On April 9, 2024 BioCity Biopharma reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for a Phase 1 study of BC2027 (Press release, Biocity Biopharmaceutics, APR 9, 2024, View Source [SID1234641953]). BC2027, which is BioCity’s second first-in-class antibody drug conjugate (ADC) approved for clinical development, targets Glypican 3 (GPC3), a proteoglycan found in the outer membrane of cancer cells. BioCity’s first ADC, BC3195, which is directed against another novel target called placental-cadherin (CDH3), a cell adhesion molecule that confers invasiveness and metastatic properties to cancer cells, is also in clinical trials.

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GPC3 is specifically up-regulated in the most common type of liver cancer, hepatocellular carcinoma (HCC), several types of lung and esophageal cancer, and other malignancies, although rarely or not expressed in normal liver tissues, making GPC3 a rational treatment target for cancers that express it. Recently, clinical activity has been noted with chimeric antigen receptor (CAR) T cells and other therapies targeting GPC3, demonstrating the potential of GPC3 as a therapeutic target.

BC2027 binds with very high affinity to GPC3 and efficiently internalizes into cancer cells where it releases its cancer killing payload. In addition to directly killing cancers cells in which it enters, BC2027’s cancer activity is enhanced as it kills other cancer cells indirectly via a "bystander effect". In preclinical studies, BC2027 was also quite safe and tolerable while demonstrating robust anticancer activity with greater than 90% inhibition of tumor growth in some well-established cancers. These findings indicate the potential for BC2027 to be a novel, safe, and effective cancer treatment.

The uniqueness of GPC3 as a target also suggests that BC2027 may in part overcome the challenges of cancer drug resistance. Dr. Yong Jiang Hei, CEO of BioCity, noted that "Drug resistance has increasingly become a challenge in cancer treatment. BioCity aims to develop next generation therapies with the potential to delay and overcome drug-resistance. Among different strategies, developing novel ADCs is an important approach to address the inherent drug resistance of HCC and many other cancers, as well as secondary drug resistance resulting from available anticancer therapies." He added, "Now BioCity has two first-in-class, novel ADCs in global clinical development, thereby resulting in a competitive edge as BioCity’s ADCs are clearly differentiated. The company will strive to advance the clinical development of these exciting ADC therapeutics to meet the unmet clinical needs and benefit patients worldwide as early as possible." Dr. Hei says.

HCC and GPC3

Liver cancers are highly prevalent worldwide with approximately 860,000 newly diagnosed cases and 750,000 ①deaths annually. Among liver cancers, 90% are HCC. In addition, the poor prognosis of the disease represents a significant unmet medical need.

In recent years, with the rapid development of systemic therapies for HCC, the standard of care for advanced HCC has evolved from traditional chemotherapy to multi-kinase inhibitors and immune checkpoint inhibitors, or the combination of the two. However, the efficacy of these therapies is limited and further advances in treatment are urgently needed.

GPC3 is highly expressed in more than 70% HCC and the expression level correlates with the extent of disease progression. Therefore, GPC3 is a specific tumor marker and closely related to disease prognosis, making it a promising target for the treatment of HCC②.

On April 9, 2024 MEDSIR, a leading company dedicated to the strategic design of independent clinical research, reported in the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), a premier event that brings together scientists, clinicians, industry professionals, advocates, and other stakeholders in the field of cancer research, presenting the results of two sub-studies focused on biomarkers: transFal, focused on patients with HR+/HER2- advanced breast cancer and METSGain, centered on patients with early breast cancer (Press release, MedSIR, APR 9, 2024, View Source [SID1234641952]).

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Both studies underscore the importance of utilizing biomarkers. Their early detection has been shown to increase patient survival rates by aiding in selecting the most appropriate treatment for patients.

In the context of personalized medicine, biomarkers are also important for tailoring treatments for individual patients based on their unique biological characteristics, allowing for more precise and effective medical interventions.

MEDSIR’s mission is to improve therapeutic responses, thereby enhancing patient lives. Through translational studies that use samples from groundbreaking trials, such as PARSIFAL and PHERGain, MEDSIR aims to elevate clinical practice for the benefit of patients.

Mario Mancino, PhD, Translational Research Manager at MEDSIR, expressed enthusiasm: "We are thrilled to present our research at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). Our commitment to advancing personalized medicine through biomarkers underscores our dedication to improving patient outcomes."

These findings represent significant strides in understanding and leveraging biomarkers for personalized cancer care, offering new hope to patients and paving the way for more effective treatment strategies tailored to individual patients’ biological profiles.

transFAL: Unlocking Biomarkers for HR+/HER2- Advanced Breast Cancer

MEDSIR introduced the results of the transFAL study, aimed at uncovering biomarkers of response or resistance to palbociclib in combination with endocrine therapy-based regimens for patients with HR+/HER2- advanced breast cancer. The study, analyzing samples from the PARSIFAL trial, revealed significant insights into biomarker associations with treatment response. Notably, high expression of Ki67 and CDK6, along with elevated ctDNA density at baseline, were correlated with shorter progression-free survival and overall survival. These findings illuminate potential avenues for understanding and overcoming resistance to CDK4/6 inhibitors, marking a significant step forward in personalized cancer treatment.

