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Item 1. Business

2024-04-01 compared with 2023-03-02 · 532 added, 603 removed, 591 unchanged (66% of the section changed)

We are a clinical-stage biotechnology company discovering and developing tumor-activated immuno-oncology, or I-O, therapies with the goal of significantly improving outcomes for people living with cancer without the systemic side effects of current I-O treatments.

We are leveraging our proprietary geographically precise solutions, or GPS, platform to build a pipeline of novel, tumor-activated molecules, including cytokines and other biologics, which are designed to optimize their therapeutic index by localizing anti-tumor activity within the tumor microenvironment.

We are leveraging our proprietary platform to build a pipeline of novel, tumor-activated I-O molecules that are designed to optimize the therapeutic index by localizing anti-tumor activity within the tumor microenvironment, including tumor-activated cytokines and antibodies (including bispecifics) and immune cell engagers (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

Current I-O therapies have curative potential for patients with cancer;

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Our molecules are engineered to localize activity within the tumor microenvironment with minimal systemic effects, resulting in the potential to achieve enhanced anti-tumor activity and increasing the population of patients who may be eligible to receive our medicines.

Our most advanced tumor-activated, clinical-stage product candidates are XTX202, an interleukin 2, or IL-2, therapy, XTX301, an interleukin 12, or IL-12, therapy and XTX101, an Fc-enhanced, anti-CTLA-4 monoclonal antibody, or mAb.

In addition to our clinical-stage product candidates, we are continuing to leverage our GPS platform and expertise in developing tumor-activated I-O therapies as we seek to expand our pipeline of discovery-stage programs and develop additional tumor-activated immunotherapies, including product candidates with a range of tumor targeting approaches.

XTX202 is an investigational tumor-activated beta-gamma biased (non-alpha), engineered IL-2 molecule designed to potently stimulate CD8+ effector T cells and natural killer, or NK, cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the tumor microenvironment.

We are currently evaluating XTX202 in an ongoing Phase 1 clinical trial in patients with advanced solid tumors.

The Phase 1 trial is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of multiple ascending doses of XTX202 with the goal of establishing a recommended Phase 2 dose, or RP2D, for XTX202 as a monotherapy in patients with advanced solid tumors.

We recently completed dosing patients at the 1 mg/kg dose level (dose level four) and are currently enrolling patients at the 1.4 mg/kg dose level (dose level five) in monotherapy dose-escalation (Part 1A) of the clinical trial.

Importantly, no signs of vascular leak syndrome, or VLS, including hypotension or decreases in albumin (an early sign of VLS) or hemodynamic compromise, have been observed in patients to date.

Monotherapy dose expansion (Part 1B) of the Phase 1 clinical trial is open for enrollment, and we plan to initiate patient enrollment in a Phase 2 clinical trial evaluating XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic renal cell carcinoma, or RCC, in April 2023.

In addition, we plan to report preliminary anti-tumor activity, safety, pharmacokinetic, or PK, and pharmacodynamic, or PD, data from the Phase 1/2 clinical trial in the third quarter of 2023, which we anticipate will include approximately 15-20 patients across a range of solid tumors treated at the 1 mg/kg dose or higher across all cohorts in the Phase 1/2 clinical trial.

XTX301 is an investigational tumor-activated, engineered IL-12 molecule designed to potently stimulate anti-tumor immunity and reprogram the tumor microenvironment of poorly immunogenic “cold” tumors towards an inflamed, or “hot,” state.

In November 2022, we announced clearance of our investigational new drug application, or IND, by the U.S.

Food and Drug Administration, or FDA, for XTX301 for evaluation in patients with advanced solid tumors.

We recently opened clinical trial sites and are actively screening patients for enrollment at a starting dose of 5.0 μg/kg (0.005 mg/kg) in monotherapy dose-escalation for our Phase 1 clinical trial evaluating the safety and tolerability of XTX301 in patients with advanced solid tumors.

We anticipate reporting preliminary safety data from the Phase 1 clinical trial into at least the third dose level in the fourth quarter of 2023.

XTX101 is an investigational Fc-enhanced, tumor-activated anti-CTLA-4 mAb designed to deplete regulatory T cells when activated (unmasked) in the tumor microenvironment and improve upon the therapeutic index of existing anti-CTLA-4 therapies.

We are currently evaluating XTX101 in an ongoing Phase 1 clinical trial in patients with advanced solid tumors.

The Phase 1 clinical trial is a first in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of XTX101 for the treatment of adult patients with advanced solid tumors.

We recently completed enrollment in monotherapy dose-escalation (Part 1A) of the Phase 1 trial, and enrollment in monotherapy dose-expansion (Part 1B) of the Phase 1 trial is ongoing.

In addition, we have determined an RP2D of 150 mg once every six weeks, or Q6W.

anticipate reporting preliminary safety, PK, PD and anti-tumor activity data from the Phase 1 clinical trial in the second quarter of 2023.

As previously announced, we plan to continue to explore strategic opportunities to advance XTX101 with a partner beyond the current Phase 1 clinical trial.

In addition to our most advanced product candidates, we believe our proprietary GPS platform has the potential to develop additional product candidates using a range of approaches to achieve tumor-activation and derive a clinically meaningful improvement in therapeutic index.

We currently have worldwide development and commercialization rights to all of our product candidates.

Our most advanced tumor-activated, clinical-stage product candidates are XTX101, an Fc-enhanced, anti-CTLA-4 monoclonal antibody, or mAb, XTX301, an interleukin 12, or IL-12, therapy, and XTX202, an interleukin 2, or IL-2, therapy.

In 2023, we presented clinical data across these programs showing initial clinical validation for each of these molecules and our tumor-activated approach.

In addition to our clinical-stage product candidates, we are continuing to leverage our differentiated research platform and expertise in developing tumor-activated I-O therapies to advance preclinical development for tumor-activated bispecific molecules and immune cell engager molecules (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

XTX101 is an investigational tumor-activated, Fc-enhanced, high-affinity binding anti-CTLA-4 mAb designed to block CLTA-4 and deplete regulatory T cells when activated (unmasked) in the tumor microenvironment and improve upon the therapeutic index of existing anti-CTLA-4 therapies.

In the third quarter of 2023, we entered into a co-funded clinical trial collaboration with F.

Hoffmann-La Roche Ltd., or Roche, to evaluate XTX101 in combination with atezolizumab (Tecentriq®) in a multi-center, open-label Phase 1/2 clinical trial.

We are currently evaluating the safety and tolerability of the combination in patients with advanced solid tumors in the Phase 1 dose escalation portion of the clinical trial.

We plan to select a recommended Phase 2 dose, or RP2D, for XTX101 in combination with atezolizumab in the second quarter of 2024, and subject to the results of the Phase 1 combination dose escalation portion of the trial, we plan to initiate the Phase 2 portion of the trial for XTX101 in combination with atezolizumab in patients with microsatellite stable colorectal cancer, or MSS CRC, in the third quarter of 2024.

In addition, we plan to report initial Phase 2 data for XTX101 in combination with atezolizumab in approximately 20 patients with MSS CRC in the fourth quarter of 2024 and in approximately 20 additional patients (40 patients total) in the first quarter of 2025.

XTX301 is an investigational tumor-activated IL-12 designed to potently stimulate anti-tumor immunity and reprogram the tumor microenvironment of poorly immunogenic “cold” tumors towards an inflamed or “hot” state.

In March 2024, our wholly-owned subsidiary Xilio Development, Inc., or Xilio Development, entered into an exclusive license agreement with Gilead Sciences, Inc., or Gilead, pursuant to which it granted Gilead an exclusive global license to develop and commercialize XTX301 and specified other molecules directed at IL-12.

For more information, please see “—License and Collaboration Agreements—Exclusive License Agreement with Gilead” below.

We are currently evaluating XTX301 in an ongoing Phase 1 first-in-human, multicenter, open-label clinical trial designed to evaluate the safety and tolerability of XTX301 as a monotherapy in patients with advanced solid tumors.

In January 2024, we reported preliminary safety data into the third dose level in the Phase 1 dose escalation and anticipate reporting safety, pharmacokinetic, or PK, and pharmacodynamic, or PD, data for XTX301 in the fourth quarter of 2024.

XTX202 is an investigational tumor-activated, beta-gamma biased IL-2 designed to potently stimulate CD8+ effector T cells and natural killer, or NK, cells without concomitant stimulation of regulatory T cells, or TREGs, when activated (unmasked) in the tumor microenvironment.

In March 2024, we announced updated data from our Phase 2 clinal trial evaluating XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic renal cell carcinoma, or RCC, who have progressed on standard-of-care treatment.

Together with previously reported data, we believe these additional data further validate our tumor-activated approach and support the broad potential for XTX202 as a combination therapy.

In March 2024, we also announced plans to explore strategic opportunities to continue to develop XTX202 in combination with other agents and, as part of a strategic portfolio reprioritization, plans to discontinue further investment in XTX202 as a monotherapy.

Future Opportunities

In addition to our most advanced product candidates, we believe our proprietary platform technology has the potential to develop additional product candidates using our tumor-activated masking approach, which is designed to achieve tumor-specific molecule activation and derive a clinically meaningful improvement in therapeutic index.

We are currently leveraging our differentiated platform technology, and our unique expertise in masking antibodies and cytokines, to develop a new generation of tumor-activated bispecific molecules and immune cell engager molecules.

Subject to obtaining sufficient additional capital, we plan to advance XTX501, our tumor-activated PD-1/IL-2 bispecific development candidate, into IND-enabling studies.

We also plan to continue to make focused investments in our promising research-stage pipeline for additional tumor-activated bispecific molecules and immune cell engager molecules (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

We will continue to evaluate opportunities for better tolerated and more efficacious combination therapies, using product candidates from across our portfolio with other cancer therapies, to increase the potential for curative regimens in oncology.

