On January 10, 2024 Debiopharm, an independent biopharmaceutical company headquartered in Switzerland, and ThinkingNodeLife.ai (TNL), a trailblazer in AI Digital Cells Lab in USA, reported a collaborative partnership aimed at advancing the development of a cutting-edge cancer drug (Press release, Debiopharm, JAN 10, 2024, View Source [SID1234639194]). This strategic alliance leverages the unique capabilities of TNL’s AI Digital Cells Lab platform and Debiopharm’s deep pharmaceutical expertise to bring cancer drugs into new frontiers of innovation.

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Key Highlights of the Partnership: 1) Expanding Indications: The partnership will harness TNL’s AI Digital Cells Lab platform to explore additional indications for one of Debiopharm’s cancer drugs. 2) Drugs’ Combination Identification: Utilizing TNL’s AI digital knockdowns, it will identify valuable combinations with other drugs in development, enhancing the therapeutic potential of Debiopharm’s cancer drug. 3) Mechanism of Action Validation: TNL’s mechanistic digital cell clones will be instrumental in validating the mechanism of action of Debiopharm’s cancer drug, ensuring a deep understanding of its efficacy. 4) Drugs’ Comparison: TNL’s digital cell clones will provide comparative analysis, allowing Debiopharm to assess its cancer drug against other existing cancer treatments. 5) Biomarker Discovery: TNL partnership will focus on identifying valuable predictive biomarkers.

"We’re intrigued to discover what this collaboration with ThinkingNodeLife.ai will bring to the advancement of our oncology drug programs. Integrating AI-powered solutions into our research processes, such as TNL’s AI-Enabled Digital Cells Lab platform, aligns with our aim to adopt smarter practices in our R&D, in order to broaden drug application to more cancer types and speed up the time it takes to bring new drugs to patients," explained Bertrand Ducrey, CEO of Debiopharm.

"We are excited to start this strategic partnership with Debiopharm, a highly esteemed and innovative Swiss pharmaceutical company. We are confident that the synergy between TNL’s unique Digital Cell Clones Lab platform and Debiopharm’s profound expertise in drug R&D will show the transformative potential of AI-enabled Digital Labs from disease-target discovery to the optimization of clinical trials. As we look forward to an exhilarating 2024, we believe this partnership will pave the way for significant advancements in the field of drug R&D for the benefit of the patients," explained Khai Pham, CEO of ThinkingNodeLife.ai

On January 10, 2024 According to preclinical research published online today in Cell, one of the world’s premier scientific journals, researchers with City of Hope, one of the largest cancer treatment and research organizations in the United States, reported that a type of immune cell in the human body known to be important for allergy and other immune responses can also attack cancer (Press release, City of Hope, JAN 10, 2024, View Source [SID1234639193]).

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Furthermore, these cells, called human type 2 innate lymphoid cells (ILC2s), can be expanded outside of the body and applied in larger numbers to overpower a tumor’s defenses and eliminate malignant cells in mouse models with cancer.

"The City of Hope team has identified human ILC2 cells as a new member of the cell family capable of directly killing all types of cancers, including blood cancers and solid tumors," said Jianhua Yu, Ph.D., a professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope and the study’s senior author. "In the future, these cells could be manufactured, preserved by freezing, and then administered to patients. Unlike T cell-based therapies, such as CAR T cells, which necessitate using the patient’s own cells due to their specific characteristics, ILC2s might be sourced from healthy donors, presenting a distinct potential therapeutic approach as an allogeneic and ‘off-the-shelf’ product."

In previous research focused on mouse cells, ILC2s had not consistently shown promise when tested for their cancer-killing abilities.

However in the highly translational labs at City of Hope, researchers prioritized the examination of human cells and found that human ILC2s do not work the same as mouse ILC2s.

"Typically, mice are reliable models for predicting human immunity, so it was a real surprise in the field to find that human ILC2s function as direct cancer killers while their mouse counterparts do not," said Michael Caligiuri, M.D., who is a co-senior author of the study and also a City of Hope professor in the Department of Hematology & Hematopoietic Cell Transplantation. "It is remarkable that something has evolved so distinctly in going from mouse to human."

