Slide 1: Unleashing the Potential of Immuno-Oncology Therapies
1 Unleashing the Potential of Immuno-Oncology Therapies August 14, 2023 © 2023 Xilio Therapeutics, Inc.
Slide 2: Forward-Looking Statements and Disclaimers
2 Forward-Looking Statements and Disclaimers This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans, timing and expectations related to: reporting prelimin
Slide 3: Immuno-Oncology Therapy has Curative Potential but is Often Limited by Systemic Toxicity
3 Immuno-Oncology Therapy has Curative Potential but is Often Limited by Systemic Toxicity • Immuno-oncology (IO) therapies have transformed the treatment landscape and long-term outlook for some patients with advanced cancer • Treatment potential for some of the most exciting IO targets has been im
Slide 4: Xilio's Novel Tumor-Activated Molecules Designed to Overcome Limitations
4 Xilio’s Novel Tumor-Activated Molecules Are Designed to Overcome the Limitations of Systemically Active Treatments Cleavage Site Half-Life Extension Domain Effector Domain Masking Domain Antibody Example Cytokine Example • Harness and focus the power of the immune system to fight cancer • Novel de
Slide 5: Molecules Designed to Be Selectively Activated in the TME by MMPs
5 Xilio’s Molecules Are Designed to Be Selectively Activated in the TME by MMPs In vitro recombinant MMP kinetic cleavage assay Tumor Plasma Spleen Liver Kidney Lung 0 2 4 6 Fold Difference in % Active Drug in Tumor or Normal Tissues vs Plasma (Avg) Tumor-specific activation +MMPs No MMP 0 500 1000
Slide 6: Pipeline Programs
6 Program Initial Tumor Types Mechanism of Action Discovery IND-Enabling Phase 1 Phase 2 Phase 3 Antibody Program XTX101 (1) Advanced Solid Tumors and MSS CRC Anti-CTLA-4 Cytokine Programs XTX202 (2) Advanced RCC and Melanoma IL-2 XTX301 (3) Advanced Solid Tumors IL-12 Multifunctional Program Multif
Slide 7: CTLA-4 Evolving Paradigm and Opportunity for Tumor-Activated Anti-CTLA-4
7 CTLA-4 Evolving Paradigm and Opportunity for a Tumor-Activated Anti-CTLA-4
Slide 8: Ipilimumab Data Demonstrated Transformative Potential of High Dose Anti-CTLA-4
Trial conducted by Bristol Myers Squibb. 8 Ascierto et al., J Immunother Cancer (2020); Larkin et al., N Engl J Med (2015); Wolchok et al., Lancet (2010); Hamid et al., J Transl Med (2011); Lebbe et al., J Clin Oncol (2019); Weber et al., J Clin Oncol (2012). AE: adverse event; irAE: immune-related
Slide 9: CTLA-4's Changing Paradigm: Fc Enhancement and High Dose Improve Outcomes
9 CTLA-4’s Changing Paradigm: Fc Enhancement to Drive ADCC and High Dose Improves Outcomes 1. Bullock AJ, Grossman JE, Fakih MG, et al: ESMO World Congress on Gastrointestinal Cancer 2022. Abstract LBA-09. Presented June 29, 2022. 2. Phase 1 data reported by Agenus Inc. on January 21, 2023, at ASCO
Slide 10: XTX101 Tumor-Activated Anti-CTLA-4
10 XTX101 Tumor-Activated Anti-CTLA-4
Slide 11: XTX101: Tumor-Activated, High Affinity Binding, Fc-Enhanced Anti-CTLA-4
11 Inactive State Active State topspin MMP Activation ADCC-enhanced Fc Variable Domain Variable Domain Activated XTX101 designed to: • bind and block CTLA-4 checkpoint • drive potent ADCC against TREGs that highly express CTLA-4 XTX101: Tumor-Activated, High Affinity Binding, Fc-Enhanced Anti-CTLA-4
Slide 12: XTX101 Preclinical Anti-Tumor Activity
