Xilio Therapeutics, Inc. · NASDAQ:XLO
Xilio Therapeutics — Corporate Update (May 2023)
54 slides from Xilio Therapeutics's corporate update, May 25, 2023
Slide 1: Unleashing the Potential of Immuno-Oncology Therapies
1 Unleashing the Potential of Immuno-Oncology Therapies May 25, 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 data fro
Slide 3: Deep Expertise to Build a Transformational Immuno-Oncology Company
3 Deep Expertise to Build a Transformational Immuno-Oncology Company Proven Track Record in Biotech and Pharma Developing Novel Therapies • Collectively contributed to >25 NDAs, sNDAs and BLAs supporting 15 approved, marketed therapies • Directly contributed to approved oncology therapies: pembroliz
Slide 4: Immuno-Oncology Therapy has Curative Potential but is Limited by Systemic Toxicity
4 • 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 impeded by dose-limiting systemic toxicity Immuno-Oncology Therapy has Curative Potential b
Slide 5: Xilio's Tumor-Activated Molecules Designed to Overcome Limitations of Systemic Treatments
5 Xilio’s Novel Tumor-Activated Molecules are Designed to Overcome the Limitations of Systemically Active Treatments • Harness and focus the power of the immune system to fight cancer • Novel design to outsmart tumors — using tumor growth activity against itself - Tumor proteases activate a switch i
Slide 6: Molecules Designed to be Selectively Activated in the TME by MMPs
6 Xilio’s Molecules are Designed to be Selectively Activated in the TME by MMPs MMP-based activation in vitro High activation efficiency across human solid tumors ex vivo Tumor-specific activation in vivo In vitro recombinant MMP kinetic cleavage assay Tumor Plasma Spleen Liver KidneyLung 0 2 4 6 Fo
Slide 7: Building a Pipeline of Novel Tumor-Activated Immuno-Oncology Therapies
7 Program Initial Tumor Types Mechanism of Action Discovery IND-Enabling Phase 1 Phase 2 Phase 3 Antibody Program XTX101 (1) Advanced Solid Tumors Anti-CTLA-4 Cytokine Programs XTX202 (2) Advanced RCC and Melanoma IL-2 XTX301 (3) Advanced Solid Tumors IL-12 Multifunctional Program Multifunctional Ad
Slide 8: CTLA-4 Evolving Paradigm and Opportunity for a Tumor-Activated Anti-CTLA-4
8 CTLA-4 Evolving Paradigm and Opportunity for a Tumor-Activated Anti-CTLA-4
Slide 9: Ipilimumab Data Demonstrated Transformative Potential of High Dose Anti-CTLA-4
9 Ipilimumab Data Demonstrated Transformative Potential of High Dose Anti-CTLA-4 Trial conducted by Bristol Myers Squibb. 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 (201
Slide 10: CTLA-4's Changing Paradigm: Fc Enhancement and High Dose Improve Outcomes
10 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 11: XTX101 Tumor-Activated Anti-CTLA-4
11 XTX101 Tumor-Activated Anti-CTLA-4
Slide 12: XTX101: Tumor-Activated, High Affinity Binding and Fc-Enhanced Anti-CTLA-4
12 Inactive State Active State topspin MMP Activation Masking Domain Variable Domain Variable Domain Masking Domain Cleavage Sites ADCC-enhanced Fc ADCC-enhanced Fc Variable Domain Variable Domain Activated XTX101 designed to: • bind and block CTLA-4 checkpoint • drive potent ADCC against TREGs that
Slide 13: XTX101 Preclinical Profile Differentiated from Ipilimumab and AGEN1181
13 XTX101 Preclinical Profile Differentiated from Ipilimumab (10x potency, TREG depletion, safety) and AGEN1181 (safety) XTX101 is 10-fold more potent than ipilimumab(1) in in vivo studies 1. Ipilimumab analog comprising a monoclonal antibody of identical amino acid sequence to ipilimumab that was p
Slide 14: Preliminary Phase 1 Clinical Trial Data for XTX101
14 Preliminary Phase 1 Clinical Trial Data for XTX101
Slide 15: Patients Enrolled in Phase 1 Trial (Parts 1A and 1B) for XTX101
