On December 18, 2024 Break Through Cancer reported to have launched a collaborative cohort for a Phase 1 study of RMC-6236, a compound developed by Revolution Medicines that is designed to suppress multiple RAS proteins that drive human cancers, including pancreatic cancer, non-small cell lung cancer and colorectal cancer (Press release, Break Through Cancer, DEC 18, 2024, View Source;utm_medium=rss&utm_campaign=collaboration-with-revolution-medicines-to-study-biomarkers-for-rason-multi-selective-inhibitor-in-pancreatic-cancer [SID1234649193]).

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The ongoing phase 1 trial of RMC-6236 (NCT05379985) is exploring the safety, tolerability and antitumor activity of RMC-6236 in patients with common KRAS mutations (including G12D, G12V and G12R) in metastatic pancreatic ductal adenocarcinoma (PDAC)— the most common and highly aggressive type of pancreatic cancer, with an average 5-year survival rate of only 3% for metastatic cases. Patient blood and tumor tissue samples from a dedicated collaboration cohort within this trial will be analyzed by The Conquering KRAS in Pancreatic Cancer TeamLab, funded jointly by Break Through Cancer and the Lustgarten Foundation, using advanced multi-omic and spatial profiling approaches to search for biomarkers able to predict tumor response and how cancer cells adapt to the therapy. Such biomarkers are being studied to help doctors quickly know if a patient is or is not responding to a therapy, and whether they would benefit from combination therapies.

Beyond assessing patient outcomes, the trial is uniquely designed to deepen the understanding of the biology of KRAS-mutant pancreatic cancers. By studying patient samples and biopsies in the lab, researchers will use advanced technologies to explore how PDAC evolves under treatment, the biological impact of RAS inhibition, and the mechanisms underlying resistance. This comprehensive approach will provide critical insights into the complex interplay of tumor biology and drug response.

Cancer-causing RAS proteins drive a significant number of all human cancers, including over 90% of PDAC, and many KRAS G12 mutations in particular are prevalent in human cancers. Many KRAS-targeted cancer therapies target only single KRAS mutations, while RMC-6236 was designed to inhibit the full spectrum of cancer-causing KRAS mutations, as well as other cancer-causing RAS family member mutations as well.

"We’re delighted to have the opportunity to work with Break Through Cancer and the Lustgarten Foundation on this unique cohort within our Phase 1 study for RMC-6236," said Wei Lin, M.D., Chief Medical Officer at Revolution Medicines. "The funded investigators at Break Through Cancer will use the latest scientific techniques to examine the biological effects of RMC-6236 on pancreatic tumors in patients in our clinical trial. We hope to glean insights into the mechanisms of response and resistance to RMC-6236, which will guide us to develop potential combination therapies based on our RAS(ON) inhibitors to improve patient outcomes."

The multi-center trial is being conducted by Revolution Medicines with clinical investigators at Break Through Cancer participating institutions, including Dana-Farber Cancer Institute, Johns Hopkins Kimmel Cancer Center, The University of Texas MD Anderson Cancer Center, and Memorial Sloan Kettering Cancer Center. The work is powered by Break Through Cancer’s TeamLab model of "radical collaboration," which enables real-time data and discovery sharing in laboratories across these clinical sites and in MIT’s Koch Institute for Integrative Cancer Research. Alongside this trial, TeamLab members are also investigating mechanisms of resistance to RMC-6236 and are searching for additional signaling pathways that could be promising targets for future therapeutics.

"Our mission is to drive innovation through collaboration, and this trial represents an extraordinary opportunity to do just that," said Tyler Jacks, president of Break Through Cancer; founding director of MIT’s Koch Institute for Integrative Cancer Research; David H. Koch (1962) Professor of Biology. "Together with Revolution Medicines and our TeamLab investigators, we’re applying advanced technologies and multi-institutional expertise to tackle one of the toughest challenges in oncology – pancreatic cancer.

On December 18, 2024 ALX Oncology Holdings Inc. ("ALX Oncology" or "the Company") (Nasdaq: ALXO), a clinical-stage biotechnology company advancing therapies that boost the immune system to treat cancer and extend patients’ lives, reported that the updated results from its Phase 2 ASPEN-06 clinical trial have been accepted for oral presentation at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium, which will be held in San Francisco from January 23 – 25, 2025 (Press release, ALX Oncology, DEC 18, 2024, View Source [SID1234649192]).

