On April 8, 2022 Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) ("Corbus" or the "Company"), an immunology company, reported the first preclinical data for CRB-601 are being presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held from April 8-13, 2022, in New Orleans, LA (Press release, Corbus Pharmaceuticals , APR 8, 2022, View Source [SID1234611799]). CRB-601 is a potent and selective αvb8 integrin monoclonal antibody designed to block the activation of TGFb in the local tumor microenvironment. TGFb is thought to be the only ligand of the αvb8 integrin. Inhibiting its ability to bind to αvb8 could therefore play an important role in the regulation of this pleiotropic cytokine. The in vitro preclinical data presented demonstrate the high affinity of CRB-601 for αvb8 and the resulting effect on TGFb. The data also show significant inhibition of tumor growth in a syngeneic model of colon cancer (MC38) by CRB-601, both as a single agent and in combination with anti PD-1 treatment. These effects are supported by the coincident increase in CD8-positive T cells in the tumor microenvironment.

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"The increase of tumor infiltration by T-cells stimulated by CRB-601 is quite exciting. The effects of CRB-601 are consistent with the proposed mechanism of blocking TGFb activation, which can potentially enable an anti-tumor immune response and be an effective adjunct to immune checkpoint therapies. We are excited to bring this mechanism of action to the clinic and define the potential benefit it could bring to patients," commented Rachael Brake, Ph.D., Chief Scientific Officer of Corbus.

Corbus is currently developing CRB-601 as a potential treatment for solid tumor cancers, and the program is advancing toward an IND submission in the first half of 2023.

The AACR (Free AACR Whitepaper) poster is available on the Company’s website at: www.corbuspharma.com/AACRposter

Additionally, Corbus has published an updated Corporate Presentation providing an overview of the Company’s full portfolio on its website at: ir.corbuspharma.com/presentations

On April 8, 2022 Iterion Therapeutics, Inc., a venture-backed, clinical-stage biotechnology company developing novel cancer therapeutics, reported that three posters involving research into tegavivint will be presented at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, including initial results from a Phase 1 study of tegavivint in patients with desmoid sarcomas (Press release, Iterion Therapeutics, APR 8, 2022, View Source [SID1234611796]). AACR (Free AACR Whitepaper) 2022 is being held April 8-13, 2022, in New Orleans.

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Tegavivint is a potent and selective first-in-class small molecule inhibitor of Transducin Beta-like Protein One (TBL1), a novel downstream co-factor in the Wnt/beta-catenin signaling pathway. Increased expression beta-catenin and TBL1 are associated with metastasis and poor prognosis in a broad range of tumor types. Tegavivint’s targeting of TBL1 prevents TBL1/beta-catenin complex formation, specifically inhibiting beta-catenin’s oncogenic transcriptional activity without disrupting key cell membrane functions that have been linked to toxicity common to other drugs in this pathway.

The first poster, titled, "A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors," will be presented on Tuesday, April 12, 2022, at 9:00 a.m., CDT, during the Phase I Clinical Trials 2 session (poster board number 10; abstract number CT185). The poster details results from the dose-escalation portion of a Phase 1 trial of tegavivint in adult patients with progressive, unresectable desmoid sarcoma. The primary objective of the study was to evaluate the safety and tolerability of tegavivint administered once weekly and to determine a recommended phase 2 dose (RP2D). As described in the poster, tegavivint was well tolerated with grade 3 treatment related adverse events (TRAEs) reported in four patients for hypophosphatemia, stomatitis, headache, and elevated ALT; no grade 4 or 5 TRAEs were observed. No dose-limiting toxicities (DLT) were observed, and the maximum tolerated dose (MTD) was not declared. Objective responses (WHO and RECIST) were observed at multiple dose levels and the clinical benefit rate was 82% (n = 14). The RP2D was declared based on lack of DLTs, pharmacologically relevant plasma concentrations, and preliminary efficacy. In conclusion, tegavivint’s preliminary efficacy and favorable safety profile supported continued development through a dose expansion arm of the study, data from which will be presented at a future conference.

