Xilio Therapeutics, Inc. · NASDAQ:XLO
Xilio Therapeutics — 2021 Next-Gen Cytokines Summit
27 slides from Xilio Therapeutics's conference presentation, Sep 22, 2021
Slide 1: Engineering Geographically Precise Activation of Cytokines to Achieve Improved Therapeutic Benefit in Oncology and Beyond
ENGINEERING GEOGRAPHICALLY PRECISE ACTIVATION OF CYTOKINES TO ACHIEVE IMPROVED THERAPEUTIC BENEFIT IN ONCOLOGY AND BEYOND SEPT EMBER 22, 2021
Slide 2: Disclosure of Interest
Disclosure of Interest Natalia Malkova is a full-time employee and equity holder of Xilio Therapeutics Inc (“Xilio”) XTX202 and XTX301 are investigational agents discovered and in development by Xilio 2
Slide 3: Today's I-O agents offer curative potential but are limited due to systemic toxicity
Today’s I-O agents offer curative potential but are limited due to systemic toxicity Compelling Efficacy Dose-limiting Toxicity • Improved survival achieved with high dose • Multi-organ AEs and peripheral side effects of potent ipilimumab (anti-CTLA-4) at 10 mg/kg I-O therapy can be lethal • 10-year
Slide 4: Today's I-O agents offer curative potential but are limited due to systemic toxicity
Today’s I-O agents offer curative potential but are limited due to systemic toxicity Compelling Efficacy Dose-limiting Toxicity • Improved survival achieved with high dose • Multi-organ AEs and peripheral side effects of potent ipilimumab (anti-CTLA-4) at 10 mg/kg I-O therapy can be lethal • 10-year
Slide 5: GPS-enabled therapies are designed to unlock the full potential of immuno-oncology
GPS-enabled therapies are designed to unlock the full potential of immuno-oncology Geographically precise solutions (GPS) are designed to solve this problem by localizing the desired I-O effect in the tumor Xilio’s GPS Platform: Engineer highly potent I-O molecules Designed to be systemically in
Slide 6: GPS platform components designed to work synergistically to improve I-O therapeutic index
GPS platform components designed to work synergistically to improve I-O therapeutic index GPS-enabled Cytokine Tumor Microenvironment-Activated Cytokine 2 Masking domain 2 1 3 Linker sequences Cytokine 3 1 Active 3 cytokine 4 MMP-dependent cleavage at the tumor Protease cleavage site Molecule enters
Slide 7: Building a robust pipeline of tumor-selective cytokine and checkpoint inhibitor programs
Building a robust pipeline of tumor-selective cytokine and checkpoint inhibitor programs Advancing two lead programs into clinic CTLA-4 IL-2 IL-12 IL-15 Mechanism Tumor-Selective Program of Action Discovery IND-enabling Phase 1 Phase 2 Phase 3 XTX101 Anti-CTLA-4 XTX202 IL-2 XTX301 IL-12 XTX401 IL-15
Slide 8: XTX202: Tumor-Selective IL-2 Product Candidate
XTX202 TUMOR-SELECTIVE IL-2 PRODUCT CANDIDATE 8
Slide 9: High-dose IL-2 offered curative potential, but usage limited by vascular leak syndrome
High-dose IL-2 offered curative potential, but usage limited in patients due to life-threatening vascular leak syndrome High-dose IL-2 resulted in overall survival >10 years, Limited use of high-dose IL-2 mostly in patients who achieved a CR* in patients with cancer Must have normal cardiac — and pu
Slide 10: Avoiding IL-2 receptor α reduces immune suppression and supports immune activation
Avoiding IL-2 receptor α reduces immune suppression and supports immune activation Intermediate-affinity High-affinity βγ receptor αβγ receptor Tregs: regulatory T cells; CD8+: immune activating T cells; NK: natural killer cells Adapted from Border (2012) Nature 10
Slide 11: Not-α IL-2 has potential to increase potency in preclinical models and cancer patients
Not-α IL-2 has potential to increase potency in preclinical models and cancer patients • Not-α IL-2 matches efficacy of wild-type IL-2 at the same dose and schedule in mice • Not-α IL-2 reduces activation of immune suppressive Treg cells compared to wild-type IL-2 • XTX202 is engineered to avoid bin
Slide 12: Not-α IL-2 did not affect regulatory T cells in periphery in vivo
Not-α IL-2 did not affect regulatory T cells in periphery in vivo Peripheral Blood CD8+ T cells Peripheral Blood NK cells Peripheral Blood Tregs **** 40 30 **** 1.5 (as % of CD45+ live cells) (as % of CD45+ live cells) (as % of CD45+ live cells) **** CD4+Foxp3+CD25+ 30 Nkp46+CD3- 20 1.0 **** ** CD8
Slide 13: Not-alpha IL-2 induced peripheral activity consistent with IL-2 activity in non-human primates
Not-alpha IL-2 induced peripheral activity consistent with IL-2 Activity in non-human primates Lymphocytes Albumin 15 10 **** Vehicle Vehicle relative to pre-dose 0 Not-α IL-2 Fold change 10 Not-α IL-2 % change -10 -20 5 **** * -30 ** *** *** 0 -40 0 10 20 30 0 10 20 30 Days post-treatment start Day
