On July 15, 2024 Integrated DNA Technologies (IDT), a global leader in CRISPR genome editing solutions, reported a licensing agreement with SeQure Dx, a company focused on off-target analysis for preclinical and clinical gene modification customers, bolstering IDT’s complete CRISPR portfolio comprised of world-class RUO to CGMP solutions from design to analysis (Press release, INTEGRATED DNA TECHNOLOGIES, JUL 15, 2024, View Source [SID1234644880]). The licensing agreement enables IDT to support cell and gene therapy developers through all phases of their CRISPR-based therapeutic programs by providing comprehensive off-target analysis services, powered by SeQure Dx’s GUIDE-seq technology, alongside IDT’s award-winning rhAmpSeq CRISPR Analysis System.

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"Off-target effects continue to be a primary concern in genome editing and are still not fully understood," said Sandy Ottensmann, VP/General Manager, Gene Writing & Editing Business Unit at IDT. "With an increasing pipeline of CRISPR-based therapeutics that are entering and progressing in trials, the delivery of safer and more efficient genome editing platforms to the clinic becomes paramount. IDT’s expanded off-target analysis capabilities demonstrate a transformational shift we are making to support cell and gene therapy developers in their transition to the clinic, in a drive to make life-changing therapies as safe as possible."

Dr. Keith Joung, Scientific Founder of SeQure Dx, added, "SeQure’s best-in-class off-target nomination and confirmation platforms will seamlessly complement IDT’s CRISPR-based portfolio of products and services. By combining SeQure’s & IDT’s innovative technologies, this will enhance precision and safety in gene editing, bringing transformative solutions to researchers and patients worldwide."

The licensing agreement with SeQure Dx expands IDT’s comprehensive off-target analysis capabilities by providing the company access to SeQure Dx’s next generation sequencing-based gene editing off-target analysis technology, GUIDE-seq. Originally developed by Keith Joung’s group at Massachusetts General Hospital, GUIDE-seq is a widely used off-target nomination assay, making it an excellent starting point for developing and evaluating CRISPR-focused therapeutics. Broadly used by academic researchers, biotechs, large pharma and biopharma companies to help characterize potential off-target events in their genome editing results, GUIDE-seq provides genome-wide, unbiased identification of double-stranded breaks by sequencing. It has contributed in part to the successful development and release of multiple therapeutics.

IDT’s CRISPR Innovation Journey

Last year, to help address development and manufacturing challenges in a capacity-constrained market for CGMP/Q7 services, IDT opened a therapeutic oligonucleotide manufacturing facility in the U.S. to support the increased demand for high-quality cell and gene therapy components. These critical reagents are foundational to delivering on the promise of therapies to patients and are key to accelerating the path to clinic for developers.

With IDT’s proprietary rhAmpSeq CRISPR Analysis System, regulatory expertise, RUO to CGMP manufacturing capabilities, and dedicated support team, customers can expect differentiated off-target analysis services from a single provider for their CRISPR therapeutic development. Launched in 2021, IDT’s rhAmpSeq CRISPR Analysis System is an end-to-end solution for characterizing and quantifying the full array of on- and off-target genome editing events in CRISPR research products. The novel tool, endorsed by renowned scientists, continues to grow in popularity as an assay for off-target confirmation, and enables the robust analysis of resulting next generation sequencing data. For more information about IDT’s comprehensive off-target analysis services and capabilities, visit https://go.idtdna.com/OTE-analysis-request-consult.

On July 15, 2024 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported that data published in the journal Cell demonstrate that neoadjuvant monotherapy with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib results in a high response rate and reshapes the tumor microenvironment (TME), providing new targets for immunotherapy and combination regimens in patients with homologous recombination deficiency (HRD) positive ovarian cancer (Press release, Zai Laboratory, JUL 15, 2024, View Source [SID1234644879]). The study revealed niraparib preferentially suppresses certain immune cells that support the growth of HRD-positive ovarian tumors.

