 animals showed tumor regression and no detectable tumors for 100 days

RESULTSTHOR-707 Promotes the Establishment of Persistent Memory T Cell Responses, PreventingCT-26 Tumor Growth in Surviving Animals Challenged ByRe-injection ofCT-26 Cells Surviving Balb/c mice werere-challenged by injection ofCT-26 cells at 120 and 180 days after the original challenge With no additionalTHOR-707 treatment over there-challenge period,CT-26 tumors fail to grow in all surviving animals treated withTHOR-707THOR-707 promotes the establishment of durable immunological memory againstCT-26 tumors, observed as an overall increase in peripheral memory T cells (CD3+), including memory CD8+ T cells PD Readouts pSTAT5 and Ki67 in CD8+ T and Treg Cells.Ki-67 Correlates With Proliferation of CD8+ T Cells But Not Treg Cells in NHP Cynomolgus monkeys were dosed with 30, 100, 300 or 1,000 mg/kg ofTHOR-707 (IV bolus). Blood samples were collected for measurement of pSTAT5, Ki67 and cell counts via flow cytometry All doses induced pSTAT5 at near-maximal levels (>85% cells positive) in CD8+ T and CD4+ Treg cells (Tregs) The proliferation marker Ki67 showed dose-dependent elevation at both cell types, reaching near-maximal levels at 100 mg/kg for both cell types Peripheral CD8+ T cells reached maximal expansion at 100 mg/kg. Treg cells failed to show significant expansion

RESULTSTHOR-707 Dosed QW, Q2, Q3W and Q4W Elicited Similar Expansion of Lymphocytes in NHP After Each Dose, With No Expansion of Eosinophils Cynomolgus monkeys were given three IV 100 mg/kg doses ofTHOR-707 QW, Q2, 3 or 4W On all three dosing schedules,THOR-707 induced maximal lymphocyte expansion on day 7 following each dose, without expanding eosinophils responsible for VLSTHOR-707 Dosed QW, Q2, 3 & 4W Showed Similar Expansion of Peripheral CD8+ T Cells in NHP. Ki67 Expression Increased³60% After Each Dose Following each dose, Ki 67 expression reached³60% and correlated with expansion of CD8+ T Cells for all dosing schedulesTHOR-707 did not induce the proliferation of peripheral CD4+ regulatory T cells at any schedule CD8+ T Cells Ki67 Expression CD8+ T Cell ProliferationTHOR-707 Does Not Induce Vascular Leak Syndrome in NHPTHOR-707 was well tolerated in cynomolgus monkeys. Diarrhea was observed in some animals at the highest dose level of 1,000 mg/kg No indicators of VLS: no elevations in body or lung weights as measures of edema were observed CONCLUSIONSTHOR-707 is an engineeredIL-2 Synthorin with a targeted single site PEG bioconjugate. It has reduced CD4+ Treg bias with retained activity at CD8+ T and NK cells The pegylation site inTHOR-707 exhibits low potential forMHC-II presentation. The highly stable, irreversible PEG bioconjugate further decreases the risk for immunogenicity In the mouseCT-26 syngeneic tumor model,THOR-707 significantly increased the amount of TILs (TIL fraction) as well as the TCR repertoire diversity (lower clonality score) of infiltrating T cells Changes in TIL clonality are observable in the peripheral compartment InCT-26 tumors,THOR-707 remodels TILs to Teff, memory Teff and cytolytic NK cells, and promotes T cell andIFN-g gene expression signature consistent with increased Teff cytolytic functionTHOR-707 showed anti-tumor activity both as single agent and in combination with aPD-1 checkpoint inhibitor

RESULTSTHOR-707 Single Agent or Combined with Pembrolizumab Did Not Elicit Release of Cytokines Associated with Cytokine Release Syndrome from Human Whole Blood Human whole blood was incubated withTHOR-707 concentrations covering the range of Cmax values observed in the NHP toxicology study (37.9 – 99.5% receptor occupancy at CD8+ T cells, as measured by induction of pSTAT5), and 90 mg/kg of pembrolizumab (expected Cmax of clinical dose) After 24 h of incubation, low amounts ofIFN-g were released in aTHOR-707 dose-dependent manner relative to positive controlanti-CD3 (10 mg/mL). Yet, combination with pembrolizumab did not significantly elicited further increases inIFN-g release at anyTHOR-707 level The range ofTHOR-707 concentrations (0.15 to 45 µg/mL) was selected based on monkey exposure data from the GLP NHP toxicity study, the highest dose exposure from which is expected to be higher than the maximum tolerated dose (MTD) in humans. Furthermore, the highest concentration in the assay gives a safety factor of >3X over this high-dose concentration in monkey as can be observed from the Cmax values in Table 2.THOR-707 Combined With Nivolumab Increased the Strength of T Cell Receptor Signaling in an Ex Vivo Human Mixed Lymphocyte Reaction Model System The effect ofTHOR-707 alone and in combination with nivolumab on TCR signaling was studied using a human mixed lymphocyte reaction model. Two concentrations ofTHOR-707 reflected 15.7 and 62.6% receptor occupancy at CD8+ T cells, as measured by induction of pSTAT5 After 5 days of incubation, mismatched lymphocytes releasedIFN-g in aTHOR-707 concentration-dependent manner. This effect was greatly enhanced byPD-1 blockage with nivolumab. This is expected, because mismatched antigen-presenting cells expressPD-L1, which restricts TCR levels of signaling in response toTHOR-707 This study demonstrates the potential forTHOR-707 andPD-1 inhibitors to potentiate tumor antigen-driven TCR responses in Teffs Anti-tumor responses were durable and protected surviving animals in two consecutiveCT-26re-challenges, demonstrating the establishment of persistent Tmem populations In NHP, after repeat dosing at 100 mg/kg,THOR-707 showed similar lymphocyte and CD8+ T cell expansion when dosed QW, Q2, 3 and 4 WTHOR-707 does not induce VLS in NHP at doses up to 1,000 mg/kg (>99.9% receptor occupancy at cynomolgus CD8+ T cells). In an ex vivo human whole blood system,THOR-707 did not induce the release of cytokines associated with CRS or VLS at concentrations up to 99.5% receptor occupancy at CD8+ T cells In that same ex vivo system, the checkpoint inhibitor pembrolizumab did not increase the release ofIFN-g in response toTHOR-707, indicating a lowered risk for autoimmune adverse events for this combinationTHOR-707 and another checkpoint inhibitor, nivolumab, demonstrated synergistic effects for antigen-mediated TCR activation in a human mixed lymphocyte reaction culture system