On June 19, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported that China’s National Medical Products Administration (NMPA) has approved the clinical trial application for GFH375 (VS-7375) in an open-label, multi-center phase I/II study targeting advanced solid tumor patients with KRAS G12D mutation (Press release, GenFleet Therapeutics, JUN 19, 2024, View Source [SID1234644443]). G12D mutation is the most prevalent KRAS mutation detected in human cancers, and no G12D-targeted therapies have been approved yet.

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GFH375 is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. According to the latest preclinical findings posted at 2024 AACR (Free AACR Whitepaper) annual meeting, GFH375 demonstrated preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models; moreover, GFH375 holds the potential for treating G12D-mutant cancers with brain metastases.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs. The first program selected is GFH375, which represents a significant milestone as the GenFleet’s first product to achieve overseas out-licensing at preclinical stage and the IND approval in China, underscoring the company’s expertise in the development of RAS-targeted therapies.

The study (GFH375X1101) will be conducted at ~40 hospitals, including the prominent Shanghai Chest Hospital. In phase I, the study aims to evaluate the safety/tolerability and preliminary efficacy of GFH375 in advanced G12D-mutant solid tumor patients. Additionally, the phase I trial will determine the recommended phase II dose (RP2D). Progressing into Phase II, the study will further assess the efficacy of GFH375 for patients of advanced solid tumors including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – three cancer types with highest prevalence of G12D mutation; the study will also investigate the underlying mechanisms of patients’ response and resistance to the treatment.

"I am excited that the clinical trial application for GFH375 has been approved. The therapeutic landscape for G12D-mutant cancers remains challenging with limited treatment options, highlighting the significant unmet medical needs in this population. The G12D mutation is one of the most prevalent KRAS mutations and the development of G12D-targeted therapies has garnered significant attention recently. We eagerly await favorable safety and efficacy outcome for GFH375 in the upcoming trial, with the hope of introducing a novel life-saving treatment for patients." stated Dr. Shun Lu, professor of Dept. of Medical Oncology, Shanghai Chest Hospital.

"We are delighted to enter in a clinical trial to assess the clinical benefits of our G12D targeted program in monotherapy setting and explore the possibilities of synergistic effects that may arise from potential combination regimen in future. GenFleet’s expertise in developing RAS-targeted therapies has been exemplified by the successful development of fulzerasib (GFH925, a KRAS G12C inhibitor) and the NDA acceptance of its monotherapy for NSCLC in China. This allows GenFleet to be well positioned to advance our second RAS pathway inhibitor GFH375 into the clinical trial, as well as other RAS-inhibiting therapies in our pipeline." stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet.

References:

1. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma, NPJ Precision Oncology, Feb. 2024

2. Next batter up! Targeting cancers with KRAS G12D mutations, Trends in Cancer (Cell Press), Nov. 2023

3. Pan-KRAS inhibitor disables oncogenic signaling and tumor growth, Nature, May 2023

About KRAS G12D mutation and GFH375

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alterations are the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.

GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain rights inside of the Chinese mainland, Hong Kong, Macau, and Taiwan.

On June 19, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported that the National Medical Products Administration of China has approved golidocitinib for the treatment of adult patients with relapsed or refractory (r/r) peripheral T-Cell lymphoma (PTCL) whose disease has progressed on or were refractory to at least 1 prior systemic therapy (Press release, Dizal Pharma, JUN 19, 2024, View Source [SID1234644442]). To date, golidocitinib is the first and only approved Janus kinase 1 (JAK1) selective inhibitor for r/r PTCL patients globally.

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PTCL is a heterogeneous group of aggressive T-cell/natural killer (NK) cell non-Hodgkin lymphomas (NHL). Patients with PTCL face an extremely high risk of disease relapse even if they achieved tumor remission following first-line conventional therapy. The outcome for relapsed or refractory patients is extremely poor, with a 3-year survival rate of 23% and a median overall survival (mos.) of 5.8 months. Although couple of drugs have been granted conditional approval by regulatory agencies in the relapsed or refractory setting, their single agent activities have been modest, with objective response rates (ORRs) lower than 30%.

