On June 24, 2022 Bold Therapeutics, a clinical-stage biopharmaceutical company, reported that they will be attending the Metals in Medicine Gordon Research Conference focusing on Advancing the Use of Metal-Based Compounds and Nanotheranostics for Personalized Medicine (Press release, Bold Therapeutics, JUN 24, 2022, View Source [SID1234616254]). The conference will be held in Andover, New Hampshire from June 26 to July 1, 2022, bringing together over 150 academic, industry, and government experts.

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Adam Carie, Director of CMC & Nonclinical Development, will be presenting on behalf of Bold Therapeutics in the "Clinical Advances for Metals in Medicine" session. He is joined by Shane Harrypersad, Senior Scientist, CMC.

This presentation will include previously embargoed data (shown below) recently presented at the 2022 American Society of Cancer Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in a session entitled "BOLD-100-001 (TRIO039): A Phase 1b dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid cancers: Interim safety, tolerability, and efficacy." In addition to demonstrating that BOLD-100 was safe and generally well-tolerated, this data showed remarkable outcomes in the treatment of 3rd line or later treatment-resistant metastatic colorectal cancer (mCRC) in combination with FOLFOX – including in patients that had previously failed on FOLFOX alone. In the initial six patients, Progression-Free Survival (PFS) significantly exceed expected PFS for this patient population, handily exceeding the current best-in-class approved therapies for 3rd line mCRC, Bayer’s Stivarga (regorafenib) and Taiho’s Lonsurf (trifluridine and tipiracil).

While only the earliest efficacy data from the Phase 1b portion of the study was available for presentation at ASCO (Free ASCO Whitepaper), the colorectal arm of the BOLD-100-001 Phase 2 trial has since fully enrolled (N=22) and Bold Therapeutics expects to announce additional efficacy data in mCRC by year-end.

Bold Therapeutics’ BOLD-100 is a first-in-class ruthenium-based small molecule therapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition; and (2) induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest. Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies ranging from traditional chemotherapies to targeted therapies to immuno-oncology agents. BOLD-100 is currently being studied in a multinational Phase 2 trial in the treatment of advanced gastrointestinal cancers actively enrolling at 13 clinical sites: six in Canada; two in the U.S.; and five in South Korea.

"Bold Therapeutics is excited to present these remarkable results at the Gordon Research Metals in Medicine Conference showcasing the cutting-edge, multi-disciplinary work being performed at Vancouver-based Bold Therapeutics" noted Dr. Carie. "With our Phase 2 clinical trial well underway at sites in Canada, the United States, and South Korea, we are excited to connect with other leaders in the development of metal-based oncology therapeutics with a goal of improving outcomes for patients. With unique expertise in metallochemistry and manufacturing, translational research and rapid and efficient early-stage clinical development, Bold Therapeutics is actively seeking additional preclinical-stage metal-based therapeutics to in-license, develop and commercialize."

In parallel, Bold Therapeutics is actively seeking global development partners to support two additional parallel Phase 2 studies: (1) BOLD-100 in combination with a proteasome inhibitor (e.g. Takeda’s Velcade (bortezomib) or Amgen’s Kyprolis (carfilzomib)) in the treatment of multiple myeloma; and (2) BOLD-100 in combination with a standard-of-care agent in the treatment of bladder cancer. Compelling preclinical data supporting these development initiatives is available under confidentiality.

On June 24, 2022 Genor Biopharma (Stock code: 6998.HK) reported that the company has entered into a cooperative development agreement (the "Cooperative Development Agreement") with Suzhou Abogen Biosciences Co., Ltd ("Abogen") to jointly develop globally innovative mRNA products and related pharmaceuticals (Press release, Genor Biopharma, JUN 24, 2022, View Source [SID1234616255]).

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According to the Cooperative Development Agreement, the Group’s biological antibody development platform will be integrated with Abogen’s mRNA technology platform to enable the Group and Abogen to jointly research and develop mRNA drugs for tumor treatment.