12 1. Ipilimumab analog comprising a monoclonal antibody of identical amino acid sequence to ipilimumab that was produced at Xilio for research purposes. CR: complete regression. Left panel: MB49 cells were inoculated subcutaneously into C57BL/6-huCTLA-4 mice. When tumors reached approximately 150 m
Slide 13: Phase 1 Clinical Trial Data for XTX101
13 Phase 1 Clinical Trial Data for XTX101
Slide 14: 29 Patients Enrolled in Phase 1 Trial for XTX101
14 Data cutoff date: August 3, 2023. 29 patients have been dosed across all dose levels, including 20 patients dosed in Phase 1A and 9 patients dosed in Phase 1B. 1. Among the 29 patients dosed, data was not available for two patients as of the data cutoff date. 2. Eligible histology includes, but i
Slide 15: 150 mg Q6W Identified as RP2D for XTX101 in Phase 1A
15 150 mg Q6W Identified as RP2D for XTX101 in Phase 1A Data cutoff date: May 2, 2023 AUC: area under the curve; Cmax: maximum concentration; DL: dose level; DLT: dose-limiting toxicity; Q3W: once every three weeks; RP2D: recommended Phase 2 dose. DL5: 150 mg Q6W N=5 DL1: 7 mg Q3W N=2 No DLT DL2: 20
Slide 16: XTX101 Treatment-Related Adverse Events
16 AE Category / Term All TRAEs with ≥10% incidence in any category All Patients at Q3W (7-180 mg) (n=18) RP2D 150 mg Q6W (n=9) Any Grade 3 Any Grade 3 Diarrhea or Colitis 7 (39%) 4 (22%) 1 (11%) 1 (11%) Diarrhea 5 (28%) 1 (6.0) 1 (11%) 1 (11%) (1) Colitis 5 (28%) 4 (22.0) 0 0 Nausea 3 (17%) 0 0 0 V
Slide 17: XTX101 Demonstrated Evidence of Anti-Tumor Activity in Phase 1
17 66% 62% 57% 51% 41% 25% 24% 17% 15% 14% 13% 10% 0% -5% -7% -52% +20% -30% -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 cSCC: cutaneous squamous cell carcinoma Data cutoff date: August 3, 2023. XTX101 Demonstrated Evidence of Anti-Tumor Activity in Phase 1 Trial (Phase
Slide 18: Prolonged Anti-Tumor Activity in a Patient with PD-L1 Negative NSCLC
18 -100 -80 -60 -40 -20 0 20 40 60 80 100 0 5 10 15 20 25 30 35 40 Weeks from First Dose Partial Response Stable Disease +20% -30% New Lesion Data cutoff date: August 3, 2023. As of the data cutoff date, treatment ongoing for one NSCLC patient with confirmed partial response, and all other patients
Slide 19: XTX101 Anti-Tumor Activity in a Patient with PD-L1 Negative NSCLC
19 XTX101 Anti-Tumor Activity in a Patient with PD-L1 Negative NSCLC and Hepatic Metastases • Patient: 66-year-old, female • Diagnosis: Stage 4 NSCLC, PD-L1 negative • Previous Treatment: 1 line of chemotherapy - 4 cycles of paclitaxel and carboplatin - Complete response (CR) - Progressed (four mont
Slide 20: Primary Lung Lesion Decreased in Size on XTX101 Monotherapy
20 Primary Lung Lesion Decreased in Size and Developed Cavitation on XTX101 Monotherapy Baseline After 9 Weeks of XTX101 After 18 Weeks of XTX101 20
Slide 21: Hepatic Metastases Resolved on XTX101 Monotherapy
21 Hepatic Metastases Resolved on XTX101 Monotherapy After 9 weeks of XTX101 Baseline After 18 weeks of XTX101 21
Slide 22: XTX101 Tumor-Selective Activity Shown by Minimal Peripheral PD Changes
22 PR: partial response XTX101 Tumor-Selective Activity Demonstrated by Minimal Changes in Peripheral PD Markers in PD-L1 Negative NSCLC Patient with Confirmed PR Fold Change from Baseline in Peripheral PD Markers of Anti-CTLA-4 Activity Pretreatment = baseline On-treatment = cycle 4, day 7
Slide 23: XTX101 Clinical Development Path