March 2024 Private Placement

On March 28, 2024, we entered into a securities purchase agreement with certain existing accredited investors, including Bain Capital Life Sciences and Rock Springs Capital, to issue and sell an aggregate of 1,953,125 shares of our common stock at a price of $0.64 per share and prefunded warrants to purchase up to an aggregate of 15,627,441 shares of our common stock at a purchase price of $0.6399 per prefunded warrant share, through a private investment in public equity financing.

The prefunded warrants will have an exercise price of $0.0001 per share of common stock, be immediately exercisable and remain exercisable until exercised in full.

We anticipate receiving aggregate gross proceeds from the private placement of approximately $11.3 million, before deducting placement agent fees and expenses payable by us.

The private placement is expected to close on April 2, 2024, subject to the satisfaction of customary closing conditions.

We expect to use the proceeds from the private placement to fund working capital and other general corporate purposes.

Our Approach—Improving the Therapeutic Index of I-O Therapies

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Similar to cytokines, checkpoint inhibitors have shown the potential to provide meaningful improvements in survival for patients with cancer, but the utilization of these therapies, beyond those that target the immune proteins PD(L)-1, is also limited largely by toxicity.

Finally, immune cell engagers, including T cell engaging bispecific molecules, have demonstrated encouraging clinical activity, but treatment is typically associated with significant toxicities including cytokine-release syndrome and on-target/off-tumor cytotoxicity.

Our goal is to overcome the limitations of current I-O therapies by developing products with an improved efficacy-to-toxicity ratio, or therapeutic index.

The toxicities for cytokines and checkpoint inhibitors stem from their activity outside of the tumor microenvironment.

Our GPS platform is designed to overcome these systemic toxicities by creating tumor-activated molecules and unleashing the activity of cytokines and checkpoint inhibitors in the tumor microenvironment.

These molecules are intended to be inactive until they reach the tumor microenvironment, where they are activated, resulting in localized clinical activity with minimal dose-limiting toxicities.

To achieve this tumor selectivity, we apply our GPS platform, which includes engineered features and a proprietary protein masking technology that render our molecules inactive until reaching the tumor.

Our GPS platform also enables PK and protease-dependent activation, resulting in geographically localized anti-tumor activity.

The toxicities for cytokines, checkpoint inhibitors and immune cell engagers stem from their activity outside of the tumor microenvironment.

Our proprietary platform is designed to overcome these systemic toxicities by creating tumor-activated molecules and unleashing the activity of tumor-activated cytokines and antibodies

(including bispecifics) and immune cell engagers (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers) in the tumor microenvironment.

These molecules are intended to be inactive until they reach the tumor microenvironment, where they are activated by the unique conditions of the tumor microenvironment, resulting in localized clinical activity with minimal dose-limiting toxicities.

To achieve this tumor selectivity, we apply our platform, which includes engineered features and a proprietary protein masking technology that seeks to minimize interaction with healthy tissue and cells by rendering our molecules inactive until reaching the tumor.

Our platform is also designed to enable optimal PK by preventing undesired binding and elimination outside of the tumor microenvironment, resulting in geographically localized pharmacology.

The engineered features are designed to ensure that our product candidates are stable molecules with well-understood properties and a reproducible manufacturing approach.

Leveraging our GPS platform, we intend to develop a number of additional product candidates using a range of tumor targeting approaches, with the goal of achieving a clinically meaningful improvement in their therapeutic index.

We also plan to evaluate opportunities for better tolerated and more efficacious combination therapies, using product candidates from across our portfolio with other cancer therapies, to increase the potential for curative regimens in oncology.

Beyond oncology, we also plan to apply our GPS platform to other disease areas in which the immune system is dysregulated, such as in autoimmune and inflammatory diseases.

Our vision is to transform the lives of patients with cancer by harnessing the power of highly potent, tumor-selective I-O therapies that deliver deep and durable clinical responses.

By leveraging our GPS platform, we aim to discover, develop and, ultimately, commercialize I-O therapies that overcome the known limitations of today’s approaches and provide effective, tolerable and durable therapeutic options for patients and their physicians.

By leveraging our proprietary platform for tumor-activated molecules, we aim to discover, develop and, ultimately, commercialize I-O therapies that overcome the known limitations of today’s approaches and provide effective, tolerable and durable therapeutic options for patients and their physicians.

In order to achieve these goals, the key elements of our strategy are to:

● Efficiently progress XTX202, our tumor-activated IL-2, through initial Phase 1 clinical proof-of-concept data, and if successful, expand clinical development for multiple cancer indications as a monotherapy and in combination with other therapies, including in combination with XTX301, our tumor-activated IL-12.

XTX202 is a tumor-activated beta-gamma biased (non-alpha), engineered IL-2 molecule designed to potently stimulate CD8+ effector T cells and NK cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the tumor microenvironment.

We are currently evaluating XTX202 as a monotherapy in an ongoing Phase 1 clinical trial in patients with advanced solid tumors, and we anticipate initiating patient

enrollment in a Phase 2 clinical trial evaluating XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic RCC in April 2023.

In addition, we plan to report preliminary anti-tumor activity, safety, PK and PD data from the Phase 1/2 clinical trial in the third quarter of 2023, which we anticipate will include approximately 15-20 patients across a range of solid tumors treated at the 1 mg/kg dose or higher across all cohorts in the Phase 1/2 clinical trial.

Subject to these interim trial results and establishing initial clinical proof-of-concept for XTX202, we plan to complete the Phase 2 trial evaluating XTX202 as monotherapy in patients with RCC and melanoma with the goal of determining the potential to conduct monotherapy registration-enabling trials for XTX202.

In parallel to the completion of the planned Phase 2 monotherapy trial, we plan to initiate a Phase 1/2 trial evaluating XTX202 in combination with an anti-PD-1/PD-L1 for the treatment of patients with non-small cell lung cancer, or NSCLC.

Subject to the results from this combination study, we anticipate initiating registration-enabling clinical trials for XTX202 in combination with an anti-PD-1/PD-L1 in patients with NSCLC.

We also plan to explore the potential for XTX202 in combination with other therapies, including combinations with XTX301, our tumor-activated IL-12, and potential collaborations with cell therapies or anti-cancer vaccines.

● Efficiently progress XTX301, our tumor-activated IL-12, through initial Phase 1 monotherapy dose-escalation, and if successful, expand clinical development for multiple “hot” and “cold” tumors as a monotherapy and in combination with other therapies.

IL-12 plays a key role in bridging innate and adaptive cellular immunity, making it a compelling target for immunotherapy.

However, life-threatening toxicity observed with systemically active IL-12, including severe liver toxicity, have limited the therapeutic potential of IL-12 agents.

XTX301, our tumor-activated IL-12, is designed to potently stimulate anti-tumor immunity and reprogram the tumor microenvironment of poorly immunogenic “cold” tumors towards an inflamed, or “hot,” state.

We anticipate reporting preliminary safety data from the Phase 1 clinical trial into at least the third dose level in the fourth quarter of 2023.

Subject to achieving a minimal target dose, we would continue monotherapy dose-escalation of the Phase 1 clinical trial and initiate treatment in cohorts of patients with both “cold” and “hot” tumors to determine the potential for anti-tumor activity.

Following an assessment of anti-tumor effect as a monotherapy in selected tumor types, we also plan to explore the combination potential of XTX301 with an anti-PD-1/PD-L1 and with XTX202, our tumor-activated IL-2 product candidate, prior to initiation of registration-enabling clinical trials.

Subject to the successful completion of trials showing the ability to combine XTX301 with other I-O agents and immune activation in “cold” tumors, we would plan to explore potential registration-enabling trials in both “hot” tumors, such as head and neck cancer and NSCLC, and in “cold” tumors, such as microsatellite stable colorectal cancer, or MSS CRC, and pancreatic cancer.

Report Phase 1 monotherapy data for XTX101 and explore strategic opportunities to advance XTX101 with a partner.

We are currently evaluating XTX101 in an ongoing Phase 1 clinical trial in patients with advanced solid tumors.

We recently completed enrollment in monotherapy dose-escalation (Part 1A) of the Phase 1 trial, and enrollment in monotherapy dose-expansion (Part 1B) of the Phase 1 trial is ongoing.

In addition, we have determined an RP2D of 150 mg Q6W, and we anticipate reporting preliminary safety, PK, PD and anti-tumor activity data from the Phase 1 clinical trial in the second quarter of 2023.

As previously announced, we plan to continue to explore strategic opportunities to advance XTX101 with a partner beyond the current Phase 1 clinical trial.

Broadly expand our portfolio by applying the versatility and reproducibility of our GPS platform to develop novel I-O therapies for cancer.

We have prioritized efforts to develop novel I-O therapies based on the therapeutic activity of I-O agents established in other clinical trials, while recognizing that the benefit of many of these I-O agents, particularly cytokines, has been historically hampered by issues of short half-life, poor bioavailability and significant toxicity.

By leveraging the insights and capabilities of our GPS platform and our leadership team, we aim to systematically create novel molecules, including cytokines, mAbs and multi-functional biologics, that overcome these challenges to safely localize their potent activity to the tumor microenvironment.

We believe that our GPS platform, which enables us to develop molecules with the potential to trigger anti-tumor immunity while limiting systemic exposure to improve tolerability, is broadly applicable in oncology and has the potential to develop a number of additional product candidates using a range of tumor targeting approaches, with the goal of achieving a clinically meaningful improvement in their therapeutic index.

Build a fully-integrated I-O company by independently commercializing approved products in indications and key geographies where we believe we can maximize our product candidates’ value.

We currently own all worldwide development and commercialization rights to our product candidates and programs, which we believe have been optimally selected based on our extensive preclinical data, including data with disease-specific animal models and biomarkers, supporting their potential for clinical success.

To maximize the full potential and value of our pipeline, we intend to retain key development and commercialization rights for our product candidates in key indications and geographies where we believe we can ultimately commercialize successfully on our own, if approved.