As an innovative, platform and integrated company with the ability to carry out innovative medical research and development, preclinical research, clinical development, registration, Chemistry, Manufacturing and Controls (CMC) development and commercialised manufacturing, the Company strives to develop globally innovative advantageous products with patents around the world. At present, the Company has successfully established the global first-in-class ("FIC")/ best-in-class ("BIC") differential research and development platform for early identifying bi-specific/multi-specific antibodies in immune-oncology. Innovation and exploration of FIC/BIC potential have been conducted in multi-dimension based on the in-depth understanding of our research and development team regarding targeted antibody molecular biology, cell biology and immunological mechanisms. To date, a number of projects for discovering bi-specific/multi-specific antibodies with FIC/BIC potential have been initiated. The Company is optimistic about the prospects of the application of mRNA technology in the pharmaceutical field. Through this cooperation, the Company expects to fully leverage the Company’s early exploration of highly differential FIC/BIC potential and the advantages of the respective platforms of both parties to accelerate the exploration and research and development of potential mRNA drugs for tumor treatment.

On June 24, 2022 (the "Closing Date"), G1 Therapeutics, Inc. (the "Company"), as borrower, and Hercules Capital, Inc. and certain of its affiliates (collectively, the "Lender") reported that entered into a third amendment (the "Third Amendment") to amend that certain loan and security agreement, dated as of May 29, 2020, as amended by the First Amendment to Loan and Security Agreement, dated as of March 31, 2021 (the "First Amendment") and the Second Amendment to Loan and Security Agreement, dated as of November 1, 2021 (the "Second Amendment"); the loan and security agreement, as amended by the First Amendment, the Second Amendment and the Third Amendment, the "Loan and Security Agreement"), under which the Lender has agreed to lend the Company up to $150.0 million, to be made available in a series of tranches, subject to specified conditions (Filing, 8-K, G1 Therapeutics, JUN 24, 2022, View Source [SID1234616242]). The total loan amount outstanding is $75.0 million. The Third Amendment extends the time for drawing the Tranche 1D Advance (as defined in the Loan and Security Agreement) of up to $25.0 million from September 15, 2022 to December 31, 2022.

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The Third Amendment adds a minimum cash covenant whereby the Company must maintain unrestricted cash equal to at least 50% of the outstanding debt, and such percentage shall decrease upon the Company achieving specified net product revenue of COSELA. The Third Amendment further provides for a minimum revenue covenant that, beginning August 15, 2022, with the reporting of the financial results for the second fiscal quarter ended June 30, 2022, and tested monthly, the Company must have achieved net product revenue of COSELA of at least 80% of the amounts projected in the Company’s forecast. Testing of the minimum revenue covenant shall be waived at any time in which either (a) the Company’s market capitalization exceeds $750.0 million and the Company maintains unrestricted cash equal to at least 50% of the total amounts funded, or (b) the Company maintains unrestricted cash equal to at least 100% of the total amounts funded.

The foregoing description is only a summary of certain provisions of the Third Amendment and is qualified in its entirety by reference to the Third Amendment, a copy of which will be filed as an exhibit to the Company’s Quarterly Report on Form 10-Q for the quarter ending June 30, 2022 and will be incorporated by reference herein.

On June 24, 2022 Chimeric Therapeutics Ltd (ASX:CHM) reported the first ever trial studying NK cells in combination with IL-2 and Vactosertib, using Chimeric’s CORE NK platform cells (Press release, Chimeric Therapeutics, JUN 24, 2022, View Source [SID1234616225]).

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The Phase 1B investigator-initiated trial has been approved by the US Food and Drug Administration (FDA) and will enrol 12 patients at UH Seidman Cancer Center in Ohio, with either locally advanced or metastatic colorectal cancer or relapsed/refractory blood cancers.

Chimeric’s CORE NK platform is a novel NK cell therapy platform of ex-vivo expanded non-HLA*-matched universal donor NK cells.

Safety and early efficacy demonstrated
The CORE NK platform was studied in a Phase 1A clinical trial demonstrating safety and an early efficacy signal in patients with metastatic colorectal cancer and refractory haematological malignancies.

