Exhibit 99.1
THOR-809: AnIL-2 Engineered From an Expanded Genetic Alphabet for the Potential Treatment of Autoimmune Disorders Marcos E. Milla, Carolina E. Caffaro, Lina Ma, Ingrid B. Joseph, David B. Chen, Taylor Ismaili, Kristine M. San Jose, Yelena Pavlova, Namit Singh, Lilia K. Koriazova, Hans R. Aerni, Michael J. Pena, Jerod L. Ptacin INTRODUCTION RESULTS RESULTS CD4+ regulatory T cells (Tregs) play a crucial role in maintaining immune Screening in Mice Identified MultipleIL-2 SynthorinsTHOR-809 Pharmacokinetics in NHP homeostasis. Treg dysfunction is associated with multi-organ autoimmune With Differentiated Ex Vivo Pharmacology Single subcutaneous dose ofTHOR-809 administered at t=0 (AI) and inflammatory-related diseases1. At high doses, recombinantinterleukin-2 is approved to treat melanoma and renal cell carcinoma. At low Analysis of pSTAT5 activation in freshly isolated human PBMCs identifiedTHOR-809 Pharmacokinetic Parameters inNon-human Primates doses,IL-2 selectively induces proliferation of Tregs through activation of the Synthorins with diverse potency profilesTHOR-809 0.12 mg/kgTHOR-809 0.67 mg/kg high-affinity alpha-beta-gammaIL-2 receptor(IL-2Rαβγ), resulting in immune 10000 suppression, without activating the beta-gammaIL-2 receptor(IL-2Rβγ) Multiple Synthorins covering a broad Treg potency range and CD8/Treg Test Article Mean expressed on CD8+ T effector cells (Teffs) and natural killer (NK) cells. ratios were selected for mouse PK/PD profiling (ng/mL) 1000 Dose Unit Parameter value Therapeutic benefit of low doseIL-2 has been demonstrated in chronic graft- 1000 ht1/2 17.2 versus-host disease andHCV-induced vasculitis2,3. Treg-mediated THOR-designed 809THOR-809 downmodulation byIL-2 of the immune effector function that prevents N88R novel constructs—100 0.12mg/kg h*ng/mL AUC last 18,349 antigen recall may reset immune tolerance in select AI disorders. 50 800 V91K THOR ng/mL Cmax 361 EC THOR-designed 10 We applied our expanded genetic alphabet platform using a novel, fully- 600 constructs based on h t1/2 18.0 synthetic DNA base pair, to create optimized biologics with enhancedIL-2 sites targetedTHOR-809 h*ng/mL AUC last 71,940 pharmacological properties. Using this platform, we developed a site-specific, CD8/Treg 400THOR-809 on select benchmark Plasma 0 0.67mg/kg covalently bound mono-pegylatedIL-2 that selectively expands peripheral compounds 0 24 48 72 96 120 144 168 192 ng/mL Cmax 1,358 Tregs in mice andnon-human primates (NHP). Hours post-dose 200IL-2 N88R/D109THOR-809 was identified as anIL-2 variant that maximized proliferation ofTHOR-809 Induces Treg Expansion in NHP peripheral Tregs, with an optimal PK/PD profile and a strong preference for 0 N88THOR-809 induced large-scale expansion of peripheral Tregs in blood Treg proliferation relative to Teffs (no expansion) and NK cells (minimal 10 100 1000 10000 100000 1000000 Treg Percentage in Total Blood Cells expansion). These properties correlated with extended half-life and sustained EC at Tregs (pg/mL) exposure. In NHPs, subcutaneous dosing ofTHOR-809 demonstrated dose- 50 VehicleTHOR-809 0.67 mg/kgPre-dose dependent proliferation of peripheral Tregs with no detectable proliferation of 25 Teffs or NK cells up to 200 mcg/kg. Key FindingsTHOR-809 0.2 mg/kgTHOR-809 0.07 mg/kg Our results support continued investigation ofTHOR-809 as a treatment for The pSTAT5 signal reports on receptor engagement and activation. singlets 20 BUV395 AI disorders. We observed loose coupling