SQ3370 / Shasqi - LARVOL DELTA

SQ3370-001: Phase 1/2a Study of SQ3370 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=53 | Terminated | Sponsor: Shasqi, Inc. | N=145 ➔ 53 | Recruiting ➔ Terminated; Sponsor's decision

Enrollment change • Trial termination • Oncology • Solid Tumor

Development of a First-in-Class Click Chemistry-Based Cancer Therapeutic, from Preclinical Evaluation to a First-in-Human Dose Escalation Clinical Trial. (PubMed, Clin Cancer Res) - P1/2 | "The first-in-class Click Activated Protodrugs Against Cancer-based cancer therapeutic SQ3370 uses a clickable pretargeting agent that reacts with a chemically attenuated clickable payload of doxorubicin (Dox) and releases the active cytotoxic drug in situ. SQ3370, the first demonstration of click chemistry within the human body in a clinical setting, facilitated the delivery of chemotherapy to tumors and unlocked additional biological effects such as favorable immune responses that may benefit patients with metastasis. Consistent safety, toxicology, pharmacokinetic, and immune activation results observed across species highlight the translatability of the technology and position click chemistry as a powerful new modality for the development of targeted cancer therapeutics."

Journal • P1 data • Preclinical • Oncology • Solid Tumor • CD8

A first-in-human, Phase 1/2a, open-label study of SQ3370, a first-in-class doxorubicin-based click chemistry therapeutic, in patients with advanced solid tumors. (PubMed, medRxiv) - P1/2 | "Objective clinical activity was observed, but ORR was comparable to standard Dox. ▪ SQ3370 is a click chemistry-enabled, pre-targeting therapeutic and the first use of in vivo click chemistry in humans ▪ SQ3370 up to15x standard doxorubicin dose in patients with solid tumors was safe with no DLTs reported▪ In Phase 2a, SQ3370 provided an unconfirmed objective response rate of 14.3% and disease control rate of 71.4% in patients with advanced sarcomas▪ Tumor size reductions seen in both injected and non-injected lesions, potentially due to systemic anti-tumor responses."

Journal • P1/2 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD8

Applying Learnings From Clinical Development of SQ3370 to Optimise Development of Novel Tumour-Targeted Therapies (ADC London 2025) - "• Discussing safety and efficacy results from the phase 2 clinical programme of SQ3370 • Reviewing learnings from the clinical study and how they have informed design principles going forward • Highlighting data from Shasqi’s lead asset targeting CEACAM5"

Clinical • Oncology • CEACAM5

Doxorubicin-based click chemistry therapeutic activates potent cytotoxic immune responses in advanced sarcoma patients in a phase 1/2a clinical trial (SITC 2024) - P1/2 | "We conducted a Phase 1/2a clinical trial to evaluate the safety and efficacy of SQ3370, which uses an intratumorally injected activator (SQL70) with a systemically injected doxorubicin protodrug (SQP33). Further exploration is warranted to examine these enhanced immune effects in classically cold tumors and in combination with other immunotherapies. Ethics Approval This study was approved by each of the institution's Ethics Board."

Clinical • Metastases • P1/2 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD8

SHASQI TO PRESENT AT WORLD ADC AND SITC CONFERENCES (PRNewswire) - "The presentations and posters will share data from Shasqi's novel Click Activated Protodrugs Against Cancer (CAPAC) technology, a pre-targeting approach using in-vivo click chemistry to enable preferential drug exposure in tumors versus normal tissues. This can be used to improve the therapeutic index of potent cytotoxic drugs or radioisotopes....Shasqi is seeking to establish new and advance existing conversations with partners around the applications of their CAPAC pre-targeting technology at both World ADC and SITC."

P1/2 data • Preclinical • Oncology • Sarcoma • Solid Tumor

Phase 2a results of SQ3370, a doxorubicin-based click chemistry therapeutic in patients with advanced STS: Planned interim analysis. (ASCO 2024) - P1/2 | "SQ3370 is the first clinical click chemistry-based cancer therapy, and this is the 1st clinical trial to explore doses greater than 3x Dox in STS patients. The results show that the bp activates protodrug, which is not a vesicant, and releases Dox in patients. Click chemistry favorably alters PK and safety of the Dox payload."