"We are very excited to report research describing tegavivint’s unique properties and therapeutic potential in multiple poster presentations at AACR (Free AACR Whitepaper) 2022; particularly the results of our first-in-man Phase 1 clinical study," said Rahul Aras, PhD, CEO of Iterion. "Taken together, these results demonstrate inhibition of TBL1 as a clinically viable strategy to curtail nuclear beta-catenin oncogenic activity in multiple cancer indications."

Dr. Aras continued, "Importantly, results from the dose-escalation part of the Phase 1 study of tegavivint in patients with progressive desmoid sarcomas demonstrated the drug to be well-tolerated and indicated clinical activity in this difficult-to-treat disease. While regarded as a high value oncology target, nuclear beta-catenin has historically been considered undruggable through conventional drug development. Upstream approaches targeting the Wnt/beta-catenin pathway have not clinically advanced, typically because of toxicity in early phase clinical development. However, we believe tegavivint’s ability to selectively disrupt the interaction of beta-catenin and TBL1 results in the specific degradation of nuclear beta-catenin without impacting key cell membrane functions that have been linked to previously reported toxicity. The Phase 1 data presented at AACR (Free AACR Whitepaper) 2022 demonstrate this capability, which we are now further investigating in three separate, ongoing clinical trials of tegavivint in AML, non-small cell lung cancer, and pediatric solid tumors."

The second poster, titled, "Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma," will be presented virtually by Kengo Nakahata, MD, PhD, Postdoctoral Associate, Texas Children’s Hospital on Friday, April 8, 2022, at 12:00 p.m., CDT. The poster reports results from a pre-clinical study examining the influence of tegavivint on the osteosarcoma (OS) tumor immune microenvironment and potential combination with anti-PD1 antibody therapy. Data from the study indicated that tegavivint as a monotherapy significantly suppressed the growth of murine OS tumors (p<0.05), while anti-PD1 monotherapy did not show any significant anti-tumor activity. Combining anti-PD1 with tegavivint was able to further improve overall anti-tumor activity. Tegavivint treatment was also associated with an intratumoral increase in CD8-positive T-cells and NK cells compared with control tumors.

The third poster, titled, "Novel combination therapies against AML with 3q26 lesions and EVI1 overexpression," will be presented virtually by Christine Birdwell, Research Scientist, MD Anderson Cancer Center on Tuesday April 12, 2022, at 9:00 a.m., CDT. The poster describes a study examining the potential for tegavivint as a therapy against AML models harboring 3q26 lesions and EVI1 overexpression. EVI1 overexpression is known to confer poor response to therapy and, subsequently, inferior relapse-free and overall survival in AML. As reported in the poster, in vitro treatment with tegavivint dose-dependently induced apoptosis in AML cell lines and patient-derived AML cells with 3q26.2 lesions with and without monosomy. Furthermore, in vivo studies demonstrated that tegavivint combined with BCL2 inhibitor, venetoclax, significantly reduced AML burden and improved overall survival in mouse models, without toxicity, compared to treatment with each drug alone.

On April 8, 2022 Second Genome, a biotechnology company that leverages its proprietary platform to discover and develop precision therapies and biomarkers, reported data demonstrating the Company’s CXCR3 chemokine receptor modulator, SG-3-06686 (referred to as SG-3-00802DC in the AACR (Free AACR Whitepaper) presentation), enhances effector T cell migration to improve the immune system’s activity against tumors, and showed anti-tumor activity in preclinical models as a monotherapy and in combination with anti-Programmed Death Protein-1 (PD-1) treatment (Press release, Second Genome, APR 8, 2022, View Source [SID1234611794]). The data is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held April 8–13 virtually and in New Orleans, Louisiana.

