On April 4, 2024 Caris Discovery, the therapeutic research arm of Caris Life Sciences (Caris), the leading next-generation AI TechBio company and precision medicine pioneer, reported a multi-year strategic partnership with Merck KGaA, Darmstadt, Germany, which operates its healthcare business as EMD Serono in the U.S. and Canada, to accelerate the discovery and development of first-in-class antibody-drug conjugates (ADC) for cancer patients (Press release, Caris Life Sciences, APR 4, 2024, View Source [SID1234641800]).

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"We are thrilled to join forces with Merck KGaA, Darmstadt, Germany, to discover targets with the first-in-class potential to advance the next wave of transformational ADC therapeutics," said Brian Lamon, PhD, Chief Business Officer of Caris. "This partnership adds to our portfolio of external pipeline programs and is a strong validation of our highly differentiated, orthogonal multi-omics approach to discovering truly novel targets that may be harnessed to eradicate tumors."

Under the terms of the agreement, Merck KGaA, Darmstadt, Germany, will provide Caris with an upfront payment as well as research funding. In addition, Caris will be eligible for discovery, development, regulatory and sales-based milestone payments that may total up to $1.4 billion along with tiered royalties. Merck KGaA, Darmstadt, Germany will receive an exclusive global license to develop, manufacture and commercialize ADC therapeutics for selected targets.

"We are dedicated to addressing high unmet needs across multiple cancer types," said Paul Lyne, Global Head of Research Unit Oncology for the Healthcare business sector of Merck KGaA, Darmstadt, Germany. "Through close collaboration with Caris, utilizing their unique discovery platform, we complement our internal ADC capabilities to develop novel first-in-class ADCs and ultimately strengthen our potential to expand our oncology portfolio."

Caris Discovery leverages the scale of Caris’ core molecular profiling business to discover novel, druggable targets that would be otherwise inaccessible through more traditional approaches. Through the convergence of its proprietary ADAPT Biotargeting platform, a contemporaneous patient tissue repository, a suite of sophisticated AI and machine learning capabilities, and its dedicated 59,000 square foot discovery research laboratory, Caris Discovery aims to identify and validate new therapeutic targets that can be harnessed by its biopharma partners to develop the next generation of oncology therapies. Under this partnership, targets discovered and validated by Caris can be pursued by Merck KGaA, Darmstadt, Germany. Merck KGaA, Darmstadt, Germany will be responsible for the preclinical and clinical research, as well as the development and commercialization of drug candidates emanating from these programs.

"Caris Discovery is uncovering novel unexplored targets in patient populations where precision therapeutics have yet to be developed," said Milan Radovich, PhD, Senior Vice President and Chief Scientific Officer at Caris. "We are proud to be working closely with Merck KGaA, Darmstadt, Germany, to bring new therapeutic options to cancer patients together."

On April 4, 2024 Aethon Therapeutics, Inc., a biotechnology company discovering and developing novel antibody therapeutics designed to attack cancer cells in tandem with targeted covalent inhibitor cancer therapies, reported that it has entered into a collaboration agreement with Revolution Medicines, Inc., a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers (Press release, Aethon Therapeutics, APR 4, 2024, View Source [SID1234641799]). Under the terms of the agreement, Aethon will use its HapImmune platform to discover novel bispecific antibodies to mount an immune attack directed towards cancer cells hit by Revolution Medicines’ RAS(ON) inhibitors, with the goal of fueling tumor clearance and helping to establish immune memory.

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The terms of the agreement provide for a multi-year collaboration under which Aethon is responsible for conducting preclinical work, with full reimbursement by Revolution Medicines. Revolution Medicines has an option to conduct any clinical development of products that may arise from the collaboration. The arrangement provides for both upfront and potential downstream payments covering future development and commercialization activities should Revolution Medicines exercise its option.

"Aethon has proprietary expertise in creating and developing novel, cancer-specific drug-target peptide conjugates that seek out and bind to neoantigens created by different classes of covalent inhibitor anti-cancer therapies. This collaboration with Revolution Medicines represents an important validation of Aethon’s HapImmune platform and an exciting opportunity to potentially enhance RAS targeting by combining the power of highly selective immune cell attack with Revolution Medicines’ novel RAS(ON) inhibitors," said Raj Chopra, M.D., Ph.D., CEO of Aethon Therapeutics and Head of Oncology and Venture Partner at Apple Tree Partners.

