On August 12, 2024 Biosyngen reported that the U.S. Food and Drug Administration (FDA) has approved its BRG01, an EBV-specific CAR-T cell therapy, to proceed with a pivotal Phase lI clinical trial (Press release, BioSyngen, AUG 12, 2024, View Source [SID1234645754]). This marks the first cell therapy to enter Phase lI trials in both the U.S. and China for the treatment of relapsed/metastatic EBV-positive nasopharyngeal carcinoma, demonstrating a breakthrough in solid tumor treatment.

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The Center for Drug Evaluation (CDE) of the National Medicinal Product Administration (NMPA) in China had previously granted approval for the pivotal Phase II clinical trial of BRG01. Patient enrollment for the Phase I clinical trial in China and the U.S. began in late January this year, with all participants having completed the BRG01 infusion. The Phase I study has successfully concluded dose-limited toxicity (DLT) observation and efficacy evaluation in nine patients with advanced nasopharyngeal carcinoma who had at least one prior immune checkpoint inhibitor treatment, including PD-1 antibodies.

Preliminary data indicates that BRG01 demonstrates exceptional safety and preliminary efficacy. All patients are late-stage cancer patients failing standard treatment including checkpoint inhibitors. BRG01 is well tolerated and expanded in patient with no dose-limiting toxicity. More efficient disease control and tumor shrinkage effects were observed with dose escalation. 75% patients in the high dose group showed necrosis and metabolic reduction of tumor lesions as determined by PET-CT.

Biosyngen aims to expedite BRG01’s clinical development and commercial availability, offering new hope for nasopharyngeal cancer patients worldwide. This FDA’s approval underscores BRG01’s potential in tumor and anti-viral therapies and recognizes Biosyngen’s innovation and R&D capability in cellular immunotherapy.

Biosyngen has established itself as a leading biotech with a portfolio of cell therapies, including CAR-T, TCRT, and TIL, addressing various solid tumors and hematologic malignancies. The company’s multiple products have been granted approval to proceed with Phase I/II clinical trials in the U.S. and China, targeting a range of solid tumors such as lung and liver cancer.

Looking ahead, with Biosyngen’s efficient execution and rapid development progress, the company anticipates further clinical breakthroughs in solid tumor cell therapies, providing new treatment options and hope for patients.

On August 12, 2024 Ascentage Pharma (6855.HK), a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing both first- and best-in-class therapies for malignancies, reported that it has been cleared by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) to initiate a registrational Phase III study of lisaftoclax (APG-2575), one of the company’s key drug candidates, in combination with azacitidine (AZA) for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS) (Press release, Ascentage Pharma, AUG 12, 2024, View Source [SID1234645753]). This clears the fourth registrational Phase III study of lisaftoclax, marking another major milestone in the clinical development of the drug.

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This study (GLORA-4) is a multi-center, randomized, double-blind, pivotal registrational Phase III trial to evaluate the efficacy of lisaftoclax in combination with AZA in newly-diagnosed adult patients with higher-risk MDS.

As a heterogeneous myeloid clonal disease originating from hematopoietic stem cells, MDS commonly occurs in older population with a median age of onset of 70 years and an incidence rate that increases with age.1 MDS is characterized by the abnormal growth of myeloid cells. Its clinical manifestations include hematopoietic failure, refractory cytopenia, and the propensity for high-risk patients to progress to acute myeloid leukemia (AML). Data show that approximately 10% of low-risk patients and 50% of high-risk patients with MDS would progress to AML and thereafter face a dismal prognosis.2

At present, there are limited treatment options for patients with MDS and the treatment outcome for most patients remains relatively poor. Demethylation agents (AZA or decitabine) are the current standard first-line treatment for patients with higher-risk MDS. Studies showed that compared to conventional care regimens, monotherapy with AZA can improve the overall survival of patients with MDS.3 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only available curative treatment for MDS. However, the complex characteristics of MDS and the old ages of patients have resulted in the intolerability of chemotherapies that limited the rate of transplantation, and the high rate of transplantation-associated mortality among patients with MDS. The low survival rate of patients with higher-risk MDS underscores an urgent unmet medical need for novel therapies and medicines that can offer higher efficacies.

