On October 7, 2021 Nuvalent, Inc., (Nasdaq: NUVL), a biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported that new preclinical data on Thursday supporting advancement of its parallel lead programs in non-small cell lung cancer (NSCLC) (Press release, Nuvalent, OCT 7, 2021, View Source [SID1234590932]). NVL-520, a ROS1-selective inhibitor, and NVL-655, an ALK-selective inhibitor, were specifically designed to solve for the dual challenges of kinase resistance and selectivity which limit the activity and durability of currently available cancer therapies.

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The data are available via three on-demand "short-talk" posters 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), which runs from Oct. 7 through Oct. 10. The presentations detail additional preclinical evidence that NVL-520 and NVL-655 1) were active against both wild-type and various known resistance variants of ROS1 or ALK, respectively; 2) were brain-penetrant with the potential to address brain metastases; and 3) selectively inhibited their targets compared to the structurally related tropomyosin receptor kinase B (TRKB), thereby minimizing the potential for off-target TRKB-related central nervous system (CNS) adverse events. The posters will also be available on the Nuvalent website.

"The Nuvalent discovery team operates under an ethos of thorough investigation, with the goal of ensuring that we nominate drug candidates that best embody the product profiles we have defined in close collaboration with physician-scientists," said Henry Pelish, Ph.D., Vice President of Biology at Nuvalent and a presenting poster author. "This is exemplified in our approach to comprehensive in vitro characterization of target selectivity compared to the structurally similar kinase TRKB during the discovery and early development of both NVL-520 and NVL-655, which we detail here.

"Our physician-scientist collaborators are instrumental not only in helping us to identify the desired product characteristics that we believe are most impactful to treatment paradigms today, but also in furthering the investigation of our compounds," continued Dr. Pelish. "It has been a privilege to work closely alongside Dr. Aaron Hata’s group at Mass General Cancer Center to generate the new data presented here in support of the broad preclinical activity of NVL-520 against ROS1 wild type and resistance variants. We look forward to continued collaboration as we work to advance NVL-520 and NVL-655 into clinical studies, and further mature our discovery programs."

Aaron N. Hata, M.D., Ph.D., is a Nuvalent scientific advisor and co-author whose lab at Mass General Cancer Center in Boston focuses on advancing targeted therapies for patients with lung cancer.

"Resistance mutations, off-target adverse events, and brain metastases present significant challenges in the development of the next-generation of targeted therapies for kinases such as ROS1 and ALK," said Dr. Hata. "I am encouraged by the growing body of preclinical data showing that both NVL-520 and NVL-655 maintained selective inhibition of their targets even in the presence of a wide variety of resistance mutations and displayed the important combination of both TRKB selectivity and brain penetrance to open up the potential to treat brain metastases while avoiding off-target CNS adverse events. Together, this combination of characteristics may have the potential to drive more durable responses for patients."

The U.S. Food and Drug Administration has cleared the company’s Investigational New Drug application for NVL-520. Nuvalent plans to initiate the Phase 1 portion of a First-in-Human (FIH) Phase 1/2 clinical trial for NVL-520 in patients with advanced ROS1-positive NSCLC and other solid tumors in the second half of 2021. Nuvalent plans to initiate the Phase 1 portion of a FIH Phase 1/2 clinical trial investigating NVL-655 in advanced ALK-positive NSCLC and other cancers during the first half of 2022.

AACR-NCI-EORTC Presentation Overview:

*Presenting author

Title: Preclinical Antitumor Activity of NVL-520 in Patient-Derived Models Harboring ROS1 Fusions, Including G2032R Solvent Front Mutation
Authors: Amit Deshpande, Satoshi Yoda, Anupong Tangpeerachaikul, Nancy E. Kohl, Joshua C. Horan, Aaron N. Hata, Henry E. Pelish*
Poster Number: P249

Summary of Presentation:

NVL-520 is a potent, highly selective, and brain-penetrant ROS1 inhibitor as previously demonstrated by in vitro and in vivo studies.
NVL-520 demonstrated potent activity against multiple additional ROS1+ NSCLC patient-derived in vitro cell line (PDC) and in vivo xenograft (PDX) models.
Activity was observed irrespective of fusion partner and against both the wild-type and TKI-resistant solvent front mutation (G2032R) ROS1 kinase domain.
Pharmacodynamic analysis of tumors from mice treated with NVL-520 revealed a dose-dependent reduction in ROS1 levels, markers of downstream signaling, and cell proliferation across multiple models of ROS1-driven disease.
Title: NVL-655 Exhibits Antitumor Activity in Lorlatinib-Resistant Subcutaneous and Intracranial Models of ALK-Rearranged NSCLC
Authors: Anupong Tangpeerachaikul*, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish
Poster Number: P244