"We are delighted to have the opportunity to work with Aethon and exploit their novel and innovative platform," said Steve Kelsey, M.D., president, research and development at Revolution Medicines. "Through our own publications, and those of other leaders in the field, we have become increasingly aware of the interaction between oncogenic RAS activation and anti-tumor immunity. This collaboration represents an important component of our long-term vision to optimize treatments for patients with RAS-driven cancers."

Beyond the programs being advanced in partnership with Revolution Medicines, Aethon has additional programs targeting validated covalent small molecules that inhibit RAS, EGFR, and BTK. "Aethon is discovering its own proprietary covalent inhibitors that target known oncogenes and tumor suppressors to create cancer-specific neoantigens as targets for engaging the immune system. This includes CD3+T cells and T cell subsets. Our significant progress on this front is very encouraging," Dr. Chopra said.

On April 4, 2024 The PHERGain clinical trial, developed by MEDSIR – a company dedicated to promoting independent clinical research in oncology internationally reported that it has been published in the prestigious journal The Lancet, following positive results showing that one-third of patients with localized HER2-positive breast cancer can be cured without requiring chemotherapy, drastically reducing side effects (Press release, MedSIR, APR 4, 2024, View Source [SID1234641798]).

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This study marks a milestone by using an adaptive design to personalize treatment in the neoadjuvant/adjuvant setting for patients with localized HER2-positive breast cancer. The main goal was to evaluate the feasibility of an adaptive therapeutic strategy based initially on exclusive treatment with dual HER2 blockade using trastuzumab and pertuzumab, with the addition of chemotherapy based on early response observed by PET-CT and complete pathological response.

The trial was led by MEDSIR researchers Dr. Javier Cortés, Dr. Antonio Llombart-Cussac, and Dr. José Pérez. "The results of this study bring us closer to the end of chemotherapy in a significant percentage of patients with this type of tumor," says Dr. Javier Cortés, the principal investigator of the study.

The initial results of the PHERGain clinical trial showed that early assessment of response to exclusive preoperative treatment without chemotherapy based on trastuzumab and pertuzumab, using PET-CT, could identify around 40% of patients with localized HER2-positive breast cancer who achieved a complete pathological response. These positive results were published in the journal Lancet Oncology in 2021.

Results from the second primary objective, which aimed to analyze invasive disease-free survival at three years in all patients who followed this adaptive treatment strategy, were initially presented in Chicago during the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2023 and have now been published in The Lancet.

According to the PHERGain study, 30% of patients with localized HER2-positive breast cancer could forego chemotherapy while maintaining excellent survival. Additionally, patients who eventually had to receive chemotherapy due to an insufficient response did not compromise their prognosis.

The study results demonstrate that 94.8% of all patients who followed this adaptive therapeutic strategy, regardless of whether they received chemotherapy or not, remain cancer-free three years after surgical intervention following treatment. This percentage is even higher (96.4%) in patients who did not have to receive chemotherapy. The study involved researchers from 45 centers in 7 European countries and included 356 patients with localized HER2-positive breast cancer.

The obtained results have been considered extraordinarily relevant and represent a new therapeutic option to be carefully considered in routine clinical practice, as they show that many patients can be treated safely and effectively without chemotherapy without compromising their prognosis. Additionally, it highlights the importance and benefit of adaptive clinical trials, focused on individualized patient care, compared to classic designs that pit two already closed treatment options against each other.

This is the first study that gradually adjusts the treatment for each patient based on their response to therapy, moving towards more personalized medicine, which was achieved with the global participation of academic and clinical collaborators, whose contribution has been significant in this clinical trial.

On April 4, 2024 IRBM, a leader in the field of drug discovery, reported that it will be disclosing new data on two of its most promising internal assets at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting occurring in San Diego, April 5-10 (Press release, IRBM, APR 4, 2024, View Source [SID1234641797]). The data will reveal insights into the novel compounds developed to address critical unmet needs in cancer treatment.