Finding a New Function

To test human ILC2s, Yu and the team first isolated the cells from a blood sample. Then, they developed a novel platform, which in four weeks can expand ILC2s 2000-fold from those harvested in the body. They next injected these ex-vivo expanded ILC2s into mice engrafted with human acute myeloid leukemia (AML) or solid tumors, including pancreatic cancer, lung cancer, and glioblastoma. The results showed that this ILC2 population could kill these tumors via a previously unknown cancer-killing mechanism.

"One convincing and direct piece of evidence appeared when we placed one ILC2 and one tumor cell directly together and found that the tumor cell died, but the ILC2 cell survived," explained Yu. "This proves that the ILC2s directly killed the cancer cell in that absence of any other cell."

Yu noted that the ILC2s do not need to come from the cancer patient’s own cells, meaning that there may be the possibility of harvesting and freezing ILC2s from healthy donors for ILC2 treatment options in the future.

Investigating Killer Cells

Yu and Caligiuri have been investigating a different type of cancer killer called natural killer cells, or NK cells, for decades. In fact, Yu is founding director of the Natural Killer Cell Biology Research Program at City of Hope, a national leader in the field.

Yu and Caligiuri said ILC2s now represent a new member of the cytotoxic immune effector cell family, alongside NK cells and CD8+ T cells, which help the body fight against cancer. They are excited to see how researchers might be able to harness the collective power of these different killer cells to better fight other diseases as well.

Next Steps

Yu and Caligiuri caution that because they are still in the early days of understanding ILC2s’ cancer-killing functions, many questions remain. However, they plan to continue to work with their collaborators to understand and learn more about human ILC2s now that they know the cells are killers.

"We aim to really expand the applications of these findings, potentially beyond cancer treatments," Yu said, noting that ILC2s may even work against viruses, such as COVID-19. "Additionally, we are working towards translating our discovery into tangible clinical benefits."

The team has already jumped at least one hurdle in getting ILC2s to clinical trials, which is having enough of the product to test. ILC2s are rare in the body, Caligiuri said. The team has a platform to grow them quickly.

"You have to be able to expand these cells for human clinical trials and one of the exciting things is that we are on the right track," Caligiuri said. "At City of Hope, we have the advantage of access to our good manufacturing practices-compliant facilities that can manufacture cells for us and speed discoveries into clinical trials."

The study team also included lead authors Zhenlong Li, Rui Ma, and Hejun Tang from the Yu and Caligiuri labs, as well as David Artis, Ph.D., the Michael Kors Professor of Immunology and director of the Jill Roberts Institute for Inflammatory Bowel Disease Research at Weill Cornell Medicine. The work was supported by grants from the National Institutes of Health and The Leukemia & Lymphoma Society.

On January 10, 2024 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported The New England Journal of Medicine (NEJM) has published data from the registrational Phase 1/2 TRIDENT-1 study evaluating repotrectinib (TPX-0005) in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancers (NSCLCs) (Press release, Zai Laboratory, JAN 10, 2024, View Source [SID1234639192]). Repotrectinib is a tyrosine kinase inhibitor (TKI) that has shown robust anti-tumor activity against ROS1+ cancers in preclinical models. In the TRIDENT-1 study, repotrectinib demonstrated high response rates and durable activity in patients with ROS1+ NSCLC, including patients with TKI-naïve and TKI-pretreated tumors, ROS1 G2032R resistance mutations and brain metastases. Treatment with repotrectinib was generally well tolerated with a manageable safety profile compatible with long-term administration.

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Turning Point Therapeutics, a wholly owned subsidiary of the Bristol-Myers Squibb Company, sponsored and designed the global, registrational TRIDENT-1 study. In August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib. As part of its exclusive license agreement with Turning Point Therapeutics to develop and commercialize repotrectinib in Greater China (mainland China, Hong Kong, Taiwan, and Macau), Zai Lab participated and enrolled 81 patients for this trial.

Every year in China, more than 800,000 people are newly diagnosed with lung cancer, and NSCLC accounts for approximately 85% of the cases. ROS1 rearrangements occur in ≤2% of patients with NSCLC1. Brain metastases are common among patients with ROS1+ NSCLC and intracranial activity of approved ROS1 TKIs can be suboptimal.