In addition, we intend to pursue strategic collaborations where a collaborator may have geographic operations or other capabilities that are synergistic or additive to our own.

Leverage the broad applicability of our GPS platform through strategic collaborations in autoimmune diseases.

We believe the collective components of our GPS platform and the reproducibility it enables in our drug discovery and development efforts present a meaningful opportunity for us to leverage our GPS platform not only in oncology but also in multiple therapeutic areas beyond oncology, such as in autoimmune and inflammatory diseases.

We plan to explore strategic collaborations that would enable us to accelerate the development of additional product candidates or programs as well as expand our capabilities, pipeline opportunities and product offerings, particularly where a collaborator may have expertise or capabilities that are synergistic or additive to our own.

● Rapidly advance clinical development for XTX101, our tumor-activated, Fc-enhanced anti-CTLA-4, through our co-funded clinical collaboration with Roche.

In the third quarter of 2023, we entered into a co-funded clinical trial collaboration with Roche to evaluate XTX101 in combination with atezolizumab (Tecentriq®) in a multi-center, open-label Phase 1/2 clinical trial.

We are currently evaluating XTX101 in combination with atezolizumab (Tecentriq®) in Phase 1 combination dose escalation.

We plan to select a RP2D for XTX101 in combination with atezolizumab in the second quarter of 2024, and subject to the results of the Phase 1 combination dose escalation portion of the trial, we plan to initiate the Phase 2 portion of the trial for XTX101 in combination with atezolizumab in patients with MSS CRC in the third quarter of 2024.

● Rapidly advance clinical development for XTX301, our tumor-activated IL-12, through our partnership with Gilead.

In March 2024, we entered into an exclusive license agreement with Gilead to develop and commercialize XTX301, as well as other molecules directed at IL-12.

We are currently evaluating XTX301 in Phase 1 monotherapy dose escalation, and we anticipate reporting safety, PK and PD data for XTX301 in the fourth quarter of 2024.

Under our license agreement with Gilead, we are responsible for conducting clinical development for XTX301 in the ongoing Phase 1 clinical trial through an initial planned Phase 2 dose expansion, and then following the delivery by us of a specified clinical data package for XTX301, Gilead can elect to transition responsibilities for the development and commercialization of XTX301 to Gilead, subject to the terms of the license agreement and payment by Gilead of a transition fee.

● Explore opportunities for strategic partnerships to evaluate XTX202, our tumor-activated, beta-gamma biased IL-2, in combination with other agents.

In March 2024, we announced additional data from our Phase 2 clinical trial evaluating XTX202 in patients with metastatic RCC or unresectable or metastatic melanoma.

Together with previously reported data, we believe these additional data further validate our tumor-activated approach and support the broad potential for XTX202 as a combination therapy.

● Leverage our promising research platform to advance differentiated, tumor-activated bispecific molecules and immune cell engager molecules (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

We believe our proprietary platform technology has the potential to develop additional product candidates using our tumor-activated masking approach.

In particular, we are currently leveraging our

differentiated platform technology and our unique expertise in masking antibodies and cytokines to develop a new generation of tumor-activated bispecific molecules and immune cell engager molecules.

Subject to obtaining sufficient additional capital, we plan to advance XTX501, our tumor-activated PD-1/IL-2 bispecific development candidate, into IND-enabling studies.

● Leverage the broad applicability of our proprietary platform for tumor-activated I-O molecules through strategic collaborations and partnerships.

We believe the collective components of our proprietary platform technology and the reproducibility it enables in our drug discovery and development efforts present a meaningful opportunity for us to leverage our platform in combination with other agents in oncology.

We plan to continue to explore strategic collaborations and partnership that would enable us to access capital, accelerate the development of our current product candidates or additional product candidates or programs, evaluate our current or additional product candidates in combination with other agents, and expand our capabilities, pipeline opportunities and product offerings, particularly where a collaborator may have expertise or capabilities that are synergistic or additive to our own.

The discovery of a role for immunotherapy in the treatment of cancer was made more than 100 years ago, when William Coley treated patients with heat-treated bacterial toxins, resulting in a profound anti-tumor effect in some of those patients.

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Anti-PD-1/PD-L1 checkpoint inhibitors have been used broadly because they generally achieve efficacy with minimal systemic toxicity, enabling their administration at their maximally effective doses.

Anti-PD-1/PD-L1 treatments have become the most widely utilized immunotherapy agent in oncology, with FDA approvals in more than a dozen separate tumor types and $27 billion in worldwide sales in 2020.

Anti-PD-1/PD-L1 treatments have become the most widely utilized immunotherapy agent in oncology, with the U.S.

Food and Drug Administration, or FDA, approvals in more than a dozen separate tumor types and $27 billion in worldwide sales in 2020.

Our mission is to overcome the limitations of cytokine therapies and checkpoint inhibitors, such as anti-CTLA-4, and make immunotherapies beyond anti-PD-1/PD-L1 treatments more accessible, efficacious and safe for patients with cancer.

The promise and limitations of cytokines

Cytokines are small signaling proteins that serve as master regulators of the body’s response to inflammation and immune attack.

There are multiple cytokines, including IL-2, which are approved in a range of oncology and non-oncology indications.

Aldesleukin, a high-dose IL-2 therapy, was first approved in 1992 as a monotherapy for patients with

melanoma and RCC.

In addition, cytokines have shown potential beyond oncology with approvals for the treatment of patients with multiple sclerosis, resulting in cytokines becoming a key treatment option for a range of conditions.

However, cytokines have not achieved therapeutic success in a broad population of patients because their use has been limited by severe toxicity, including fatal outcomes.

We believe XTX202, our tumor-activated IL-2 product candidate, and XTX301, our tumor-activated IL-12 product candidate, each have the potential to overcome these limitations and deliver a therapeutic dose with low systemic toxicity and the ability to achieve a broad therapeutic index.

The promise and limitations of checkpoint inhibitors

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This has reduced the use of anti-CTLA-4 mAbs both as a monotherapy and in combination therapy.

We believe XTX101, our Fc-enhanced, tumor-activated anti-CTLA-4, has the potential to overcome these limitations and deliver the full clinical benefit of anti-CTLA-4 mechanisms without the dose-limiting toxicities associated with existing CTLA-4 treatments.

We believe XTX101, our tumor-activated, Fc-enhanced high affinity binding anti-CTLA-4, has the potential to overcome these limitations and deliver the full clinical benefit of anti-CTLA-4 mechanisms without the dose-limiting toxicities associated with existing CTLA-4 treatments.

The promise and limitations of cytokines

Cytokines are small signaling proteins that serve as master regulators of the body’s response to inflammation and immune attack.

There are multiple cytokines, including IL-2, which are approved in a range of oncology and non-oncology indications.

Aldesleukin, a high-dose IL-2 therapy, was first approved in 1992 as a monotherapy for patients with melanoma and RCC.

Similarly, IL-12 development has been relentlessly pursued due to its unique potential to treat immunologically cold tumors, but currently there are no approved IL-12 therapies.

Cytokines such as IL-2 and IL-12 have not achieved therapeutic success in a broad population of patients because their use has been limited by severe toxicity, including fatal outcomes.

We believe XTX301, our tumor-activated IL-12 product candidate, has the potential to overcome these limitations and deliver a therapeutic dose with low systemic toxicity and the ability to achieve a broad therapeutic index.

We also believe that XTX202, our IL-2 product candidate, has broad potential as a combination therapy based on the safety, PK and PD data reported to date from our Phase 1 and Phase 2 clinical trials.

I-O Combinations

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The potential of our tumor-activated molecules to minimize the systemic toxicity of I-O could allow us to combine I-O agents to meaningfully improve survival in a broader range of tumor types.

We are currently evaluating XTX101, our anti-CTLA-4 product candidate, in combination with atezolizumab, and as discussed above, we plan to explore opportunities to continue to develop XTX202, our IL-2 product candidate, in combination with other agents.

Our Solution:

Our GPS Platform Enables Tumor-Activated I-O Molecules Designed to Optimize Their Therapeutic Index

Our Proprietary Platform Enables Tumor-Activated I-O Molecules Designed to Optimize Their Therapeutic Index

I-O therapies have curative potential for patients with cancer.

However, this potential has been significantly curtailed to date by dose-limiting toxicities that result from activity of the therapeutic molecule outside the tumor microenvironment.

We believe that geographic localization of the activity of I-O agents to the tumor microenvironment can overcome these dose-limiting toxicities and enable maximal therapeutic benefit for patients.

We believe that selectively targeting the activity of I-O agents to the tumor microenvironment can overcome these dose-limiting toxicities and enable maximal therapeutic benefit for patients.

Tumor-selective activation could be achieved by harnessing unique characteristics of the tumor microenvironment to activate therapeutic molecules locally that have minimal or non-detectable levels of activity outside of the tumor microenvironment.

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MMPs are dysregulated in the tumor microenvironment, resulting in preferential activity of MMPs in the tumor microenvironment by comparison to non-tumor, healthy tissues.

As a result, we believe that our GPS platform,

which is designed to harness tumor MMP activity, can activate our molecules selectively within the tumor microenvironment while maintaining minimal or non-detectable levels of activity outside of the tumor microenvironment.

Our GPS platform enables us to engineer a broad range of immune-modulatory molecules, including cytokines, antibodies and multi-functional molecules, that contain masking domains designed to minimize their activity outside of the tumor microenvironment and turn on selectively in the tumor microenvironment where they are preferentially activated by tumor MMPs.

As a result, we believe that our platform for tumor-activated molecules, which is designed to harness tumor MMP activity, can design molecules that selectively activate within the tumor microenvironment while maintaining minimal or non-detectable levels of activity outside of the tumor microenvironment.

Our platform enables us to engineer a broad range of immune-modulatory molecules, including tumor-activated cytokines and antibodies (including bispecifics) and immune cell engagers (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers), that contain masking domains designed to minimize their activity outside of

the tumor microenvironment and turn on selectively in the tumor microenvironment where they are preferentially activated by tumor MMPs.