15 25 Patients Enrolled in Phase 1 Trial (Parts 1A and 1B) for XTX101 with a Wide Range of Advanced and Treatment Refractory Solid Tumors Data cutoff date: May 2, 2023 1. Eligible histology includes, but is not limited to, the following: melanoma, squamous cell skin cancer, NSCLC, head and neck squa
Slide 16: XTX101 Administered at 150 mg Q6W Identified as the RP2D in Part 1A
16 XTX101 Administered at 150 mg Q6W Identified as the RP2D in Part 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
Slide 17: XTX101 150 mg Q6W Provided a 2-fold Higher Cmax Compared to Ipilimumab
17 XTX101 Administered at 150 mg Q6W Dose Provided a 2-fold Higher Cmax Compared to Ipilimumab at 10 mg/kg (Adjusted for 10x Higher Potency) 1. FDA Center for Drug Evaluation and Research, Clinical Pharmacology and Biopharmaceutics Review of ipilimumab. https://www.accessdata.fda.gov/drugsatfda_docs
Slide 18: XTX101 150 mg Q6W Identified as Optimal Dose / Schedule
18 XTX101 Administered at 150 mg Q6W Identified as Optimal Dose / Schedule AE Category / Term All TRAEs with ≥10% incidence in any category All Patients at Q3W (7-180 mg) (n=18) 180 mg Q3W (n=6) RP2D 150 mg Q6W (n=7) Any Grade 3 Any Grade 3 Any Grade 3 Diarrhea or Colitis 7 (39%) 4 (22%) 2 (33%) 2 (
Slide 19: Clinical Case: Tumor-Selective Activation in a NSCLC Patient Dosed with XTX101
19 Clinical Case Tumor-Selective Activation in a NSCLC Patient Dosed with XTX101 Administered at 150 mg Q6W
Slide 20: XTX101 Anti-Tumor Activity in a Patient with PD-L1 Negative NSCLC
20 XTX101 Anti-Tumor Activity in a Patient with PD-L1 Negative NSCLC with 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 mon
Slide 21: Primary Lung Lesion Decreased in Size and Developed Cavitation on XTX101
21 Primary Lung Lesion Decreased in Size and Developed Cavitation on XTX101 Monotherapy Baseline After 9 Weeks of XTX101 After 18 Weeks of XTX101
Slide 22: Hepatic Metastases Resolved on XTX101 Monotherapy
22 Hepatic Metastases Resolved on XTX101 Monotherapy After 9 weeks of XTX101 Baseline After 18 weeks of XTX101
Slide 23: XTX101 Tumor-Selective Activity Demonstrated by Minimal Peripheral PD
23 XTX101 Tumor-Selective Activity Demonstrated by Minimal Peripheral PD in the Patient with PD-L1 Negative NSCLC and a Confirmed PR Data cutoff date: May 2, 2023. PR confirmed after the data cutoff date on May 17, 2023. PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors PR i
Slide 24: XTX101 Differentiated Clinical Profile Supports Continued Development in Combination With PD-(L)1
24 XTX101 Differentiated Clinical Profile Supports Continued Development in Combination With a PD-(L)1 • RP2D defined at 150 mg Q6W with differentiated safety profile - N=1 reversible Grade 3 GI toxicity after 2 doses at RP2D - No immune-related endocrine or skin toxicity - No infusion reactions • P
Slide 25: Clinical Development Plan for XTX101
25 Clinical Development Plan for XTX101 Data cutoff date: May 2, 2023 1. Eligible histology includes, but is not limited to, the following: melanoma, squamous cell skin cancer, NSCLC, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, RCC, urothelial carcinoma, MSS instabilit
Slide 26: XTX202 Tumor-Activated, Beta-Gamma IL-2
26 XTX202 Tumor-Activated, Beta-Gamma IL-2
Slide 27: High-Dose IL-2 has Curative Potential but is Limited by High Systemic Toxicity
27 High-Dose IL-2 has Curative Potential but is Limited by High Systemic Toxicity High-dose IL-2 resulted in PFS >10 years, mostly in patients who achieved a CR Data represents all patients that received high dose IL-2 (no control group). NR: no response; PFS: progression free survival. High-Dose IL
Slide 28: XTX202: Tumor-Activated, Beta-Gamma IL-2 Designed to Overcome Limitations