"The results from the TRIDENT-1 study suggest repotrectinib results in high and durable response rates in patients with ROS1+ NSCLC, in the settings of both treatment naïve, treatment resistant, and intracranial disease, which may address the limitations of first-generation TKIs," said Rafael G. Amado, M.D., president, head of Global Oncology Research and Development, Zai Lab. "We look forward to advancing the development of repotrectinib in Greater China as a next generation treatment in this clinical setting."

TRIDENT-1 is a registrational, first-in-human Phase 1/2 study assessing the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1+ NSCLC. In the study, 519 patients received one or more doses of repotrectinib, with 103 treated in Phase 1 and 416 treated in Phase 2. Primary endpoints were maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) and confirmed objective response rate (ORR), as assessed by blinded independent central review (BICR) using RECIST v1.1 (Phase 2). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety.

Based on the results of this trial, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) accepted the New Drug Application (NDA) for repotrectinib submitted by Zai Lab for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC, after granting priority review in May 2023. In November 2023, the U.S. Food and Drug Administration approved repotrectinib for use in adult patients with locally advanced or metastatic ROS1+ NSCLC in the United States.

About Repotrectinib

Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) targeting the ROS1 and NTRK oncogenic drivers of advanced solid tumors, including non-small cell lung cancer (NSCLC). Patients with tumor harboring ROS1 and NTRK gene fusions treated with approved targeted therapies often develop resistance mutations, eventually leading to tumor progression. Repotrectinib is the first next-generation TKI for ROS1-positive metastatic NSCLC and tumors with NTRK fusions, uniquely designed to address key drivers of disease progression.

In China, repotrectinib has been granted four Breakthrough Therapy Designations from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in ROS1-positive metastatic NSCLC patients who have not been treated with a ROS1 TKI; ROS1-positive metastatic NSCLC patients who have previously been treated with a ROS1 TKI and who have not received prior platinum-based chemotherapy; ROS1-positive metastatic NSCLC patients who have previously been treated with a ROS1 TKI and one prior line of platinum-based chemotherapy; and patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with prior TRK tyrosine kinase inhibitors (TKIs).

Zai Lab has an exclusive license agreement with Turning Point Therapeutics, a wholly owned subsidiary of the Bristol-Myers Squibb Company, to develop and commercialize repotrectinib in Greater China (mainland China, Hong Kong, Taiwan and Macau).

On January 10, 2024 WuXi Biologics ("WuXi Bio") (2269. HK), a leading global Contract Research, Development, and Manufacturing Organization (CRDMO), reported that its Research Service Unit (R in CRDMO) has signed a research service agreement with BioNTech SE (Nasdaq: BNTX, "BioNTech"), a next generation immunotherapy company pioneering novel therapies for cancer and other serious diseases (Press release, WuXi Biologics, JAN 10, 2024, View Source [SID1234639191]).

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Under the terms of the agreement, WuXi Biologics leverages its proprietary antibody discovery technology platforms (R in CRDMO) to discover two undisclosed targets of preclinical investigational monoclonal antibodies for BioNTech to develop next-generation therapeutic product candidates. WuXi Biologics will receive a $20 million upfront payment for granting exclusive rights to these investigational monoclonal antibodies to BioNTech and is eligible to receive additional payments, including payments for research, development, regulatory, and commercial milestones, as well as tiered royalties.

Dr. Chris Chen, CEO of WuXi Biologics, commented, "Our unique CRDMO model is proven again. We are very pleased to support BioNTech’s growing innovative pipeline with antibodies discovered through our leading integrated discovery platforms. This agreement demonstrates our continued recognition as an industry leader in discovery service solutions, and further validates our ability to provide integrated discovery technology platforms for global partners to develop new modalities. We are looking forward to working with BioNTech with the aim of bringing potential new therapeutics with improved outcomes to patients worldwide."

WuXi Biologics offers a full spectrum of both end-to-end and modular discovery services – from idea to preclinical candidate identification – using industry-leading technology platforms and comprehensive discovery capabilities. The company’s discovery technology platforms for the generation, characterization, engineering, optimization and selection of novel antibody and biologic therapeutics include: hybridoma technology; single B cell cloning technology; phage display and yeast display technology; immune and synthetic human scFv and VHH libraries; human IgG transgenic platforms through an OmniAb and Alloy partnership; WuXiBody and SDarBody bispecific/multispecific antibody platforms; and other antibody and biologics generation and optimization technologies. All technology platforms are supported by WuXi Biologics’ comprehensive research material generation and assay development capabilities.