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"We are excited about our pre-clinical data that show the ability of this potential mechanism to go beyond checkpoint blockade as an emerging new immunologic strategy for treating cancers. Checkpoint inhibitor therapy has been transformative for the clinical outcome of cancer patients and additional new checkpoint targets, such as TIGIT/LAG3, continue to be added to this important treatment approach. However, if the proper immune cells are underrepresented or lacking in the tumor microenvironment, these interventions tend to be less effective, and a significant portion of patients have limited or transient benefit. To augment and improve anti-tumor efficacy, we need to develop new therapeutics to better facilitate the ability of effector cells to access the tumor microenvironment. CXCR3 pathway modulation is a well validated and exciting approach to potentially enhance effector cell recruitment and improve existing immunotherapy interventions," said Joe Dal Porto, Ph.D., Chief Scientific Officer of Second Genome. "We look forward to submitting an investigational new drug (IND) application for SG-3-06686, a potential first in class CXCR3 immune modulator, in early 2023."

This data presentation can be accessed during the online-only poster session at the AACR (Free AACR Whitepaper). The information is provided below:

Session Category: Clinical Research Excluding Trials
Session Title: Immuno-oncology
Abstract Number: 6349
Title: Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the
immune system to enhance anti-tumor immunity

SG-3-06686 is a potent CXCR3 chemokine receptor engager that acts as a positive allosteric modulator to increase receptor activity to the three known ligands (CXCL9/10/11). It has demonstrated to increase the activity of CXCL11 on CXCR3 activation by greater than 10-fold from a nM to a pM range with similar effects on CXCL9 and CXCL10. This activity in turn drives strong antitumor activity in several preclinical cancer models.

The poster (#6349) entitled, "Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the immune system to enhance anti-tumor immunity," will be available for on-demand viewing on the AACR (Free AACR Whitepaper) website and will also be made available on the Company’s website at View Source

On April 8, 2022 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and collaboration partner Redx Pharma (AIM: REDX) reported data showing the pan-RAF kinase inhibitor, JZP815, was active in multiple RAF- and RAS-mutant tumor pre-clinical models, with a pharmacokinetic profile that may provide drug exposure required for target engagement in humans (Press release, Jazz Pharmaceuticals, APR 8, 2022, View Source [SID1234611792]).

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"As a precision pan-RAF inhibitor with a differentiated mechanism of action, JZP815 is a promising drug candidate for several types of difficult-to-treat solid tumors, including colorectal cancer, non-small cell lung cancer, melanoma and ovarian cancer," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "By not inducing paradoxical pathway activation, which can stimulate the growth of certain cancers, JZP815 may offer a significant advancement in the pan-RAF inhibitor class with the potential to address unmet patient need. We look forward to submitting the investigational new drug application for JZP815 this year."

JZP815 targets specific components of the mitogen-activated protein kinase (MAPK) pathway, namely all three RAF proteins – ARAF, BRAF and CRAF – that when activated by oncogenic mutations, can be a frequent driver of human cancer.

Pre-clinical data of JZP815 administered orally as both a monotherapy and in combination with mitogen-activated protein kinase (MAPK) pathway inhibitors were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting (AACR) (Free AACR Whitepaper). Key findings of several pre-clinical models include1:

JZP815 inhibited all 3 RAF kinase family members (ARAF, BRAF, CRAF) at low-to-sub nanomolar potencies in biochemical assays.
JZP815 did not induce significant paradoxical pathway activation, observed with approved first generation BRAF-selective inhibitors, while demonstrating equivalent cellular potencies for MAPK pathway inhibition driven by either mutant RAF monomers or dimers or mutant RAS-induced RAF dimers in tumor cells.
JZP815 significantly inhibited tumor growth, including inducing tumor regression, as a single agent in multiple mouse xenograft solid tumor models harboring RAS and/or BRAF mutations.
JZP815’s pharmacokinetic profile sustained on-target pathway pharmacodynamic responses in a predictable dose and time dependent manner.
JZP815 demonstrated enhanced activity when combined with inhibitors of other MAPK pathway components including MEK1/2, SOS1, SHP2 and EGFR inhibitors in both class 2 and class 3 mutant BRAF patient-derived tumor cells ex vivo, and KRAS mutant NSCLC and colorectal cancer xenografts in vivo.
The full Jazz presentation abstract, titled, "JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models" is available at View Source!/10517/presentation/15283.

