Theratechnologies Presents New In Vivo TH1902 Preclinical Data Demonstrating Tumor Growth Inhibition of Human Cancer Stem-Like Cells (CD133+) in Both Triple-Negative Breast and Ovarian Cancers AACR Annual Meeting 2022

On April 8, 2022 Theratechnologies Inc. ("Theratechnologies" or "the Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported the Company’s participation in three poster presentations at the 2022 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) to be held April 8-13, 2022 at the Ernest N. Morial Convention Center in New Orleans, Louisiana (Press release, Theratechnologies, APR 8, 2022, View Source [SID1234611681]).

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Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer, Theratechnologies commented, "The exciting new data in triple negative breast and ovarian cancer demonstrate remarkable promise of TH1902 in preclinical studies as a potential treatment for these sortilin expressing cancers. The presence of cancer stem cells (CSCs) is associated with aggressive disease, unregulated tumor growth, increased migration of cancer cells, invasion, self renewal and resistance to standard chemotherapy and radiation. Failure to eliminate these cells with current treatments leads to resistance and progression and there are few therapies that have been shown to target CSCs. In preclinical models treated with TH1902, there was marked tumor growth inhibition of cancer stem-like cells with no impact on healthy tissue. This further validates our hypothesis that TH1902 may be effective in hard-to-treat, resistant cancers."

Highlights of the poster presentations included:

AACR Poster #1853 – TH1902, a SORT1 docetaxel peptide-drug conjugate, inhibits tumor growth of human cancer stem-like cells (CD133+) from both triple-negative breast cancers and ovarian cancers

Cancer stem cells, typically associated with CD133 expression, represent a small proportion of cells residing within most tumors and which have high metastatic potential and enhanced drug resistance. In cancer indications such as triple negative breast and ovarian cancers, CSC have also been shown to be involved in vasculogenic mimicry. The study examined the efficacy of TH1902 against cancer stem-like cells and its ability to circumvent some of the known drug resistance phenotypes associated with CSCs. Results included:

The proprietary peptide TH19P01 – Uptake of TH19P01 was exhibited in both cancer stem-like cell lines, but was inhibited by either sortilin ligands or gene silencing, suggesting that the peptide is highly targeted to sortilin expression which is absent in healthy cells.

In vitro – TH1902 induced a marked increase in cell apoptosis – In contrast to docetaxel alone, not only did TH1902 induce cell apoptosis but also produced cell cycle arrest but did not affect healthy tissue.

In vitro — TH1902 bypasses the P-gp efflux pump – Where P-gp inhibitors can restore cell cycle arrest induced by docetaxel, TH1902 was unaffected.

In vivo — triple negative breast and ovarian cancer models – TH1902 significantly inhibited growth of cancer stem-like cell tumor when administered weekly for 3 cycles at a dose equivalent to the MTD of docetaxel and TH1902 treated mice exhibited an increased tolerability when compared to those treated with docetaxel alone.

TH1902 demonstrated better efficacy at doses equivalent to docetaxel – As a single agent in breast and ovarian cancer stem-like cell xenograft tumor models, TH1902 showed better efficacy as compared to docetaxel alone. Better efficacy was also observed in the ovarian tumor model for the TH1902-carboplatin combination as compared to paclitaxel- or docetaxel-carboplatin combinations.

An 80% decrease in tumor growth was observed in TH1902 treated models while tumor volumes diminished about 35% in docetaxel mouse models – The results demonstrated that TH1902 exerts superior anticancer activity as compared to docetaxel alone in CD133+ triple negative breast and ovarian cancer stem-like cell animal models.

AACR Poster #1076 – The peptide-drug conjugate TH1902 inhibits growth of subcutaneous melanoma xenografts and formation of lung metastases in a syngeneic mouse model

Highlights of the study demonstrated Theratechnologies’ proprietary peptide-drug conjugate, TH1902, demonstrated better and sustained efficacy in melanoma subcutaneous xenograft models at doses equivalent to the MTD of docetaxel. Mice treated with TH1902 showed prolonged survival by up to 263%, whereas docetaxel alone increased survival by only 19%.