Lisaftoclax is a novel, orally administered Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat the patients with malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is expected to be the first Bcl-2 inhibitor for which an NDA will be filed for chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) in China and the second anywhere globally that has demonstrated clinical activity for the treatment of patients with CLL and entered pivotal registrational studies. In published clinical results released at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, the drug candidate lisaftoclax has demonstrated clinical benefit and tolerability in patients with higher-risk MDS.4

"There is considerable unmet clinical need for patients with MDS. Lisaftoclax, a Bcl-2 inhibitor, has already shown promising clinical benefit and tolerability in early studies in patients with MDS," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "We are very encouraged by this approval for initiation of the registrational Phase III study in the first-line treatment of patients with higher-risk MDS, as it clears the way for the fourth registrational Phase III study of lisaftoclax. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will actively press ahead with the clinical trials of lisaftoclax for the benefit of more patients."

*Lisaftoclax is an investigational drug that has not been approved in any country or region.

On August 12, 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 granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) for the treatment of locally advanced or metastatic urothelial carcinoma that has failed previous platinum-based chemotherapy and PD-(L)1 inhibitor therapy (Press release, Mabwell Biotech, AUG 12, 2024, View Source [SID1234645752]).

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The designation as a breakthrough therapy is aimed at expediting the development process of drug candidates for serious diseases, with the drug candidates included having demonstrated significant efficacy or safety advantages compared to existing therapies in early clinical trials.

For drug candidates included in the breakthrough therapy list, CDE will prioritize the allocation of resources to facilitate communication and provide guidance to promote drug development, which will benefit the further advancement of the clinical development progress and the speed of market review and approval. This will help to expedite the development process of 9MW2821 and meet the unmet clinical needs of Chinese patients.

About 9MW2821

9MW2821 is the first site-specific conjugated novel Nectin-4 targeting ADC developed by Mabwell using ADC platform, and is the first drug candidate to enter clinical study among the Nectin-4-targeting ADCs developed by Chinese companies, and also 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. In 2024, 9MW2821 has been granted Fast Track Designation by FDA for the treatment of advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC), recurrent or metastatic CC progressed on or following prior treatment with a platinum-based chemotherapy regimen, and locally advanced or metastatic Nectin-4 positive triple-negative breast cancer (TNBC); 9MW2821 has been granted Orphan Drug Designation by FDA for the treatment of EC, and also Breakthrough Therapy Designation by China NMPA.

9MW2821 achieves site-specific modification of antibody through proprietary conjugation 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.

On August 12, 2024 Plus Therapeutics, Inc. (Nasdaq: PSTV) ("Plus" or the "Company"), a clinical-stage pharmaceutical company developing targeted radiotherapeutics with advanced platform technologies for central nervous system (CNS) cancers, presented data in a podium presentation updating the progress of its ReSPECT-LM clinical trial of Rhenium (186Re) Obisbemeda (Rhenium Nanoliposome, 186RNL) in leptomeningeal disease (LM) (Press release, Plus Therapeutics, AUG 12, 2024, View Source;_hsenc=p2ANqtz-_7iHFh0KC8ADHT3IGm6h7byl9V4K0V69JyOE9qDTPXopUgBVfARSb1X2ufy9S8Czy3EIXS309imxXx6d5vPJC9WIkhuA&_hsmi=319707572&utm_content=319707572&utm_source=hs_email [SID1234645751]). The data were presented at the 2024 Society for NeuroOncology (SNO)/American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) CNS Metastases Conference August 8-10, 2024 in Denver, Colorado.

