On April 8, 2024 Sapience Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery and development of peptide therapeutics to address oncogenic and immune dysregulation that drive cancer, reported the presentation of new data on its clinical and pipeline programs during three poster presentations at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10, 2024, in San Diego, CA (Press release, Sapience Therapeutics, APR 8, 2024, View Source [SID1234641904]).

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"At AACR (Free AACR Whitepaper) 2024, we are thrilled to present foundational data that support our growing clinical and preclinical pipeline of peptide therapeutics against difficult-to-drug targets, such as β-catenin, C/EBPβ, and c-Jun (AP-1 complex)," said Jim Rotolo, Ph.D., SVP, Research and Translational Sciences. "These data demonstrate the ability of our lead SPEARs, ST316 and ST101, to positively impact the tumor immune microenvironment, providing further evidence of their therapeutic promise. We look forward to ST316 and ST101 continuing to advance through clinical development and moving our AP-1 program into IND-enabling studies."

Sapience scientists will present non-clinical immune-oncology results from both of its clinical programs, ST316, a first-in-class antagonist of β-catenin, and ST101, a first-in-class antagonist of C/EBPβ. Sapience will also present its first disclosure of pre-clinical data describing JunAP, its first-in-class AP-1 complex antagonist targeting the interaction of c-Jun with Fra1.

Poster presentation details and abstract highlights include:

Title: "ST316, a clinical peptide antagonist of beta-catenin, induces anti-tumor immune responses by multiple mechanisms of action"
Session Title: Inflammation in Tumor Initiation and Progression
Location: Poster Section 4
Abstract Number: 5332
Date and Time: Tuesday, April 9, 2024, 1:30 PM to 5:00 PM

ST316 is a first-in-class peptide antagonist of the interaction between β-catenin and its co-activator, BCL9, a complex that drives oncogenic gene expression in multiple cancers where aberrant Wnt/β-catenin pathway signaling is observed, and impacts the tumor immune microenvironment by promoting immunosuppressive myeloid-derived suppressor cell (MDSC) and tumor associated macrophage (TAM) populations. ST316 is currently being evaluated in a Phase 1-2 study (NCT05848739) enrolling patients with selected advanced solid tumors likely to harbor abnormalities of the Wnt/β-catenin signaling pathway.

In nonclinical studies, Sapience evaluated the ability of ST316 to enhance anti-tumor immune responses in combination with anti-PD-1 and anti-TIGIT therapies.
ST316 increases the ratio of proinflammatory M1 macrophages to immunosuppressive M2 macrophages, decreases PD-L1 expression on M2 macrophages and decreases PD1 expression on CD8+ T cells.
ST316 promotes cell surface expression of CD155/PVR to activate T cells in the presence of anti-TIGIT antibody.
In nonclinical in vivo studies, ST316 in combination with anti-PD-1 treatment displays significant anti-tumor activity with accompanied reduction in M2 macrophages.
These data support a paradigm in which ST316 promotes a shift to an immune-active tumor microenvironment via multiple mechanisms, including driving macrophage polarization toward an M1 immune-promoting phenotype, augmenting activity of cytotoxic T cells, and increasing expression of the checkpoint activator CD155/PVR on cancer cells.
Title: "ST101, a clinical C/EBPβ-antagonist peptide, promotes an immune-active tumor microenvironment by multiple cellular mechanisms"
Session Title: The Tumor Microenvironment as a Drug Target
Location: Poster Section 13
Abstract Number: 2909
Date and Time: Monday, April 8, 2024, 1:30 PM to 5:00 PM

ST101 is a peptide antagonist of C/EBPβ that is being evaluated in a Phase 2 clinical study in patients with recurrent and newly diagnosed glioblastoma (NCT04478279).

Sapience evaluated the effect of ST101 on immunosuppressive cell populations and on activation of cytotoxic T cells in macrophage co-culture systems.
ST101 inhibits the immunosuppressive M2 macrophage program, resulting in polarization of macrophages to the proinflammatory M1 phenotype and increasing cytotoxic T cell activation.
In animal models, ST101 enhances the activity of anti-PD-1 treatment by increasing the M1/M2 ratio in the TAM population.
Gene expression analysis of clinical biopsies indicates that ST101 modulates the tumor immune microenvironment by suppressing genes required for M2 macrophage polarization, resulting in an enhanced CD8/Treg ratio.
ST101 represents a novel approach to enhance anti-tumor immune activity and these data suggest its utility for combination strategies in cancers with poor response to immune checkpoint inhibition.
Title: "JunAP, a peptide antagonist against the activator protein 1 transcription factor complex, demonstrates cancer cell cytotoxicity, reduced invasion in vitro and tumor regression in vivo in TNBC models"
Session Title: Oncogenic Transcription Factors
Location: Poster Section 18
Abstract Number: 3051
Date and Time: Monday, April 8, 2024, 1:30 PM to 5:00 PM

AP-1 complexes have been identified as novel therapeutic targets in cancer due to their role in tumor growth, invasion, metastasis, angiogenesis and chemoresistance.
AP-1 complexes consisting of c-Jun and Fra1 are implicated in the survival of a diverse set of tumors.
JunAP targets and blocks c-Jun and Fra1 dimerization, inhibits AP-1 transcriptional activity and inhibits AP-1-dependent cell survival and invasion in vitro.
JunAP demonstrates potent anti-tumor activity in vivo in mouse triple negative breast cancer and melanoma tumor models.
More information can be found on the 2024 AACR (Free AACR Whitepaper) website.

About ST316

ST316 is a first-in-class peptide antagonist of the interaction between β-catenin and its co-activator, BCL9, a complex that drives oncogene expression in multiple cancers where aberrant Wnt/β-catenin pathway signaling is observed. ST316-101 (NCT05848739) is a first-in-human, open-label, Phase 1-2 dose-escalation and expansion study designed to determine the safety, tolerability, PK, PD and early efficacy of ST316. The Phase 1 dose-escalation portion of the Phase 1-2 study is enrolling and dosing patients with select advanced solid tumors that are known to harbor abnormalities of the Wnt/β-catenin signaling pathway. The Company expects to complete the Phase 1 portion of the study in the first half of 2024. Following completion of the study’s Phase 1 portion, the recommended dose will advance to the Phase 2 dose expansion portion of the study in colorectal cancer patients.

About ST101

ST101, a first-in-class antagonist of C/EBPβ, is currently being evaluated in the Phase 2 portion of an ongoing Phase 1-2 clinical study in patients with recurrent GBM (rGBM) (NCT04478279). In an ongoing window-of-opportunity sub-study, ST101 is being evaluated as a monotherapy in rGBM and in combination with radiation and temozolomide in newly diagnosed GBM, with patients receiving ST101 before and after surgical resection. ST101 has been granted Fast Track designation for rGBM from the U.S. FDA and orphan designations for glioma from the U.S. FDA and the European Commission.