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ASPEN-06 is a randomized, multi-center, international trial (NCT05002127) evaluating evorpacept, ALX Oncology’s investigational CD47-blocking therapeutic that uniquely combines a high-affinity CD47-binding domain with an inactivated proprietary Fc domain, in combination with trastuzumab, CYRAMZA (ramucirumab) and paclitaxel (collectively, TRP) against TRP alone for the treatment of patients with HER2-positive gastric/gastroesophageal junction cancer, where all patients had received an anti-HER2 agent in prior lines of therapy.

The updated results from the ASPEN-06 study will be detailed in the following oral presentation:

Title: Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC)
Abstract Number: 332
Presenter: Kohei Shitara, MD, Director of the Department of Gastrointestinal Oncology, at National Cancer Center Hospital East, Kashiwa in Japan
Presentation Date and Time: Thursday, January 23, 2025, from 9:15 a.m. – 10:00 a.m. PST
Session Information: Rapid Oral Abstract Session A: Cancers of the Esophagus and Stomach
Location: Level 2 Ballroom

Copies of the presentations will be available on the Publications section of ALX Oncology’s website following presentation at the meeting.

On December 18, 2024 Clarity Pharmaceuticals (ASX: CU6) ("Clarity" or "Company"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported the expansion of its pipeline with a novel FAP-targeted radiopharmaceutical for the diagnosis and treatment of cancer (Press release, Clarity Pharmaceuticals, DEC 18, 2024, View Source [SID1234649191]).

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FAP is expressed on cancer associated fibroblasts (CAFs), a particular cell type found in the tumour microenvironment (cancer ‘infrastructure’ called the tumour stroma). CAFs are found in a broad range of cancers (e.g. breast, colorectal, pancreatic, lung, brain and ovarian cancers), but only minimally in normal tissue, making FAP a promising pan-cancer target for both imaging and treatment of cancers1. CAFs form part of the environment surrounding the cancer cells, and they can promote cancer growth and the spread of the tumour throughout the body2. Targeting the tumour stroma is an alternative way to treat cancer whereby the architecture of the tumour mass is targeted rather than the tumour cells directly.

Clarity’s Targeted Copper Theranostic (TCT) targeting FAP was developed at the benchtop of Australian science, with a clear understanding of other FAP-targeted radiopharmaceuticals in development and the intent of overcoming the low uptake and retention of these agents in tumours. This was achieved by utilising some novel chemistry, and by combining an industry leading FAP inhibitor with the proprietary SAR chelator technology. The SAR Technology enables the use of copper-64 (64Cu) for imaging and copper-67 (67Cu) for the targeted treatment of various cancers.

Similar to how Clarity developed its PSMA-targeted prostate cancer agent as a dimer, SAR-bisPSMA, which was designed to improve tumour uptake and retention, the Company created a novel dimer for its FAP-targeted radiopharmaceutical, SAR-bisFAP. With the benefit of comparing this novel molecule to other FAP radiopharmaceuticals in development as well as to a monomer equivalent (SAR-monoFAP), the dimer SAR-bisFAP has shown increased tumour uptake and retention over 24 hours in pre-clinical models.In addition to comparing the mono and dimer versions of the product, Clarity compared the dimer, 64Cu-SAR-bisFAP, to an industry standard FAP-targeted monomer called 68Ga-FAPI-46. Using a FAP-expressing melanoma cell line (SK-MEL187) in this experiment, at 1-hour post-injection 64Cu-SAR-bisFAP had approximately 4 times the uptake in the cancer compared to 68Ga-FAPI-46. The improvements in uptake and retention of 64/67Cu-SAR-bisFAP compared to first-generation FAP compounds, such as FAPI-46, are key attributes for the development of next-generation radiopharmaceuticals.

Clarity is currently conducting additional investigations to enable a Phase I clinical trial, which could commence in late 2025. Research into the potential clinical use of Clarity’s FAP agent has begun with several pre-clinical studies in diagnostics (utilising 64Cu-SAR-bisFAP), which will be followed by exploring treatment opportunities of cancers based on their unmet medical needs (using 67Cu-SAR-bisFAP).