Golidocitinib was approved based on findings from JACKPOT8 Part B (JACKPOT8B) study, the multinational pivotal study to evaluate the efficacy and safety of golidocitinib in r/r PTCL as a monotherapy. The primary endpoint was the objective response rate (ORR), assessed by an independent review committee (IRC). Full analysis of the study was simultaneously published in The Lancet Oncology and presented in oral session at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

In JACKPOT8B study, golidocitinib demonstrated superior and durable antitumor efficacy and a favorable safety profile in r/r PTCL patients, compared with existing treatment options. At the data cut-off date August 31, 2023, the ORR was 44.3% including a complete response (CR) rate of 23.9% per IRC. Tumor responses were observed across various PTCL subtypes. The median duration of response (mDoR) was 20.7 months and 53.8% of patients were still responding.

"Golidocitinib features novel mechanism and unique molecular design, positioning it as the first oral JAK1 only inhibitor for the treatment of r/r PTCL. Multiple studies have clearly demonstrated its favorable pharmacokinetic properties and significant clinical benefit," said Jun Zhu, MD, PhD at the Department of Lymphoma, Peking University Cancer Hospital and Institute, the leading principal investigator of the JACKPOT8B study, "Golidocitinib achieved an ORR of 44.3% and a DoR of 20.7 months in r/r PTCL. It’s approval and market launch provide a much needed option for doctors to treat PTCL patients."

Dizal was the first to identify and validate targeting the JAK/STAT pathway as a promising therapeutic approach for PTCL, leading to the development of golidocitinib as the world’s first JAK1 only inhibitor. With > 200 to 400-fold selectivity over other JAK family members and ideal pharmacokinetic properties, golidocitinib exerts potent antitumor efficacy with a favorable safety profile.

"We are thrilled to bring golidocitinib, the world’s first JAK1 only inhibitor, to patients in China, marking the second approved innovative drug from Dizal," said Xiaolin Zhang, PhD, CEO of Dizal. "Golidocitinib yields good antitumor efficacy across different subtypes of PTCL, which differentiate golidocitinib from other targeted therapies. At Dizal, we aspire to discover and develop first-in-class and groundbreaking new medicines to address unmet medical needs around the world. With the US FDA Fast Track designation, we are expediting global development of golidocitinib to bring this exciting drug to patients worldwide."

With superior efficacy and safety profile, golidocitinib has been widely acknowledged at prestigious international congresses including ASCO (Free ASCO Whitepaper), EHA (Free EHA Whitepaper), ICML, and ASH (Free ASH Whitepaper), with six oral presentations over four consecutive years. The results of the multinational study JACKPOT8 were published in Annals of Oncology and The Lancet Oncology.

About golidocitinib (DZD4205)

Golidocitinib is currently the first and only Janus kinase 1 (JAK1) selective inhibitor being evaluated for the treatment of r/r PTCL. In June 2024, golidocitinib was approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (r/r PTCL).

At the data cut-off date of August 31, 2023, golidocitinib has demonstrated robust and durable anti-tumor efficacy, with an ORR of 44.3%. More than 50% of the patients with tumor remission achieved a complete response with a CRR of 23.9%. Per IRC assessment, mDoR reached 20.7 months. Golidocitinib was granted Fast Track Designation by the U.S. FDA for the treatment of r/r PTCL in February 2022. In September 2023, the CDE accepted its NDA and granted Priority Review for the treatment of r/r PTCL. The Phase I clinical data of golidocitinib (JACKPOT8 PART A) was published in Annals of Oncology (Impact Factor: 51.8), and global pivotal trial data of golidocitinib for the treatment of r/r PTCL (JACKPOT PART B) was published in The Lancet Oncology (Impact Factor: 54.4).

