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.

On April 17, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported the final analysis results of ORIENT-16, the Phase 3 study evaluating sintilimab in combination with chemotherapy compared to chemotherapy for the first-line treatment of advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Abstract CT078) (Press release, Innovent Biologics, APR 17, 2023, View Source [SID1234630189]).

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As of data cutoff date (September 2, 2022), a total of 650 patients were randomly assigned and received treatment, and the median follow-up was 33.9 months.

Sintilimab in combination with chemotherapy continuously demonstrated superior overall survival (OS) compared to placebo plus chemotherapy with a 41.3% reduction in the risk of death (HR 0.587 [95% CI: 0.467, 0.738]; P<0.0001) and a 6.3-month improvement in median OS (19.2 months vs. 12.9 months) in patients with CPS ≥5, and 31.9% reduction in the risk of death (HR 0.681 [95% CI: 0.571, 0.812]; P<0.0001）and a 2.9-month improvement in mOS (15.2 months vs. 12.3 months) in all randomized patients.
In all randomized patients, the estimated OS rates at 2-year and 3-year for sintilimab plus chemotherapy vs chemotherapy were 37.6% vs 20.6% and 26.0% vs 10.7%, respectively. In patients with CPS≥5, the estimated OS rates at 2-year and 3-year for sintilimab plus chemotherapy vs chemotherapy were 43.6% vs 22.0% and 29.0% vs 10.7%, respectively. In addition, OS benefits were consistent in all prespecified subgroup analyses.
The safety profile of this final analysis was consistent with that observed in previously reported interim analysis, and no additional safety signals were identified with additional 15-month follow-up.
The principal investigator of the ORIENT-16 study, Prof. Jianming Xu from the Fifth Medical Center of People’s Liberation Army General Hospital, stated, "ORIENT-16 is the first phase 3 trial in China to demonstrate a significant overall survival benefit in patients with advanced G/GEJ cancer treated with anti-PD-1 antibody plus chemotherapy in first line setting. Sintilimab has been approved by National Medical Products Administration (NMPA) in China as the first line treatment for patients with advanced G/GEJ adenocarcinoma and this new indication has been included in the updated National Reimbursement Drug List (2022 Version), making it the first and only PD-1 inhibitor for gastric cancer included in the NRDL. This final analysis showed OS benefit of sintilimab plus chemotherapy was more evident in overall population and in patients with CPS ≥5 compared with that of interim analysis, further confirming sintilimab plus chemotharapy as a standard of care of first line treatment for G/GEJ adenocarcinoma. Gastric cancer is one of the most common malignant tumor types globally and nearly half of all cases are diagnosed in China[i]. Advanced gastric cancer generally has very poor prognosis with high unmet medical need. Approval and inclusion into the updated NRDL of sintilimab plus chemotherapy as first line standard of care for G/GEJ adenocarcinoma has bring an important new treatment option to patients with G/GEJ cancer."

Dr. Zhou Hui, Senior Vice President of Innovent, stated, "The treatment options for advanced G/GEJ cancer are relatively limited and the ORIENT-16 study aimed to address this urgent unmet medical need. Both interim and final analysis results have consistently demonstrated the significant clinical benefit of sintilimab plus chemotherapy as first-line treatment of advanced G/GEJ cancer. And we hope to enhance the accessibility of this novel immunotherapy to benefit a wider group of cancer patients. We are grateful for all the contributions made by every investigator and patient in this study. We are thrilled to share this news with the medical community and look forward to continuing our efforts to bring this innovative treatment option to market and improve outcomes for more patients with gastric cancer. Up until now, sintilimab has demonstrated improved survival in the first-line treatment of five major types of cancer – non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer. Thanks to that, sintilimab has become the only PD-1 inhibitor for the first-line treatment of five high-incidence cancer types in the NRDL."

About the ORIENT-16 Study

ORIENT-16 is a randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy, compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (ClinicalTrials.gov, NCT03745170). The primary endpoint was overall survival, in all randomized and in PD-L1 positive patients.

About Gastric Cancer

Gastric cancer is one of the most common malignant tumor types worldwide. According to GLOBOCAN estimates, there were approximately one million new cases and 769,000 new deaths of gastric cancer in 2020, making it the fifth most common cancer and third leading cause of cancer death globallyi[ii]. About half of all gastric cancer cases occurred in East Asia, mainly in Chinai. The first-line treatment of advanced gastric cancer remains limited. Currently, the 5-year survival rate of advanced or metastatic gastric cancer ranges from 5 to 20 percent. The median survival was about 1 year for patients who received chemotherapy only[iii][iv].

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells[v]. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved and included in the National Reimbursement Drug List (NRDL) for all six indications. The updated NRDL reimbursement scope of TYVYT (sintilimab injection) include:

For the treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
For the treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
For the treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
For the treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
For the treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
For the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy.
Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-TKI failed EGFR-mutated non-squamous NSCLC under review in the China’s NMPA.

Additionally, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.