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The presentation, titled, "Phase 1 Dose Escalation of Rhenium (186Re) Obisbemeda (Rhenium Nanoliposome, 186RNL) for the Treatment of Leptomeningeal Metastases (LM): Ongoing Clinical Study Update for Initial Safety and Feasibility," provided a safety and efficacy update on the single dose trial for the first 4 cohorts (n = 16 patients). The trial is currently enrolling in Cohort 5. The study was presented by Andrew Brenner, M.D., Ph.D., Professor and Kolitz/Zachry Endowed Chair Neuro-Oncology Research; Co-Leader, Experimental and Developmental Therapeutics Program, University of Texas Health, San Antonio.

Key ReSPECT-LM highlights through Cohort 4:

16 patients were treated: 8 patients had a breast cancer primary diagnosis, 4 patients had a lung cancer primary diagnosis, and 4 patients had a mix of other primary cancers
There were no dose limiting toxicities through cohort 4 and the maximum tolerated dose or maximum feasible dose was not reached
We observed a linear increase in absorbed radiation dose to the spinal fluid and ventricles and cranial subarachnoid space over 4 cohorts
In cohort 4, the mean average absorbed radiation dose to the ventricles and cranial subarachnoid space was 156 Gy vs. 1 Gy to the spleen
The majority of adverse events (AEs) across all 4 cohorts were mild or moderate and unrelated or unlikely related to the study drug
There was a mean reduction of CSF circulating tumor cells (CTCs) of 53% at 28 days post treatment vs. baseline (CTCs only performed on only Cohorts 1-3 as testing was commercially unavailable during Cohort 4)
Median overall survival for Cohorts 1-4 was 12 months with 8 of 16 patients alive at the time of analysis
"The ReSPECT-LM Phase 1 dose escalation study continues to show feasibility, safety, and a response in circulating tumor cells in LM patients treated with Rhenium (186Re) Obisbemeda," said Dr. Andrew Brenner, M.D., Ph.D., "Furthermore, a median overall survival rate of 12 months is very encouraging and is consistent with the high doses of absorbed radiation delivered and the mean circulating tumor cell reduction we have observed."

The FDA has granted Fast Track designation to Rhenium (186Re) Obisbemeda for the treatment of LM. The FDA has also granted Orphan Drug designation to Rhenium (186Re) Obisbemeda for the treatment of LM in breast cancer patients.

The ReSPECT-LM clinical trial is funded in part, by a 3-year, $17.6 million grant by the Cancer Prevention & Research Institute of Texas. Additional information about the ReSPECT-LM trial can be found here.

About Leptomeningeal Metastases (LM)

LM is a rare complication of cancer in which the primary cancer spreads to the cerebrospinal fluid (CSF) and leptomeninges surrounding the brain and spinal cord. All malignancies originating from solid tumors, primary brain tumors, or hematological malignancies have this LM complication potential with breast cancer as the most common cancer linked to LM, with 3-5% of breast cancer patients developing LM. Additionally, lung cancer, GI cancers and melanoma can also spread to the CSF and result in LM. LM occurs in approximately 5% of people with cancer and is usually terminal with 1-year and 2-year survival of just 7% and 3%, respectively. The incidence of LM is on the rise, partly because cancer patients are living longer and partly because many standard chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells, yet there are no FDA-approved therapies specifically for LM patients, who often succumb to this complication within weeks to several months, if untreated.

About Rhenium (186Re) Obisbemeda

Rhenium (186Re) Obisbemeda is a novel injectable radiotherapy specifically formulated to deliver direct targeted high dose radiation in CNS tumors in a safe, effective, and convenient manner to optimize patient outcomes. Rhenium (186Re) Obisbemeda has the potential to reduce off target risks and improve outcomes for CNS cancer patients, versus currently approved therapies, with a more targeted and potent radiation dose. Rhenium-186 is an ideal radioisotope for CNS therapeutic applications due to its short half-life, beta energy for destroying cancerous tissue, and gamma energy for real-time imaging. Rhenium (186Re) Obisbemeda is being evaluated for the treatment of recurrent glioblastoma and leptomeningeal metastases in the ReSPECT-GBM and ReSPECT-LM clinical trials. ReSPECT-GBM is supported by an award from the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), and ReSPECT-LM is funded by a three-year $17.6M grant by the Cancer Prevention & Research Institute of Texas (CPRIT).

