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Cogent Biosciences Presents New Preclinical Data Demonstrating Bezuclastinib as a Differentiated KIT Inhibitor with Minimal Brain Penetration

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).

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"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

Deciphera Presents Preclinical Data from DCC-3116 Program at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

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]).

"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.

Curis Announces New Preclinical Data Highlighting the Potential of CA-4948 in Multiple Hematologic Malignancies Presented at the AACR-NCI-EORTC Virtual Conference on Molecular Targets and Cancer Therapeutics

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]).

"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.

BridgeBio Pharma Announces First Publication of Preclinical Data for its Potentially Best-in-Class SHP2 Inhibitor Designed for Treatment of Resistant Cancer, Showing Response in Established Non-small Cell Lung Cancer Models

On October 7, 2021 BridgeBio Pharma, Inc. (Nasdaq: BBIO), a commercial-stage biopharmaceutical company that focuses on genetic diseases and cancers, reported preclinical findings for its SHP2 inhibitor, BBP-398, in non-small cell lung cancer (NSCLC) (Press release, BridgeBio, OCT 7, 2021, View Source [SID1234590923]). The results are featured in a poster presentation titled ‘BBP-398, a potent, small molecule inhibitor of SHP2, enhances the response of established NSCLC xenografts to KRASG12C and EGFRmut inhibitors’ 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) taking place virtually on October 7 – 10, 2021.

"We are excited to share our promising preclinical data in non-small cell lung cancer models, which provides a critical step in understanding the potential that BBP-398 has for patients with tumors driven by RAS or other MAPK-pathway activating mutations," said Eli Wallace, Ph.D., chief scientific officer at BridgeBio Oncology. "For patients with this type of progressive cancer, there is a serious need for more innovative medicines to be accessible as quickly as possible. Our potentially best-in-class SHP2 inhibitor could be an ideal combination agent for certain cancer patients given its promising profile of preclinical results and potential for once daily dosing."

BBP-398, developed in collaboration with the University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division, exhibits preclinical monotherapy efficacy in RTK/KRAS-driven xenograft models as well as synergy in combination with both sotorasib and osimertinib. The predicted human steady-state plasma concentration-time profiles suggest continuous once daily oral dosing of BBP-398 may achieve the desired therapeutic index for patients.

BridgeBio is currently advancing its Phase 1 dose escalation clinical trial with its SHP2 inhibitor, BBP-398, in patients with solid tumors driven by mutations in the MAPK signaling pathway, including RAS and receptor tyrosine kinase genes. More than 30% of all human cancers – including 95% of pancreatic cancers and 45% of colorectal cancers — are driven by mutations of the RAS family of genes.

BridgeBio’s precision oncology programs are driven by the Company’s molecular dynamics and RAS structural biology platforms, which are enabled by our broad partnerships with the Lawrence Livermore National Laboratory and National RAS Initiative, respectively.

BridgeBio’s SHP2 inhibitor, BBP-398, is one of the Company’s 14 programs that are in the clinic or commercial setting for patients living with genetic diseases and genetically-driven cancers.

Learn more about the preclinical data for BBP-398 at BridgeBio’s upcoming virtual R&D Day on Tuesday, October 12, 2021 at 8:30 am ET. The event will be webcast and registration information can be found here.

BridgeBio will unveil new programs, share new information about its pipeline and discuss how it is broadening the scope of its R&D engine. It will also cover the Company’s most significant near-term catalysts with a focus on the upcoming topline results for acoramidis, BridgeBio’s investigational therapy for transthyretin (TTR) amyloidosis (ATTR). ATTR is a rare heart condition with a progressive and debilitating impact on quality of life likely affecting more than 400,000 patients worldwide.

Topline acoramidis results from Part A are expected in late 2021 and from Part B in 2023. The primary endpoint at Part A is the change from baseline in a 6-minute walk distance (6MWD) in trial participants receiving acoramidis or placebo after 12 months. If the change from baseline in 6MWD in Part A is highly statistically significant, BridgeBio expects to submit an application for regulatory approval of acoramidis in 2022 to the U.S. Food and Drug Administration.

