On April 17, 2023 Presage Biosciences, a pioneer in translational oncology whose mission is understanding the complexity of drug response in the tumor microenvironment (TME), reported that it will present at the Immunology, TME Minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting (Press release, Presage Biosciences, APR 17, 2023, View Source;core-civo-technology-reveals-unexpected-effects-of-an-investigational-ubiquitination-inhibitor-on-checkpoint-blockade-301798045.html [SID1234630194]). In an independent study, Presage’s innovative multiplexed trackable microdosing platform (CIVO) was used to introduce an investigational ubiquitin inhibitor (TAK-243) alone and in combination with anti-PD1. The resulting data demonstrated that TAK-243 has potential to increase anti-tumor immunogenicity and prime tumors for response to immune checkpoint inhibition.

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The Session (MS.IM01.03 – Immune Checkpoints at Tumor Beds, #3476) is titled "TAK-243 increases tumor immunogenicity enhancing systemic anti-tumor immune response and tumor regression in combination with immune checkpoint inhibition in a syngeneic model of lymphoma" and will be presented live on April 17, 2023 from 3:52pm-4:07pm EST.

"We are excited to showcase these novel findings on the TME and how we have paired CIVO with sophisticated spatial profiling to translate preclinical findings to human disease" said Richard Klinghoffer, Presage’s Chief Executive Officer. "We continue our work with fellow innovators in oncology to deliver key translational data early in the clinical development process."

After AACR (Free AACR Whitepaper) 2023, Presage Biosciences’ CIVO technology will be further showcased at two events:

The 4th Annual International Phase-0/Microdosing Stakeholder Meeting in Boston, MA on April 24th. Presage is featured speaker, panel moderator and sponsor at this year’s event;
Life Science Innovation Northwest (LSINW) in Seattle, WA on April 25. LSINW is the Pacific Northwest’s largest annual life science conference.
About CIVO

Comparative In Vivo Oncology (CIVO) is Presage’s patented platform that enables multiplexed intratumoral microdosing and generation of deep spatial biology insights. Presage’s CIVO technology and analysis capabilities are unparalleled at providing insight into drug-exposed areas of the intact tumor microenvironment. Presage is pairing the use of CIVO with molecular profiling technologies in both preclinical and Phase 0 trials in order to inform and de-risk oncology drug development.

On April 17, 2023 Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) ("Corbus" or the "Company"), a precision oncology company, reported details of new pre-clinical data on CRB-601, its avβ8 blocking antibody, presented as a poster at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, held April 14-19, 2023 in Orlando, FL (Press release, Corbus Pharmaceuticals, APR 17, 2023, View Source [SID1234630193]).

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The poster titled "CRB-601, an avβ8 blocking antibody, prevents activation of TGFβ and exhibits anti-tumor activity associated with immune cell remodeling of the tumor microenvironment" explores the relationship between CRB-601 antitumor activity, PK and its binding to the αvβ8 receptor in the tumor. In addition, the impact on TGFβ pathway signaling and tumor immune cell population are also presented. Tumor growth was evaluated in mice bearing orthotopically implanted murine breast cancer EMT6 or colon cancer MC38 and treated with CRB-601.

CRB-601 exhibited dose dependent tumor growth inhibition (TGI) in the EMT6 tumor model which was significantly augmented in combination with anti-PD1 therapy. These effects were associated with changes in tumor micro-environment (TME) immune cell populations with marked increases in infiltrating T cells, NK cells and M1 polarized macrophages. Efficacy correlated with cell surface αvβ8 occupancy by CRB-601. CRB-601 treatment downregulated phosphorylation of SMAD proteins pSMAD2 and pSMAD3, consistent with blockade of the canonical TGFβ signaling pathway.

Rachael Brake, PhD, Chief Scientific Officer of Corbus stated: "We are building on our early efficacy. We can now demonstrate that CRB-601 has robust anti-tumor activity alone and as a combination partner with anti-PD-1 and that these effects are associated with documented receptor engagement, a reduction of TGFb1 levels in the tumor micro-environment (TME), and inhibition of downstream canonical TGFb signaling. Together this data reinforces the potential of this new approach in blocking activation of TGFb locally in the TME."

On April 17, 2023 Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory disease, reported data presentations on two first-in-class programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting held in Orlando, Florida, on April 14–19, 2023 (Press release, BioTheryX, APR 17, 2023, View Source [SID1234630192]). The presentations highlight preclinical data for bifunctional degraders of cyclin-dependent kinase (CDK) 4/6 for the treatment of solid tumors, and bifunctional degraders of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers. Additionally, the Company has nominated BTX-9341 as a development candidate for the CDK4/6 degrader program and has commenced IND-enabling studies.