Specifically, MMPs enzymatically cleave a protease cleavage site incorporated in a peptide linker that connects the masking protein domain to the active agent.

This separates the mask from the active agent, enabling the unmasked agent to promote an anti-tumor response within the tumor microenvironment.

Key features of our tumor-activated molecules exemplify the engineering approach that underpins our GPS platform.

Key features of our tumor-activated molecules exemplify the engineering approach that underpins our platform.

Each feature contributes to multiple characteristics of the molecule that are designed to enable tumor selective biological activity and tumor growth inhibition while minimizing toxicity outside of the tumor microenvironment.

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a protease cleavage site;

a half-life extension domain for cytokine molecules, as appropriate;

the active engineered molecule (i.e., an engineered cytokine or antibody).

a cleavable or retained half-life extension domain for cytokine, immune cell engager and bispecific molecules, as appropriate;

the effector domain (i.e., an engineered cytokine, antibody or immune cell engager).

The engineered features are designed to ensure that our product candidates are stable molecules with well-understood properties and a reproducible manufacturing approach.

In preclinical studies, we have successfully applied our GPS platform to cytokines, antibodies that regulate immune checkpoints and multi-functional molecules in order to promote localized anti-tumor immune responses, while avoiding the dose-limiting toxicities associated with systemic immune responses.

The graphic below illustrates XTX202, our tumor-activated IL-2, which contains a masking domain that is released by protease cleavage.

When the linker sequence, which contain a protease cleavage site, is cleaved by proteases, the masking domain is released, allowing the cytokine to bind to the target receptor.

Before cleavage by the MMP in the tumor microenvironment, the engineered cytokine has minimal or non-detectable levels of activity outside the tumor microenvironment.

We have applied our masking approach to cytokines and antibodies that regulate immune checkpoints, and with our earlier stage work, we have expanded the application of our platform to tumor-activated bispecific molecules and immune cell engager molecules (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

Our molecules are designed to contain a masking domain that is released by protease cleavage.

When the linker sequence, which contains a protease cleavage site, is cleaved by MMPs, the masking domain is released, allowing the unmasked molecule to bind to the target receptor, or in the case of an immune cell engager, bind to the immune cell and tumor antigen to facilitate an immune synapse.

Before cleavage by the MMPs in the tumor microenvironment, the engineered molecule is designed to minimize interaction with healthy tissue and cells outside the tumor microenvironment.

Specifically, there is no binding to target receptors, and the molecule has a long half-life outside the tumor microenvironment.

After cleavage in the tumor microenvironment, the engineered cytokine is locally activated and has a relatively short half-life.

Key Features of Xilio’s Tumor-Activated Cytokines

We believe that the characteristics of our GPS platform described above enable the following key advantages:

After cleavage in the tumor microenvironment, the engineered molecule is locally activated and has a relatively short half-life.

Key Features of Xilio’s Tumor-Activated Molecules

We believe that the characteristics of our proprietary platform for tumor-activated molecules described above will enable the following key advantages:

masking that takes advantage of multiple intra-molecular interactions, minimizing the risk of activity outside of the tumor microenvironment and therefore minimizing the risk of toxicity;

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early consideration and incorporation of manufacturing and development aspects into the design of molecules to facilitate production of high-quality drug product for clinical use;

half-life extending inactive (masked) cytokines, as appropriate, to support administration to patients on a schedule consistent with other biologics agents;

locally activating cytokine molecules that have a short half-life in the tumor microenvironment, which minimizes the risk of the released cytokine exhibiting activity outside of the tumor microenvironment and, therefore, further reduces the risk of toxicity.

We have shown preclinical validation and promising early clinical evidence of the ability of our GPS platform to develop tumor-activated cytokines and antibodies.

In preclinical studies, each of our most advanced product candidates exhibited tumor-activated biological activity, tumor growth inhibition and minimal to no toxicity outside of the tumor microenvironment.

The reproducibility of these preclinical data highlights the potential breadth of application of our GPS platform to multiple structurally diverse cytokines, antibodies and multi-functional molecules.

In our Phase 1 trial for XTX202, our tumor-activated IL-2, we have demonstrated initial clinical validation of our GPS platform, as evidenced by preliminary intratumoral PD data for two patients treated with XTX202, each of whom had an optional on-treatment tumor biopsy and were the only two patients from whom a tumor biopsy analysis was available as March 1, 2023.

For each patient, the tumor sample featured increased numbers of stromal tumor infiltrating lymphocytes, or TILs, and increased frequency of CD8+ effector T cells among these TILs.

At the time of the tumor sample, these changes occurred in each patient in the absence of peripheral changes to CD8+ effector T cells, demonstrating preliminary evidence of tumor-selective activation.

We believe our GPS platform can be applied to numerous molecules, which have potential as cancer therapies, but require localized activity within the tumor microenvironment to overcome the dose-limiting toxicities that result from activity outside of the tumor microenvironment.

Leveraging our GPS platform, we are building a pipeline of tumor-activated cytokine, checkpoint inhibitor and multi-functional immunotherapies to treat cancer.

half-life optimized molecules with prolonged half-life in the inactive (masked) state to support administration to patients on a schedule consistent with other biologics agents;

locally activating molecules that have a short half-life in the tumor microenvironment, which minimizes the risk of the activated molecule exhibiting activity outside of the tumor microenvironment and, therefore, further reduces the risk of toxicity.

Leveraging our platform technology, we are building a pipeline of tumor-activated I-O molecules to treat cancer, including tumor-activated cytokines and antibodies (including bispecifics) and immune cell engagers (including tumor-activated cell engagers and tumor-activated effector-enhanced cell engagers).

Our goal is to overcome the limitations of current I-O therapies by developing products with an improved therapeutic index.

Consistent with this goal, we selected molecules that have prior clinical validation demonstrating therapeutic benefit, but that have been limited by significant toxicities that we believe can be addressed with our approach.

We currently have worldwide development and commercialization rights to all of our product candidates.

Disease Indication

Mechanism of Action

Stage of Development

Cytokine Programs

Phase 1 monotherapy dose-escalation (Part 1A) ongoing and monotherapy dose expansion (Part 1B) open for enrollment

Phase 1 clinical trial sites open and actively screening patients for enrollment

Undisclosed Research Program

Tumor-Activated

Multi-Functional

XTX101 in combination with atezolizumab (1)

Advanced MSS CRC

anti-CTLA-4 +

Phase 1 combination dose escalation ongoing

Co-funded clinical collaboration with Roche

Advanced Solid Tumors

Phase 1 monotherapy dose escalation ongoing

Exclusive global license with Gilead

Advanced RCC and Melanoma

Phase 2 monotherapy enrollment complete (3)

Plan to explore strategic opportunities to develop in combinations (3)

Advanced Solid Tumors

PD-1/IL-2 bispecific

Development candidate (4)

Additional research-stage programs

Tumor-activated immune cell engagers

Discovery-stage

Antibody Program

Enrollment in Phase 1 monotherapy dose-escalation (Part 1A) complete;

Phase 1 monotherapy dose-expansion (Part 1B) ongoing

Plan to initially evaluate XTX202 as a monotherapy in patients with melanoma and RCC prior to evaluating XTX202 in combination with an anti-PD-1/PD-L1 for the treatment of patients with NSCLC or potential expansion into additional cancer indications as a monotherapy or combination therapy.

Plan to initially evaluate XTX301 as a monotherapy in patients with advanced solid tumors.

Plan to explore opportunities for strategic collaborations to advance XTX101 with a partner beyond the current Phase 1 clinical trial.

Our development strategy for our clinical-stage, tumor-activated cytokine product candidates is focused on the following:

achieve an acceptable safety profile while maintaining dose levels sufficient to confer localized anti-tumor activity in the tumor microenvironment;

achieve clinical proof-of-mechanism for our GPS platform by showing tumor-selective activation, as demonstrated by increased tumor fighting immune cells in patient tumors, including CD8+ effector T cells and NK cells, without an increase in tumor fighting immune cells in the periphery;

establish clinical proof-of-concept for each product candidate, as demonstrated by monotherapy anti-tumor activity in patients treated at the target dose level for such product candidate;

demonstrate the ability to administer our product candidates in combination with other therapies, so they can be explored and administered with relevant standard-of-care agents to potentially improve patient outcomes.

Assuming we successfully achieve an improved therapeutic index during our initial clinical trials, we plan to proceed into an expansive set of registration-enabling clinical trials across a range of tumor types.

Evaluating XTX101 in combination with atezolizumab (Tecentriq®) in Phase 1 combination dose escalation trial and planned Phase 2 combination trial in MSS CRC.

Evaluating XTX301 in Phase 1 monotherapy dose escalation for the treatment of advanced solid tumors.

Plan to discontinue further investment in XTX202 as a monotherapy.

Plan to advance in IND-enabling studies, subject to sufficient additional capital.

XTX101, Our Clinical-Stage, Tumor-Activated, Fc-Enhanced, High Affinity Binding Anti-CTLA-4 Product Candidate

XTX101 is an investigational tumor-activated, Fc-enhanced, high-affinity binding anti-CTLA-4 mAb designed to block CLTA-4 and deplete TREGs when activated (unmasked) in the tumor microenvironment and improve upon the therapeutic index of existing anti-CTLA-4 therapies.

In the third quarter of 2023, we entered into a co-funded clinical trial collaboration with Roche to evaluate XTX101 in combination with atezolizumab (Tecentriq®) in a multi-center, open-

label Phase 1/2 clinical trial.

We are currently evaluating the safety and tolerability of the combination in patients with advanced solid tumors in the Phase 1 dose escalation portion of the clinical trial.

Subject to the results of Phase 1 combination dose escalation, we plan to evaluate the safety and efficacy of the combination in the Phase 2 portion of the clinical trial in patients with microsatellite stable colorectal cancer.