On August 13, 2024 Boundless Bio (Nasdaq: BOLD), a clinical-stage oncology company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable oncogene amplified cancers, reported business updates for the company’s top strategic priorities and provided financial results for the second quarter of 2024 (Press release, Boundless Bio, AUG 12, 2024, View Source [SID1234645749]).

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"At Boundless, we’re on a bold mission to pioneer a new category of cancer treatment for patients with oncogene amplified cancer who are in dire need of new therapeutic options," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "In the second quarter of 2024, we continued to advance our first clinical-stage ecDTx, BBI-355, began dosing patients with our second ecDTx, BBI-825, and completed the analytical validation and received IRB approval of our novel ecDNA diagnostic, ECHO, for deployment as a clinical trial assay in our BBI-355 POTENTIATE trial. Though we have made progress toward our goals, the number of patients enrolled thus far in the combination cohorts of the BBI-355 POTENTIATE trial is lower than originally projected. While we implement measures to accelerate enrollment, we have chosen to scale back our early discovery efforts and streamline our operations to extend our runway and help ensure we have the necessary capital for our core ecDTx programs. Moving forward, we believe we are well-positioned to move our lead programs through initial clinical proof-of-concept data readouts and remain steadfast in advancing this innovative approach for patients with high unmet need."

Strategic Priorities for Core Programs

Boundless Bio has outlined its core portfolio priorities to support the achievement of potential near-term catalysts and long-term patient impact. Through 2025, the company’s core strategic priorities remain:

•
Executing the ongoing Phase 1/2 POTENTIATE (Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA) clinical trial of its lead ecDNA directed therapeutic candidate (ecDTx), BBI-355, a novel, oral CHK1 inhibitor, to generate initial proof-of-concept in solid tumor cancer patients with driver oncogene amplifications;
•
Executing the ongoing Phase 1/2 STARMAP (Study Targeting Acquired Resistance: MAPK Amplifications) clinical trial of its second ecDTx, BBI-825, a novel, oral RNR inhibitor, to generate initial proof-of-concept in colorectal cancer patients with BRAFV600E or KRASG12C mutations and resistance oncogene amplifications;
•
Advancing the company’s third ecDTx program, directed to a novel, previously undrugged kinesin target essential for ecDNA segregation, into IND-enabling studies; and
•
Deploying its proprietary ecDNA diagnostic in the clinic to identify ecDNA+ patients who are most likely to benefit from its ecDTx therapeutics.

In alignment with its strategic priorities, Boundless Bio has narrowed its discovery research work and, as a result, modestly reduced its workforce. The company believes the combination of these operational efficiencies and its cash, cash equivalents, and short-term investments of $179.3 million as of June 30, 2024, provides an operating runway into the fourth quarter of 2026.

BBI-355, a novel, oral, potent, selective CHK1 inhibitor targeting replication stress for cancer patients with driver oncogene amplifications

•
The company presented preclinical and clinical pharmacodynamic data on BBI-355 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2024.
•
Enrollment is progressing in the Phase 1/2 POTENTIATE clinical trial evaluating BBI-355 as a single agent and in combination with targeted therapies in patients with locally advanced or metastatic solid tumors with oncogene amplifications.
•
To date, no new safety signals have been observed, and there has been no evidence of combinatorial toxicity in the dose escalation cohorts evaluating BBI-355 in combination with either the EGFR inhibitor erlotinib or the FGFR inhibitor futibatinib.
•
The initial pace of enrollment in the combination cohorts has been slower than anticipated. The company has recently implemented multiple initiatives to help accelerate enrollment, including engaging with next-generation sequencing vendors to identify patients, adding new clinical sites in the US, and preparing for the initiation of ex-US sites.
•
Based on its current projections, the company now anticipates reporting initial clinical proof-of-concept data from POTENTIATE in the second half of 2025.