Clinical • Metastases • P2a data • Anemia • Fatigue • Hematological Disorders • Neutropenia • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Thrombocytopenia

CAPAC: A Modular Platform for TumourTargeted Drug Activation Using Click Chemistry In Vivo (ADC London 2024) - "An introduction to Shasqi and how the CAPAC platform leverages click chemistry for tumortargeted drug activation • An overview of non-clinical and clinical results for SQ3370, providing proof-of-principal for using click chemistry in humans • Future vision of CAPAC, including preclinical results using antibodies to activate high potency payloads at tumours"

Preclinical • Oncology

phase I clinical results of SQ3370, a doxorubicin-based click chemistry therapeutic in advanced solid tumor patients (ESMO 2023) - P1/2 | "Conclusions SQ3370 is the first clinical click chemistry-based cancer therapy. The results show the following: the biopolymer activates protodrug in patients; that the Dox protodrug is not a vesicant; PK data demonstrates activation of protodrug; reaction achieves liberation of Dox; click chemistry favorably alters PK and safety of the payload."

Clinical • Metastases • P1 data • Oncology • Sarcoma • Solid Tumor

CAPAC: a modular platform that can improve the safety and efficacy of existing cancer therapies (AACR 2023) - P1/2 | "Our lead clinical candidate SQ3370 (SQL70 biopolymer + SQP33, doxorubicin protodrug), is being evaluated in a Phase 2a study in solid tumors (NCT04106492)...Because the tumor targeting agent (i.e., biopolymer) is separate from the protodrug, it enables the flexibility of interchanging different protodrugs with different mechanism of actions such as tubulin inhibitors (e.g., paclitaxel), topoisomerase inhibitors (e.g., exatecan), immune activators (e.g., TLR agonists), and others...This modularity enables the rapid access of therapeutic combinations. Moreover, as the click chemistry activation is independent of biological characteristics of tumors, CAPAC payloads are highly translatable across species and accelerate the path to the clinic."

Clinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

SQ3370, a doxorubicin-based click chemistry therapeutic, promotes a shift from an immunosuppressive towards a T-cell permissive tumor microenvironment in patients (AACR 2023) - P1/2 | "Our assessment of immune changes after SQ3370 treatment confirms that observations in preclinical models are translatable to humans, as similar T-cell supportive immune changes were observed in syngeneic tumor models with SQ3370. Consistency between immune responses in clinical and preclinical samples underlines the translatability of the click chemistry-based drug and suggests that its broad therapeutic potential may be further enhanced with combined immunotherapies."

Biomarker • Clinical • Tumor microenvironment • Oncology • Solid Tumor • CD8 • GZMB

A click chemistry-activated auristatin protodrug (TCO-MMAE) demonstrates potency and safety with antibody and intratumoral tumor-targeting agents (AACR 2023) - P1/2 | "The lead candidate SQ3370 consists of an intratumorally (IT) injected tetrazine (Tz)-modified biopolymer and an intravenously (IV) administered trans-cyclooctene (TCO)-modified doxorubicin (Dox) protodrug. Anti-tumor activity was observed in multiple preclinical models for the TCO-MMAE protodrug in combination with both biopolymer and Fab targeting agents. These results highlight the power of click chemistry to activate a protodrug at the tumor site, independent of tumor biology, the molecular format or delivery method of the targeting agent."

Clinical • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Kidney Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Renal Cell Carcinoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • HER-2

[PREPRINT] SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species (bioRxiv) - P1/2 | N=145 | NCT04106492 | Sponsor: Shasqi, Inc. | "SQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370's safety, toxicology, and PK profiles were highly translatable across species."