In a lung B16-F10 metastasis model, different regimens of TH1902 significantly reduced the number of lung metastatic nodules when compared to docetaxel alone.

AACR Poster #1079 – Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin

Highlights of the poster detailed efficacy of TH1902 against SORT1+ ovarian (ES-2, SKOV-3. A-2780) and endometrial (AN3-CA) tumor models. In vitro, TH1902 enabled a more than twofold increase in apoptosis (cell death) as compared to docetaxel alone. In vivo xenograft tumor models, mice treated with TH1902 over two weeks exhibited a statistically significant 78% decrease in tumor size. Highlights demonstrated TH1902 treated mice showed prolonged tumor regression as compared to mice treated with docetaxel alone.

Mice treated with TH1902 in combination with carboplatin demonstrated better efficacy than other combinations. Results indicated that TH1902 possesses an in-vivo efficacy superior to that of docetaxel against ovarian and endometrial cancers in the animals tested and that TH1902 can be safely combined with carboplatin to reach optimal inhibition of tumor growth.

All three posters will be available on our website following the conclusion of the meeting.

Biomea Fusion Reports Preclinical Data on BMF-219 and Trial in Progress Presentations at AACR 2022 Annual Meeting

On April 8, 2022 Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported new data at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrating BMF-219’s potent and highly effective activity in multiple preclinical models of DLBCL, MM, and KRAS human ex vivo tumor models and cell lines in poster presentations (Press release, Biomea Fusion, APR 8, 2022, View Source [SID1234611679]). In addition, the company presented a Trial In Progress (TIP) poster presentation detailing the design of Biomea’s ongoing Phase I clinical trial (COVALENT-101).

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The preclinical and TIP presentations can be viewed on Biomea’s website at View Source

"Today, we unveiled a dataset in which single agent BMF-219 demonstrated pronounced cytotoxic activity across multiple liquid and solid tumor types that we will be pursuing in the clinic. These data clearly show BMF-219’s powerful cell-killing activity in a broad spectrum of tumor types, including a very robust pan-KRAS effect," said Steve Morris, MD, Biomea’s Chief Medical Officer. "In liquid and solid tumor preclinical studies, BMF-219 has demonstrated a highly differentiated profile from both non-covalent menin inhibitors as well as clinical-stage and FDA-approved covalent KRAS G12C inhibitors. We are very excited to see how this differentiated profile translates in the clinical setting across multiple liquid and solid tumors."

In comparison to two highly specific KRAS G12C inhibitors, BMF-219 exhibited broader potency across KRAS-mutated cell lines (G12C, G12D, G13D, and G12V) and ex vivo PDX tumor models indicating pan-KRAS activity with over 90% growth inhibition in most of these models. Additionally, BMF-219 showed the potential to increase the depth of response across G12C cell lines, notably achieving a higher percentage of cell killing in G12C colorectal cancer cells compared to the commercially available KRAS inhibitor sotorasib and another clinical-stage KRAS inhibitor. Additionally, BMF-219 exhibited robust growth inhibition as a single agent against high-grade B-cell lymphoma cell lines that are known to have low response to standard of care, as well as in multiple MM cells with TP53 and RAS mutations at similar drug concentrations.

A targeted pan-KRAS inhibitor has the potential to treat the 25-35% of NSCLC, 40-45% of CRC, and ~90% of pancreatic cancer patients who have KRAS-mutant tumors. If approved, BMF-219 could be an effective treatment for relapsed/refractory DLBCL and MM, where patients have a significant unmet need despite a large armamentarium of therapeutic options. Additionally, we believe BMF-219 has the potential to be an effective therapeutic option for menin-dependent acute leukemias, including the >45% of AML patients that are believed to have menin-dependent disease.

