On October 7, 2021 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported that new data with PH-894, Phio’s self-delivering RNAi compound targeting the bromodomain-containing protein 4 (BRD4) at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Phio Pharmaceuticals, OCT 7, 2021, View Source [SID1234590927]). The data presented add to the growing body of evidence that BRD4 not only plays a role in tumor cells, but can also regulate T cell function and that PH-894 can reprogram T cells to provide enhanced immunotherapeutic activity.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data we presented today at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting demonstrates silencing BRD4 with our INTASYL compound PH-894 has a significant impact on T cell function and phenotype promoting T cell activation and immunosuppression in the tumor microenvironment," said Simon Fricker, Phio’s Vice President of R&D. "Our new data shows how BRD4 can regulate immune cells activity and therefore BRD4 silencing with PH-894 could become an important approach to treat cancer."

In this study conducted in collaboration with the Karolinska Institutet in Sweden, it was shown that PH-894 resulted in a strong, concentration dependent and durable silencing of BRD4 in T cells, which in an in vivo study translated to pronounced and dose associated inhibition of tumor growth. These data demonstrate that Phio’s PH-894 INTASYL compound can reprogram T cells to provide enhanced immunotherapeutic activity.

"We are very excited by these data, which suggest that PH-894’s potency is not solely a consequence of its direct effect on tumor cells, but also its ability to reprogram and activate T cells to further boost the anti-cancer effect. As such, we are working hard on IND-enabling studies to bring this promising compound to the clinic," continued Dr. Fricker.

Phio’s presentation detailing the data presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) titled, "Targeting BRD4 in T cells with self-delivering RNAi PH-894 for immunotherapy" will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

On October 7, 2021 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported preclinical data providing further evidence of bezuclastinib as a differentiated, potent, and selective KIT inhibitor (Press release, Cogent Biosciences, OCT 7, 2021, View Source [SID1234590926]). The data were presented in a virtual poster at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Today Cogent presented new preclinical data that reinforces bezuclastinib’s selectivity for targeting KIT mutations while demonstrating minimal brain penetration," said Andrew Robbins, President and CEO of Cogent Biosciences. "We are excited with bezuclastinib’s differentiated profile among KIT inhibitors and continue to work quickly to have three clinical trials for AdvSM, NonAdvSM and GIST patients open for enrollment in 2021."

Preclinical studies evaluated the selectivity of bezuclastinib, and other KIT mutant inhibitors, against closely related kinases including PDGFRα, PDGFRβ, and CSF1R. Inhibition of these kinases has been linked to off-target toxicities such as edema and pleural effusions. Comparative screening was performed against a broad spectrum of 71 ion channels, transporters, enzymes, and cell based models, confirming prior evidence that bezuclastinib is a potent and unique inhibitor of KIT A-loop mutations (exon 17/18). In head-to-head studies comparing KIT mutant inhibitors, bezuclastinib demonstrated no activity against closely related kinases, in contrast to other KIT mutant inhibitors with demonstrated potency against PDGFRα and PDGFRβ.

In a nonclinical safety pharmacology study in rodents, bezuclastinib and another KIT A-loop mutant inhibitor were evaluated at doses which closely correlate with clinical exposures previously shown in clinical studies of GIST patients. After three days, bezuclastinib demonstrated minimal brain penetration with a low brain to plasma ratio. These data are supported by a separate neurobehavioral study of bezuclastinib in rodents in which no CNS-related effects were observed. The absence of brain penetration is a preferred feature for a KIT mutant inhibitor as CNS-related adverse events have been observed clinically with some commercially available mutant KIT inhibitors.

Poster Presentation Details for Bezuclastinib:
Title: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration
Virtual Poster Number: P257
Date/Time: All poster presentations are made available by the conference at the opening of the meeting on October 7, 2021, at 9:00 am ET.