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"Biotheryx is advancing first-in-class bifunctional degraders developed through our PRODEGY platform to overcome common resistance mechanisms to existing inhibitors and provide differentiated treatment possibilities for people facing cancer," said Philippe Drouet, President and Chief Executive Officer of Biotheryx. "At AACR (Free AACR Whitepaper), we are proud to share encouraging preclinical data that highlights the potential of these exciting programs. BTX-9341, our oral CDK4/6 development candidate, has demonstrated superior efficacy in preclinical models of ER+/HER2- breast cancer when compared to CDK4/6 inhibitors, superior blood-brain-barrier penetration while importantly also showing the ability to be effective in models resistant to existing CDK4/6 inhibitors. Similarly, in preclinical KRAS mutant cancer models, our SOS1 degraders resulted in greater than 90% degradation of SOS1 in tumors and led to significant tumor growth inhibition."

AACR 2023 Presentation Details:

Title: Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer and triple negative breast cancer
Presenter: Hannah Majeski, Ph.D., Principal Scientist – Biology
Abstract #: 1553
Session: Cell Cycle/Cell Proliferation Inhibitors for Cancer Therapy
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET

Highlights:

CDK4/6 inhibitors are used to treat estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer, but some patients have exhibited innate resistance, and many are shown to develop acquired resistance after three years on therapy.
Biotheryx’s CDK4/6 bifunctional degraders demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation. This potency was shown to be superior to CDK4/6 inhibitors and due to Cereblon-mediated target degradation.
CDK4/6 bifunctional degraders were active in a CDK4/6 inhibitor resistant cell line and in multiple PDX CDK4/6 inhibitor resistant organoid models.
CDK4/6 bifunctional degraders exhibited good tumor exposure when dosed orally, and induced a dose-dependent reduction in CDK4, CDK6, and pRB levels in MCF7 xenograft tumors. This resulted in dose dependent tumor growth inhibition and superior efficacy compared to CDK4/6 inhibitors.
These degraders have also shown blood brain barrier penetration and superior inhibition of tumor growth in an MCF7 intracranial mouse model compared to a CDK4/6 inhibitor.
The combination of the enhanced efficacy, activity in resistant cell lines and blood brain barrier penetration demonstrate the potential for CDK4/6 degraders in a range of potential cancer indications.
Title: Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers
Presenter: Kyle Begovich, Ph.D., Senior Scientist – Biology
Abstract #: 1578
Session: New Therapeutic Targeted Agents
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET

Highlights:

KRAS is the most frequently mutated cancer-causing oncogene and is mutated in over 20% of all human cancers, including an estimated 90% of pancreatic tumors and 45% of colorectal tumors. Combinational therapeutic approaches are needed to avoid drug resistance in the treatment of KRAS mutant cancers, such as coupling KRAS inhibition with a blockade of its guanine exchange factor (GEF), SOS1, to keep KRAS in its inactive state as well as prevent upstream pathway reactivation.
Biotheryx SOS1 degraders demonstrated antiproliferative effects across a range of KRAS-mutated cell lines. Consistent with this notion, treatment with SOS1 degraders in KRAS-mutant xenograft models resulted in greater than 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent.

SOS1 degraders also exhibited synergistic effects with other RAS/MAPK inhibitors in in vitro studies as well as KRAS-mutant xenograft models.

These data support the potential of SOS1 degradation as a valuable treatment option for a range of KRAS mutant cancers.

Following the presentations at the meeting, PDF copies of the presentations and posters will be available in the "Publications and Presentations" section of Biotheryx’s website.

On April 17, 2023 Convergent Therapeutics Inc., a clinical-stage biotechnology company, reported the details of a plenary presentation of a dose-escalation study evaluating the efficacy and safety of its lead asset, CONV01-α (225Ac−J591), a prostate-specific membrane antigen (PSMA)-targeted monoclonal antibody linked to actinium-225 (225Ac) (Press release, Convergent Therapeutics, APR 17, 2023, View Source [SID1234630191]). The plenary talk will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando on Monday, April 17 by Jones T. Nauseef (M.D., Ph.D.), an Assistant Professor of Medicine in the Division of Hematology & Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and a genitourinary medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. The title of the presentation is "Phase I dose-escalation study of fractionated dose 225Ac-J591 for metastatic castration resistant prostate cancer."

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This presentation will focus on safety and efficacy data from a Weill Cornell Medicine-sponsored phase I/II dose-escalation study (NCT04506567) in patients with metastatic castration resistant prostate cancer. Across the 23 patients evaluable for response via prostate specific antigen (PSA), a fractionated dose-intense regimen of CONV01-α (225Ac−J591) demonstrated safety and notable activity. 96% of patients showed a decline in PSA levels, 70% of patients had a best PSA decline of ≥50%, and 26% of patients had a best PSA decline of ≥90%. The most common hematologic adverse events were thrombocytopenia, neutropenia, and anemia. The most common non-hematologic adverse events observed were low grade (Gr 1-2) fatigue, pain flare, xerostomia, and elevated AST.

"We are pleased by the results of this cohort of our study of fractionated dose 225Ac-J591 that demonstrated few high-grade attributable adverse events," said Dr. Nauseef. "Reductions in PSA as well as CTC responses demonstrate promising preliminary evidence of efficacy. We are excited by the potential of 225Ac-J591 for treatment of patients with metastatic castration resistant prostate cancer."