Jazz acquired JZP815 from Redx Pharma, and the two companies are collaborating on this pre-clinical research. Jazz plans to submit an IND for JZP815 this year.

About JZP815
JZP815 is an investigational, pre-clinical stage pan-RAF kinase inhibitor that was discovered and developed using state-of-the-art screening methodologies and medicinal chemistry. JZP815 targets specific components of the mitogen-activated protein kinase (MAPK) pathway that, when activated by oncogenic mutations, can be a frequent driver of human cancer. JZP815 potently inhibits both monomer- and dimer-driven RAF signaling (e.g., RAS-induced), prevents paradoxical pathway activation induced by BRAF selective inhibition, and is active against class 1, class 2, and class 3 BRAF mutants, as well as BRAF fusions and CRAF mutants. JZP815 is not currently approved for use anywhere in the world. JZP815 is part of Jazz’s growing early-stage R&D pipeline focused on precision oncology in solid tumors.

On April 8, 2022 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies, reported preclinical data characterizing next-generation pan-variant EGFR inhibitors that will be detailed in a live poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting, being held April 8-13, 2022 in New Orleans, Louisiana (Press release, Theseus Pharmaceuticals, APR 8, 2022, View Source [SID1234611790]). The poster highlights advanced lead compounds for use in non-small cell lung cancer (NSCLC) that have been observed to potently inhibit the kinase activity, both in vitro and in vivo, of all major single-, double-, and triple-mutant EGFR variants, including T790M and C797S, with selectivity over wild-type EGFR and the ability to penetrate the central nervous system (CNS).

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"Up to half of all non-small cell lung cancer tumors are driven by activating mutations (single-mutants) in EGFR and up to 90 percent of those mutations are found in exons 19 and 21. Furthermore, as patients progress through lines of treatment, a substantial percentage of patients’ tumors may develop one or more additional EGFR mutations (double- and triple-mutants) that cause resistance to treatment," said William Shakespeare, Ph.D., President of Research and Development at Theseus. "At Theseus, we have developed a series of potent and selective, single molecule, fourth-generation EGFR inhibitors that are designed to inhibit all major classes of EGFR activating and resistance mutations that contribute to later-line clonal heterogeneity in patients who have been failed by current approved therapies. We are finalizing preclinical studies to characterize our lead compounds and look forward to designating a development candidate in the third quarter of this year."

The preclinical data presented at AACR (Free AACR Whitepaper) demonstrates that pan-variant EGFR inhibition of all major single-, double-, and triple-mutants, including T790M and C797S, with selectivity over wild-type, is achievable with a single molecule. Detailed findings show that:

Theseus’ lead compounds potently inhibited all major single-, double-, and triple-mutant EGFR variants in vitro, demonstrating cellular IC50 values between 2-12 nM.
Lead compounds displayed favorable selectivity over wild-type EGFR, with ratios between 11- to 88-fold.
An advanced lead compound demonstrated tumor regressions in mice against variants associated with both 1st and 2nd line osimertinib clinical failure – i.e., C797S double- and triple-mutants – at well-tolerated doses.
This lead compound also demonstrated a brain:plasma ratio consistent with predicted activity against CNS metastatic disease.
Studies to further characterize lead compounds are under way, with additional data expected to be presented at a scientific conference in the second half of 2022.

Presentation details:

Poster Title: Discovery of potent and selective next-generation EGFR inhibitors with activity against single, double, and triple mutant EGFR variants including T790M and C797S

Poster Number: 3342

Presenter: Wei-Sheng Huang, Ph.D., Vice President of Chemistry

Session Date and Time: Live presentation on Tuesday, April 12TH, 1:30pm – 5pm CT

About NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 2.2 million cases of lung cancer diagnosed in 2020. Up to half of NSCLC patients have tumors that are driven by activating mutations in the epidermal growth factor receptor (EGFR) and up to 90 percent of those mutations are found in exons 19 and 21. [Most] patients’ tumors, in response to treatment, develop one or more additional EGFR mutations, causing resistance and rendering current therapies ineffective.