The presentation is available on the Cogent Biosciences website at: View Source

On October 7, 2021 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported preclinical data providing further evidence of bezuclastinib as a differentiated, potent, and selective KIT inhibitor (Press release, Cogent Biosciences, OCT 7, 2021, View Source [SID1234590926]). The data were presented in a virtual poster at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Today Cogent presented new preclinical data that reinforces bezuclastinib’s selectivity for targeting KIT mutations while demonstrating minimal brain penetration," said Andrew Robbins, President and CEO of Cogent Biosciences. "We are excited with bezuclastinib’s differentiated profile among KIT inhibitors and continue to work quickly to have three clinical trials for AdvSM, NonAdvSM and GIST patients open for enrollment in 2021."

Preclinical studies evaluated the selectivity of bezuclastinib, and other KIT mutant inhibitors, against closely related kinases including PDGFRα, PDGFRβ, and CSF1R. Inhibition of these kinases has been linked to off-target toxicities such as edema and pleural effusions. Comparative screening was performed against a broad spectrum of 71 ion channels, transporters, enzymes, and cell based models, confirming prior evidence that bezuclastinib is a potent and unique inhibitor of KIT A-loop mutations (exon 17/18). In head-to-head studies comparing KIT mutant inhibitors, bezuclastinib demonstrated no activity against closely related kinases, in contrast to other KIT mutant inhibitors with demonstrated potency against PDGFRα and PDGFRβ.

In a nonclinical safety pharmacology study in rodents, bezuclastinib and another KIT A-loop mutant inhibitor were evaluated at doses which closely correlate with clinical exposures previously shown in clinical studies of GIST patients. After three days, bezuclastinib demonstrated minimal brain penetration with a low brain to plasma ratio. These data are supported by a separate neurobehavioral study of bezuclastinib in rodents in which no CNS-related effects were observed. The absence of brain penetration is a preferred feature for a KIT mutant inhibitor as CNS-related adverse events have been observed clinically with some commercially available mutant KIT inhibitors.

Poster Presentation Details for Bezuclastinib:
Title: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration
Virtual Poster Number: P257
Date/Time: All poster presentations are made available by the conference at the opening of the meeting on October 7, 2021, at 9:00 am ET.

The presentation is available on the Cogent Biosciences website at: View Source

On October 7, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported the presentation of preclinical data from the Company’s first-in-class selective ULK kinase inhibitor, DCC-3116, in combination with EGFR inhibitors in non-small cell lung cancer (NSCLC) models at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Deciphera Pharmaceuticals, OCT 7, 2021, View Source [SID1234590925]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented today show that DCC-3116 inhibits the autophagy that develops as a resistance mechanism after treatment with EGFR inhibitors in multiple EGFR-mutant NSCLC cell lines and that DCC-3116 decreases tumor burden when combined with EGFR inhibitors. These findings are particularly important as EGFR is mutated in approximately 30% of NSCLC patients, the vast majority of whom develop resistance to EGFR inhibitors," said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. "These results reinforce the broad potential of autophagy inhibition as a mechanism to address the challenge of drug resistance in the treatment of cancer."

Results from the study, presented in a poster titled "DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, synergizes with EGFR inhibitors osimertinib and afatinib in NSCLC preclinical models" are summarized below. The poster presentation is available on-demand via the meeting website and on the Company’s website at www.deciphera.com/presentations-publications.

In Vitro Data Show Ability of DCC-3116 to Reduce Autophagy that Develops as a Resistance Mechanism after Treatment with EGFR Inhibitors in NSCLC Cell Lines

– EGFR inhibitors gefitinib, erlotinib and osimertinib, and the ErbB-family inhibitor, afatinib, activated autophagy three to four-fold over basal levels as measured by pATG13, a cellular substrate of autophagy-initiating kinases ULK1/2, in the EGFR exon 19-deleted HCC827 NSCLC cell line. DCC-3116, a potent inhibitor of ULK1 and ULK2, was shown to inhibit both basal and EGFR-induced phosphorylation of pATG13.

