On April 7, 2024 Edgewood Oncology, a clinical-stage biotechnology company focused on delivering BTX-A51 to patients with hematologic malignancies and genetically-defined solid tumors, reported the publication of new preclinical data from a study of BTX-A51 in human liposarcoma (LPS) conducted by Dana-Farber Cancer Institute and Hebrew University-Hadassah Medical School to be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2024 in San Diego (Press release, Edgewood Oncology, APR 7, 2024, View Source [SID1234641851]). BTX-A51 is a first-in-class, small molecule, multi-selective kinase inhibitor of casein kinase 1 alpha (CK1α) as well as the transcriptional regulators cyclin-dependent kinases 7 and 9 (CDK7 and CDK9) that synergistically co-targets master regulators of cancer to promote programmed cell death, or apoptosis.

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The presentation (Abstract 604), "Targeting casein kinase 1 alpha (CK1alpha) and transcriptional CDKs (CDK7/9) in human liposarcomas," highlighted findings for BTX-A51 in preclinical human models of LPS. The data demonstrate that BTX-A51 has preclinical efficacy in treating patient-derived LPS in cell lines and human xenograft models and provides insight into the synergy gained by inhibiting both CK1α and CDK9.

"Dedifferentiated liposarcomas (DDLPS) are rare tumors derived from precursors of fat cells which can occur anywhere in the body. Patients with metastatic DDLPS face a life-threatening disease in need of more effective therapeutic options, which we hope to develop by taking advantage of vulnerabilities in LPS that have been uncovered by recent research on the abnormal DNA and other molecular characteristics of LPS," said George Demetri, M.D., Professor of Medicine and director of the Sarcoma Center at Dana-Farber. "Based on these data, we believe that it is justified to move BTX-A51 into a clinical trial for patients with LPS, which we will plan to open soon for enrollment."

Liposarcomas are universally characterized by amplification of the mouse double minute 2 homolog (MDM2) gene, which leads to destruction of the normal (non-mutated, also known as "wild type") p53. The data demonstrate that BTX-A51 significantly reduces the abnormal overexpression of MDM2 in multiple patient-derived LPS cell lines, leading to upregulation of p53 expression and ultimately apoptosis. Finally, BTX-A51 was demonstrated to be well-tolerated and effective in an LPS patient-derived xenograft model.

"We’re pleased that investigators at Dana-Farber have taken an interest in BTX-A51, which is currently being evaluated in a Phase 2 combination study with azacitidine in patients with relapsed or refractory (R/R) AML," said David N. Cook, Ph.D., chief executive officer of Edgewood Oncology. "These data also suggest the potential for BTX-A51 in cancers with MDM2 amplifications, a group of genetically defined tumors that span multiple tissue types suggesting broader potential."

Additional Details about the Study

Using three different CDK9-selective inhibitors in human LPS cell lines, the authors showed that CDK9 inhibition suppressed cell growth and induced apoptosis by decreasing MDM2 levels while inducing expression of p53. It was also demonstrated that the potency of CDK9 inhibitors is significantly enhanced upon CK1α depletion. These data led to the investigation of BTX-A51, which targets CK1α and CDK9 as well as CDK7, in LPS cells and has previously been shown to inhibit these kinases with nanomolar efficacy in AML models. BTX-A51 potently reduced expression of MDM2 with marked induction of p53, resulting in apoptosis of LPS cells. BTX-A51 also reduces expression of MCL1 and primes LPS cell lines and primary LPS cells for BIM-induced apoptosis, as demonstrated by BH3 profiling. Importantly, preliminary in vivo data in an LPS patient-derived xenograft model reveal that BTX-A51 is well-tolerated under conditions that inhibit tumor growth.

On April 7, 2024 Affini-T Therapeutics, Inc., a precision immunotherapy company unlocking the power of T cells against oncogenic driver mutations, reported that management is presenting data from the company’s oncogenic driver programs targeting HLA-A*11:01 KRAS G12D and HLA-A*02:01 p53 R175H at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego (Press release, Affini-T Therapeutics, APR 7, 2024, View Source [SID1234641850]). In addition, the team is presenting two trial-in-progress posters for Affini-T’s Phase 1 clinical-stage programs targeting KRAS G12V, the company-sponsored AFNT-211 study and the Fred Hutchinson Cancer Center investigator-initiated AFNT-111 study at AACR (Free AACR Whitepaper).

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"We are excited to be at AACR (Free AACR Whitepaper) unveiling new preclinical data, which includes a closer look at the promise of our novel non-viral TRAC-knocked-in T cell therapy for the treatment of p53 R175H-mutant solid tumors," said Loïc Vincent, Ph.D., Chief Scientific Officer, Affini-T Therapeutics. "We are also proud to present preclinical data from our cell therapy targeting KRAS G12D, which highlights the promising potential of our proprietary non-viral knock-in THRIVE platform. These findings continue to motivate our team as we advance programs leveraging TCR-engineered T cells as potential paradigm-shifting treatments for patients with solid tumor cancers."