The new study seeks to build upon responses observed during the initial CORE NK clinical trial, by co-administering the CORE NK cells with subcutaneous IL-2 and oral Vactosertib.

Study looks at combination
IL-2 is known to activate NK cells by stimulating proliferation and enhancing function.

Vactosertib is an oral TGF-β receptor inhibitor that can potentially disrupt the TGF-β signalling pathway, which has been shown to limit the effectiveness of immune therapies like NK cells.

"Vactosertib has never been used in combination with NK cells in the clinic, but it has been used in humans in other clinical trials," said UH Seidman oncologist Dr J Eva Selfridge, assistant professor at Case Western Reserve University School of Medicine in Ohio, who will lead the upcoming trial.

NK cells can "actually make it into the tumours"
"The goal of using it in this trial is to disrupt the TGF-β signaling pathway that is so strong in colorectal cancer and cells. We want to shut down that TGF-β signaling pathway so that the NK cells can actually make it into the tumours. Once they’re there, they have a chance of being active instead of just being silenced right away."

Dr. Selfridge says she is hopeful this new clinical trial at UH Seidman Cancer Center will present patients with more and better options for treatment and care: "T cell-directed immunotherapy is only available for 5% or less of cancer patients, but immunotherapy is really the only way we have to cure people with metastatic disease," she said.

"We’re just beginning our study, but ultimately the goal is to find immune therapies that work long-term."

Busy clinical pipeline
The study adds to CHM’s busy clinical pipeline, with now four clinical trials in progress or planned within 9 months.

"With the initial positive results seen in the Phase 1A clinical trial with our CORE NK Platform cells, we have been eager to accelerate the development opportunities for it," said Chimeric CEO Jennifer Chow.

"This study looks to combine novel therapeutics to overcome the challenges that are commonly thought to limit disease responses to NK cells.

"We hope that this combination will allow us to see more complete responses in patients with difficult to treat diseases, like the one seen in the Phase 1A study that has resulted in complete tumour eradication for more than 15 months now."

On June 24, 2022 Green3Bio, a subsidiary of Greenfire Bio, reported a publication in the Journal of Clinical Investigation1 led by researchers at The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors, including GRN-300 sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors (Press release, Greenfire, JUN 24, 2022, View Source [SID1234616243]).

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Zhen Lu, M.D., and Robert Bast, M.D., and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to enhance PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance.

The major findings from the preclinical research study include:

GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity
The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300
GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis
Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC.
These findings provide strong preclinical evidence supporting future clinical trials to determine whether the combination will benefit patients with ovarian and triple negative breast cancers. Animal studies, particularly those with olaparib and GRN-300, did not show significant toxicity based on weight loss. Pre-clinical toxicology studies in rodents and dogs showed no hematologic toxicity, which is particularly important for combination with PARPi.

"Patients with ovarian and triple-negative breast cancers are in great need for more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition," said Steve Morris, MD (Chairperson, Scientific Advisory Board of Greenfire Bio). He added, "The GRN-300 preclinical data published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through SIK2/3 inhibition to help change the combination treatment paradigm in gynecologic and breast cancers, irrespective of BRCA mutation status."

Ajit Gill, CEO and founder of Greenfire Bio, commented that "This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve treatment of ovarian and other cancers – both as a single agent and in combination with existing therapies such as the PARP inhibitor olaparib that is indicated for the treatment of ovarian and breast cancers under the tradename Lynparza."

These data further support the preclinical proof-of-concept for SIK2 inhibitors as potential cancer therapeutics in combination with carboplatin for hard-to-treat ovarian cancer, recently published in Cancers, and they support the continued efforts in our first-in-human clinical trial ongoing at MD Anderson.

About Ovarian Cancer

According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%.

About GRN-300

GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play [an] oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth & inhibition in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as a single agent and in combination with paclitaxel is currently being evaluated in a Phase 1a/1b Clinical Study in subjects with Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers (ClinicalTrials.gov Identifier: NCT04711161).