Poster Presentation Details

Details for the upcoming presentations are as follows:

Anti-tumor activity of irreversible menin inhibitor, BMF-219, in high-grade B-cell lymphoma and multiple myeloma preclinical models (Abstract #1205)

Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Targets and Pathways
Session Date and Time: Tuesday, April 12, 2022 9:00 AM – 12:30 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 24
Poster Board Number: 23
Permanent Abstract Number: 2654

Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors (Abstract #1202)

Session Category: Experimental and Molecular Therapeutics
Session Title: Signaling Pathway Inhibitors
Session Date and Time: Tuesday, April 12, 2022 9:00 AM – 12:30 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 25
Poster Board Number: 8
Permanent Abstract Number: 2665

COVALENT-101: ​A Phase 1 study of BMF-219, a novel oral irreversible menin inhibitor, as a single agent in patients with relapsed/refractory (R/R) acute lymphocytic/acute myeloid leukemia (ALL/AML), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM) (NCT05153330)​ (Abstract #7613)

Session Category: Clinical Trials
Session Title: Phase I Trials in Progress 1
Session Date and Time: Tuesday, April 12, 2022 9:00 AM – 12:30 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 34
Poster Board Number: 10
Permanent Abstract Number: CT210

C4 Therapeutics Presents Clinical Data from Cohort A of the Ongoing Phase 1/2 Clinical Trial of CFT7455, a Novel IKZF1/3 Degrader

On April 8, 2022 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported that data from Cohort A of its ongoing Phase 1/2 clinical trial of CFT7455, a novel degrader targeting IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL) (Press release, C4 Therapeutics, APR 8, 2022, View Source [SID1234611676]). The data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on Tuesday, April 12, 2022, at 9 AM CT by Sagar Lonial, M.D., FACP.

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"The early clinical data from the ongoing Phase 1/2 trial demonstrates that CFT7455’s differentiated pre-clinical profile, including enhanced PK and increased activity, has translated to the clinical setting," said Dr. Sagar Lonial, professor and chair, department of hematology and medical oncology, Winship Cancer Institute, Emory University. "Single agent CFT7455 has demonstrated preliminary evidence of clinical activity in a population of highly refractory and heavily pre-treated multiple myeloma patients. We continue to enroll patients in the ongoing clinical trial with the goal of providing a new treatment option for myeloma and lymphoma patients."

"We are encouraged by the early clinical observations and the potential of CFT7455 to be a next-generation therapy to treat multiple myeloma and non-Hodgkin’s lymphomas," said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. "We believe this initial data highlights the ability of our TORPEDO platform to develop highly potent and selective degraders that have the potential to demonstrate deep and durable degradation of intended targets in the clinical setting. We will leverage the unique properties of CFT7455 to optimize its schedule and increase the therapeutic index as we progress to a recommended Phase 2 dose."

CFT7455 Phase 1/2 Clinical Trial
C4T designed CFT7455 to be highly potent and selective against its intended targets, IKZF1/3. The Phase 1/2 trial is designed to primarily investigate safety, tolerability, and anti-tumor activity. Secondary and exploratory objectives are to characterize the PK and pharmacodynamic profile of CFT7455. The Phase 1 portion of the study explores CFT7455 as a single agent in patients with relapsed or refractory (RR) MM and NHL, as well as in combination with dexamethasone in patients with RRMM. Following identification of a recommended dose(s) and schedule(s), the Phase 2 portion of the trial is expected to expand to the following four investigational arms: (1) in RRMM, single agent CFT7455; (2) in RRMM, CFT7455 combined with dexamethasone; (3) in peripheral T-cell lymphoma, single agent CFT7455; and (4) in mantle cell lymphoma, single agent CFT7455.

Cohort A, the first cohort in the clinical trial, explored CFT7455 as a single agent and enrolled five patients with MM. All patients in Cohort A were highly refractory and heavily pre-treated, having received a median of five prior lines of therapy (range of 4-14), including both lenalidomide and pomalidomide. The starting dose in the trial was 50 μg and all patients in Cohort A received single agent CFT7455 for 21 days of the 28-day treatment cycle. The data cut-off date was January 14, 2022. At the time of this data cut-off, two patients remained on therapy; however, these patients have since discontinued treatment.

