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".

On April 4, 2024 ProfoundBio, a clinical-stage biotechnology company dedicated to developing novel antibody-drug conjugate (ADC) therapies for patients with cancer, reported its participation at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place from April 5-10 in San Diego, California (Press release, ProfoundBio, APR 4, 2024, View Source [SID1234641795]). ProfoundBio will showcase its innovative ADC programs through an oral presentation on its EGFR- and cMET-dual targeting ADC PRO1286, a poster presentation detailing preclinical data of a SLITRK6-directed ADC PRO1106, and a late-breaking poster presentation on a CD98-directed ADC developed in partnership with Huahui Health, a clinical-stage biotechnology company.

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"We are pleased to share our latest research at the AACR (Free AACR Whitepaper) Meeting this year," stated Zhu Chen, Ph.D., Chief Scientific Officer of ProfoundBio. "These presentations underscore our commitment to leveraging our proprietary ADC platforms to target some of the most challenging cancers. With PRO1286, PRO1106, and our CD98-directed ADC, we are aiming to provide patients with more effective and tolerable treatment options, and look forward to sharing the latest findings with the scientific community."

Key Presentations at AACR (Free AACR Whitepaper) 2024

Abstract #

Presentation Title

Date/Time

Session Track

Presenter(s)

2050

Preclinical characterization
of PRO1106, a novel and
promising SLITRK6-directed
sesutecan ADC

April 8,
2024,
9:00 AM –
12:30 PM

Poster Session,
Experimental and
Molecular
Therapeutics

Zhu Chen,
ProfoundBio

6580

A novel EGFR x cMET
bispecific ADC PRO1286
demonstrated broad
antitumor activity and
promising tolerability in
preclinical models

April 9,
2024,
3:05 PM –
3:20 PM

Minisymposium,
Experimental and
Molecular
Therapeutics,
Chemistry

Zhu Chen,
ProfoundBio

LB425

A tumor microenvironment –
targeting CD98-directed ADC
confers robust anti-tumor
activity in multiple cancers
with favorable
pharmacokinetics and safety
profiles in preclinical models

April 10,
2024,
9:00 AM –
12:30 PM

Late-Breaking
Poster Session,
Experimental and
Molecular
Therapeutics

Bin Chen,
Huahui Health

Zhu Chen,
ProfoundBio

About ProfoundBio’s ADC Programs

FRα-Targeted ADC: Rinatabart sesutecan (Rina-S, PRO1184)

Rina-S is a FRα-targeted ADC being developed as a novel treatment option for patients with ovarian and endometrial cancer, and other FRα-expressing cancers. Rina-S is comprised of a FRα-directed antibody conjugated to sesutecan, ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, at a homogeneous drug-to-antibody ratio (DAR) of 8. Exatecan is a potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect. The linker component of sesutecan is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of exatecan, enabling high DAR and efficient delivery of the exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC. Rina-S is currently being evaluated in a Phase 1/2 clinical trial (NCT05579366) and has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer.

CD70-Targeted ADC: PRO1160

PRO1160 is an ADC consisting of a CD70-targeted antibody conjugated to ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, sesutecan. CD70 is a protein expressed on both solid tumors and hematological malignancies including renal cell carcinoma, nasopharyngeal carcinoma, and non-Hodgkin lymphoma, yet is largely absent in normal tissues. With preclinical results showcasing encouraging pharmacokinetics, efficacy, and tolerability, PRO1160 is emerging as a potential advancement in the treatment of these cancers and is currently being evaluated in a Phase 1/2 clinical trial (NCT05721222).

PTK7-Targeted ADC: PRO1107

PRO1107 is an ADC consisting of a PTK7-targeted antibody conjugated to ProfoundBio’s novel, proprietary hydrophilic MMAE-based linker-drug, LD343, at a homogeneous DAR of 8. MMAE is a potent, membrane-permeable microtubule inhibitor that has been clinically validated as an ADC payload with multiple marketed vedotin ADCs at a DAR of 4. The linker component of LD343 is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of MMAE, enabling high DAR and efficient delivery of the MMAE payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC. PRO1107 is currently being evaluated in a Phase 1/2 clinical trial (NCT06171789).