Background on CTLA-4

CTLA-4 is an immune checkpoint protein that is well-established as playing a central role in the development of tumors.

The scientific insight that led to the early development of CTLA-4 therapeutics is attributable to investigators recognizing CTLA-4 as a protein on T cells that acts as a brake on T cell activation.

By removing this brake, T cells were freed to attack cancer.

This work led to the development and FDA approval of ipilimumab, a CTLA-4 mAb, for the treatment of unresectable or metastatic melanoma at a dose of 3 mg/kg in 2011 and in additional indications in subsequent years.

While anti-CTLA-4 therapies such as ipilimumab have demonstrated meaningful efficacy across a range of tumor types, autoimmune toxicities have significantly limited their use to date.

Clinical trials have shown that 20% of ipilimumab-treated melanoma patients survive at least three years, and a subset survive for 10 years or longer.

Ipilimumab remains one of the most impactful drugs for these patients;

however, the number of patients who benefit from treatment with ipilimumab remains limited due to its toxicity.

Investigation of dose-response in two third-party clinical trials of melanoma patients showed that higher doses of ipilimumab are likely to increase the proportion of patients who benefit;

however, the increased dose also resulted in an unacceptable toxicity profile for most patients.

In a Phase 2 trial of ipilimumab conducted by Bristol-Myers Squibb Company, a dose range of 0.3 mg/kg to 10 mg/kg was tested and efficacy was measured both by response rate and by clinical outcome.

Both the response rate and median overall survival, or mOS, were higher at 10 mg/kg than at 3 mg/kg, with the 0.3 mg/kg dose determined as being ineffective.

The rate of severe AEs was 25% at the 10 mg/kg dose, 7% at the 3 mg/kg dose and 0% at the ineffective dose of 0.3 mg/kg.

Similarly, as shown in the table below, in a Phase 3 trial conducted by Bristol-Myers Squibb Company, mOS was higher at the 10 mg/kg dose but resulted in unacceptable toxicity for most patients.

Therefore, we believe that achieving a three-fold increase in therapeutic index would be transformational.

High-Dose Ipilimumab Improved Survival but Resulted in Unacceptable Toxicity

Adverse Events:

Gr 3/4 irAEs / disconts.

Ipilimumab has shown preliminary evidence of promising anti-tumor activity in a range of tumor types outside of its currently approved indications, but successful additional approvals have been limited due to its toxicity.

For example, ipilimumab has been observed to be more active when combined with the anti-PD-1/PD-L1 antibody nivolumab.

However, the combination of ipilimumab and nivolumab has been shown to cause a greatly increased rate of immune-related toxicity when compared to treatment with either ipilimumab or nivolumab as a monotherapy.

Clinical results from patients who express high-affinity FcγR polymorphisms have shown improved responses to ipilimumab, but efforts to improve the potency of the antibody have been limited by perceived toxicity risk.

There remains a critical need to develop safe and effective forms of anti-CTLA-4 mAbs that can achieve efficacious doses within the tumor microenvironment.

Our Solution:

XTX101, a Tumor-Activated, Fc-Enhanced Anti-CTLA-4

XTX101 is a clinical-stage, tumor-activated, Fc-enhanced anti-CTLA-4 mAb that is designed to improve upon the therapeutic index of existing anti-CTLA-4 therapies by overcoming potency and tolerability limitations.

Our goal is to demonstrate an improved safety profile enabling higher anti-CTLA-4 exposure in the tumor that will result in increased efficacy.

In preclinical studies, we observed the following tolerability and activity profile of XTX101:

further improves checkpoint inhibition and enhances antibody-dependent cellular cytotoxicity to deplete immune-suppressive TREGs in the tumor microenvironment;

reduced peripheral immune activity due to masking of the CDR sequences;

activation by protease-dependent release of the masks, which acts selectively in the tumor microenvironment and minimizes toxicity associated with systemic immune activation.

XTX101 is designed to enhance the desirable features of an anti-CTLA-4 antibody while mitigating the known limitations of anti-CTLA-4 antibodies due to toxicity.

We expect this combination of features to result in an increased therapeutic index.

Tumor-Activated Design Components of XTX101

Preliminary Phase 1 Monotherapy Data Presented in May 2023

In May 2023, we announced initial Phase 1 monotherapy dose escalation data for XTX101.

As of a data cutoff date of May 2, 2023, 25 patients had been treated with XTX101, including dose levels ranging from 7 mg to 180 mg administered once every three weeks, or Q3W, and one dose level at 150 mg administered once every six weeks, or Q6W.

Of these patients, 20 patients were dosed in monotherapy dose-escalation and five patients were dosed in monotherapy dose-expansion.

Patients had a wide range of advanced and treatment-refractory solid tumors, including colorectal cancer, or CRC, non-small cell lung cancer, or NSCLC, and pancreatic cancer.

In addition, 76% of patients had been previously treated with at least three prior lines of anti-cancer therapy, and 44% had been previously treated with at least one I-O agent.

As of the data cutoff date, three patients were continuing on treatment with XTX101, and 22 patients had discontinued treatment with XTX101.

Preliminary Safety Data

A recommended Phase 2 dose, or RP2D, and schedule of 150 mg Q6W was determined based on the favorable preliminary safety, PK and PD data for XTX101.

At the RP2D, no dose-limiting toxicities were observed, and there was no reported evidence of immune-related endocrine or skin AEs that are commonly associated with systemically active anti-CTLA-4 agents.

In addition, evidence of effective masking of XTX101 was demonstrated by low levels of unmasked drug detected in peripheral circulation, and XTX101 achieved target PK exposure at the RP2D, reaching the targeted area under the curve, or AUC, and peak concentration, or C max .

As of the data cutoff date of May 2, 2023:

● Across all dosing levels and dosing intervals, no Grade 4 or Grade 5 treatment-related AEs were reported by investigators.

● Among seven patients who received XTX101 administered at the RP2D of 150 mg on a Q6W dosing schedule, the most common treatment-related AEs (≥10% incidence) of any grade reported by investigators were diarrhea (14%), fatigue (14%) and decreased appetite (14%).

In these patients, no treatment-related colitis or infusion related reaction of any grade was observed.

Investigators reported only one Grade 3 treatment-related AE of diarrhea, which occurred after two doses and resolved after five days without steroid use.

This patient tolerated two additional doses of XTX101 after dose reduction to 75 mg Q6W without any symptom recurrence.

At the RP2D of 150 mg Q6W, this was the only patient with a dose reduction due to an AE, and no patients discontinued treatment due to a treatment-related AE.

● Among 18 patients who received XTX101 administered on a Q3W dosing schedule, the most common treatment-related AEs (≥10% incidence) of any grade reported by investigators were diarrhea (28%), colitis (28%), infusion related reaction (28%), nausea (17%), vomiting (17%) and abdominal pain (11%).

Of these, investigators reported the following Grade 3 treatment-related AEs:

diarrhea (6%), colitis (22%) and infusion related reaction (17%).

Infusion related reactions were associated with antidrug antibodies.

Across all dose levels administered Q3W, two patients had dose reductions due to AEs, and four patients discontinued treatment due to an infusion related reaction.

Preliminary Anti-Tumor Activity Data

A partial response, or PR, was observed at nine weeks in one patient with advanced PD-L1 negative NSCLC with hepatic metastases treated with XTX101 at the 150 mg Q6W dose level and confirmed after the data cutoff date at week 27.

The only treatment-related AE reported for this patient was Grade 1 fatigue.

In addition, PD markers for anti-CTLA-4 reported for this patient showed minimal immune activation in peripheral circulation, demonstrating evidence of tumor-selective activation of XTX101.

Updated Phase 1 Monotherapy Data Presented at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in December 2023

In December 2023, we reported updated Phase 1 monotherapy data for XTX101 at the ESMO Immuno-Oncology Congress.

As of a data cutoff date of November 13, 2023, 36 patients with advanced solid tumors had been administered XTX101 monotherapy, including 18 patients at the RP2D and schedule of 150 mg Q6W.

Patients treated at the RP2D of 150 mg Q6W were heavily pre-treated, with 83% of patients receiving three or more lines of anti-cancer therapy and 56% previously treated with an immunotherapy.

Preliminary Safety Data

At the RP2D of 150 mg Q6W, 18 patients (including nine patients previously reported) were evaluable for safety as of the data cutoff date of November 13, 2023:

● Safety data were consistent with previously reported results.

XTX101 monotherapy was generally well-tolerated with treatment-related AEs primarily Grade 1 or 2, and no patients discontinued treatment due to a treatment-related AE.

In addition, as previously reported, only one patient had a dose reduction due to an AE.

● The most common treatment-related AE of any grade (≥10% incidence) reported by investigators was fatigue (11%).

● As previously reported, investigators reported only two Grade 3 treatment-related AEs:

Grade 3 treatment-related AE of diarrhea, which occurred after two doses and resolved after five days without steroid use, and one Grade 3 treatment-related AE of dermatitis.

In addition, no Grade 4 or 5 treatment-related AEs were reported by investigators across all dosing levels and dosing intervals.

Preliminary Anti-Tumor Activity Data

At the RP2D of 150 mg Q6W, 12 patients were evaluable for anti-tumor activity as of the data cutoff date:

● As previously reported, a confirmed PR was observed in a patient with Stage 4 PD-L1 negative NSCLC, including complete resolution of liver metastases.

The confirmed PR continued through 36 weeks of treatment with XTX101, with the patient discontinuing treatment after week 36 due to an unrelated AE.

● Additional data reported demonstrated a disease control rate, or DCR, of 33% in late-line and I-O refractory patients administered XTX101 monotherapy at the RP2D of 150 mg Q6W, consisting of the confirmed PR in the NSCLC patient and stable disease in three patients (triple-negative breast cancer, melanoma and MSS CRC (n=1 each)).