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This Zai Lab-supported study also showed that targeted clearance of infiltrating regulatory T cells (eTregs) using Zai Lab’s investigational CCR8 antibody, ZL-1218, significantly sensitized niraparib against HRD tumors, resulting in decreased tumor burden in pre-clinical models.

"Given the prevalence of HRD in cancer and its role in rendering tumors vulnerable to PARP inhibition, this study fills the knowledge gap regarding the impact of HRD and related therapies on the tumor microenvironment," said Professor Qinglei Gao, Chief of Gynecologic Oncology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. "By decoding the tumor-reactive T cells in the HRD-positive TME that are regulated by eTregs, these findings have profound implications for future oncology research and therapeutic development for HRD-positive ovarian cancer and other HRD-related cancers."

To investigate the effects of HRD, neoadjuvant therapies, and their interactions on the TME, investigators utilized tumor tissues from a clinical study (NCT04507841) evaluating niraparib for the neoadjuvant treatment of unresectable ovarian cancer. In parallel, tissue samples from patients receiving neoadjuvant chemotherapy (NACT) were also collected.

Profiling of these samples yielded valuable data delineating the divergence in TME between HRD-positive vs. homologous recombination-proficient (HRP) tumors, as well as their respective phenotypic evolution following the introduction of neoadjuvant therapies.

Key findings of the study included:

Patients receiving neoadjuvant monotherapy with niraparib achieved 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively.
Overall, the safety profile of NANT was manageable, and no new safety signal was observed, with hematologic toxicities as the most common treatment-related adverse events.
The results indicate that NANT is an effective neoadjuvant treatment option for controlling disease progression in patients with HRD-positive high-grade serous ovarian cancer (HGSOC).
eTregs were identified as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells.
The addition of the CCR8 antibody, ZL-1218, to niraparib showed a significantly pronounced inhibitory effect on eTregs in pre-clinical models, suppressing tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
"Zai Lab is pleased to support this important translational research which breaks new ground in our understanding of the tumor microenvironment in HRD-positive ovarian cancer," said Rafael G. Amado, M.D., President, Head of Global Research and Development, Zai Lab. "By identifying new immunotherapeutic targets in the TME, these findings could bolster efforts to improve outcomes for patients with HRD+ tumors."

On July 15, 2024 GRAIL, Inc. (NASDAQ: GRAL), a healthcare company whose mission is to detect cancer early when it can be cured, reported an update on the PATHFINDER 2 and NHS-Galleri registrational clinical trials evaluating the Galleri multi-cancer early detection (MCED) test (Press release, Grail, JUL 15, 2024, View Source [SID1234644877]). GRAIL has completed the PATHFINDER 2 study’s planned enrollment of more than 35,000 participants who are eligible for guideline-recommended cancer screening at more than 30 healthcare institutions in North America. In addition, GRAIL has completed the third and final round of study visits for the NHS-Galleri trial, which enrolled more than 140,000 participants.

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"The PATHFINDER 2 and NHS-Galleri studies will significantly expand our existing clinical validation and performance evidence for the Galleri test. By supplementing our robust clinical evidence program with more than 35,000 participants in the U.S. for PATHFINDER 2 and over 140,000 participants in England for NHS-Galleri, we will continue our generation of additional performance, safety, and clinical utility data," said Bob Ragusa, Chief Executive Officer at GRAIL. "Both studies were designed to enroll a diverse participant population, representative of socio-economic, ethnicity, gender and age differences, and we are proud of the diversity of the study populations. The data from these studies, as well as supplemental data from our other clinical studies, will support our premarket approval application submission for Galleri to the FDA, which is currently in process with a modular submission under a Breakthrough Device Designation from the FDA. We look forward to seeing results from the first 25,000 individuals enrolled in the PATHFINDER 2 study in the second half of 2025 and final results from the NHS-Galleri trial in 2026."