"These critical results are an important confirmation of the major activity and safety profile of CONV01-α (225Ac−J591)," said Dr. Philip Kantoff, CEO of Convergent Therapeutics. "We are continuing to advance CONV01-α (225Ac−J591) as an impactful therapeutic to fill an unmet need in prostate cancer."

On April 17, 2023 Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported the first preclinical data from its lead compound FX-909, a novel, small molecule peroxisome proliferator-activated receptor gamma (PPARG) inhibitor to potentially treat patients with advanced urothelial cancer (UC), in an oral presentation and poster format at the AACR (Free AACR Whitepaper) Annual Meeting being held in Orlando, FL from April 14-19, 2023 (Press release, Flare Therapeutics, APR 17, 2023, View Source [SID1234630190]).

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"These initial findings suggest that FX-909 could become a backbone therapy for patient populations harboring the luminal subtype of UC, much like ER therapies in the luminal subtype of breast cancer," said Rob Sims, Ph.D., Chief Scientific Officer and Co-founder of Flare. "We are eager to continue advancing FX-909, which will be further evaluated in a Phase 1 trial that will begin later in the year. This will be a milestone moment for Flare, as we are the first company slated to enter the clinic with a small molecule inhibitor targeting the PPARG transcription factor for advanced UC."

Flare is building a pipeline of potentially first-in-class therapies against genetically validated transcription factor targets, initially focused on cancer. Although challenging to drug, elusive transcription factors remain high-value targets across numerous disease categories, most notably oncology. Treatments that target cell lineage have become mainstay therapies in breast and prostate cancer, through the successful inhibition of the estrogen receptor (ER) and androgen receptor (AR) transcription factors. Similar to ER and AR, PPARG drives luminal cell identity and accounts for two thirds of all advanced UC, highlighting its potential as a therapeutic target.

The oral presentation, titled, "Discovery of FX-909, a first-in-class inverse agonist of the peroxisome proliferator-activated receptor gamma (PPARG) lineage transcription factor, to potentially treat patients with the luminal subtype of advanced urothelial cancer (UC)," shows that administration of FX-909 elicited durable tumor regressions in animal models of UC. The projected human starting dose of 50 mg/kg is also anticipated to be pharmacologically active.

Additional key takeaways are as follows:

FX-909 is a highly selective and potent covalent small molecule inhibitor of PPARG (cellular EC50, 1 nM), showing >2000-fold selectivity for PPARG over PPARA/PPARD (related transcription factors) – acting through a mechanism that promotes a repressive conformation of PPARG.
FX-909 inhibited cell growth in UC cell lines with activated PPARG signaling but had no effect on cell lines without activated PPARG.
FX-909 administered orally twice a day caused tumor regression in PPARG-amplified and RXRA-mutant UC xenograft models at 1 mg/kg doses, and tumor eradication at 3 mg/kg doses.
FX-909 demonstrated predictable, on-target and reversible pharmacology in normal tissues at supra-pharmacologic doses, mimicking PPARG loss-of-function mutations with notable remodeling in adipose tissue and the normal urothelium.
The poster presentation titled, "Development of a surrogate tissue pharmacodynamic (PD) assay for potential clinical use with FX-909, a novel inhibitor of the urothelial luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG)," outlines the FX-909-dose dependent expression of PPARG target genes as markers of PD response in tumor, adipose and skin tissue from mouse xenograft, and normal rat and normal human skin preclinical models.

"Based on our observation of the consistent correlation of PPARG target gene expression patterns in tumor and normal tissues, we have elected to develop a normal skin PD biomarker assay to support early assessment of FX-909 biological activity in our Phase 1 study," said Michaela Bowden, Ph.D., Chief Development Officer of Flare. "These findings reinforce the importance of uncovering valuable translational insights and applying them to further guide our drug development process, potentially enabling us to reduce the burden of repeated, invasive tumor biopsy collections for patients with late-stage cancer by offering surrogate skin biopsies as a viable alternative."

Additional key takeaways are as follows:

In a rat pharmacology study, 30% of all genes that responded to FX-909 treatment in skin displayed a similar dose-dependent response profile in fat.

PPARG target genes including FABP4/Fabp4, AGT/Agt, IVT/Ivd and ARG1/Arg1 are repressed across different species and/or tissues, exemplified by dose-dependent suppression of FABP4/Fabp4 (a target gene for PPARG) and showing a strong correlation (r=0.98, p value=0.003) between tumor and skin tissues.
Skin explant models bridge the interspecies translational gap for studying FX-909-mediated effects, where preliminary evidence shows on-target regulation of genes involved in known PPARG-mediated processes.

About Urothelial Cancer

Bladder cancer is the third most common cancer in men in the United States alone. Each year, there are more than 83,000 new cases diagnosed among men and women, and about 25% of those cases are classified as muscle-invasive UC. This disease has high rates of recurrence and the five-year survival rate is approximately 15% in metastatic cases. The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC cases. Recurrent genetic alterations in PPARG, including focal amplification, missense mutations, and fusions, as well as hotspot mutations in its binding partner, retinoid X receptor alpha (RXRA) are characteristic of this molecular subtype.