Summary of Data from Cohort A:

Safety

Four patients received single agent CFT7455 at the starting dose of 50 μg per day. Two of these patients were dose reduced to 25 μg per day due to neutropenia, a known on-target toxicity associated with IKZF1/3 degraders.
The fifth patient enrolled at a starting dose of 25 μg per day based on the recommendation of the safety review committee.
Two dose-limiting toxicities (DLTs) were observed at the 50 μg per day starting dose, both consistent with on-target activity:
Grade 4 neutropenia lasting more than 5 days
A delay (more than 7 days) in initiating treatment in Cycle 2, in the setting of persistent Grade 3 neutropenia
No patient experiencing neutropenia had a concurrent infection or fever.
There were no serious adverse events reported and no adverse events resulted in death or treatment discontinuation.
Pharmacokinetics and Pharmacodynamics

CFT7455 was rapidly absorbed, with a plasma half-life of approximately two days. Accumulation of drug was observed up to four-fold by day 15 and achieved exposures at 50 μg that were equivalent to predicted highly active exposures based on pre-clinical studies.
CFT7455 demonstrated deep and durable degradation of IKZF1/3, as quantified by mass spectrometry, throughout Cycle 1.
Efficacy

Responsiveness was measured based on International Myeloma Working Group (IMWG) criteria.
Three patients had best observed reductions in the difference of serum free light chain (dFLC) ranging from 41 percent to 78 percent. One patient had an increase of 56 percent in dFLC.
The patient who achieved a 78 percent reduction in dFLC did not achieve a partial response under IMWG criteria due to the presence of measurable plasmacytomas, which were assessed as stable.
Three patients had a best response of stable disease. Two patients had a best response of progressive disease.
Next Steps for CFT7455
C4T has completed modeling of the Cohort A data and believes alternative dosing regimens are expected to increase the therapeutic index by allowing time for adequate neutrophil maturation during the days off drug, with limited impact on efficacy. Patients are enrolling in Cohort B1, exploring CFT7455 as a monotherapy for RRMM, and Cohort C, exploring CFT7455 as a monotherapy for NHL. Cohorts B1 and C have a starting dose of 25 μg per day at an alternative dosing schedule. Each cohort will proceed with dose finding in parallel, with the goal of achieving a recommended Phase 2 dose in each of MM and NHL.

Investor Webcast Information
C4T will host an investor webcast today, Friday, April 8, 2022, at 2 PM ET, with Sagar Lonial, M.D., FACP to discuss the CFT7455 clinical data being presented at AACR (Free AACR Whitepaper). To access the call, please dial 866-374-5140 or 404-400-0571 and provide the conference ID: 66856580. The webcast can be also accessed under "Events & Presentations" in the Investors section of the company’s website at www.c4therapeutics.com. A replay of the webcast will be available on C4T’s website for 30 days following the event.

Imvax Presents New Data on Tumor-Derived Immunotherapies in Glioblastoma, Other Solid Tumors at AACR Annual Meeting 2022

On April 8, 2022 Imvax, Inc., a clinical-stage biotechnology company developing personalized, whole tumor-derived immunotherapies, reported that data on the activity of the company’s tumor-derived immunotherapies in glioblastoma and other solid tumors at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 in New Orleans, La (Press release, Imvax, APR 8, 2022, View Source;utm_medium=rss&utm_campaign=imvax-presents-new-data-on-tumor-derived-immunotherapies-in-glioblastoma-other-solid-tumors-at-aacr-annual-meeting-2022 [SID1234611673]).

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"Imvax has developed a unique tumor-derived immunotherapy approach that we believe has potential to extend the promising results seen with cell-based therapies in blood cancers to the more challenging category of solid tumors. The data we are presenting at AACR (Free AACR Whitepaper) validates the transformative potential of our immunotherapeutic platform to multiple types of solid tumors," said John P. Furey, Chief Executive Officer. "We are eager to continue to advance programs in gynecological, liver, and other cancers, as well as to initiate our Phase 2b clinical trial in our lead indication, glioblastoma, later this year."