P1/2 data • Preprint • Oncology • Solid Tumor

SQ2270, a Novel MMAE-based Therapeutic, Promotes Tumor Growth Inhibition and Extensive Immune Cell Infiltration in the RENCA Cancer Model (SITC 2022) - P1/2 | "SQ3370, the lead asset, uses a Doxorubicin protodrug and is being evaluated in a Phase 1 clinical trial in solid tumors ( NCT04106492 ). (2) Protodrug, an attenuated therapy activated by click chemistry, is infused systemically. (3) Protodrug is captured by its click chemistry partner through a rapid covalent reaction between tetrazine and TCO moieties, followed by localized release of the active drug"

Preclinical • Oncology • Solid Tumor • CD8 • GZMB • PD-1 • PTPRC

Combination of click chemistry-based SQ3370 with immunotherapies enhances antitumor effect in murine tumors with minimized systemic toxicity (SITC 2021) - P1 | "While anthracyclines such as doxorubicin (Dox) may provide added benefit by inducing anti-tumor immune activation,1 their overall effect is limited by cumulative dose cardiotoxicity.2 Here, we present the Click Activated Protodrugs Against Cancer (CAPAC) platform that activates cytotoxic protodrugs at the tumor using click chemistry...Results Combining SQ3370 with endosomal TLR agonists such as poly I:C (TLR3a), imiquimod (TLR7a) or CpG ODN (TLR9a) resulted in improved tumor growth inhibition and survival in MC38 tumor-bearing mice compared with monotherapy. Combination with STING agonist, ADU-S100, also enhanced antitumor efficacy...SQ3370, CAPAC's lead candidate, improves safety and efficacy as compared to conventional Dox, and combination of SQ3370 with immunotherapy shows enhanced benefit. SQ3370 is being evaluated in a Phase I study in advanced solid tumors (NCT04106492)."

IO biomarker • Preclinical • Oncology • Solid Tumor • TLR3

[VIRTUAL] SQ3370-001 is a multi-center open-label phase I dose-escalation study to test a novel intratumoral and systemic approach to treat advanced solid tumors (SITC 2020) - P1 | "Here, we present SQ3370, a novel approach that activates doxorubicin (Dox) at the tumor site while avoiding systemic toxicities commonly associated with the therapy, and also potentially activates an immune response against tumors. Western IRB, on behalf of The Angeles Clinic and Research Institute and Henry Ford Health System IRB Office; IRB Tracking Number: 20200758.4. Bellberry Limited Human Research Ethics Committee, on behalf of Royal North Shore Hospital and Chris O’Brien Lifehouse; Application Number: 2019-10-848."

Clinical • P1 data • Oncology • Solid Tumor

[VIRTUAL] Click Activated Protodrugs Against Cancer (CAPAC) platform enhances the safety, pharmacokinetics, and antitumor efficacy of cancer therapies in vivo (ESMO 2021) - P1 | "Then, SQP33, a trans-cyclooctene (TCO)-modified protodrug of Doxorubicin (Dox) is given systemically as 5 daily doses. SQ3370 enables higher concentrations of the active drug at the tumor site and minimizes systemic adverse effects associated with conventional chemotherapy. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities."

PK/PD data • Preclinical • Oncology • Solid Tumor

CLICK ACTIVATED PROTODRUGS AGAINST CANCER (CAPAC) PLATFORM ENHANCES ANTITUMOR EFFICACY, SAFETY AND PHARMACOKINETICS OF CANCER THERAPEUTICS (CTOS 2021) - P1 | "Then, SQP33, a trans-cyclooctene (TCO)-modified protodrug of Doxorubicin (Dox) is given as 5 daily intravenous doses. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by expanding the pharmacological capabilities of drugs with known efficacy such as Dox. SQ3370, CAPAC s lead candidate, demonstrates enhanced safety and efficacy in vivo, as compared to the conventional Dox, and is being evaluated in a Phase I study in patients with advanced solid tumors (NCT04106492)."