– Treatment of the EGFR T790M-mutated NSCLC cell line H1975 with osimertinib or afatinib, which inhibit the T790M mutation, induced autophagy three-fold over basal levels while treatment with gefitinib or erlotinib, which are not able to inhibit the T790M mutation, did not induce ULK-mediated ATG13 phosphorylation. DCC-3116 potently inhibited osimertinib and afatinib-induced phosphorylation of ATG13 and inhibited the increase in autophagosomes induced by these agents.

In Vivo Data Show that Combination of DCC-3116 with EGFR Inhibitors Resulted in Significantly Greater Tumor Responses in NSCLC Xenograft Model

– The combination of DCC-3116 with osimertinib or afatinib resulted in significantly greater tumor responses than single agent treatments in the H1975 EGFR-mutant xenograft model.

The clinical development plan for DCC-3116 will initially focus on documented RAS and RAF cancer mutations, which utilize autophagy for tumor growth and survival. DCC-3116 is currently being investigated in a Phase 1, multicenter, open-label, first-in-human study designed to evaluate the safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of DCC-3116 as a single agent and in combination with trametinib, a commercially available MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene. Following the dose escalation phase, combination expansion cohorts are currently planned in patients with advanced or metastatic pancreatic ductal adenocarcinoma with KRAS or BRAF mutations, non-small cell lung cancer (NSCLC) with KRAS, NRAS, or BRAF mutations, colorectal cancer with KRAS, NRAS, or BRAF mutations, and melanoma with NRAS or BRAF mutations. Combination expansion cohorts are planned to evaluate DCC-3116 in combination with trametinib. Initial data from the Phase 1 dose escalation cohorts is expected in 2022.

About DCC-3116

DCC-3116 is an investigational first-in-class small molecule designed to inhibit cancer autophagy, a key tumor survival mechanism, by inhibiting the ULK kinase. DCC-3116 is currently being studied in a Phase 1, multicenter, open-label, first-in-human study as a single agent and in combination with trametinib, a commercially available MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene.

On October 7, 2021 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported two poster presentations with new preclinical data for CA-4948, a first-in-class small molecule IRAK4 inhibitor, at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual Conference on Molecular Targets and Cancer Therapeutics (Press release, Curis, OCT 7, 2021, View Source [SID1234590924]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"In ongoing Phase 1 clinical trials, CA-4948 has already demonstrated anti-tumor activity in non-Hodgkin’s lymphoma, acute myeloid leukemia and myelodysplastic syndromes. New preclinical data presented at AACR (Free AACR Whitepaper)-NCI-EORTC today support the potential of CA-4948 in additional hematologic cancers," said James Dentzer, President and Chief Executive Officer of Curis.

"Notably, these new preclinical data indicate that CA-4948 is synergistic with small molecules targeting BCR signaling, including both idelalisib and ibrutinib, and suggest it may help overcome or reduce secondary resistance to these therapies in marginal zone lymphoma. In addition, these data demonstrate that CA-4948 can cross the blood brain barrier and improve survival, in a dose-dependent manner, providing additional preclinical support for the study of CA-4948 in patients with primary central nervous system (pCNS) lymphoma, one of the most aggressive forms of lymphoma and a clear area of unmet need for patients." Mr. Dentzer added.

Details of the presentations are as follows:

Title: Pharmacological inhibition of IRAK-4 with CA-4948 is beneficial in marginal zone lymphoma models with secondary resistance to PI3K and BTK inhibitors
Author: Francesca Guidetti, Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
Poster Number: P073

Title: The IRAK4 inhibitor CA-4948 demonstrates antitumor activity in a preclinical model of CNS lymphoma
Author: Christina A. von Roemeling, Ph.D., Research Associate, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida
Poster Number: P243
Additional meeting information can be found on the AACR (Free AACR Whitepaper) website at:
View Source

The presentations will also be available under "Posters and Presentations" in the Pipeline: CA-4948 section of the Company’s website at www.curis.com

About CA-4948

CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutations such as SF3B1 and U2AF1.