23 XTX101 Clinical Development Path Pursuing XTX101 in Combination with Atezolizumab in MSS CRC
Slide 24: Colorectal Cancer – A Growing Threat to Young Adults
24 Colorectal Cancer (CRC) – A Growing Threat to Young Adults • In the US, colorectal cancer ranks second in cancer-related deaths overall and is the leading cause in men younger than 50 (1) - Over 150,000 patients diagnosed annually, with ~60% anticipated to have Stage 4 disease at diagnosis (1) -
Slide 25: Vast Majority of Metastatic CRC is MSS CRC with No Approved IO Treatment
25 Vast Majority of Metastatic Colorectal Cancer is MSS CRC with No Approved IO Treatment Options • MSS CRC represents the vast majority of metastatic CRC (95%) (2) - Characterized by tumors with weak immunogenicity and limited immune cells (making it a “cold tumor”) - Checkpoint inhibitors ineffect
Slide 26: Clinical Development Plan for XTX101
26 Plan to activate clinical trial sites for combination dose escalation to evaluate XTX101 in combination with atezolizumab in Q4 2023 Data cutoff date: August 3, 2023 1. Eligible histology includes, but is not limited to, the following: melanoma, squamous cell skin cancer, NSCLC, head and neck squ
Slide 27: XTX101 Clinical Trial Progress and Anticipated Milestones
27 Data cutoff date: August 3, 2023. 1. Tumor response was assessed by RECIST version 1.1. XTX101 Clinical Trial Progress and Anticipated Milestones • RP2D defined at 150 mg Q6W with differentiated safety profile • Preliminary PK analyses demonstrated dose-proportional drug exposure and limited acti
Slide 28: XTX202 Tumor-Activated, Beta-Gamma IL-2
28 XTX202 Tumor-Activated, Beta-Gamma IL-2
Slide 29: High-Dose IL-2 has Curative Potential but Limited by High Systemic Toxicity
29 Data represents all patients that received high dose IL-2 (no control group). NR: no response; PFS: progression free survival. High-Dose IL-2 has Curative Potential but Limited by High Systemic Toxicity High-Dose IL-2 • Deep and durable responses • CRs in Melanoma and RCC • High systemic toxicity
Slide 30: XTX202: Tumor-Activated, Beta-Gamma IL-2
30 XTX202: Tumor-Activated, Beta-Gamma IL-2 Designed to Overcome the Limitations of Systemically Active Molecules Cleavage Site Half-Life Extension Domain Effector Domain Masking Domain Half-Life Extension Domain Effector Domain MMP Activation Inactive State Active State Activated XTX202: • Beta-gam
Slide 31: XTX202 Demonstrated TIL Expansion and Anti-Tumor Activity Without TREG Stimulation
MC38 tumor-bearing mice were treated with either vehicle, aldesleukin (3 mg/kg BID) or XTX202 10mg/kg QDx5. Tumor volume was recorded at day 5 post first dose and tumor infiltrating immune cells were phenotyped and 31 enumerated using flow cytometry. One-way ANOVA was performed to determine statisti
Slide 32: XTX202 in Combination with Anti-PD-1 Preclinical Activity
32 Enhancement of In Vivo Activity and Evidence of Memory Response for XTX202 in Combination with Anti-PD-1 0 20 40 60 80 100 0 50 100 Days post-treatment start Probability of Survival Rechallenge ** 0 5 10 15 20 0 500 1000 1500 Days post-treatment start Tumor volume (mm³ + SEM) Naive XTX202 2mg/kg
Slide 33: Clinical Development Plan for XTX202