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "Our commitment to always putting science first at Clarity has placed us in an enviable position in radiopharmaceuticals globally. This has allowed us, yet again, to create a novel product at the benchtop to overcome the shortcomings of competing radiopharmaceuticals by increasing the uptake and retention of the molecule over time. Coupled with the use of the perfect pairing of copper isotopes, this facilitates the use of same-day and next-day imaging, addressing the issue of low sensitivity of short half-life products using gallium-68 and fluorine-18, as well as potentially enhancing the therapeutic benefit through increasing the amount and retention of the product at the site of tumours. This is especially the case for FAP-targeted radiopharmaceuticals that offer so much hope as a pan-cancer but suffer the issue of low uptake and retention at the tumour site.

"We are excited to continue growing our pipeline of TCTs through our Discovery Program, utilising the unique advantages of copper isotopes, enabled by our proprietary SAR Technology. Unlike other chelator technologies that leak copper in vivo, the SAR Technology securely holds copper over time, unlocking a myriad of advantages of the "perfect pairing" of copper-64 for imaging and copper-67 for therapy, such as next-day imaging, supply, logistical and environmental advantages. Having strong intellectual property around the SAR Technology, as well as our novel products, with over 28 patent families now within the Company, we continue expanding our pipeline of next-generation radiopharmaceuticals. The development of these new products is only possible due to the utilisation of great chemistry combined with new promising targets and our proprietary chelator, thereby enabling a multitude of new products for indications with high unmet needs. By going back to the drawing board and conducting comprehensive research and testing, we were able to create a unique product that achieves the outcomes we were looking for of improving uptake and retention in tumours. The tumour targeting, retention and pharmacokinetic data we have seen to date with SAR-bisFAP is impressive, and we look forward to progressing this product in clinical trials and are excited to explore the pan-cancer targeting potential in a range of indications with high unmet needs."

About 64/67Cu-SAR-monoFAP and 64/67Cu-SAR-bisFAP
64/67Cu-SAR-monoFAP and 64/67Cu-SAR-bisFAP are unregistered products. Their safety and efficacy have not been assessed by health authorities such as the US Food and Drug Administration (FDA) or the Therapeutic Goods Administration (TGA). Outcomes from human clinical trials may differ from pre-clinical findings. There is no guarantee that these products will become commercially available.

On December 17, 2024 HighField Biopharmaceuticals, a clinical stage company using lipid-based therapeutics to treat cancer, diabetes and other diseases, reported that the Center for Drug Evaluation of China’s National Medical Products Administration has granted clearance of the company’s Investigational New Drug (IND) application to begin a clinical trial of HF50 in patients with advanced solid tumor cancers (Press release, HighField Biopharmaceuticals, DEC 17, 2024, View Source [SID1234649187]).

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"This is a highly significant milestone for our company and for patients," said Yuhong Xu, Ph.D., CEO and Scientific Founder of HighField. "HF50 is a T cell Redirecting Antibody Fragment-anchored Liposome, or TRAFsome, with two different antibodies attached; the first binds to T cells and the second binds to tumor cells. It is the first-of-its-kind liposomal T cell engager to emerge from our platform of immunoliposomes, and the first to enter clinical trials."

In addition to converting T cells into an army of cancer destroyers, HF50 also carries a payload that releases in the tumor microenvironment to facilitate the anti-tumor immune reactions.

The design of the TRAFsome T cell engagers builds upon the success of HighField’s LipoADCplexTM platform. The first product from this platform is K1, which contains the anti-HER2 antibody for binding to tumor cells and delivering cancer killing drugs. K1 is in clinical trials and has shown very good safety profiles in cancer patients.

"Once we proved the LipoADCplexTM platform could be safer, cheaper and more effective than ADCs (antibody-drug conjugates), the next logical step is to enlist immune cells with a second antibody to enable immunotherapy against the target cells," Dr. Xu explained. "T cell engagers can be very powerful. But over stimulation may result in high risk of toxicity and T cell exhaustion."

The Phase 1 open-label, dose escalation and dose expansion trial of HF50 will evaluate the safety, tolerability, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy in patients with advanced solid tumors. The trial is expect to begin in 1Q2025.

"As a T cell engager, HF50 has advantages over bispecific antibody constructs and even CAR T cells," Dr. Xu said. "The liposomal T cell engagers can integrate three specific activities. The first is to activate T cells; the second is to direct the T cells to target cells; and the third is to release the payload to facilitate the immune responses."

Dr. Xu added, "The TRAFsomes can be made modularly with low costs. Preclinical data suggested they are much safer and more effective. We can also add different payloads to expand their application to other illnesses such as autoimmune diseases and illnesses related to aging."