The R&D Day program importantly and additionally will highlight BridgeBio’s broader efforts in cardiorenal, progress in its KRAS portfolio, and advancements in its previously disclosed early-stage Mendelian programs. The Company will also be unveiling new investigational programs in gene therapy.

About SHP2
SHP2 is a protein-tyrosine phosphatase that links growth factor, cytokine and integrin signaling with the downstream RAS/ERK MAPK pathway to regulate cellular proliferation and survival. Overactivity of the SHP2 pathway, often driven by distinct genetic mutations, is a critical contributor to many forms of cancer, and is a mechanism of resistance to several targeted therapies. Estimated to affect approximately 500,000 patients in the United States and the European Union, cancers that are driven by hyperactive MAPK signaling, including certain RAS mutations such as KRASG12C, may be sensitive to SHP2 inhibition.

About BBP-398
BBP-398 is a potent, selective, orally bioavailable SHP2 inhibitor that demonstrates pathway inhibition across a panel of cell lines with active MAPK signaling. The therapy is designed to be optimized for continuous once daily dosing through its pharmacokinetic profile. The inhibitor was developed through a collaboration with the University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division. BridgeBio has a non-exclusive, co-funded clinical collaboration with Bristol Myers Squibb to evaluate the combination of BBP-398 with OPDIVO (nivolumab) in patients with advanced solid tumors with KRAS mutations. The collaboration will also include the initiation of a Phase 1/2 study to evaluate the safety and preliminary efficacy of BBP-398 in combination with both OPDIVO as doublet therapy, and OPDIVO plus a KRASG12C inhibitor as triplet therapy in non-small cell lung cancer (NSCLC) with KRAS mutations, as first- and second-line treatment options. Additionally, BridgeBio previously entered into a strategic collaboration with LianBio for clinical development and commercialization of BBP-398 in combination with various agents in solid tumors such as non-small cell lung cancer, colorectal and pancreatic cancer, in mainland China and other major Asian markets.

Spectrum Pharmaceuticals Announces Presentation of Poziotinib in Combination with KRASG12C Inhibitors at the 2021 AACR-NCI-EORTC Conference

On October 7, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported the presentation of preclinical data demonstrating the synergistic impact of poziotinib when combined with KRAS inhibitors in KRASG12C mutant specific cell lines (Press release, Spectrum Pharmaceuticals, OCT 7, 2021, View Source [SID1234590922]). Jacqulyne Robichaux, Ph.D., Assistant Professor, University of Texas, MD Anderson Cancer Center is presenting a poster titled "Pan-ErbB inhibition enhances activity of KRASG12C inhibitors in preclinical models of KRASG12C mutant cancers" at the 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) being held October 7-10. The conference is hosted by the American Association for Cancer Research (AACR) (Free AACR Whitepaper), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC).

The preclinical data demonstrated that inhibition of EGFR, HER2, HER3, and HER4 signaling by the pan-ErbB inhibitor poziotinib was synergistic when combined with KRASG12C inhibitors. These results highlight the importance of HER3 and HER4 signaling, in addition to EGFR and HER2, after KRASG12C inhibition.

"We are encouraged by these promising data developed by Dr. John Heymach and the research team at MD Anderson," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "The in vitro findings presented by Dr. Robichaux illustrate well the importance of pan-HER inhibition blocking the over expression of HER receptors induced by KRAS inhibitors. Poziotinib is a potent clinical stage pan-HER inhibitor and may be optimally suited for this rational combination. These exciting findings warrant further evaluation in the clinic given the large number of patients with NSCLC and other solid tumors with KRASG12C mutations who could possibly benefit from such a combination."

The poster presentation will be available for viewing by registered participants during the conference via the meeting website beginning at 9 a.m. ET on October 7, 2021. It will also be available on the Spectrum Pharmaceuticals website at: View Source