33 As of August 14, 2023 Clinical Development Plan for XTX202 Potential to Explore Additional Phase 2 Trials for XTX202 in Combination with an anti-PD-(L)1: Melanoma, RCC, Lung Cancer Indicates potential future cohort or trial Current dose level: 4.0 mg/kg Phase 2A Monotherapy Expansion RCC Cohort P
Slide 34: XTX202 Has Achieved Dose Levels Beyond High-Dose IL-2
Aldesleukin dose if full indicated administration completed (0.037mg/kg*14 over 5 days + 9 days rest + 0.037 mg/kg*14 over 5 days). In preclinical studies, XTX202 at a total dose of 20 mg/kg had similar activity for tumor growth inhibition and 34 PD to aldesleukin at a total dose of 24 mg/kg. DO: do
Slide 35: No Peripheral Lymphocytosis Observed with XTX202 at 1 mg/kg
Mojgan 35 Ahmadzadeh, Steven A. Rosenberg 2006 DOI: 10.1182/blood-2005-06-2399. 2. ASCO 2017, Abstract #2545. 3. ASCO 2022, Abstract # 2500. Results do not represent a head-to-head trial for 3rd party products and XTX101. Peripheral lymphocytosis is a PD marker of IL-2 biology. hr: human recombinant
Slide 36: Tumor-Selective Increases in CD8+ Effector T Cells with XTX202
36 • 3.4 average increase in CD8 cell count observed in tumors treated with XTX202 from baseline • Clinical data consistent with 3.3-fold change observed in preclinical data Patients had an optional on-treatment tumor biopsy and were the only four patients treated with XTX202 for whom a tumor biopsy
Slide 37: XTX202 Clinical Trial Progress
37 XTX202 Clinical Trial Progress • Administered as an outpatient regimen • PK supports once every three-week dosing schedule • Surpassed target dose range of 1 mg/kg (dose level four) in Phase 1 monotherapy dose-escalation - No signs or symptoms of VLS observed through 2.8 mg / kg (dose level six)
Slide 38: Multiple Combination Opportunities Enabled by XTX202
38 Multiple Combination Opportunities Enabled by XTX202 Properties: Tumor-Activated, Well-Tolerated Preclinically and Clinically-Validated Target • Monoclonal antibodies • (Checkpoint inhibitors; ADCC-inducing mAbs; • T-cell engagers) Other pro-inflammatory cytokines (IL-12; IL-18) Cell therapies (T
Slide 39: XTX301 Tumor-Activated IL-12
39 XTX301 Tumor -Activated IL -12
Slide 40: The Compelling Potential of IL-12 as a Therapeutic Agent
40 • IL-12 has significant potential as a potent IO therapeutic agent in cold tumors • Poor tolerability has limited its clinical progress for decades • No currently approved IL-12 agents INFγ is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. Th1-ty
Slide 41: IL-12 Can Remodel Cold Tumor Microenvironment
41 Adapted from “Cold vs Hot Tumors”, by BioRender.com, 2022. Retrieved from https://app.biorender.com/biorender-templates Barraondo et al., Clin. Cancer Res., 2018. Nguyen et al., Front. Immunol., 2020. MDSC: myeloid-derived suppressor cells Hot Tumor IL-12 Can Remodel Cold Tumor Microenvironment T
Slide 42: XTX301: Tumor-Activated IL-12
42 XTX301: Tumor-Activated IL-12 Designed to Overcome the Limitations of Systemic Recombinant Human IL-12 Inactive State Active State MMP Activation Half-Life Extension Domain Masking Domain Effector Domain Cleavage Site Effector Activated XTX301: Domain • Optimized short half-life IL-12 (half-life
Slide 43: mXTX301 Dose-Dependent Anti-Tumor Activity Without Body Weight Loss
43 Tumor Growth Body Weight mXTX301 is a murine surrogate for XTX301. MC38 model: s.c. 0.5x106 cells; single IV dose of mXTX301 and mXTX302 on Day 0. Tumor growth data shown as mean±SEM. Tumor volume data was assessed by a two-way ANOVA followed by Bonferroni post hoc test on Day 11 compared to vehi