METSGain: Predictive Potential in Early Breast Cancer

Additionally, MEDSIR presented findings from the METSGain study, which focused on predicting the risk of distant recurrences and understanding metastatic processes in early breast cancer, analyzing data from the PHERGain trial. The study demonstrated that HER2DX risk-score measurement after treatment and tumor surgery can provide valuable insights into future distant metastases. Notably, patients with high-risk scores at surgery and less molecular changes after anti-HER2 therapy were more likely to develop metastasis, further highlighting the potential of HER2DX tool developed by REVEAL GENOMICS S.L. in guiding treatment decisions for HER2+ early breast cancer patients.

About Breast Cancer

Breast cancer is the most frequent cancer diagnosed in women with an estimated global incidence of over 2 million new cases annually and is a heterogeneous disease with multiple clinical presentations and outcomes. Risk factors include family history, advanced age, hormone exposure, alcohol consumption, or smoking. Early diagnosis, risk prediction, and ongoing research into treatments are crucial for improving the prognosis and quality of life for those affected by this disease.

On April 9, 2024 Rakovina Therapeutics Inc.), a biopharmaceutical company dedicated to improving the lives of cancer patients through the development of novel DNA-damage response inhibitor therapeutics, reported that members of the Company’s scientific team presented new data on the Company’s novel kt-3000 series at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting at the San Diego Convention Center (Press release, Rakovina Therapeutics, APR 9, 2024, View Source [SID1234641951]).

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In the presentation entitled, "Pharmacological Synthetic Lethality by Co-Inhibition of PARP and HDAC Enzymes" during yesterday’s Late Breaking Experimental and Molecular Therapeutics Research session at the conference, Rakovina discussed conceptual insights on how co-inhibition of these enzymes can eliminate cancer cells with an intact DNA repair machinery.

"We are very proud of our continued progress in our quest to find new treatments for cancer," said Rakovina Executive Chair Jeffrey Bacha. "The research was led by our President and Chief Science Officer Dr. Mads Daugaard, and we continue to be highly encouraged about the direction of our pre-clinical research."

"The combination of PARP and HDAC inhibition activity in one single drug candidate showed strong anti-tumor cell activity in DNA repair-proficient cells where single agent PARP inhibitors have limited effects", said Dr. Daugaard. "Our research continues to support the idea that the development of bifunctional PARP-HDAC inhibitors may provide a novel therapeutic opportunity for tumors with resistance to first-generation PARP inhibitors".

According to Bacha, first-generation PARP inhibitors have become an important standard-of-care in the treatment of several major solid tumors, including subsets of breast, lung and prostate cancers, generating nearly USD $3 billion in annual revenue. Resistance to PARP inhibitors develops over time so continued innovation is needed to meet the need for new and better treatments.

Dr. Daugaard said, "Lead candidates from our kt-3000 series dual-function PARP-HDAC inhibitors demonstrate the ability to overcome resistance to treatment and potentially treat cancers that would normally respond poorly to treatment with first-generation PARP inhibitors (such as Ewing Sarcoma, or any other DNA repair-proficient types of cancer). This novel approach not only addresses the unmet need, but also opens the door to potentially treat a wide range of cancers currently outside the scope of the first-generation PARP inhibitors.

Development of Rakovina Therapeutics’ kt-3000 series is supported, in part, by the St. Baldrick’s Foundation Martha’s BEST Grant for All, which is aimed at developing new treatments for Ewing sarcoma, an aggressive bone and soft tissue cancer in children and young adults.

Collaborators on this project include the Vancouver Prostate Centre, Vancouver, Canada; Rakovina Therapeutics, Vancouver Canada; the Department of Urologic Sciences, the Department of Pathology and Laboratory Medicine and the Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.

The AACR (Free AACR Whitepaper) is celebrating its 115th year and expects over 21,000 attendees from around the world.

The Company recently announced a strategic evolution in its business model that places Rakovina at the forefront of artificial intelligence-driven (AI), precision research for cancer drug development. (See press release of March 27, 2024.)

On April 9, 2024 Syntara Limited (ASX: SNT) reported that it has reached the 50% recruitment milestone in its Phase 2 trial evaluating SNT-5505, in combination with ruxolitinib, treating the bone marrow cancer myelofibrosis (Press release, Syntara, APR 9, 2024, View Source [SID1234641950]).

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Recruitment for the open-label study commenced in December 2023 with the 8th patient in the 15-patient trial dosed earlier this week, keeping Syntara on track for completion of recruitment by the end of H1 2024.

The trial is being conducted across 19 clinical trial sites in the USA, Australia, South Korea and Taiwan. SNT-5505 is a pan-LOX inhibitor and the lead asset in Syntara’s drug discovery pipeline.

Syntara anticipates reporting on 6-month results of the trial in an interim data update at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in December 2024. The interim data is expected to allow Syntara to engage with and discuss pivotal study design with the FDA in Q1 2025, with the full 12-month data set to be available by mid-2025.