Preliminary Pharmacokinetic Data

As previously reported, consistent with the tumor-selective design for XTX101, preliminary pharmacokinetic analyses demonstrated 96% activation of XTX101 in a melanoma tumor and 73% activation in a metastatic liver lesion in a CRC patient, compared to minimal peripheral activation of XTX101 of 13% in both patients.

Cytokine Programs

The major focus in our cytokine programs is the development of tumor-activated cytokines with exemplary clinical activity and tolerability.

These cytokine programs include our clinical-stage, tumor-activated product candidates, XTX202 (IL-2) and XTX301 (IL-12), as well as discovery-stage programs for oncology and autoimmune diseases.

These cytokine programs include our clinical-stage, tumor-activated product candidates, XTX301 (IL-12) and XTX202 (IL-2), as well as discovery-stage programs for oncology.

XTX301, Our Clinical-Stage, Tumor-Activated IL-12 Product Candidate

XTX202 is an investigational tumor-activated beta-gamma biased (non-alpha), engineered IL-2 molecule designed to potently stimulate CD8+ effector T cells and NK cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the tumor microenvironment.

We are currently evaluating XTX202 as a monotherapy in an ongoing Phase 1 clinical trial in patients with advanced solid tumors.

For more information, please see the sections entitled “—Clinical Development Plans for XTX202” and “—Phase 1 Clinical Trial for XTX202” below.

In March 2024, our wholly-owned subsidiary Xilio Development entered into an exclusive license agreement with Gilead pursuant to which it granted Gilead an exclusive global license to develop and commercialize XTX301 and specified other molecules directed at IL-12.

For more information, please see “—License and Collaboration Agreements—Exclusive License Agreement with Gilead” below.

In January 2024, we reported preliminary safety data into the third dose level in the Phase 1 dose escalation and anticipate reporting safety, PK and PD data for XTX301 in the fourth quarter of 2024.

Background on IL-12

IL-12 is a potent, pro-inflammatory cytokine produced by antigen-presenting cells such as dendritic cells, macrophages and B cells.

IL-12 has two subunits, p35 and p40, that together form a heterodimer protein.

IL-12 is a key cytokine in the body’s response to pathogen infection, sending a signal to T cells, among others.

IL-12 interacts with diverse immune cells, including CD4+ T cells, CD8+ effector T cells, NK cells, monocytes and macrophages.

IL-12’s broad range of pro-inflammatory functions suggests that it could potentially be highly potent in controlling anti-cancer immunity.

IL-12 has been shown in preclinical studies to induce robust anti-tumor effects against many types of malignancies and it has been tested against multiple human cancers in clinical trials.

Recombinant human IL-12 has been evaluated in clinical trials, and anti-tumor efficacy was observed in a small number of patients across a range of tumor types.

Unfortunately, systemic IL-12 therapy has historically caused severe AEs in patients with cancer.

Life-threatening liver damage, called hepatotoxicity, was identified during the early development of previous IL-12 therapies, which severely limited the dose of IL-12 that could be administered, and further trials to evaluate efficacy were therefore conducted at sub-optimal doses due to the toxicity.

In an early Phase 2 trial of recombinant human IL-12, the MTD of 0.5 μg/kg (administered in days 1-5 in a 21-day dosing cycle) caused severe side effects in 70% of patients, or 12 of 17 patients, of whom two died from gastrointestinal bleeding and multi-organ failure, respectively.

The severe toxicities indicated that recombinant human IL-12 could not be used systemically due to rapid increases in the cytokines IFN-γ, TNF-α and IL-6 that caused a cytokine storm syndrome characterized by systemic inflammation, multi-organ dysfunction and immune cytopenias.

Efforts to overcome these systemic liabilities include alternate drug delivery approaches such as intra-tumoral administration of IL-12 encoding DNA vaccines or administration of oncolytic viruses expressing IL-12.

Despite activity in individual lesions, cancer is a systemic disease that cannot be cured with local therapy once it has reached an advanced stage.

Therefore, to unleash the potential for IL-12 in the majority of patients with advanced or metastatic cancer, an IL-12 that can be administered systemically but act locally at the tumor site is needed.

The failure of systemic IL-12 to induce meaningful anti-tumor efficacy is generally attributed to tolerability, which limits the dose and, as a result, the ability to reach therapeutic concentrations within the tumor microenvironment.

Therefore, maximizing the amount of IL-12 that reaches the tumor, while minimizing exposure of non-tumor tissue, may be critical for a safe and effective anti-tumor response.

Tumor-selective activation is therefore a desirable therapeutic profile.

Our Solution:

XTX301, a Tumor-Activated IL-12

Our goal for our IL-12 program is to create a tumor-activated, extended half-life IL-12 therapeutic with minimal peripheral effects.

We are using our platform technology and proprietary approach to achieve systemic delivery of tumor-activated IL-12, which we believe would have potential as a monotherapy and in combination with other therapies.

The design of our masked IL-12 cytokine molecule is closely related to that of our masked IL-2 cytokine molecule, described below, which illustrates the flexibility and robustness of our cytokine engineering approach.

The masking domain is designed to prevent binding to the cell-surface IL-12 receptor, unless the linker containing the protease site is cleaved by proteases preferentially active in the tumor microenvironment.

The half-life extension domain is designed to overcome the short circulating half-life of the native cytokine and the overall molecule is designed to enhance the efficiency of manufacturing.

Tumor-Activated Design Components of XTX301

We have undertaken extensive preclinical studies that demonstrated the ability of XTX301 to induce potent anti-tumor activity and PD changes consistent with known IL-12 biology.

Importantly, these effects on the tumor were observed without inducing concomitant systemic toxicity, which provides evidence that the masking design was performing as intended in preclinical studies.

Preliminary Phase 1 Dose Escalation Safety Data Reported in January 2024

In January 2024, we reported preliminary safety data into the third dose level in the Phase 1 clinical trial.

As of a data cutoff date of January 5, 2024, nine patients had been treated with XTX301 in the outpatient setting in Phase 1 dose escalation at three dose levels ranging from 5 ug/kg to 45 ug/kg administered once every three weeks.

XTX301 was generally well-tolerated across all dose levels with no dose-limiting toxicities observed in patients as of the data cutoff date.

We anticipate reporting safety, PK and PD data for XTX301 in the fourth quarter of 2024.

XTX202, Our Clinical-Stage, Tumor-Activated IL-2 Product Candidate

XTX202 is an investigational tumor-activated, beta-gamma biased IL-2 designed to potently stimulate CD8+ effector T cells and NK cells without concomitant stimulation of TREGs when activated (unmasked) in the tumor microenvironment.

In March 2024, we announced updated data from our Phase 2 clinal trial evaluating XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic RCC who have progressed on standard-of-care treatment.

Together with previously reported data, we believe these additional data further validate our tumor-activated approach and support the broad potential for XTX202 as a combination therapy.

Background on IL-2

Extensive clinical evidence of the promise and limitations of cytokines

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When administered locally, IL-2 has been shown to be clinically active and well-tolerated, shrinking local cancerous lesions and reducing malignant effusions.

However, when administered systemically, treatment with IL-2 has been shown to induce severe toxicities, including VLS, myocardial infarction, or heart attack, acute renal failure and immune-mediated neuropathy.

However, when administered systemically, treatment with IL-2 has been shown to induce severe toxicities, including vascular leak syndrome, or VLS, myocardial infarction, or heart attack, acute renal failure and immune-mediated neuropathy.

This toxicity profile greatly limits its current use.

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IL-2 anti-tumor activity and toxicity are both dependent on the amount of IL-2 administered.

Therefore, in order

to provide the greatest benefit to patients, the goal is to engineer a form of IL-2 that can minimize systemic effects while harnessing and directing activity to the tumor microenvironment.

Therefore, in order to provide the greatest benefit to patients, the goal is to engineer a form of IL-2 that can minimize systemic effects while harnessing and directing activity to the tumor microenvironment.

Rationale for non-alpha IL-2

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The critical challenge in the development of IL-2 therapies is to improve patient tolerability without reducing efficacy.

Deploying the key structural components of our GPS platform, we have designed XTX202 with three key features designed to overcome this:

Deploying the key structural components of our platform technology, we have designed XTX202 with three key features designed to overcome this:

(1) avoidance of binding to CD25, the IL-2α receptor subunit, in order to reduce the activation of Treg cells that inhibit immune response, while maintaining effective activation of CD8+ and NK cells that promote an anti-tumor immune response;

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and (3) a removable protease-cleavable protein mask that prevents XTX202 from binding and signaling until the mask is removed by the MMPs that are preferentially active within the tumor microenvironment.

Tumor-Activated Design Components of XTX202

These key features are intended to ensure that XTX202 is released and activated preferentially within the tumor microenvironment, where it has been designed to bind to lymphocytes.

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The unmasked XTX202 is then rapidly internalized by these lymphocytes, shortening the systemic half-life of the active (unmasked) molecule and localizing its activity to the tumor.

Overview of preclinical studies and data

We have undertaken extensive preclinical studies to demonstrate the two key characteristics of XTX202:

(1) anti-tumor activity and (2) minimal or no evidence of systemic toxicity.

In order to assess this, we compared XTX202 to both aldesleukin and a non-masked version of the molecule, which we refer to as XTX200, a non-α IL-2 with the same half-life extension domain feature but no mask to block IL-2 function systemically.

XTX200 also serves as a surrogate for other non-α IL-2 molecules currently being investigated by others.

This was done to assess the activity of our masking technology and compare XTX202 against high-dose IL-2.

We believe that these studies collectively provide preclinical proof-of-concept with an improved therapeutic index due to tumor microenvironment-dependent activation of XTX202 that, if replicated in clinical trials, could result in significant benefits to patients with a variety of cancer types.