About the PATHFINDER 2 Study (NCT05155605)
PATHFINDER 2 is a prospective, multi-center, interventional study evaluating the safety and performance of Galleri in a population of individuals aged 50 years and older who are eligible for guideline-recommended cancer screening in the United States. PATHFINDER 2 is being conducted pursuant to an FDA-approved investigational device exemption (IDE) application and began enrolling in December 2021. The primary objectives of the study are 1) to evaluate the safety and effectiveness of GRAIL’s MCED test based on the number and type of diagnostic evaluations performed in participants who receive a cancer signal detected test result, and 2) to evaluate the performance of GRAIL’s MCED test across various measures, including positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, and cancer signal origin (CSO) prediction accuracy. Participants who receive a cancer signal detected result undergo additional diagnostic testing based on the predicted CSO to determine if a cancer is present. Secondary objectives include utilization of guideline-recommended cancer screening procedures after use of the MCED test, and participant reported outcomes (PRO) over several time points, including an assessment of participants’ anxiety and satisfaction with the MCED test. Timepoints for collection will include baseline measurement prior to testing, post-results, and post-diagnostic resolution for positive test results.

The PATHFINDER 2 study is being conducted with leading healthcare institutions across the United States, including Cleveland Clinic, Duke University Health System, Flushing Hospital Medical Center, Henry Ford Health System, Hoag, Inova, Jamaica Hospital Medical Center, Kelsey-Seybold Clinic, Mayo Clinic, Morehouse School of Medicine, Ochsner Health, Oregon Health & Science University, Sarah Cannon, Sutter Health, University of Oklahoma, University of Pittsburgh, Virginia Commonwealth University, Weill Cornell Medicine, and others.

About the NHS-Galleri Trial (NCT05611632)
In 2020, NHS England selected GRAIL to assist with the United Kingdom’s ambitions for early cancer detection and to assess Galleri for potential population screening on a national scale. In 2021, we initiated the NHS-Galleri trial, a fully enrolled prospective randomized controlled clinical utility trial of over 140,000 participants between the ages of 50 and 77 at the time of enrollment, to evaluate the implementation of Galleri alongside the existing NHS standard of care screenings. The primary objective of the trial is to assess whether implementation of Galleri can reduce the incidence of late-stage cancers through early cancer detection. The trial aimed to enroll a representative population sample to promote health equity and was fully enrolled in just over 10 months.

The trial is designed for participants to provide three blood draws over a two-year period, with the first draw taken at enrollment. As a randomized controlled trial, half of the trial participants have received the Galleri test, and half have had their blood sample stored for future analysis. Any participant in the interventional arm with a cancer signal detected result has been referred for further diagnostic workup within the NHS. All other participants and their physicians remain blinded as to which arm of the study they are in. The NHS-Galleri trial design was published in Cancers in 2022.

Collaborators include Queen Mary University of London, King’s College London Cancer Prevention Trials Unit, and NHS England.

On July 15, 2024 Sumitomo Pharma America, Inc. (SMPA) reported that the U.S. Food and Drug Administration (FDA) granted Fast Track designation to DSP-5336 for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with a KMT2A rearrangement, also known as, mixed lineage leukemia rearrangement (MLLr) or nucleophosmin mutation (NPM1m) (Press release, Sumitomo Dainippon Pharma, JUL 15, 2024, View Source [SID1234644876]). DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction, which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2,3

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FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs.

"For patients and families facing a diagnosis of relapsed or refractory acute myeloid leukemia, significant unmet medical needs remain – and we share in their urgency to identify and advance new treatment pathways," said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. "We are encouraged by FDA’s decision and look forward to working closely with the agency as we continue our clinical development of DSP-5336."

Updated data from the ongoing open-label, dose escalation and optimization portion of the Phase 1/2 study for DSP-5336 were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress, building on preliminary data presented at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Objective response was observed in 57% (12/21) of patients, which included responses in patients with both Nucleophosmin 1 (NPM1) mutation and KMT2A (MLL) rearrangement. The proportion with complete remission or complete remission with partial hematologic recovery (CR/CRh) was 24% (5/21 patients).

To date, DSP-5336 remains well-tolerated with no dose limiting toxicity (DLT) observed and no significant cardiac signal nor treatment-related discontinuations or deaths. No significant drug-drug interactions with azoles have been identified and repeat dosing results in minimal to no pharmacokinetic accumulation. Importantly, no differentiation syndrome (DS) prophylaxis was needed, and the three cases of DS reported (5%) were manageable and did not result in intensive care unit (ICU) stays or discontinuation of DSP-5336.