On December 17, 2024 Akamis Bio, a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene (T-SIGn) therapy platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors, reported $60 million in funding linked to the close of a Series A Prime financing round and entry into a strategic partnership for the development of its lead clinical candidate, NG-350A (Press release, Akamis Bio, DEC 17, 2024, View Source [SID1234649185]).

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The new funding will support the company’s work to advance NG-350A through a Phase 1b clinical proof-of-concept (PoC) study in patients with locally advanced rectal cancer (LARC). NG-350A is an intravenously delivered, transgene-armed tumor gene therapy designed to drive intratumoral expression of a CD40 agonist monoclonal antibody in both primary and metastatic epithelial-derived solid tumors. The Phase 1b PoC study, known as FORTRESS (NCT06459869), will evaluate clinical complete response (cCR) rates to NG-350A in combination with chemoradiotherapy (CRT) in adult patients with LARC and at least one risk factor for local or distant recurrence.

The Series A Prime financing was led by Sedgwick Yard, a global biotech venture capital firm with Greater China roots. In a separate transaction, Akamis Bio entered into a licensing agreement granting Xuanzhu Biopharma the Greater China Region Rights to NG-350A. Under the terms of the licensing agreement, Akamis Bio is eligible to receive undisclosed upfront payments plus regulatory and sales milestones, as well as tiered royalties in the high single- to low double-digit range on Greater China Region NG-350A sales.

"We are grateful for this strong vote of confidence in NG-350A, the T-SIGn platform and the Akamis Bio team. The Sedgwick Yard-led Series A Prime financing and Xuanzhu Biopharma licensing deal demonstrates our shared commitment with these partners to rapidly advancing NG-350A while also demonstrating the broader potential of T-SIGn," said Howard Davis, PhD, CEO of Akamis Bio. "Compelling clinical data from our prior studies have shown the consistent safety profile of T-SIGn, as well as the potential of intravenously-delivered NG-350A to drive sustained transgene expression capable of altering the tumor microenvironment. Our aim over the next 12-18 months is to deliver clinical proof-of-concept data for NG-350A via the FORTRESS study."

"We believe T-SIGn offers a true platform approach and that NG-350A is just the beginning of what we anticipate will become a robust pipeline of IV-delivered, tumor-targeted immunotherapies. We are very confident in the scientific and drug development acumen of the Akamis Bio management team, as well as in their ability to deliver on this opportunity to advance the standard of care for patients with difficult to treat solid tumors," said Richard Shen, Managing Director, Sedgwick Yard.

A recently published paper in the Journal for ImmunoTherapy of Cancer (JITC), described data from the FORTITUDE first-in-human dose escalation study in patients with metastatic/advanced epithelial tumors that provided initial proof-of-mechanism for NG-350A and highlighted the advantages of its intravenous route of administration. These data demonstrated the consistent safety profile of NG-350A, as well as providing strong evidence of tumor-selective delivery, replication and transgene expression. Additionally, this study demonstrated that intravenous delivery of NG-350A results in a superior overall pharmacokinetic and pharmacodynamic profile, with no apparent disadvantages versus intratumoral injection.

"We are thrilled to partner with Akamis Bio to develop and commercialize NG-350A in the Greater China Region. The T-SIGn platform has the potential to revolutionize the treatment of advanced metastatic solid tumors, and we look forward to working closely with the Akamis Bio team to bring this novel tumor gene therapy to patients," said Jiakui Li, PhD, CEO of Xuanzhu Biopharma.

Linked to the close of the Series A Prime financing, Akamis Bio added two new members to its Board of Directors: Richard Shen, Managing Director, Sedgwick Yard, and Adrian Chan, Managing Director, Sedgwick Yard.

About T-SIGn

Akamis Bio’s T-SIGn therapeutics are based on a replication competent, chimeric group B adenovirus backbone which has been adapted via directed evolution to home specifically to both primary and metastatic epithelial-derived solid tumor tissue following intravenous delivery. Once at the tumor site, T-SIGn therapeutics can drive the intratumoral expression of multiple transgene payloads, turning solid tumor cells into "drug factories" while leaving healthy tissue unaltered and intact. The intratumoral expression of immunologically active biomolecules and therapeutic proteins can result in the remodeling of the solid tumor microenvironment, triggering robust antitumor immune responses. T-SIGn therapeutics have the potential to be used in the monotherapy setting, as well as in combination with other immuno-oncology agents to target the key mechanisms that tumors use to evade the immune system.