between pSTAT5 and readouts of cell 15 A::CD25 proliferation, including Ki67 and Treg counts. As a result, compound profiling in —7 days post-dose Synthorx Expanded Genetic Code Platform: A Synthetic for Treg expansion and activation in vivo (mouse) was required to select 10 —387 371 Treg% — Optimized DNA Base Pair Biologics Encodes Novel Amino Acids to Create Functional candidates with Screen superior pharmacodynamic For Treg Expansion properties. in Mice Identified CD4 5 CompComo-561-582-A::FOXP3PEX-Y Base Pair creates new codons that specificallyTHOR-809 0D-1 Pre 24 36 72 120 168 192 240 312 360 528 FlowplotshowingTreg population(CD25+FoxP3+)in encode novel amino acid chemistry into proteins Hours post-dose CD4+ cellspre-andpost-dose Maximum Fold Increase in Treg % in Total Blood Cells Site-Specific Bioconjugation A single subcutaneous dose (~0.9mg/kg) of the indicated Synthorin variant wasTHOR-809 Does Not Expand CD8+ T or NK cells in NHP administered to C57/Bl6 mice. Flow cytometry was used to quantitate Treg Minimal change in peripheral CD8+ T cells and NK cells in blood post-dose Novel amino acid installation creates a (CD4+ CD25+ FoxP3+) expansion in peripheral blood. dedicated, specific and stable chemical VehicleTHOR-809 0.12 mg/kgTHOR-809 0.67 mg/kg attachment site 30 Fold change in CD8+ T cell Fold change NK cell % in Designed to bioconjugate moieties for % in total blood cells total blood cells improved properties: e.g. PEG 10 10 of Treg% 20 change 8 change 8 Specificity fold 6 fold 6 receptor binding 4 4 Improved target selectivity through altered Fold Change in Singlets 10 N88R in singlets singlets Polymer-Conjugates 2 in 2 809 — Increased half-life Max CD8+% 0 NK% 0 Epitope shielding through covalent and PEGylatedmutein Fc—V91K mutein THORD-1Pre 24 36 72 120168192240312360528D-1Pre 24 36 72 120168192240312360528 0 Hours post-dose Hours post-dose stable PEG attachment viabio- Vehicle A B C D E F G H I J KTHOR-809 Plots normalized topre-dose percentage of each cell type. orthogonal chemistry Synthorin ConstructTHOR-809 Induces Treg Biomarkers of Activation and Engineered Cells Install a Novel Amino Acid UtilizingTHOR-809 Shows Increased Exposure in Mice Proliferation in NHPA-D represent otherIL-2 AI constructs made by Synthorx Quantitation of induction of biomarkers in peripheral blood Tregs using flowX-Y to Produce Therapeutic Proteins with Optimized A cytometry (pSTAT5,Ki-67, CD25) Properties 100000 B VehicleTHOR-809 0.12 mg/kgTHOR-809 0.67 mg/kg Production system for Synthorins in E. coli levels 10000THOR-809THOR-809 PEGylated N88R mutein pSTAT5Ki-67 Novel Amino Acid enters cells; used C 100 100 Study Details X and YTPs enter via by aminoacyl tRNA synthetase to Plasma 1000 D Mice SubQ dosing 80 80 transporter chargeX-Y tRNAs Single dose of 67+ 100 0.90 mg/kg for all 60 —60 molecules PSTAT5+ Ki (ng/mL) 10 cells 40 Treg 40X-Y containing % plasmids IL2 % 2 2 —1 encode PEG 0 0 product withD-1 Pre 2 8 24 3672120168192240312360528D-1 Pre 2 8 24 3672120168192240312360528X-Y codon and 0.1 0 20 40 60 80 100 120 140 160 180 200 Hours post-dose Hours post-dose matchingX-Y mRNA withX-Y codon matches Time (h) 5000 CD25 tRNA gene with tRNA displaying anticodonTHOR-809 Expands Tregs in Mice 4000 Comparison ofTHOR-809 and a PEGylatedIL-2 N88R mutein MFI Translation machinery decodesX-Y codons construct for Treg expansion in peripheral blood using flow cytometry. CD25 3000 to introduce nAA into Synthorin proteins 2000 VehicleTHOR-809 0.9 mg/kg