"Management of AML continues to be challenging with limited options for which there are currently no approved targeted therapies to treat AML with KMT2A (MLL) rearrangements or NPM1 mutations, leaving a serious unmet medical need," said Jatin Shah, M.D., Chief Medical Officer – Oncology at SMPA. "DSP-5336 has shown promising clinical activity, and menin inhibitors have tremendous potential to impact the outcomes of these types of acute leukemia. We are excited by these early results and FDA Fast Track Designation, and look forward to working closely with the agency and our collaborators to rapidly advance this program with the goal of providing a well-tolerated and effective targeted treatment option for patients with relapsed or refractory acute myeloid leukemia."

Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells, in the bone marrow. Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.4 Approximately 30% of AML patients have NPM1 mutations6 and 5-10% of AML patients have KMT2A (MLL) rearrangements.5

About DSP-5336
DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.1,3 DSP-5336 reduced the expression of the leukemia-associated genes HOXA9 and MEIS1, and increased the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.7,8 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. The FDA granted Fast Track Designation for DSP-5336 for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in June 2024.

On July 15, 2024 Mabwell (688062.SH), an innovative biopharmaceutical company with entire industry chain, reported its novel Nectin-4 targeting ADC (R&D code: 9MW2821) has been approved by the NMPA to enter Phase II clinical trial as monotherapy or in combination with a PD-1 inhibitor for the treatment of triple-negative breast cancer (TNBC) (Press release, Mabwell Biotech, JUL 15, 2024, View Source [SID1234644875]).

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The Phase II clinical trial recently approved aims to evaluate the efficacy and safety of 9MW2821 as monotherapy or in combination with a PD-1 inhibitor in patients with locally advanced or metastatic TNBC. The study includes two cohorts: Cohort A will enroll patients with locally advanced or metastatic TNBC who have previously received taxane/anthracycline-based chemotherapy and topoisomerase inhibitor based antibody-drug conjugate treatment, and will receive 9MW2821 monotherapy; Cohort B will enroll patients with locally advanced or metastatic TNBC who have not previously received systemic therapy, and will receive a combination treatment of 9MW2821 and a PD-1 inhibitor.

Clinical results previously presented at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting showed that among the 20 patients with locally advanced or metastatic TNBC treated by 9MW2821 and evaluable for efficacy assessment, the objective response rate (ORR) and disease control rate (DCR) were 50.0% and 80.0% respectively. The median progression-free survival (mPFS) was 5.9 months, and the median overall survival (mOS) was not yet reached, with one patient achieved complete response (CR) and had been in CR for 20 months and is currently sustained to be CR. Additionally, 9MW2821 has recently been granted Fast Track Designation (FTD) by the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic Nectin-4 positive TNBC.

About 9MW2821

9MW2821 is the first site-specific conjugated novel Nectin-4-targeting ADC developed by Mabwell using ADC platform and automated high-throughput hybridoma antibody molecular discovery platform, and is the first drug candidate to enter clinical study among the Nectin-4-targeting ADCs developed by Chinese companies, and the first therapeutic drug candidate targeting Nectin-4 in the world to reveal clinical efficacy data of cervical cancer (CC), esophageal cancer (EC) and breast cancer. 9MW2821 has been granted FTD by FDA for the treatment of advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) in Feb. 2024, and also respectively granted Orphan Drug Designation (ODD) and FTD for the treatment of EC and recurrent or metastatic CC progressed on or following prior treatment with a platinum-based chemotherapy regimen in May 2024. Then, it has been granted FTD for the treatment of locally advanced or metastatic Nectin-4 positive TNBC in July, 2024.

9MW2821 achieves site-specific modification of antibody through proprietary conjugate technology linkers and optimized ADC conjugation process. After injection, 9MW2821 can specifically bind to Nectin-4 on the cell membrane surface, be internalized and release cytotoxic drug, and induce the apoptosis of tumor cells.