BBI-825, a novel, oral, potent, selective RNR inhibitor targeting ecDNA assembly and repair for cancer patients with resistance oncogene amplifications

•
In April 2024, the company announced the first patient had been dosed with BBI-825 in the Phase 1/2 STARMAP clinical trial.
•
Multiple dose levels have been completed in the single-agent, dose-escalation portion of the STARMAP clinical trial and, to date, BBI-825 has demonstrated oral bioavailability and has been generally well-tolerated. Initial clinical proof-of-concept data from the trial are expected in the second half of 2025.

ecDTx 3, a novel kinesin program involved in ecDNA segregation

•
The company’s third ecDTx program, directed to a previously undrugged kinesin target essential for ecDNA segregation whose inhibition is synthetic lethal to ecDNA-enabled cancer cells, is currently advancing through lead optimization.

ECHO, a proprietary diagnostic for detection of ecDNA amplified oncogenes

•
The company’s proprietary ecDNA diagnostic, referred to as ECHO (ecDNA Harboring Oncogenes), is designed to detect ecDNA in patient tumor specimens. ECHO was previously determined by the FDA to be a non-significant risk device for use as a clinical trial assay (CTA) in the BBI-355 POTENTIATE trial.
•
ECHO has now been analytically validated and institutional review board (IRB)-approved for use as a CTA in the BBI-355 POTENTIATE trial.

Second Quarter 2024 Financial Results

•
Cash Position: Cash, cash equivalents, and short-term investments totaled $179.3 million as of June 30, 2024.
•
R&D Expenses: Research and development (R&D) expenses were $14.7 million for the second quarter of 2024 compared to $11.1 million for the same period in 2023.
•
G&A Expenses: General and administrative (G&A) expenses were $4.7 million for the second quarter of 2024 compared to $2.9 million for the same period in 2023.
•
Net Loss: Net loss totaled $17.0 million for the second quarter of 2024 compared to $12.4 million for the same period in 2023.

About BBI-355

Boundless Bio’s lead ecDTx, BBI-355, is a novel, oral, selective small molecule inhibitor of checkpoint kinase 1 (CHK1) being studied in the ongoing, first-in-human, Phase 1/2 POTENTIATE clinical trial (NCT05827614) in cancer patients with oncogene amplifications. CHK1 is a master regulator of cells’ response to replication stress (RS). RS is elevated in cancer cells with oncogene amplification, including on ecDNA, and, because of this, represents a key vulnerability of those cells. BBI-355 was designed to exploit the elevated RS in ecDNA-enabled oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells.

About BBI-825

Boundless Bio’s second ecDTx, BBI-825, is a novel, oral, selective small molecule inhibitor of ribonucleotide reductase (RNR) being studied in the ongoing, first-in-human, Phase 1/2 STARMAP clinical trial (NCT06299761) in colorectal cancer patients with BRAFV600E or KRASG12C mutations and resistance gene amplifications. In preclinical studies, BBI-825 demonstrated low double digit nanomolar RNR inhibition and tumor growth inhibition, including regressions, in both the prevention and treatment of amplification-mediated resistance in mitogen-activated protein kinase (MAPK) pathway-activated tumors. RNR is the rate-limiting enzyme responsible for cellular de novo synthesis of deoxynucleotide triphosphates (dNTPs), the building blocks of DNA, and is essential to the assembly and repair of ecDNA. BBI-825 was shown to dysregulate ecDNA-reliant cancer cell dNTP pools, deplete ecDNA, and was synthetic lethal in multiple oncogene amplified preclinical cancer models.