On June 19, 2024 Theralase Technologies Inc. ("Theralase" or the "Company") (TSXV: TLT) (OTCQB: TLTFF), a clinical stage pharmaceutical company dedicated to the research and development of light and/or radiation activated small molecules and their formulations, intended for the safe and effective destruction of various cancers, bacteria and viruses, reported that it’s lead drug formulation, Rutherrin, has demonstrated an ability to provide a complete response in a Non-Small Cell Lung Cancer ("NSCLC") animal model (Press release, Theralase, JUN 19, 2024, View Source [SID1234644441]).

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Theralase recently press released its latest research, using a well-established Lewis Lung Cancer ("LLC1") orthotopic model, representing NSCLC. In this model, mouse lungs are implanted with lung cancer cells, inducing these mice to develop very aggressive, fast growing and metastatic lung tumors.

The mice were treated with x-ray radiation only as a control and x-ray activated Rutherrin as the active arm. The mice treated with x-ray activated Rutherrin demonstrated up to a 4-fold reduced tumor progression, based on Computerized Tomography ("CT") scan assessment of tumor volumes.

These results demonstrate that animals treated with a combination of Rutherrin and radiation therapy showed an increase in median survival from 26 to 35 days, versus radiation only. In scientific publications, mouse survival of 9 days has been equated to the equivalent of 1 year survival in humans, but more importantly, is that one animal treated with the x-ray activated Rutherrin (which had a positive lung tumor verified by CT scan) demonstrated a complete response and is now considered cancer free.

Dr. Arkady Mandel, M.D., Ph.D., D.Sc., Chief Scientific Officer of Theralase stated, "The latest preclinical research demonstrates the ability of x-ray activated Rutherrin to eradicate lung cancer in an animal model. This is initial research and through optimization, Theralase hopes to achieve a complete response in a much greater percentage of animals, but this initial data is extremely encouraging. As a result of this latest success, Theralase has committed to bringing this technology to market through the systematic research and development of this cutting-edge clinical therapy to safely and effectively destroy various cancers in patients. As a direct result, our list of cancer targets has increased from bladder cancer, which in the late stage of clinical development, to encompass brain cancer, lung cancer and various blood-based cancers, such as: leukemia, lymphoma and multiple myeloma."

Roger DuMoulin-White, B.E.Sc., P.Eng., Pro.Dir., President and Chief Executive Officer of Theralase stated, "This latest research symbolizes the significant progress Theralase has made over the last few years in the research and development of world-class systemic and targeted therapies for the treatment of various hard-to- treat cancers, such as: bladder cancer, brain and lung cancer. Pending sufficient capitalization and completion of a Good Laboratory Practice ("GLP") toxicology analysis for Rutherrin, Theralase plans to commence clinical studies for brain cancer, lung cancer and various blood-based cancers. If proven safe and effective in humans, Theralase hopes to change the paradigm of how patients diagnosed with cancer are treated in the future."

About Lung Cancer:

Lung cancer is the leading cause of cancer death worldwide. Most patients die of progressive metastatic disease despite aggressive local and systemic therapies. The survival rate for lung cancer depends on the type, stage and age of the patient, with the overall 5-year survival rate for all types of lung cancer about 26.6%. Lung cancer is histologically classified into two main types: Small Cell Lung Cancer ("SCLC"), which accounts for approximately 15% of the patients diagnosed with lung cancer and Non-Small Cell Lung Cancer ("NSCLC"), which accounts for approximately 85%.

On June 19, 2024 TAE Life Sciences reported a significant presence at the 20th International Congress on Neutron Capture Therapy (ICNCT), taking place in Krakow, Poland, from June 24 to 28, 2024 (Press release, TAE Life Sciences, JUN 19, 2024, View Source [SID1234644438]). This biennial event is the premier conference for advancements in the field of boron neutron capture therapy (NCT) and serves as a vital platform for researchers, clinicians, and industry professionals to share their latest findings and technological advancements in all aspects of BNCT.

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The 20th ICNCT conference will feature presentations, workshops, and discussions on various aspects of neutron capture therapy, including basic research, clinical applications, technological advances, materials and compounds, and case studies.