The key findings of our XTX202 preclinical studies are as follows:

XTX202 demonstrated minimal signaling through the IL-2 receptor when masked, and MMP activation of XTX202 restored full potency of IL-2 signaling in in vitro assays illustrating the tight, protease-dependent control of IL-2 activity conferred by XTX202;

XTX202 activated an immune response in the tumor but not in peripheral organs, demonstrating geographically selective tumor PD activity in vivo in mice;

XTX202 matched the tumor growth inhibition activity of XTX200 and aldesleukin, without activation of immune response outside of the tumor microenvironment, thereby avoiding the systemic toxicity (VLS and enlargement of the spleen, or splenomegaly), body weight loss and mortality in mice that were associated with the doses of XTX200 or aldesleukin required for tumor growth inhibition;

XTX202 was well-tolerated in non-human primates, or NHPs, with no evidence of VLS or systemic immune activation in non-tumor, healthy tissue, whereas XTX200 induced both;

XTX202 exhibited a half-life of greater than one week in NHPs, compared to a half-life of less than 0.5 days for XTX200.

Based on these data, we believe that circulating levels of masked XTX202 can be achieved with clinically meaningful concentrations of activated (unmasked) XTX202 within tumors and that any unmasked cytokine of XTX202 that reaches the systemic circulation will be rapidly cleared with minimal systemic AEs.

We then used syngeneic mouse tumor models to evaluate the activity of XTX202 in vivo .

In these mouse tumor models, we observed tumor-activated PD effects of XTX202 and robust monotherapy activity against established tumors.

Importantly, these experiments were conducted with XTX202 and not mouse surrogates.

We examined established B16F10 melanoma tumors for PD evidence of XTX202 activity and compared the results to activity seen systemically.

These data were compared to the non-masked control XTX200 and the vehicle-treated negative controls.

Animals received 10 mg/kg of XTX202 or 0.36 mg/kg of XTX200, the non-masked control, on day zero and day three.

The presence of CD8+ effector T cells was used as a measure of immune activation.

The figure below depicts activity in B16F10 melanoma tumors on the left and in the spleen, a peripheral immune organ, on the right.

We observed that both XTX202 and XTX200 induced an increase in CD8+ effector T cells in the tumor compared to vehicle control, while, in the spleen, expansion observed following XTX202 was limited compared to non-masked XTX200, which induced a significant expansion of splenic CD8+ effector T cells.

XTX202 Tumor Selectivity in B16F10 Tumor Mice

In a separate experiment, we compared the effect of aldesleukin and XTX202 on tumor growth and the level of intra-tumoral CD8+ effector T cell, NK cell and TREG infiltration.

MC38 tumor-bearing mice were treated with either vehicle, aldesleukin (3 mg/kg twice per day, or BID) or XTX202 (10 mg/kg once every five days, or Q5D) and tumor volumes, as well as intra-tumoral immune cell infiltration were assessed on day five post-treatment.

As illustrated in the figure below, XTX202 and aldesleukin treatment resulted in tumor growth inhibition, as well as increased CD8+ effector T cell and NK cell infiltration compared to vehicle.

In contrast to aldesleukin, XTX202 treatment did not result in significantly increased intra-tumoral TREG frequencies compared to vehicle.

In a separate experiment, we compared the ability of XTX202, XTX200 and aldesleukin to inhibit growth of established MC38 colon cancer tumors in mice.

Prior experiments had demonstrated that 0.5 mg/kg of XTX200 dosed once every three days, or Q3D, and 3 mg/kg of aldesleukin BID for five days were the maximum tolerated doses, or MTDs, in mice

for these molecules.

Previous experiments had also demonstrated that XTX202 was well-tolerated in mice at doses up to at least 25 mg/kg dosed Q3D, with reversible, mild decrease in body weight and no mortality, and no decrease in body weight at 10 mg/kg.

In this study, on day zero, animals received 10 mg/kg of XTX202, a well-tolerated dose for this molecule, or XTX200 at an MTD of 0.5 mg/kg on day zero and day three, or aldesleukin at an MTD dose of 3 mg/kg BID on days zero through four.

As shown in the below figure, on day 5 post-dose, a well-tolerated dose of XTX202 demonstrated comparable activity to aldesleukin or non-masked IL-2 at their MTDs.

XTX202 Tumor Growth Inhibition Was Comparable to Non-Masked Control XTX200 and Aldesleukin

We also conducted a preclinical study in a second syngeneic tumor model, using mice bearing established MB49 bladder cancer tumors.

On day zero, mice received 2 mg/kg of XTX202, or 0.4 mg/kg of systemically active non-masked XTX200 every two days.

Aldesleukin was given twice daily at 3 mg/kg for three days.

As a result of the removal of one mouse from a study cohort due to mortality or unacceptable body weight loss, the tumor progression curve for that cohort has been censored.

As shown in the left panel in the figure below, a well-tolerated dose of 2 mg/kg of XTX202 achieved similar activity to the non-masked IL-2 at its MTD of 0.4 mg/kg.

As shown in the right panel, XTX202 at 2 mg/kg had no observed effect on weight gain compared to animals that received vehicle control.

By contrast, 0.4 mg/kg of the non-masked molecule led to significant weight loss.

The dose of aldesleukin required to match XTX202 activity was not tolerated in this study and resulted in animal mortality by day five.

The tumor growth inhibition observed with the 2 mg/kg dose of XTX202 was comparable to the activity of the non-masked engineered IL-2 surrogate at its MTD, but body weight loss and mortality were seen in the aldesleukin group and activity could not be determined effectively.

Effects of XTX202 on Tumor Growth Inhibition and Body Weight in MB49 Tumor Mice

In the same MB49 tumor study, in animals in which effective tumor growth inhibition was observed, blood samples were collected on day five from all surviving animals.

These samples were evaluated for changes in immune cell populations in the blood by fluorescent activated cell sorting.

XTX202 did not cause an increase in circulating CD8+ effector T cells, NK cells or TREGs.

In contrast, XTX200 caused an increase in circulating CD8+ and NK cells, but no effect on TREGs, and aldesleukin had variable but stimulatory effects on all three cell types.

XTX202 Did Not Affect Immune Cells in the Periphery

These preclinical data collectively support the hypothesis that the activity of XTX202 is limited to the tumor microenvironment.

The lack of expansion of the CD8+ T cell, NK cell or Treg cell populations in the peripheral blood suggest that XTX202 achieved tumor growth inhibition while exhibiting no evidence of activity outside of the tumor microenvironment.

By contrast, the non-masked molecule XTX200 and aldesleukin both showed significant increases in immune cell populations in the blood, demonstrating that these molecules are both active outside of the tumor microenvironment.

This conclusion was further supported by measurements of animal health in the bladder cancer tumor model.

As shown in the figure below, we did not observe XTX202 to induce splenomegaly, while significant increases in spleen size were observed in animals treated with either XTX200 or aldesleukin.

Similarly, XTX202 did not lead to VLS in treated mice as demonstrated by the lack of pulmonary edema, shown in the right panel.

By contrast, XTX200 or aldesleukin administration resulted in vascular leak and pulmonary edema.

Splenomegaly and Pulmonary Edema Observed in Mice with

Aldesleukin and Non-Masked XTX200, But Not with XTX202

Tolerability of XTX202 and XTX200 was also evaluated in NHP studies.

All animals were administered a single IV infusion of either XTX200 at 0.73 mg/kg or a masked analog of XTX202 at 1.0 mg/kg.

Peripheral lymphocyte counts and serum albumin levels were monitored for four weeks post-administration.

The data show that at a molar equivalent dose, the masked molecule does not result in lymphocytosis or hypoalbunemia that is induced by the unmasked version of the same non-alpha molecule (XTX200).

XTX202 Overcame Toxicity of Non-Masked XTX200 in NHPs

XTX202 was evaluated in a repeat-dose toxicology study in NHPs in compliance with FDA’s good laboratory practices, or GLPs.

The study evaluated vehicle and 1, 10 and 25 mg/kg doses of XTX202 given once weekly intravenously.

As shown in the figure below, we observed dose dependent lymphocyte expansion following administration of XTX202, with the 1 mg/kg group showing no systemic expansion.

These results were further supported by analysis of circulating albumin.

A decrease in serum albumin levels is an indication of VLS.

Serum albumin remained within the normal range for the 1 mg/kg and 10 mg/kg dosing groups, indicating no systematic expansion occurred and demonstrating minimal or no systemic toxicity for XTX202 in those dosing groups.

The results from this repeat-dose GLP toxicology study in NHPs demonstrated that XTX202 was well-tolerated with the highest non-severely toxic dose, or HNSTD, equal to 10 mg/kg when administered once per week for four weeks.

XTX202 Toxicology in a GLP NHP Study Demonstrated Favorable Tolerability

The circulating half-life and PK properties of masked XTX202 and non-masked control cytokine were evaluated in a preliminary NHP study.

Drug levels were measured with a custom enzyme-linked immunosorbent assay following a single IV infusion of 1 mg/kg of XTX202 or the molar equivalent of XTX200 at 0.7 mg/kg.

PK parameters were calculated using a non-compartmental analysis.

As shown in the table below, XTX202 exhibited a half-life of 5.3 days, whereas the half-life of the non-masked XTX200 was shorter at 1 day.

The half-life extension moiety and the decrease in target-mediated disposition due to masking of IL-2 result in the longer half-life of XTX202.

These data support starting with a dosing schedule of intravenous administration once every three weeks, or Q3W.

Measured PK Parameters in Single Dose NHP Study

XTX202 (masked at 1 mg/kg)

XTX200 (unmasked at 0.73 mg/kg)

Based on these data, we believe that circulating levels of masked XTX202 can be achieved with clinically meaningful concentrations of activated (unmasked) XTX202 within tumors and that any unmasked cytokine of XTX202 that reaches systemic circulation will be rapidly cleared with no systemic AEs.

We believe that our preclinical data support clinical development of XTX202 for the treatment of a range of cancer indications, both as a monotherapy and in combination with other agents.