On January 10, 2024 Ascentage Pharma (6855.HK), a commercial stage global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that Dr. Dajun Yang, the company’s Chairman and CEO, gave a speech at the 42nd Annual J.P. Morgan Healthcare Conference (Press release, Ascentage Pharma, JAN 10, 2024, View Source [SID1234639190]). In the presentation, Dr. Yang provided an update on Ascentage Pharma’s recent major milestones and the formidable competitiveness the company has built in the field of hematologic malignancies, all achieved under its patient-centric global innovation strategy.

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Approvals for multiple global registrational Phase III trials mark new milestones in global innovation
As an innovative drug company pursuing a patient-centric global innovation strategy, Ascentage Pharma has achieved major milestones with its global expansion in 2023, including approvals for multiple global registrational Phase III studies of olverembatinib (HQP1351) and lisaftoclax (APG-2575), two of the company’s key drug candidates.

In-house developed by Ascentage Pharma, the novel drug olverembatinib is the first and only China-approved third-generation BCR-ABL inhibitor that filled a major treatment gap for Chinese patients with drug-resistant CML. In July 2023, the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) approved a global registrational pivotal Phase III study of olverembatinib, Ascentage Pharma’s lead drug candidate, in combination with chemotherapy versus imatinib in combination with chemotherapy for the treatment of newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This approval marks a major milestone that could potentially pave the way for olverembatinib to become the first tyrosine kinase inhibitor (TKI) approved in China for the treatment of patients with Ph+ ALL in the first-line setting.

In August 2023, the US Food and Drug Administration (FDA) cleared a global registrational pivotal Phase III study of the Bcl-2 inhibitor lisaftoclax, another one of Ascentage Pharma’s key drug candidates, in previously treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This regulatory clearance marked a major step in the global clinical development of lisaftoclax as it can potentially accelerate the drug’s journey to market as the world’s second approved Bcl-2 inhibitor, further validating the company’s capabilities in innovation and global clinical development.

Two months after that, lisaftoclax achieved another breakthrough with a clinical trial approval by the China CDE for a global registrational pivotal Phase III study of lisaftoclax combined with the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib, versus immunochemotherapy for the first-line treatment of naïve patients with CLL/SLL.

Olverembatinib approved for a new indication while having its global first-in-class potential further validated
Ever since launching olverembatinib, Ascentage Pharma has stepped up the commercialization of the drug and achieved a range of breakthroughs. In January 2023, as a frontrunner among National Major New Drug Development designated drugs in China, olverembatinib was included into the China 2022 National Reimbursement Drug List (NRDL), thus saw its accessibility and affordability drastically improved.

In November 2023, the NMPA approved a new indication of olverembatinib for the treatment of adult patients with chronic-phase chronic myeloid leukemia (CML-CP) resistant and/or intolerant of first-and second-generation TKIs, allowing a broader population of patients with CML to benefit from the drug.

At the recently concluded 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, eleven abstracts on olverembatinib were selected for presentations, including two Oral Presentations, making 2023 the sixth consecutive year in which data of olverembatinib were selected for Oral Presentations at the meeting. This is another indication of the strong global best-in-class potential of olverembatinib.

Data from the Chinese study of olverembatinib (HQP1351CC203), selected for an Oral Presentation at ASH (Free ASH Whitepaper) 2023, showed that in patients with CML-CP resistant and/or intolerant to prior treatment with TKIs, the olverembatinib arm achieved statistically significant improvement in event-free survival (EFS) compared to the control arm that was treated with the best available therapy (BAT), thus meeting the primary endpoint of the study with markedly improved prognosis for patients with CML in the olverembatinib arm, compared to those in the control arm.

Meanwhile, results from the US study of olverembatinib were equally encouraging. After releasing preliminary results of the US study in an Oral Report at the ASH (Free ASH Whitepaper) Annual Meeting in 2022, at ASH (Free ASH Whitepaper) 2023, Ascentage Pharma presented updated data from a larger patient sample that showed the favorable clinical benefit and tolerability of olverembatinib, as a monotherapy and in combinations, in heavily pretreated patients with CML and Ph+ ALL, particularly those who have failed prior treatment with the third-generation TKI ponatinib or the allosteric STAMP inhibitor asciminib. These results suggest that olverembatinib has global potential as an effective new therapy for patients with CML or Ph+ ALL.