Poster presentation details are as follows:

AFNT-212: A TRAC-knocked-in KRAS G12D-specific TCR-T cell product enhanced with CD8αβ and a chimeric cytokine receptor for treatment of solid cancers

Abstract #5973, Session: Adoptive Cell Therapies 1: Tumor Antigen-Specific T-cells and TCR-T
Session Date/Time: Sunday, April 7, 2024, 1:30 PM – 5:00 PM
Presenting Author: Loïc Vincent, Ph.D., Chief Scientific Officer, Affini-T Therapeutics
Summary: AFNT-212-engineered TCR-T cells showed high functional avidity and in vitro cytotoxicity against KRAS G12D-positive tumor cell lines, including CL40 (colon), PANC-1 and HPAF-II (pancreas), SK-LU-1 (lung), HuCCT1 (cholangiocarcinoma), etc. Additionally, engineered TCR-T cells demonstrated robust and durable anti-tumor activity in vivo and low risk of off-target/off-tumor toxicity. Affini-T’s proprietary non-viral knock-in (KI) THRIVE platform achieved high transgene integration efficiency and cell growth to yield relevant numbers of engineered TCR-T cells for clinical application. The study supports the planned clinical investigation of the novel KRAS G12D mutant TCR-engineered CD4+ and CD8+ T cell therapy in 2024.
Non-viral engineered T cell therapy specific for the hotspot mutation p53 R175H that integrates signal 1 (TCR), signal 2 (co-stimulation) and signal 3 (cytokine) and co-opts FasL-dependent apoptosis to achieve a coordinated antitumor CD4/8 T cell response

Abstract #7242, Session: Adoptive Cell Therapies 1: Tumor Antigen-Specific T-cells and TCR-T
Session Date/Time: Sunday, April 7, 2024, 1:30 PM – 5:00 PM
Presenting Author: Gary Shapiro, Ph.D., VP Biology Discovery, Affini-T Therapeutics
Summary: The tumor suppressor TP53 is the most frequently mutated gene across human cancers, with a highly recurrent arginine to histidine hotspot alteration in codon 175 leading to novel tumor-dependent functions. In this study, we reported the use of a novel CRISPR-Cas nuclease system to knock in a six-gene multi-cistronic cassette into the TRAC locus with high efficiency. We employed several strategies to maximize the potency and durability of a TCR-T cell product targeting the p53 R175H oncogenic driver, TCR, co-stimulation and cytokine signaling – which delivered full stimulation of both CD8+ and CD4+ T cells. These data support the planned clinical development of a novel non-viral TRAC-knocked-in T cell therapy for the treatment of p53 R175H-mutant solid tumors.

On April 7, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), reported that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024) (Press release, Ascentage Pharma, APR 7, 2024, View Source;ascentage-pharma-presents-results-from-three-studies-at-2024-american-association-of-cancer-research-annual-meeting-302109949.html [SID1234641849]). This year’s AACR (Free AACR Whitepaper) annual meeting will be held from April 5-10 2024, in San Diego, California, USA.

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"We are pleased to present the preclinical research data of four assets in our pipeline at the AACR (Free AACR Whitepaper) 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need."

The details of these three preclinical studies are as follows:

Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms

Abstract#: 1971

Time: Monday April 8, 2024, 9:00 AM – 12:30 PM (Pacific Time)

Introduction:

Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D).
Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors.
The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients.
Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action.
Conclusions:

Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo.
Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers.
Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines.
In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers.
Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa)

Abstract#: 3223

Time: Monday April 8, 2024, 1:30 PM – 5:00 PM (Pacific Time)

Introduction:

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies.
Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3.
MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis.
The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models
Conclusions:

In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis.
APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo.
Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis.
Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa.
APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC)

Abstract#: 4569

Time: Tuesday April 9, 2024, 9:00 AM – 12:30 PM (Pacific Time)

Introduction:

Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis.
FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes.
FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target.
The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer.
Conclusions:

APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines.
FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner.
APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model.
The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model.
These promising results support the future clinical development of this combination treatment for ovarian cancer.

On April 7, 2024 Laekna (2105.HK) reported that the company has presented two internally-discovered preclinical candidates, in addition to a poster presentation on a clinical trial, at the 2024 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in San Diego, California (Press release, Laekna Therapeutics, APR 7, 2024, View Source [SID1234641848]). The presentations featured preclinical data of two novel selective inhibitors, LAE119, a novel PARP1 selective inhibitor and trapper, and LAE120, a novel selective USP1 inhibitor.