In head-to-head preclinical tumor model studies, XTX202 achieved activity with 2-10 mg/kg dosed Q3D comparable to aldesleukin at 3 mg/kg dosed BID.

XTX202 was well-tolerated up to 10 mg/kg repeated administration over four weeks in NHPs, whereas the published MTD for aldesleukin in NHPs is 25 ug/kg daily for 28 days.

Therefore, in our preclinical studies, XTX202 demonstrated a calculated improvement in overall therapeutic index compared to aldesleukin.

While there can be no assurances that these results will be replicated in clinical trials, we believe these preclinical data demonstrate XTX202 has the potential to deliver high concentrations of IL-2 selectively to the tumor while minimizing peripheral toxicity.

We expect this to allow dose-escalation to achieve intra-tumor cytokine levels high enough to induce local T cell and NK cell activation, proliferation and anti-tumor cytotoxicity.

In addition to the monotherapy potential for XTX202, we believe the combination of XTX202 with additional agents, including anti-PD-1/PD-L1 agents that are widely used in a range of solid tumors, has the potential to ultimately lead to the widest utilization of XTX202 in cancer patients.

Based on preclinical data, we believe XTX202 has the potential to provide enhanced anti-tumor activity when combined with an anti-PD-1/PD-L1.

As shown in the figure below, in preclinical studies, XTX202 combined with an anti-PD-1/PD-L1 induced complete responses in a preclinical setting where neither XTX202 nor the anti-PD-1/PD-L1 were able to achieve complete responses as a monotherapy.

In these preclinical studies, mice with complete responses rejected rechallenge with tumor, indicating evidence of the development of a memory response.

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 of XTX202 with anti-mPD-1 further improved anti-tumor activity with TGI 92% on Day 13 (Data presented as mean ±SEM, two-way ANOVA followed by post hoc Dunnett’s test, *P < 0.05;

**P < 0.005).

The treatment with XTX202 alone or in combination with anti-mPD-1 improved animal survival from 19 days to 27.5 and 38 days, respectively (Geham-Breslow-Wilcoxon test, **P < 0.01).

A mouse with complete regression of MB49 tumor after combination therapy with XTX202 and anti-mPD-1 was resistant to tumor rechallenge with autologous MB49 tumor implanted on the opposite flank.

Clinical Development Plans for XTX202

We are currently evaluating XTX202 in monotherapy dose-escalation (Part 1A) in an ongoing Phase 1 clinical trial in patients with advanced solid tumors, and monotherapy dose expansion (Part 1B) is open for enrollment.

The Phase 1 trial is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of multiple ascending doses of XTX202 with the goal of establishing recommended Phase 2 dose, or RP2D, for XTX202 as a monotherapy in patients with advanced solid tumors.

We plan to initiate patient enrollment in a Phase 2 clinical trial evaluating XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic RCC in April 2023.

The planned Phase 2 clinical trial for XTX202 is a multi-center, open-label trial designed to evaluate the safety and anti-tumor activity of XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic RCC at the RP2D.

Subject to the results from this combination study, we anticipate initiating registration-enabling clinical trials for XTX202 in combination with an anti-PD-1/PD-L1 in patients with NSCLC.

The figure below shows our Phase 1/2 trial design for XTX202 in RCC, melanoma and other indications to evaluate its activity as both a monotherapy and in combination with other agents.

Phase 1 Clinical Trial for XTX202

As of March 1, 2023, a total of 16 patients have been treated with XTX202 in the outpatient setting at five dose levels ranging from 0.27 mg/kg to 1.4 mg/kg Q3W in Part 1A for the Phase 1 clinical trial, and Part 1B is open for enrollment.

No signs of VLS, including hypotension or decreases in albumin (an early sign of VLS) or hemodynamic compromise, have been

observed in patients to date.

A maximum tolerated dose has not yet been determined, and enrollment in Part 1A and Part 1B of the clinical trial is ongoing.

In addition, we recently reported preliminary clinical intra-tumoral PD data for two patients treated with XTX202 who each had an optional on-treatment tumor biopsy and were the only two patients for whom a tumor biopsy analysis was available as of March 1, 2023.

The first patient was a melanoma patient treated with XTX202 at the 0.38 mg/kg dose level, and the second patient was an RCC patient treated with XTX202 at the 0.53 mg/kg dose level.

For each patient, as shown in the figures below, the tumor biopsy featured increased numbers of stromal TILs and increased frequency of CD8+ effector T cells among these TILs.

Importantly, in each patient, at the time of the tumor biopsy, these changes occurred in the absence of peripheral changes to either CD8+ effector T cells, demonstrating preliminary evidence of tumor-selective activation.

Renal Cell Carcinoma (RCC) Overview

RCC accounts for 2% of global cancer diagnoses and deaths annually, and the global incidence is increasing.

Most cases of RCC are discovered incidentally on imaging, and approximately one-third of cases are advanced or metastatic at the time of diagnosis.

Survival is highly dependent on the stage at diagnosis, with metastatic disease having a five-year survival rate of only 15%.

RCC is the ninth most common cancer in the United States, with approximately 79,000 estimated new cases in 2022 and approximately 13,920 deaths in 2022.

The landscape of therapeutic options has rapidly evolved such that the treatment goal, even in the metastatic setting, is to cure patients or ensure their long-term survival.

Systemic frontline therapy options now include combinations of checkpoint inhibitors and TKIs such as pembrolizumab and axitinib, nivolumab and ipilimumab, and avelumab and axitinib.

Despite these recent approvals, there remains a pressing need to identify new therapeutic targets and effective treatments since the substantial majority of patients continue to experience relapses and progression and ultimately succumb to their cancer.

As a result, cures are not commonly achieved, as in the example of pembrolizumab combined with vascular endothelial growth factor receptor-targeted TKI.

As shown in the figure below, most patients with metastatic RCC will eventually relapse even after treatment with sunitinib or pembrolizumab and axitinib as the median time to progression-free survival, or PFS, is 11.1 months and 15.1 months, respectively.

Pembrolizumab+Axitinib Improved Overall Survival in Metastatic RCC,

but Most Patients Still Relapsed Within 18 Months

In contrast to the TKI and anti-PD-1/PD-L1 combination shown above, IL-2-directed therapy offers the opportunity for durable responses and cures, as was seen in the historical aldesleukin treatment data.

Only 15% of RCC patients treated with high-dose IL-2 obtained an objective response but approximately half of these, or 7% of all patients treated, achieved a CR.

The unique feature of high-dose IL-2 is that approximately 90% of patients with RCC who achieved a CR remained permanently disease-free and off-treatment.

Assuming a successful Phase 1 dose escalation trial and identification of a RP2D, we plan to pursue a rapid Phase 2 proof-of-concept clinical trial in RCC, an indication in which recombinant IL-2 produces positive clinical responses, but in which its use is limited due to toxicity.

We believe XTX202’s characteristics can overcome these limitations and address the unmet need in RCC.

Treatment of Metastatic Melanoma with IL-2 Agents

In clinical trials evaluating recombinant IL-2 for the treatment of metastatic melanoma, recombinant IL-2 produced an ORR of 16% and produced CRs and functional cures in 6% of patients.

However, use of recombinant IL-2 has been hampered by dose-limiting toxicities.

While treatments that target PD-1 and CTLA-4 have grown to dominate the metastatic melanoma treatment landscape, many patients do not respond, and relapses are common, with a five-year survival rate of around 50% in metastatic melanoma.

We believe that a safe and effective form of IL-2 may improve initial response rates and clinical outcomes when added to checkpoint inhibitor therapy and may maintain responses in patients with melanoma who have relapsed from checkpoint inhibitor treatment.

Importantly, high-dose IL-2 has shown a response rate, including CRs in patients with melanoma despite those patients having progressed on prior treatment with an anti-PD-1/PD-L1 showing the potential for IL-2 mechanism of action-based efficacy in patients who have previously been treated with an anti-PD-1/PD-L1.

Similar to our development plan for RCC, assuming a successful Phase 1 dose escalation trial, we plan to rapidly pursue a Phase 2 proof-of-concept clinical trial in melanoma, where recombinant IL-2 has demonstrated clinical responses but has been historically limited due to toxicity.

Our clinical development plan includes the evaluation of patients with melanoma who have previously been treated with an anti-PD-1/PD-L1 to demonstrate clinical proof-of-concept.

Potential Future Indications

Beyond RCC and melanoma, we intend to explore XTX202 in additional solid tumor indications for which there is a significant unmet medical need, and for which IL-2 has previously demonstrated utility.

These indications may include NSCLC, head and neck squamous cell cancer, or HNSCC, bladder cancer and ovarian cancer.

Aldesleukin has been studied in a broad range of tumor types.

Dose-limiting toxicities have prevented most patients with cancer from receiving the high doses necessary for systemic efficacy.

Multiple clinical trials have evaluated IL-2 where localized administration is possible.

In these trials, IL-2 has induced objective responses in patients with ovarian cancer when administered in the peritoneum, in patients with bladder cancer when administered directly into the bladder and in patients with NSCLC and mesothelioma when administered into the pleural cavity.

In patients with resectable HNSCC, perioperative administration of IL-2 into the lymph nodes near the tumor resulted in increased survival in a randomized trial.

These data provide evidence that multiple tumor types are likely sensitive to IL-2 if high levels of localized exposure can be obtained.

In addition, we believe the novel design of XTX202 and preclinical and clinical data observed to date support the potential for XTX202 as a treatment in combination with other agents where tumor-activation may be required in order to combine with IL-2, including:

monoclonal antibodies, other pro-inflammatory cytokines such as IL-12 and IL-18, cell therapies such as CAR-T and CAR-NK, and cancer vaccines.

XTX301, Our Clinical-Stage, Tumor-Activated IL-12 Product Candidate

In November 2022, we announced clearance of our IND by the FDA for XTX301 for evaluation in patients with advanced solid tumors.

For more information, please see the section entitled “—Clinical Development Plans for XTX301” below.