PEG N88R mutein 0.3 mg/kg Treg Dual Pharmacology ofIL-2 is Mediated by αβγ and βγ Treg % in CD8+ T Cell % in 1000 ReceptorSub-Types 7 Total Blood Cells 7 Total Blood Cells 0D-1 Pre 2 8 24 3672120168192240312360528 Receptor Immune Cells Immune 6 6 Hours post-dose Type Activated Response 5 Singlets 5THOR-809 Induces Treg Biomarkers of Differentiation Singlets 4 in 4 and Suppressive Function in NHP High § affinity Treg Suppression in 3 % 3 Quantitation of induction of biomarkers that correlate with Treg (K ~10-11M) CD4+ Tregup-regulation cell suppressive function in peripheral blood Tregs using flow cytometry. d Tcon Suppression Treg% 2 T 2 FoxP3 and Helios are Treg transcription factors that control gene programs for Primarily Treg 1 CD8+ 1 Treg differentiation and suppressive activity. 0 0 VehicleTHOR-809 0.12 mg/kgTHOR-809 0.67 mg/kgIL-2 § Stimulation 0 1 2 3 4 5 6 7 8Pre- 1 2 3 4 5 6 7 8 FoxP3 Helios Intermediate affinity Tcon Proliferation of Tcon (2 h) Day dose Day 10000 2500 (Kd ~10-9M) reactive to Auto-antigens Broadly expressedTHOR-809 Induces Treg Activation and Biomarkers of MFI 8000 MFI 2000 CD4 Th, CD8+ T, and NK cells 6000 Suppressive Function in Mice FoxP3 Helios 1500 4000THOR-809 is Designed to Activate Tregs Without Comparison ofTHOR-809 and a PEGylatedIL-2 N88R mutein construct for Treg Treg Treg 1000 induction of biomarkers that correlate with suppressive function. 2000 Stimulating Conventional T cells (Tcons) 500 0THOR-809’s Key Differentiation VehicleTHOR-809 0.9 mg/kg PEG N88R mutein 0.3 mg/kgD-1 Pre 2 8 24 3672120168192240312360528D-1 Pre 2 8 24 3672120168192240312360528 Hours post-dose Hours post-dose 1.IL-2 receptor αβγ complex bias – Site-specific PEG tunesIL-2 CD25 FoxP3 pharmacology for preferential Treg activation and expansion over Tcon 30,000 60,000 2. Ease of use – pegylation allows for Q2W dosing and no more frequent CONCLUSIONS 3. Low risk for ADAs – Sites targeted for pegylation have low risk of MHC-II 20,000 40,000 binding and presentation. Covalent, stable PEG shields new amino acid Ex vivo Screening for PEGylated,IL-2 R biasedIL-2 compounds (MFI) – Structure Activity Relationship (SAR) screening identified multiplePEG-IL-2 Synthorin Properties 10,000 20,000 SynthorinIL-2 constructs biased forIL-2Rα – Identified compounds showed a broad range of Treg activation potency Stable PEG covalently attached to the novel amino acid installed where affinity Intensity and Tcon:Treg ratios at theIL-2 receptor § is reduced- potency at theIL-2 receptor requires ï¡ 0 0 Screening in mice identifiedTHOR-809 as a specific and effective TregPre- 0 1 2 3 4 5 6 7 8Pre- 0 1 2345 678 activatorIL-2 RαIL-2 Rα dose (2 h) Day dose (2 h) Day In mice, a single subcutaneous dose ofTHOR-809 induced: – Sustained pSTAT5 signaling in Treg cellsTHOR-809 Fluorescence Helios ICOS – Specific expansion of Tregs, not TconsIL-2 20,000 15,000 – Increase in markers of Treg differentiation and suppressive function Mean – FoxP3, CD25, Helios, and ICOS wereup-regulated Treg 15,000 In cynomolgus monkey, a single subcutaneous dose ofTHOR-809 induced: 10,000 – Dose-dependent expansion and activation of Tregs 10,000 – No observed expansion of CD8+ T (Tcon) or NK cells – Increased Treg expression of biomarkers that correlate with differentiation PEG 5,000 5,000 and suppressive functionIL-2 RβIL-2 Rβ 0 0 REFERENCESIL-2 RγIL-2 RγPre- 0 1 2 3 4 5 6 7 8Pre- 0 1 2 3 4 5 6 7 8 dose (2 h) Day dose (2 h) Day 1. 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