Platform applicability to solid tumors

Preclinical findings presented at the meeting support the applicability of Imvax’s platform to hepatocellular carcinoma and ovarian and other gynecological cancers. Utilizing murine models of those solid tumor types, researchers assessed survival and tumor burden of mice that underwent a tumor challenge after being pre-treated with Imvax’s tumor-derived combination therapy, consisting of tumor cells dosed with IMV-001, the company’s proprietary antisense component, and enclosed in a biodiffusion chamber (BDC). Control groups for each study were treated with saline filled BDCs. In all arms of the study, the BDCs were removed 48 hours after implantation, and the tumor challenge was then conducted 26 days later.

In the ovarian cancer model, 60% of IOV-001-treated mice were alive 58 days post-tumor challenge, compared to only 19% of mice in the control group (p=0.004). Circulating IFNγ was significantly higher in IOV-001-treated mice compared to controls on day 1 post-tumor challenge (p<0.001).

In the hepatocellular carcinoma model, 50% of IHV-001-treated mice were alive by 100 days post-tumor challenge; there were no survivors in the saline group beyond day 28 (p=0.004). Most of the long-term survivors had undetectable levels of tumors. At day 14 after tumor challenge, circulating IFNγ trended higher in mice treated with IHV-001, and PD1+ expression in both CD4+ and CD8+ T cell subsets was significantly lower (p=0.002) in those mice that would survive long-term.

Predictive model of glioblastoma patient response

Additional data presented at AACR (Free AACR Whitepaper) detail the creation of a predictive model of patient response to IGV-001 based on serum profiling. The model was created utilizing data from the Phase 1b study of Imvax’s IGV-001 product candidate. That study had previously reported a median progression-free survival of 17.1 months in newly diagnosed glioblastoma patients in the highest dose cohort treated with IGV-001, compared with 6.5 months in historical standard-of-care-treated patients (P=0.0025) (Andrews et al., Clin Can Res 2021).

Inputs to the model included serum profiles of a number of cytokines as well as the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. An overall survival cutoff point of 21.9 months was used to dichotomize ‘good’ versus ‘poor’ outcomes. Utilizing a training subset of 10 patients, a classification decision tree was created. Applying this trained model on the full dataset (n=33) resulted in 93.9% correct classification of patients’ actual clinical outcomes. GBM-associated cytokines IL-8, IL-5, IL-6, and IL-13 were found to be key immune-correlates of patient outcomes. As these cytokines are known to correlate with tumor burden or prognosis, this observation further validated the utility of the model.

Imvax expects to utilize data from the upcoming Phase 2b trial of IGV-001 to further bolster the model’s predictive capabilities with the objective of identifying patient populations most likely to benefit from IGV-001 immunotherapy.

Tempest Presents Promising Preclinical Data on Two Oncology Programs at the 2022 AACR Annual Meeting

On April 8, 2022 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing potentially first-in-class therapeutics that combine both targeted and immune-mediated mechanisms, reported the presentation of two poster presentations at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting reporting new preclinical data that support the company’s preclinical TREX1 and clinical TPST-1495 programs (Press release, Tempest Therapeutics, APR 8, 2022, View Source [SID1234611671]).

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The first presentation reports on new preclinical data that support TPST-1495, a novel agent designed to specifically block the cancer-promoting EP2 and EP4 prostaglandin E2 (PGE2) receptors, further differentiating TPST-1495 from other approaches targeting the PGE2 pathway. The second presentation reports on proprietary inhibitors of TREX1, a cytosolic DNA exonuclease that inhibits activation of cGAS/STING in tumor and immune cells.