TAE Life Sciences’ Contributions at ICNCT 2024:

Plenary Presentation by CEO Rob Hill:
When: Wednesday, June 26 at 11:00 AM
Topic: State of TAE Life Sciences and BNCT Future Directions
Oral Presentations:
Tuesday, June 25 at 3:00 PM: Warren Kilby will present "Pharmacokinetic modeling to extrapolate from mouse to human biodistribution data for new tissues and compounds."
Wednesday, June 26 at 3:50 PM: Chad Lee will present "Neutron Beam System for Accelerator BNCT in China: Status and Performance."
Poster Presentations:
Tuesday, June 25 from 1:30 to 3:00 PM:
Michael Torgov will present in the Chemistry of NCT Carriers poster session about "Antibody boron conjugates with a payload comprised of carborane-modified poly-L-lysine is capable of delivering boron to EGFR-expressing tumor cells."
Karen Morrison will participate in the Biology poster session about "First reported immunohistochemical studies and q-PCR expression of LAT-1 transporter in the hamster cheek pouch oral cancer model."
Thursday, June 27 from 12:00 – 1:30 PM
Chad Lee will present in the Engineering and Physics poster session about "Optical monitoring of the position and size of direct current particle beams."
Warren Kilby will present in the Medical Physics poster session about "The expected dose of radiation therapists at a high-throughput BNCT Center."
TAE Life Sciences is proud to contribute to the advancement of neutron capture therapy and to be part of this esteemed conference. We look forward to engaging with other professionals in the field, sharing our research and innovations, and exploring collaborative opportunities to further enhance the
effectiveness and application of NCT in the field of oncology.

If you’re interested in learning more about our presence at ICNCT or are planning to attend and would like to meet with the team, please email Anna Theriault at [email protected].

On June 18, 2024 Zentalis Pharmaceuticals, a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, reported that the U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on the following studies of azenosertib: the Phase 1 ZN-c3-001 dose-escalation study in solid tumors, the Phase 2 ZN-c3-005 (DENALI) study in platinum-resistant ovarian cancer (PROC) and the Phase 2 ZN-c3-004 (TETON) study in uterine serous carcinoma (USC) (Press release, Zentalis Pharmaceuticals, JUN 18, 2024, View Source [SID1234646059]). This action follows two recent deaths due to presumed sepsis in the DENALI study.

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"Patient safety is our top priority and any deaths that occur in the setting of clinical trials are unfortunate. We are working closely with the FDA to resolve this partial clinical hold as quickly as possible," said Kimberly Blackwell, M.D., Chief Executive Officer of Zentalis. "Over 500 patients have been treated with azenosertib monotherapy to date, and we believe that our data indicate a favorable therapeutic index that could potentially offer meaningful benefits to women facing PROC and USC. We have completed enrollment for Cohort 1b of the DENALI study, where we’ve enrolled more than a hundred patients, further demonstrating the support we’ve seen for having a novel oral therapy like azenosertib. We look forward to sharing these results along with overall efficacy and safety data from DENALI Cohort 1b later this year."

In addition to sharing topline results of Cohort 1b of DENALI, the Company remains on track to present results from the ZN-c3-001 and Phase 1/2 ZN-c3-006 (MAMMOTH) studies later this year. The Company will provide additional updates to the azenosertib clinical development and other data timelines following resolution of the partial clinical hold. Zentalis remains committed to the azenosertib development program and bringing this potentially practice-changing therapy to patients with gynecological malignancies.

Conference Call Details
Zentalis will host a live conference call and webcast today at 8:00 a.m. Eastern Time to provide a business update. To access the live conference call by telephone, please register at: https://register.vevent.com/register/BI24249bb9e5714044b9f4057f28565923. Upon registering, each participant will be provided with call details and access codes. The live webcast may be accessed by visiting the event link at: View Source The webcast will also be made available on the Company’s website at www.zentalis.com under the Investors & Media section. Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.