Slide 14: XTX202 provided protease-dependent control of IL-2 activity in vitro
XTX202 provided protease-dependent control of IL-2 activity in vitro • XTX202 was effectively masked and its signal through IL-2 receptor was highly attenuated in CD8+ T and regulatory T cells compared to its unmasked control XTX200. • MMP cleavage restored XTX202 activity to the level of unmasked c
Slide 15: XTX202 activated intratumoral immune response in syngeneic B16F10 melanoma mouse model
XTX202 activated intratumoral immune response in syngeneic B16F10 melanoma mouse model XTX202: active in tumor XTX202: not active systemically Tumor CD8+ T Cells Splenic CD8+ T Cells • XTX202 activated immune response in tumor, but not in spleen • Data support tumor-selective pharmacodynamic activit
Slide 16: XTX202 elicits tumor growth inhibition at well-tolerated doses in MB49 bladder cancer model
XTX202 elicits tumor growth inhibition at well-tolerated doses in syngeneic bladder cancer MB49 model Tumor XTX202 and XTX200 Treatment Inoculation Aldesleukin BID Study design Day (-10) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 20 2000 20 • XTX200 at 0.36 mg/kg Q2D Tumor volume (mm³ + SEM) and al
Slide 17: XTX202 did not affect immune cells in periphery in MB49 model
XTX202 did not affect immune cells in periphery in syngeneic bladder cancer MB49 model Peripheral Blood CD8+ T cells Peripheral Blood NK cells Peripheral Blood Tregs **** 40 30 1.5 **** (as % of CD45+ live cells) (as % of CD45+ live cells) (as % of CD45+ live cells) **** CD4+Foxp3+CD25+ 30 **** Nkp4
Slide 18: XTX202 was well-tolerated in vivo and overcame toxicity observed with aldesleukin
XTX202 was well-tolerated in vivo and overcame toxicity observed with aldesleukin Splenomegaly Pulmonary Edema (VLS) 600 **** 600 **** Lung Weight (mg) Spleen Weight (mg) *** 400 400 * 200 200 0 0 Vehicle XTX202 XTX200 aldesleukin Vehicle XTX202 XTX200 aldesleukin • XTX202 did not induce splenomegal
Slide 19: XTX202 does not induce peripheral immune cell activation in NHPs
XTX202 does not induce peripheral immune cell activation in NHPs • Cynomolgus monkeys in a 4-week repeat dose study • Dosing on study days 1, 8, 15, and 21 • XTX200 treatment resulted in a 3 to 4-fold increase in the level of proliferating CD8+ cells in NHPs over the repeat dose course (weekly x4).
Slide 20: XTX202 was well-tolerated in NHPs after weekly doses
XTX202 was well-tolerated in NHPs after weekly doses up to 10 mg/kg Lymphocytes 60 Main Study Recovery Cell Number (x103 / uL) 40 20 0 0 20 40 60 Day • XTX202 did not cause peripheral lymphocyte expansion or capillary leakage at repeat (weekly x4) doses up to 10 mg/kg in a GLP toxicology study. • XT
Slide 21: XTX202 (GPS-enabled IL-2) Summary
XTX202 (GPS-enabled IL-2) Summary • XTX202 demonstrated protease dependent activity in human PBMC-based assays. • XTX202 exhibited significant tumor growth inhibition in syngeneic mouse bladder MB49 model as a single agent with no evidence of toxicity or peripheral immune activation, thus demonstrat
Slide 22: XTX301: Tumor-Selective IL-12 Candidate
XTX301 TUMOR-SELECTIVE IL-12 CANDIDATE 22
Slide 23: IL-12 induced objective responses in patients with cancer
IL-12 induced objective responses in patients with cancer • IL-12 is a key pro-inflammatory cytokine produced by antigen presenting cells in response to pathogen infection. • IL-12 has demonstrated anti-tumor effects against a range of malignancies in preclinical studies. These effects are largely d
Slide 24: XTX301 provided protease-dependent control of IL-12 activity in vitro
XTX301 provided protease-dependent control of IL-12 activity in vitro CD8+ T cells 30 rhIL-12 XTX300 XTX301+MMP pSTAT4 (%) 20 XTX301 10 0 01 0. 1 10 10 00 0. 001 1 1 00 1 0 00 0. 01 0 00 0. 10 0 0 00 0. 10 00 0 00 10 00 0. Concentration (nM) • Compared to unmasked control XTX300, XTX301 was effectiv
Slide 25: XTX301 (GPS-enabled IL-12) Summary
XTX301 (GPS-enabled IL-12) Summary • Compared to unmasked control XTX300, XTX301 demonstrated attenuated pSTAT4 signaling and functional IFNγ secretion in primary human immune cells. • MMP activation restored potency of XTX301 signaling back to XTX300 levels. • XTX301 anti-tumor activity was evaluat
Slide 26: Conclusions
Conclusions • Tumor-selective XTX202 (IL-2) and XTX301 (IL-12) drug candidates exhibited strong protease- dependent control in vitro. • XTX202, demonstrated tumor-selective activity that resulted in significant tumor growth inhibition in syngeneic mouse bladder MB49 model and showed minimal to no ev
Slide 27: Xilio Therapeutics
x:1LiS THERAPEUTICS