"As part of our diversified pipeline of innovative therapeutics, we reported the first preclinical data from our TREX1 program demonstrating the significant anti-tumor activity of our selective inhibitors. We believe TREX1 is the most promising approach to selectively activate the STING pathway broadly in metastatic disease with systemically administered, small molecule drugs," said Tom Dubensky, Ph.D., president of Tempest. "In addition, we presented preclinical data demonstrating that selective dual antagonism of both EP2 and EP4 prostaglandin receptors with TPST-1495 is a significantly superior approach to provide therapeutic anti-tumor benefit and activate human immune cell populations in vitro, as compared to either single EP2 and EP4 antagonists or NSAIDs. These data support the enthusiasm for our ongoing Phase 1 monotherapy and combination dose escalation and optimization study."

#1333: "Dual Blockade of the EP2 and EP4 PGE2 Receptors with TPST-1495 is an Optimal Approach for Drugging the Prostaglandin Pathway"

In vivo data demonstrated that monotherapy TPST-1495 significantly reduced tumor growth in mice via both T cell-independent and T-cell dependent mechanisms. The anti-tumor effect correlated with direct anti-proliferative effects on tumors in addition to increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and other anti-tumor myeloid and adaptive immune cell populations. Demonstrating its differentiated potency, therapy with TPST-1495 resulted in a significant survival advantage as compared to therapy with single EP2 or EP4 antagonists, or the NSAID celecoxib, in the APCmin/+ spontaneous colorectal cancer tumor mouse model. Additional data demonstrated that the administration of TPST-1495 resulted in near-complete restoration of immune function in human immune cell assays, reversing prostaglandin-mediated suppression of lipopolysaccharide stimulation-induced TNF-α production, even in the presence of elevated PGE2 concentrations in which single EP4 or EP2 inhibitors were not effective.

#2075: "Systemic Small Molecule TREX1 Inhibitors to Selectively Activate STING in the TME of Metastatic Disease"

The inaugural presentation for the TREX1 program summarized the approach to develop selective TREX1 inhibitor small molecules with picomolar potency. TREX1 inhibitors were profiled in various human and mouse cell-based assays, demonstrating that inhibition of TREX1 nuclease activity resulted in increased cGAS/STING pathway signaling and production of a reporter or interferon β. The anti-tumor activity of TREX1 inhibitors was evaluated in mice given sub-therapeutic doses of doxorubicin to effect double-stranded breaks in tumor cell DNA and induce the production of TREX1, resulting in significant anti-tumor efficacy and survival.

About TPST-1495

TPST-1495 is an orally available small molecule designed to block the cancer-promoting EP2 and EP4 receptors in the prostaglandin (PGE2) pathway, while sparing the homologous but differentially active EP1 and EP3 receptors. PGE2 signaling through EP2 and EP4 has been observed to enhance tumor progression through the stimulation of tumor proliferation, enhanced angiogenesis and suppression of immune function in the tumor microenvironment. Tempest has conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP2 and EP4 and observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro, as well as significantly increased anti-tumor activity in mouse models of human colorectal cancer. Tempest is currently evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and possible anti-tumor activity of monotherapy and combination therapy TPST-1495 in a multicenter Phase 1a/1b dose and schedule optimization study in subjects with advanced solid tumors, with the potential to expand in indications known to be prostaglandin-driven, including colorectal cancer, or CRC, and in a tumor indication-agnostic, biomarker-selected cohort.

About TREX1

Genetic evidence from human disease and mouse genetic knock-out studies identify the Stimulator of Interferon Genes (STING) pathway as a critical innate immune sensor for the development of immunity. Tumor cells can evolve to avoid immune recognition through inactivating the STING pathway by diverse mechanisms, indicating that it is important to generating tumor-specific immunity. Selective activation of the STING pathway may be achieved through targeted inhibition of TREX1, a cytosolic DNA exonuclease that modulates cGAS/STING signaling, which is overexpressed in tumor cells. Tempest is developing TREX-1 inhibitors with oral pharmacokinetics. In vitro and in vivo studies have shown that the company’s compounds enhance the activation of the STING pathway in DNA-stimulated human and mouse cells. Furthermore, preclinical results in several tumor models have shown synergies of its TREX-1 compounds with low doses of doxorubicin, demonstrating significant therapeutic anti-tumor efficacy and survival.