28 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 29: XTX202 Demonstrated Improved Therapeutic Index In Vivo Compared to Aldesleukin
29 XTX202 Demonstrated Improved Therapeutic Index In Vivo Compared to Aldesleukin and Non-Masked Control Tumor Growth Inhibition at Day 5 Well-tolerated in NHP with no signs of VLS Left panel: XTX202 dose at 2 mg/kg every other day; non-masked control dose at 0.4 mg/kg every other day; aldesleukin d
Slide 30: XTX202 Demonstrated TIL Expansion Without Significant TREG Stimulation In Vivo
30 XTX202 Demonstrated TIL Expansion (CD8+ Effector T Cells and NK) and Anti-Tumor Activity Without Significant TREG Stimulation In Vivo 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
Slide 31: Enhancement of In Vivo Activity and Memory Response for XTX202 with Anti-PD-1
31 Enhancement of In Vivo Activity and Evidence of Memory Response for XTX202 in Combination with Anti-PD-1 Anti-tumor activity of XTX202 as a single agent and in combination with anti-mPD-1 was evaluated in hFcRn Tg32 transgenic mice bearing the murine MB49 bladder carcinoma model. The combination
Slide 32: Clinical Development Plan for XTX202
32 Clinical Development Plan for XTX202 Current dose level: 2.8 mg/kg Part 2A Monotherapy Expansion RCC Cohort Part 1A Monotherapy Dose Escalation Advanced Solid Tumors Part 2B Monotherapy Expansion Melanoma Cohort Part 2C PD-1 Combination Dose Escalation Part 1B Monotherapy PD Cohort “Hot Tumors” M
Slide 33: XTX202 Has Achieved Dose Levels Beyond High-Dose IL-2
33 XTX202 Has Achieved Dose Levels Beyond High-Dose IL-2 High-Dose IL-2 and IL-2 Clinical Molecules (doses in mg/kg) 1.036 0.006 0.024 0.030 0.090 0.364 1.400 Aldesleukin Bempegaldesleukin THOR707 Nemvaleukin MDNA11 ANV419 XTX202 Systemically Active Sytemically Active Systemically Active Systemicall
Slide 34: No Peripheral Lymphocytosis Observed with XTX202 at the 1 mg/kg Dose Level
34 No Peripheral Lymphocytosis Observed with XTX202 in Patients at the 1 mg/kg Dose Level Aldesleukin (1) hr IL-2 First Generation Bempegaldesleukin (2) NKTR-214 Second Generation Nemvaleukin Alfa (3) ALKS-4230 Second Generation Tumor-Activated XTX202 Third Generation XTX202: Decrease in ALC count o
Slide 35: XTX202 Tumor-Selective Increases in CD8+ T Cells in Melanoma Patient
35 XTX202 Clinical Patient Data: Tumor-Selective Increases in CD8+ Effector T Cells Observed in Melanoma Patient Tumor Sample at Dose Level 2 Patient had an optional on-treatment tumor biopsy and was one of the only two patients treated with XTX202 for whom a tumor biopsy analysis was available as o
Slide 36: XTX202 Tumor-Selective Increases in CD8+ T Cells in RCC Patient
36 XTX202 Clinical Patient Data: Tumor-Selective Increases in CD8+ Effector T Cells Observed in RCC Patient Tumor Sample at Dose Level 3 Patient had an optional on-treatment tumor biopsy and was one of the only two patients treated with XTX202 for whom a tumor biopsy analysis was available as of Mar
Slide 37: XTX202 Tumor-Selective Increases in CD8+ Effector T Cells in Two Patients
37 XTX202 Clinical Patient Data: Tumor-Selective Increases in CD8+ Effector T Cells Observed in Two Patients Following Treatment at Dose Levels 2 and 3 Patient #1: Melanoma patient treated with XTX202 at 0.38 mg/kg Q3W (dose level 2) Patient #2: RCC patient treated with XTX202 at 0.53 mg/kg Q3W (dos
Slide 38: Intralesional Aldesleukin CRs Associated with Increase in CD8+ T Cells
38 In Patients Treated with Intralesional Injection of Aldesleukin, CRs Associated with Increase in CD8+ T Cells: 4-fold (Gene Expression) and 10-fold (IHC) Pourmaleki et al., Cancer Immunology Research, 2022. Left image: Illustration adapted from same publication using BioRender. Right image: Diffe
Slide 39: XTX202 Clinical Trial Progress
39 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 1.4 mg / kg (dose level five)
