On October 7, 2021 Kinnate Biopharma Inc. (Nasdaq: KNTE) ("Kinnate"), a biopharmaceutical company focused on the discovery and development of small molecule kinase inhibitors for difficult-to-treat, genomically defined cancers, reported that it will be presenting design and rationale details of a Phase 1 trial (KN-8701: NCT04913285) evaluating KIN-2787 during 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, Kinnate Biopharma, OCT 7, 2021, View Source [SID1234590929]).

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KIN-2787, Kinnate’s most advanced product candidate, is an orally available small molecule pan-RAF inhibitor being developed for the treatment of patients with lung cancer, melanoma, and other solid tumors. KIN-2787 has been designed to target both monomeric and dimeric forms of the mutant BRAF kinase and minimize paradoxical activation, a liability often observed with other RAF inhibitors that can adversely impact tolerability and require addition of a MEK inhibitor to suppress pathway activation. Unlike currently available treatments that target only Class I BRAF kinase mutations, KIN-2787 targets Class II and Class III BRAF alterations, where it has the potential to be a first-line targeted therapy, in addition to covering Class I BRAF mutations. In pre-clinical studies, KIN-2787 has shown favorable pharmaceutical properties, achieves substantial systemic exposures in toxicology studies and induces regressions in human cancer xenograft models driven by BRAF Class I, II or III alterations.

"Approved BRAF inhibitors have limited clinical activity in diverse solid tumors driven by BRAF Class II or III alterations, highlighting the urgency to develop effective next-generation targeted therapies for these patients who currently have limited options," said the trial’s co-investigator and presenter Meredith McKean, MD, MPH, Associate Director, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute at Tennessee Oncology. "We are pleased to share additional details of this two-part trial with this year’s conference attendees."

KN-8701 (NCT04913285) is a first-in-human, multicenter, non-randomized, open-label, Phase 1 trial of KIN-2787 in adult patients with BRAF mutant advanced and metastatic solid tumors (AMST). KIN-2787 is given orally bid continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approximately 115 patients in two parts: Part A is a trial of dose-escalation to maximum tolerated dose open to patients with AMST driven by BRAF Class I, Class II or Class III genomic alterations. Part B will evaluate a selected dose of KIN-2787 in three cohorts of patients with melanoma, NSCLC, or other AMST, each driven by BRAF Class II or Class III alterations. Standard Phase 1 enrollment criteria are required, and key exclusion criteria include known clinically active brain metastases from non-brain tumors, and prior receipt of BRAF-, MEK-, or MAPK-directed inhibitor therapy (except for cases in which these inhibitors were used in FDA-approved indications).

"We are pleased with the progress of this first-in-human trial of KIN-2787 and grateful to all the trial participants. With poorer prognosis observed in NSCLC and melanoma patients harboring tumors driven by BRAF Class II or III alterations, there is a dire need for more effective and better tolerated therapies," said Richard Williams, MBBS, Ph.D., Chief Medical Officer of Kinnate. "We are proud to collaborate with the Sarah Cannon Research Institute and all the other sites participating in this important trial."

The KN-8701 trial is currently recruiting across three centers in the United States. For more information, please visit www.kinnate.com/patients.

The poster (#P226), titled "Design and rationale of a first in human (FIH) Phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF mutation positive solid tumors," was presented by Dr. McKean and can be accessed online at: View Source

On October 7, 2021 Kineta, Inc., a clinical stage biotechnology company focused on the development of novel immunotherapies in oncology, reported the presentation of preclinical data on the company’s new immuno-oncology program targeting CD27 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Conference on Tumor Immunology and Immunotherapy (Press release, Kineta, OCT 7, 2021, View Source;utm_medium=rss&utm_campaign=kineta-presents-preclinical-data-on-its-new-cd27-program-at-the-aacr-conference-on-tumor-immunology-and-immunotherapy [SID1234590928]). Thierry Guillaudeux, PhD, Senior Vice President Immuno-oncology at Kineta, presented a poster detailing new preclinical data on the company’s lead anti-CD27 agonist antibodies.

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CD27 is a member of the TNF receptor superfamily and plays a critical role in T-cell activation by providing a co-stimulatory signal together with its ligand CD70. CD27 is highly expressed on naïve T cells and also provides a co-stimulatory signal for NK cell activation. A major challenge in cancer immunotherapy is T cell "exhaustion". Anti-cancer T cells, through repeated stimulation, begin to lose their cancer-fighting effector functions. Once a T cell is exhausted, further stimulation becomes ineffective. CD27 agonist immunotherapy may reprogram the immune system to generate new and more diverse populations of anticancer "memory" T cells from naïve T cells to elicit a strong anti-tumor response.

"This is a significant milestone for Kineta as we expand our pipeline with another exciting immuno-oncology antibody program," said Shawn Iadonato, PhD, Chief Executive Officer of Kineta. "Our immuno-oncology strategy is to develop differentiated immunotherapies to address key mechanisms of cancer resistance including immunosuppression, exhausted T cells, and lack of tumor antigens. CD27 is a promising immunotherapy target to address exhausted T cells and restore anti-tumor T cell function".

Key results from the AACR (Free AACR Whitepaper) poster presentation include the following:

147 fully human monoclonal anti-CD27 antibodies with unique sequences were generated
Kineta’s anti-CD27 antibodies are highly specific and cross-react with cyno-CD27
Anti-CD27 agonist assay showed particularly strong induction for eight of the anti-CD27 antibodies
Human peripheral blood T cell activation assay showed increased proliferation and cytokine secretion
"We are encouraged with the results of our anti-CD27 antibodies as they performed exceedingly well across multiple preclinical experiments", said Thierry Guillaudeux, PhD, SVP Immuno-oncology at Kineta. "We are currently in lead selection and will nominate a clinical candidate to advance into IND-enabling studies in 2022."

Presentation Details:

Title: A promising cancer immunotherapy target: Novel fully human agonist antibodies against the human T-cell costimulatory receptor CD27
Date Presented: October 5-6, 2021
Presenter: Thierry Guillaudeux, PhD
Poster: Click on the link below to view the poster:
Kineta CD27 Poster Presentation at AACR (Free AACR Whitepaper) Conference on Tumor Immunology and Immunotherapy

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.

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"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).

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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

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