Clinical • PK/PD data • Oncology • Solid Tumor

FIRST-IN-HUMAN TRIAL OF SQ3370 IN RELAPSED OR REFRACTORY SOFT TISSUE SARCOMA AND OTHER SOLID TUMORS: PROOF-OF-CONCEPT FOR CLICK CHEMISTRY-BASED CAPAC PLATFORM (CTOS 2021) - P1 | "Instead, older chemotherapies such as anthracyclines (doxorubicin (Dox)) are regarded as the systemic treatment of choice for STS. SQ3370 appears to be well tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK data are consistent, indicating that high tumor levels can be achieved while limiting systemic exposure. Data supports further development of SQ3370 and dose escalation continues."

IO biomarker • P1 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Click Activated Protodrugs Against Cancer (CAPAC™): A modular platform for tumor directed oncology therapeutics (AACR 2022) - P1 | "The modular nature of the platform allows targeting strategies based on tumor’s location, antigens, or both to be combined with therapeutics utilizing multiple mechanisms of action to deliver highly effective treatments tailored to each patient.The lead clinical candidate SQ3370 consists of a tetrazine-modified sodium hyaluronate biopolymer (SQL70) that is injected at the tumor site and followed by multiple systemic doses of trans-cyclooctene (TCO)-modified protodrug based on doxorubicin (Dox). CAPAC expands the therapeutic potential of anticancer drugs by increasing exposure to tumors and minimizing systemic adverse effects. The CAPAC platform can also be combined with other therapies to modulate the immune response and modify the tumor microenvironment."

Oncology • Solid Tumor

[VIRTUAL] The CAPAC Platform maximizes therapeutic benefit and reduces systemic cytotoxic exposure in small and large animals (AACR 2021) - P1 | "Then, SQP33, a trans-cyclooctene (TCO)-modified protodrug of Doxorubicin (Dox) is given by IV infusion as 5 daily doses. The CAPAC Platform enables higher concentrations of the active drug at the tumor site and minimizes systemic adverse effects associated with conventional chemotherapy. SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (https://clinicaltrials.gov/ct2/show/NCT04106492)."

Oncology • Solid Tumor

Treatment with SQ3370, a doxorubicin-based therapeutic, corresponds with immunomodulation of the tumor microenvironment (SITC 2022) - P1/2 | "It also activates an anti-tumor immune response through induction of immunogenic cell death and modulates adaptive and innate immune cell populations. Consistency between immune responses observed in clinical samples and mouse syngeneic tumor models underlines the translatability of the SQ3370 preclinical data and suggests a window of opportunity for combination strategies with immunotherapies."

Biomarker • Tumor microenvironment • Oncology • Solid Tumor

Pharmacokinetic and immunologic data from a Phase I study of the click chemistry-based therapy SQ3370 in advanced solid tumors and soft-tissue sarcoma provides proof-of-concept for the CAPAC platform (SITC 2021) - P1 | "SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). Preclinical and clinical PK are consistent; high tumor exposure canbe achieved, so far without the typical clinical adverse events seen with IV Dox and potentiallyimproving the therapeutic index of a frequently-used chemotherapeutic agent. Trial Registration NCT04106492"

P1 data • PK/PD data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Phase I clinical & immunologic data of SQ3370 in advanced solid tumors (ESMO 2022) - P1 | "Background SQ3370 utilizes a proprietary Click Activated Protodrugs Against Cancer platform where mutually-reactive click chemistry groups release doxorubicin (Dox) at the tumor. Immunologic changes were consistent with a shift from immune suppressive to T cell permissive environments promoting cancer cell death. Dose escalation is ongoing.."

Clinical • P1 data • Oncology • Sarcoma • Solid Tumor

[VIRTUAL] Early pharmacokinetic data from a phase I study of SQ3370 in patients with advanced solid tumors provides proof-of-concept for the click chemistry-based CAPAC platform (ESMO 2021) - P1 | "SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor site while minimizing systemic exposure, is based on intratumoral injection of a protodrug-activating biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuated protodrug of Dox (SQP33). SQ3370 appears to be well tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK data are consistent, indicating that high tumor levels can be achieved while limiting systemic exposure. Dose escalation continues."

Clinical • P1 data • PK/PD data • Oncology • Solid Tumor