Slide 44: mXTX301 Immune Cell and Pathway Effects
44 mXTX301 is a murine surrogate for XTX301. Left panel: MC38 tumor bearing mice (n= 5 per group) were treated with a single IV dose of mXTX301 at 0.39 mg/kg or vehicle and immune cells were phenotyped using FACS. The number of cells for each immune phenotype was calculated per g of tissue and the r
Slide 45: mXTX301 Preferentially Activated in Tumors vs. Plasma In Vivo
mXTX301 is a murine surrogate for XTX301. 45 Left panel: Mice bearing MC38 syngeneic colorectal carcinoma tumors were dosed with mXTX301 (murine surrogate for XTX301), and the percent activated drug was measured over time in tumors and plasma. Right panel: Mice bearing MC38 syngeneic colorectal carc
Slide 46: XTX301 Preclinical Data Support Broad Therapeutic Index
46 • XTX301 was tolerated at doses up to 2.0 mg/kg Q1W x4 in NHP (HNSTD) • mXTX301 induced tumor regressions in murine model following a single dose of 0.13 mg/kg HNSTD: highest non-severely toxic dose; Q1W: once every week. XTX301 Preclinical Data Support Potential for Broad Therapeutic Index 0 24
Slide 47: Clinical Development Plans for XTX301
47 μg: micrograms. Clinical Development Plans for XTX301 Phase 1A Monotherapy Dose-Escalation Advanced Solid Tumors Phase 1B — 1 Monotherapy PD Cohort “Hot Tumors” Phase 1B — 2 Monotherapy PD Cohort “Cold Tumors” Backfill Cohort Phase 1C Combination with PD-(L)1 Dose-Escalation Advanced Solid Tumors
Slide 48: XTX301 Progress and Anticipated 2023 Clinical Milestones
48 XTX301 Progress and Anticipated 2023 Clinical Milestones • Demonstrated dose-dependent anti-tumor activity without significant body weight loss in vivo • Preferentially activated in tumors vs plasma in vivo • Preferentially activated in human patient tumors vs. plasma ex vivo • Phase 1 initiated
Slide 49: Executing on Our Vision to Deliver Tumor-Activated IO Therapies
49 Preclinical Proof-of-Concept Human Translational Proof-of-Concept Peripheral Masking In Clinic Tumor-Activation in Clinic Clinical Anti-Tumor Activity XTX101 (Anti-CTLA-4) Phase 1A Complete Phase 1B Dosing XTX202 (IL-2) Phase 1B and Phase 2 Dosing XTX301 (IL-12) Phase 1A Dosing Multifunctional (P
Slide 50: Xilio is Positioned for Multiple Anticipated Clinical Milestones
50 Xilio is Positioned for Multiple Anticipated Clinical Milestones XTX101 (Anti-CTLA-4) Reported Clinical Data Preliminary anti-tumor activity, safety and PK/PD data from Phase 1 trial (monotherapy) XTX202 (IL-2) Plan to Report Clinical Data Preliminary anti-tumor activity, safety and PK/PD data in
Slide 51: Existing Cash Sufficient to Fund Operations Into End of Q2 2024
51 Anticipate Existing Cash and Cash Equivalents Sufficient to Fund Operating Expenses and Capital Expenditure Requirements Into the End of Q2 2024 Balance Sheet June 30, 2023* December 31, 2022 Cash and Cash Equivalents $75.4M $120.4M * Unaudited Statement of Operations Three Months Ended June 30 2
Slide 52: Xilio is a Differentiated IO Company with a Proprietary Tumor-Activated Platform
52 Xilio is working to deliver highly potent, localized immunotherapies in cancer and beyond Xilio Therapeutics is a Differentiated IO Company with a Proprietary Tumor-Activated Platform and the Team to Deliver Patient Portrayal