Bispecific ADC: PRO1286

PRO1286 is a novel EGFR- and cMET-dual targeting ADC that has the potential to treat a broad range of tumors. PRO1286 is built on the clinically validated sesutecan platform and is anticipated to enter the clinic in 2024.

On April 4, 2024 Biognosys, a global leader in mass spectrometry-based proteomics, and Alamar Biosciences, Inc., a company powering precision proteomics to enable the earliest detection of disease, reported a strategic partnership aimed at advancing scientific discovery in the field of biofluid proteomics biomarkers (Press release, Biognosys, APR 4, 2024, View Source [SID1234641793]). This collaboration brings together Biognosys’ expertise in unbiased discovery through data independent acquisition mass spectrometry (DIA-MS) and Alamar’s cutting-edge immunoassays. This integrated approach enhances our understanding of biomarkers by combining deep unbiased DIA-MS discovery proteomics with highly specific and ultra-sensitive mid- and high-plex NULISA assays for low-abundance proteins such as cytokines, chemokines and important disease protein biomarkers from plasma.

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In the Industry Spotlight Theater session hosted by Alamar at the American Society for Cancer Research (AACR) (Free AACR Whitepaper) 2024 Annual Meeting in San Diego on April 9 at 12:30 pm PT, the companies will jointly present data from a collaborative study focused on Non-Small Cell Lung Cancer (NSCLC). In this study, plasma samples from a cohort of NSCLC patients were analyzed using both the Biognosys TrueDiscovery unbiased discovery platform and Alamar’s NULISAseq Inflammation Panel 250. The findings demonstrate the feasibility of integrated analysis and highlight the complementary insights derived from mass spectrometry and affinity-based assays in plasma.

Building upon this successful proof-of-concept study, Biognosys and Alamar are planning to further collaborate both commercially and scientifically as part of their strategic partnership.

NULISA Assay Services: Biognosys will offer NULISA assays from its state-of-the-art facility in Switzerland for previously hard to measure cytokines, chemokines, as well as other important disease specific markers from plasma and biofluids. These ultra-high sensitivity assays enable precise quantification of low abundance proteins, providing researchers with valuable insights into complex biological processes. They complement unbiased DIA-MS analysis of thousands of plasma proteins to elucidate systemic host response, and other inflammation or disease-related protein-fold changes.

Research Collaboration: Biognosys and Alamar will embark on a joint research initiative to explore plasma biology. By leveraging Biognosys’ unbiased discovery methods alongside Alamar’s ultra-high sensitivity assays, the teams seek to unravel biological disease mechanisms by providing a more complete picture of the plasma proteome, enabling for the first time the coverage of essentially the complete dynamic range of protein abundance in plasma.
Oliver Rinner, Ph.D., Founder and CEO of Biognosys, expressed enthusiasm about the collaboration: "We are excited to join forces with Alamar to advance proteomics research. Our combined efforts will pave the way for breakthroughs in plasma biology by analyzing in an unbiased way more than 5,000 proteins together with panels of hundreds of well characterized cytokines and other high value low abundance proteins using highly specific NULISA assays. With this approach we are aiming to cover the whole dynamic range of plasma proteins."

"We are thrilled to partner with Biognosys to provide the research community with expanded access to proteomic insights from discovery through to clinical research," said Yuling Luo, Ph.D., Chairman, Founder and CEO of Alamar. "Biognosys is a leading provider of advanced mass spec proteomics services to researchers around the world, and we look forward to adding the highest sensitivity high-multiplex immunoassays to their plasma proteomics offering."

This partnership underscores the commitment of both companies to scientific excellence and their shared vision of advancing precision medicine through innovative technologies.