Summary of Presentation:

NVL-655 is a potent and brain-penetrant ALK inhibitor as demonstrated by activity in a mouse intracranial tumor model study.
NVL-655 showed activity against a wide variety of ALK mutations, particularly G1202R+ mutations, whether as a single mutation (G1202R) or as compound mutations (G1202R/L1196M and G1202R/G1269A).
Activity was observed both in vitro and in vivo across various contexts, including fusion partners, EML4 breakpoint variants, and tumor contexts.
Title: Evaluating TRKB Activity of Novel Preclinical Brain-Penetrant ROS1 and ALK Inhibitors
Authors: Anupong Tangpeerachaikul*, Joshua C. Horan, Henry E. Pelish
Poster Number: P247

Summary of Presentation:

TRKB-related central nervous system adverse events present a key challenge for the development of brain-penetrant ROS1 and ALK therapies, as both on-target kinases exhibit ~70% kinase domain similarity to the off-target TRKB.
Nuvalent devised a multi-assay approach to evaluate TRKB inhibition and guide the discovery of selective ROS1 and ALK inhibitors, with the goal of minimizing adverse events and driving durable responses for patients.
Leveraging multiple biochemical and cell-based assays increases confidence that results are reproducible across various biological contexts.
All examined assays indicated that NVL-520 and NVL-655 were highly selective for their wild-type and treatment-resistant oncogenic targets over TRKB.

On October 7, 2021 – SELLAS Life Sciences Group, Inc. (NASDAQ: SLS) ("SELLAS" or the "Company"), a late-stage clinical biopharmaceutical company focused on developing novel cancer immunotherapies for a broad range of indications, reported that Angelos Stergiou, MD, ScD. h.c., President and Chief Executive Officer of SELLAS, will participate in two upcoming conferences:

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Laguna Biotech CEO Forum 2021 to be held at the Montage Laguna Beach hotel in Laguna Beach, CA on October 10-12, 2021.

A.G.P./Alliance Global Partners Biotech & Specialty Pharma Conference to be held virtually on Wednesday, October 13, 2021.
For more information about the conferences, or to schedule a one-on-one meeting with SELLAS management, please contact your representative directly, or send an email to A.G.P./Alliance Global Partners at [email protected], or KCSA Strategic Communications at [email protected].

On October 7, 2021 Y-mAbs Therapeutics, Inc. ("Y-mAbs" or the "Company"), NASDAQ: YMAB), a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported that the U.S. Food and Drug Administration ("FDA") has granted Rare Pediatric Disease Designation ("RPDD") for the Company’s lutetium labelled omburtamab antibody program for the treatment of medulloblastoma (Press release, Y-mAbs Therapeutics, OCT 7, 2021, View Source [SID1234590930]).

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177Lu-omburtamab-DTPA, a monoclonal B7-H3 antibody that has been radiolabeled with lutetium-177, is currently in a multicenter Phase 1 clinical trial in pediatric patients with refractory medulloblastoma, and in a multicenter Phase 1 clinical trial targeting B7-H3 positive CNS/LM tumors in adults. We believe that both indications address clear unmet medical needs.

"The RPDD makes us eligible for a Priority Review Voucher ("PRV") upon potential approval of the biologics license application for this rare pediatric cancer. Among our leading compounds under development, four now have RPDDs, and this designation for 177Lu-omburtamab-DTPA further increase our chances of ultimately receiving multiple PRVs," said Thomas Gad, founder, Chairman and President.

Dr. Claus Moller, Chief Executive Officer further notes, "We are dedicated to bring 177Lu-omburtamab-DTPA to patients who desperately need alternative methods of treatment. We are very pleased by this recognition by the FDA and look forward to expanding the ongoing Phase 1 studies with 177Lu-omburtamab-DTPA into separate Phase 2 arms."

Researchers at Memorial Sloan Kettering Cancer Center ("MSK") developed omburtamab, which is exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests in the product.

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