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Asset Highlights:

Potential first-in-class Antibody-Drug Conjugate (ADC) targeting CRLF2/TLSPR in "Ph-like" B-ALL (AM E3-SG3249) demonstrated significant preclinical efficacy, representing a pioneering approach to treating hematologic cancer characterized by poor prognosis and high relapse rates, often affecting adolescents.
Potential best-in-class brain permeable SHP2 allosteric inhibitor (I-1000233) exhibited promising results in preclinical studies, offering a new method of treating patients with RAS-driven malignancies, including challenging brain tumors and metastases.
Carlo Toniatti, MD, PhD, Chief Scientific Officer at IRBM, expressed his enthusiasm for the upcoming presentations: "The AACR (Free AACR Whitepaper) meeting presents a unique opportunity for IRBM to share our latest advancements in cancer research with the global scientific community. Our work on the CRLF2/TLSPR targeting ADC and CNS-penetrant SHP2 small molecule inhibitor exemplifies our relentless pursuit of novel therapeutic strategies that can make a significant difference in the lives of patients battling cancer. These developments reflect our deep scientific expertise and innovative spirit, underscoring IRBM’s role as a frontrunner in the integrated drug discovery industry."

The two assets, which have been progressed through the discovery phase within the public-private environment of the National Collection of Chemical Compounds and Screening Center (CNCCS), are a testament to IRBM’s integrated research capabilities, their commitment to advancing science to improve lives, and their pursuit of new and better treatments for cancer.

Details for the poster presentations are listed below.

CNS-penetrant SHP2 inhibitor:
Session Category: Experimental and molecular Therapeutics
Session Title: Kinase and phosphatase Inhibitors 2
Session Date and Time: Monday April 8, 2024, 9:00 AM -12:30 PM
Location: Poster Section 25
Poster Board Number: 24
Published Abstract Number: 1975
Presenter: Francesca Puca, PhD. Principal Research Scientist

CRLF2/TLSPR targeting ADC:
Session Category: Immunology
Session Title: Antibody-Drug Conjugates
Session Date and Time: Monday Apr 8, 2024, 1:30 PM – 5:00 PM
Location: Poster Section 2
Poster Board Number: 13
Published Abstract Number: 2610
Presenter: Claudia Dall’Armi, PhD. Senior Research Investigator

On April 4, 2024 Navrogen, Inc., a biopharmaceutical company specialized in developing therapies for cancer and immune-related disorders, reported that it will be presenting preclinical data on its next-generation anti-CD20 antibody, NAV-006, and ICAM-1 refractory antibody-drug conjugate platform at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference in San Diego, California, on April 8-9 (Press release, Navrogen, APR 4, 2024, View Source [SID1234641796]).

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CD20-targeting rituximab antibody is the standard-of-care for non-Hodgkin’s lymphoma (NHL). Recent clinical evidence suggests that high serum levels of the tumor-produced MUC16/CA125 protein has a negative impact on the efficacy of rituximab. To counteract the effects of CA125 binding to rituximab and reducing its tumor cell killing activity, Navrogen has generated a rituximab variant (NAV-006) using its BRITE proprietary technology. Navrogen will present data showing NAV-006’s superior efficacy over rituximab in animal models of human NHL. Navrogen’s screening technology has also found that CA125 inhibits other regulatory approved canonical and bispecific antibodies targeting CD19 and CD20 in relapsed/refractory NHL, underscoring a broader impact that CA125 has on biological drugs. "We are committed to combat cancers where humoral immunity is suppressed by CA125 and by other tumor-produced factors", said Dr. Luigi Grasso, Navrogen’s Chief Scientific Officer. "Our BRITE-optimized NAV-006 offers a new therapeutic modality to treat lymphoma patients with high levels of CA125 in relapsed/refractory disease".

Navrogen will also present the Humoral Immuno-Oncology (HIO) technology that has uncovered the tumor-produced protein ICAM-1, which binds to IgG1-type antibodies and inhibits their immune effector activity. "In addition to its immunosuppressive effects, we have found that membrane-bound ICAM-1 can reduce internalization of antibody-drug conjugates and their efficacy", continued Dr. Grasso. "We have engineered a trastuzumab-drug conjugate variant with superior cytotoxicity against ICAM-1 positive cancer cells. We are now building a portfolio of enhanced ADCs using this platform to advance internal as well as partnered ADC programs".