Slide 40: Anticipated Preliminary Clinical Data for XTX202 in Q3 2023
40 Anticipated Data Anticipated Preliminary Clinical Data for XTX202 in Q3 2023 * Target ORR similar to aldesleukin of ~10-15% • ~15-20 evaluable patients treated at 1 mg/kg or higher across all cohorts in Part 1A/B and Part 2A/B • Safety • PK / PD • Anti-tumor activity (ORR) *
Slide 41: Multiple Combination Opportunities Enabled by XTX202 Properties
41 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 (TIL, T-
Slide 42: XTX301 Tumor-Activated IL-12
42 XTX301 Tumor -Activated IL -12
Slide 43: The Compelling Potential of IL-12 as a Therapeutic Agent
43 The Compelling Potential of IL-12 as a Therapeutic Agent • 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 antiprol
Slide 44: IL-12 Can Remodel Cold Tumor Microenvironment Towards a Hot State
44 IL-12 Can Remodel Cold Tumor Microenvironment Towards a Pro-Inflammatory (Hot) State that Favors Anti-Tumor Immunity • CD8+ T cells and NK cells are abundant in tumor • Pro-inflammatory microenvironment • Improved prognosis and effective killing of tumor cells with immunotherapy treatment • Lack
Slide 45: XTX301: Tumor-Activated IL-12 Designed to Overcome Limitations of Recombinant IL-12
45 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 46: mXTX301 Demonstrated Dose-Dependent Anti-Tumor Activity Without Body Weight Loss
46 mXTX301 Demonstrated Dose-Dependent Anti-Tumor Activity Without Body Weight Loss In Vivo 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 as
Slide 47: mXTX301 Induced Tumor-Specific Pharmacology In Vivo
47 mXTX301 Induced Tumor-Specific Pharmacology In Vivo mXTX301 induced pro-inflammatory gene programs and broadly remodeled TME toward inflamed state mXTX301 induced specific T cell recruitment into the tumor with minimal peripheral effects CD45 CD3 CD4 CD8 0 2 4 6 Fold change over Vehicle Tumor Spl
Slide 48: mXTX301 was Preferentially Activated in Tumors vs. Plasma In Vivo
48 mXTX301 was Preferentially Activated in Tumors vs. Plasma In Vivo mXTX301 demonstrated tumor-specific activation in vivo mXTX301 treatment resulted in cleavage-dependent enhancement in activity vs non-activatable control mXTX301 is a murine surrogate for XTX301. Left panel: Mice bearing MC38 syng
Slide 49: XTX301 Preclinical Data Support Potential for Broad Therapeutic Index
49 XTX301 Preclinical Data Support Potential for Broad Therapeutic Index • 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. 0 24
Slide 50: Clinical Development Plans for XTX301
50 Clinical Development Plans for XTX301 MSI: microsatellite instability; μg: micrograms. Potential to consider combination of XTX202 (IL-2) + XTX301 (IL-12) Part 1A Monotherapy Dose-Escalation Advanced Solid Tumors Part 1B — 1 Monotherapy PD Cohort “Hot Tumors” Part 1B — 2 Monotherapy PD Cohort “Co
Slide 51: XTX301 Progress and Anticipated 2023 Clinical Milestones
51 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 52: Executing on Our Vision to Deliver Tumor-Activated Immuno-Oncology Therapies
52 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 Dosing Complete Phase 1B Dosing XTX202 (IL-2) Phase 2 Dosing XTX301 (IL-12) Phase 1A Dosing Multifunctional (PD-1/IL
Slide 53: Xilio is Positioned for Multiple Anticipated Clinical Milestones in 2023
53 Xilio is Positioned for Multiple Anticipated Clinical Milestones in 2023 XTX101 (Anti-CTLA-4) Reported Clinical Data Preliminary anti-tumor activity, safety and PK/PD data from Phase 1 trial (monotherapy) XTX202 (IL-2) Initiated Clinical Trial Enrollment in Phase 2 trial (monotherapy) XTX202 (IL-
Slide 54: Xilio is a Differentiated IO Company with a Proprietary Tumor-Activated Platform
54 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