The company is extensively exploring and validating olverembatinib’s therapeutic potential in indications other than CML, and the drug has shown particularly promising utility for the treatment of Ph+ ALL. Results from multiple studies evaluating olverembatinib in patients with Ph+ ALL were presented at ASH (Free ASH Whitepaper) 2023, including an Oral Presentation featuring a study that showed encouraging clinical benefit and favorable tolerability of olverembatinib, a potent third-generation TKI, combined with reduced-intensity chemotherapy in patients with Ph+ ALL, indicating the regimen has the potential of ushering in an era of chemotherapy-free treatment for Ph+ ALL.

While solidifying its presence and competitiveness in hematologic malignancies, Ascentage Pharma has also expeditiously advanced its clinical development of olverembatinib for the treatment of gastrointestinal stromal tumor (GIST). In 2023, the second year in which clinical results of olverembatinib in patients with GIST were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma released data that showed encouraging clinical benefit and favorable safety of olverembatinib in patients with TKI-resistant succinate dehydrogenase (SDH)-deficient GIST.

Bcl-2 inhibitor lisaftoclax showed promising clinical benefit for patients with CLL and strong therapeutic potential in AML and MM
Also during his speech, Dr. Yang reviewed the recent progress in the development of lisaftoclax, alluding to key data released at ASH (Free ASH Whitepaper) 2023.

As the first Bcl-2 inhibitor that has entered registrational pivotal trials in China and the second globally, lisaftoclax is a novel therapeutic with global best-in-class potential.

At ASH (Free ASH Whitepaper) 2023, Ascentage Pharma released results from three studies of lisaftoclax, including one study in patients with relapsed/refractory (R/R) CLL that showed an overall response rate (ORR) of 73.3%; a complete remission (CR)/CR with incomplete blood count recovery (CRi) rate of 24.4%; and a positive correlation between CR/CRi rate and dose levels, in patients who received lisaftoclax. In addition, the study observed a low incidence of tumor lysis syndrome (TLS) that is comparable to the results of earlier studies. While in long-term follow-up, the study observed a 30-month overall survival (OS) rate of 86.3% that indicated the drug’s high response rates, safety for long-term use, and potential in bringing durable survival benefit to patients with CLL.

In addition, Ascentage Pharma released the first dataset of lisaftoclax in patients with multiple myeloma (MM) and acute myeloid leukemia (AML) at ASH (Free ASH Whitepaper) 2023. These data revealed strong therapeutic potential and provide a solid foundation for the continued development of lisaftoclax in indications outside CLL. Dr. Yang also mentioned in his speech that a registrational Phase III study of lisaftoclax in AML has already been approved by the China CDE and is being initiated.

Accelerating global innovation to achieve enhanced global competitiveness
Under its overarching global innovation strategy, Ascentage Pharma has built a rich pipeline composed of highly promising drug candidates with first-in-class and/or best-in-class potentials, and is conducting more than 40 clinical studies in China, the US, Australia, Europe, and Canada. The company’s innovative and clinical development capabilities have received growing recognition from the global research community as the clinical data on a number of its drug candidates were frequently showcased at major international congresses.

In his talk, Dr. Yang outlined a series of potential catalysts for 2024, including the FDA clearance for the registrational Phase III study of olverembatinib, NDA submissions for lisaftoclax, rapid progress with multiple global registrational Phase III studies, and the NRDL inclusion of olverembatinib’s new indication.

"It is my great pleasure to attend the annual J.P. Morgan Healthcare Conference this year and have the opportunity to provide an update on the key progress we delivered in 2023," said Dr. Dajun Yang. "In the past year, we received clearance for multiple global registrational Phase III studies, taking major steps forward in our global expansion; we continuously expanded the target indications of our core drug candidates and further solidified our leadership position in the arena of hematologic malignancies. Moving forward, we will continue to execute our global innovation strategies, accelerate our global registrational Phase III studies, and make further strides fulfilling our mission of addressing unmet clinical needs in China and around the world for the benefit of more patients."