Syntara commenced the combination trial after it found encouraging efficacy and an excellent safety profile in a Phase 2 monotherapy trial of the drug, as presented at ASH (Free ASH Whitepaper) in December 2023. An effective pan-LOX inhibitor, such as SNT-5505, for myelofibrosis has Syntara’s lead asset SNT-5505 reaches 50% recruitment in Phase 2 trial; interim results expected December 2024 2 disease modifying potential for patients and would unlock a market conservatively estimated to be more than $1 billion per annum.

Syntara CEO Gary Phillips said: "We’re very pleased with the progression of recruitment in this trial as we observe the impact SNT-5505 can have in combination with the approved standard of care ruxolitinib. In addition to providing us with an opportunity to discuss a pivotal registration study with the FDA, positive developments in the trial will provide Syntara with a platform to engage with potential partners that would be complementary to our efforts to commercialise the drug."

This combination cohort of the Phase 2 MF-101 trial aims to demonstrate that SNT-5505 is safe and effective in myelofibrosis patients who are sub optimally controlled on the market leading JAK inhibitor, ruxolitinib.

SNT-5505 has previously demonstrated compelling pre-clinical data when used in combination with standard of care in other haematological malignancies such as myelodysplastic syndrome and solid tumours like those found in hepatocellular carcinoma and pancreatic cancer.

On April 9, 2024 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, and NEC Corporation (NEC; TSE: 6701), a leader in IT, network and AI technologies, reported that new data will be presented on TG4050, an individualized neoantigen cancer vaccine, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA (Press release, Transgene, APR 9, 2024, View Source [SID1234641949]). These data are highlighted in the AACR (Free AACR Whitepaper) press conference being held today and in a poster presentation which will take place tomorrow, April 10, at 9:00 a.m. PDT.

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TG4050 is based on Transgene’s myvac platform and powered by NEC’s cutting-edge AI capabilities designed to optimize antigen selection.

Key findings of the poster include:

-All 16 patients who received TG4050 are disease free after a median 18.6-month follow-up. Out of the 16 patients in the control observation arm, 3 patients have relapsed. For this head and neck cancer patient population and with current standard of care, approximately 40% of patients are expected to relapse within 24 months following surgery and adjuvant therapy (chemoradiotherapy). Also, the tumor immune contexture, expression of immune factors, mutational burden, and tumor infiltrates are associated with challenging prognoses.

-Specific cellular immune responses (CD8+ and CD4+) were detected in the 16/17 patients who received TG4050 (16 patients in the treatment arm and one patient from the observation arm treated after relapse) using stringent testing criteria. Immunogenicity or the capacity of treatment to induce immune responses are key to prevent relapses.

-TG4050 induced persistent immune responses against multiple targets in several patients. T cell responses were maintained beyond 211 days (7 months) after the initiation of the treatment. The duration of the immune response is also a key factor to fight disease over time.

Alessandro Riva, Chairman and CEO of Transgene, commented:

"We are honored by AACR (Free AACR Whitepaper)’s interest in the Phase I data generated from our individualized cancer vaccine TG4050. It is exciting to note that all patients who received TG4050 remain disease-free after a median follow-up of 18.6 months, which compares favorably to the observational arm which saw 3 out of 16 patients relapse during the same period."

"More importantly, almost all treated patients developed a specific immune response against the antigen targets we selected, providing robust proof of principle for our lead candidate. TG4050 is now starting to show a potential benefit for head and neck cancer patients at high risk of relapse. We look forward to starting the Phase II part of the trial in the adjuvant setting for head and neck cancer."

Dr. Oliver Lantz, Head of the clinical immunology laboratory at Institut Curie, added:

"The immunological data generated by TG4050 demonstrate a robust and specific cellular immune response, even under stringent measurement criteria. The diversity, depth and duration of these responses were most certainly a key factor in preventing relapse in the patients treated with TG4050."

Masamitsu Kitase, Corporate SVP and Head of the Healthcare and Life Sciences Division at NEC, concluded:

"Our state-of-the-art proprietary artificial intelligence and machine learning models have allowed us to identify immunogenic and clinically relevant mutations in all head and neck cancer patients for this TG4050 randomized Phase I trial. These tumors were characterized by a low tumor mutation burden, which presents an obstacle to designing a relevant vaccine. Our powerful platform enables us to identify mutations for individualized treatments which have now shown the first signs of clinical benefit for patients. Together with Transgene, we look forward to continuing to build on these promising data through our planned Phase II trial in the adjuvant treatment of head and neck cancer."

TG4050 is being evaluated in a randomized multicenter Phase I/II trial as a single agent in the adjuvant treatment of HPV-negative head and neck cancers (NCT04183166). Based on promising data obtained in the Phase I part of the trial, Transgene and NEC are preparing a randomized Phase II extension of this trial slated to start in the second quarter of 2024.

The poster can be viewed in-person during the poster presentation at the AACR (Free AACR Whitepaper) 2024 meeting and accessed on Transgene’s website.