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"After advancing LAE102, our internally discovered antibody against ActRIIA, into IND stage, Laekna continues to strengthen our internal discovery efforts, with new drug candidates emerging", said Dr. Justin Gu, Chief Scientific Officer of Laekna. "The MOA of LAE119 and LAE120 is synthetic lethality, both exhibit strong anti-tumor efficacy and good safety in preclinical models. LAE 119 is a PARP1-selective inhibitor with the strongest DNA-trapping activity among all the PARP inhibitors tested. It shows good activity even in tumor cells with low PARP1 protein level. LAE120 is a novel USP1 inhibitor currently at IND-enabling studies stage. It has a unique chemical scaffold differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. The quick advance of these two projects into PCC stage demonstrates the effectiveness of the close collaboration among Med Chem, Biology and AIDD (AI-driven Drug Discovery) teams. Laekna will continue our internal effort of discovery novel drug candidates to provide more options for patients."

Laekna’s internal discovery focuses on innovation, scarcity, and differentiation, covering three areas: cancer, metabolic diseases，and liver fibrosis. The company has internally discovered 14 drug candidates, among which seven have been optimized and advanced to PCC (pre-clinical candidate) stage. The company plans to have one drug candidate entering the clinical stage each year.

The Annual Meeting of AACR (Free AACR Whitepaper) is set for April 05 to 10, 2024 at the San Diego Convention Center, California, USA. It is the focal point of the cancer research community, where scientists, clinicians, other health care professionals, survivors, patients, and advocates gather to share the latest advances in cancer science and medicine. [1]

[1] View Source

Presentation details are as follows:

Title: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper

Authors: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu

Session Category: Experimental and Molecular Therapeutics

Session Title: DNA Damage and Repair

Session Date and Time: Wednesday, Apr 10, 2024 9:00 AM- 12:30 PM (PT)

Location: Poster Section 22

Poster Board Number: 27

Abstract Highlights:

LAE119 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than 1000-fold selectivity for PARP1 DNA trapping activity over PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays and shows good activity even in tumor cells with low PARP1 protein level. It demonstrates robust anti-tumor effect in BRCA2-/- DLD-1 and MDA-MB-436 Xenograft models and has minimal effects on hematologic parameters.

Full texts of the abstracts are available here.

Title: Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitors

Authors: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu

Session Category: Experimental and Molecular Therapeutics

Session Title: Novel Antitumor Agents 2

Session Date and Time: Sunday, Apr 7, 2024 1:30 PM- 5:00 PM (PT)

Location: Poster Section 27

Poster Board Number: 16

Abstract Highlights:

LAE120 is a novel, allosteric and highly potent USP1 inhibitor, displaying monotherapy potency and combination activity with PARP inhibitor in HRD (homologous recombination deficiency) cancers. It has a unique chemical structure differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. LAE120 shows robust tumor inhibitory activity in MDA-MB-436 and K562 xenograft models as a single agent and exhibits synergistic effect in combination with PARP inhibitors. LAE120 demonstrates good therapeutic window in DRF study and is currently at IND-enabling stage.

On April 7, 2024 Dizal (688192.SH) reported that the U.S. Food and Drug Administration ("FDA") has granted Breakthrough Therapy Designation (BTD) to its sunvozertinib as the first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations (Press release, Dizal Pharma, APR 7, 2024, View Source;patients-with-advanced-non-small-cell-lung-cancer-harboring-egfr-exon-20-insertion-mutations-302109862.html [SID1234641847]).

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This Breakthrough Therapy Designation (BTD) approval was based on results from the global multi-center phase I/II study (WU-KONG1). At 2023 ESMO (Free ESMO Whitepaper), Dizal reported main study results, showing sunvozertinib as a single agent with confirmed objective response rate (cORR) of 78.6% and a median progression-free survival (mPFS) of 12.4 months.

Sunvozertinib was previously granted BTDs by both the US FDA and the China Center for Drug Evaluation (CDE) for relapsed or refractory patients It was subsequently approved in China in 2023 for the treatment of patients who failed 1st line treatment. NDA submissions for US and EU approvals in the same setting is anticipated later in 2024.

"We are delighted with the FDA’s decision granting the Breakthrough Therapy Designation to sunvozertinib for first-line treatment, coming on the heels of earlier BTD approval in later lines of therapy — a clear indication of sunvozertinib’s transformative potential in the treatment of patients with EGFR exon20ins NSCLC. Multiple clinical trials have consistently demonstrated sunvozertinib’s significant clinical benefits to our patients. As a single, oral agent, it offers apparent advantages in both safety and patient compliance over chemotherapies and infusion." said Xiaolin Zhang, PhD, CEO of Dizal, "Now enrollment for the global pivotal study in relapsed and refractory setting (WU-KONG1 PART B) has been completed, and we are going to report the study results as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. A randomized global phase III study in the first line setting (WU-KONG28) is well underway. This new BTD will enable us work more closely with the FDA and accelerate its clinical development and regulatory submission."

Affecting roughly 2%-4% of NSCLC patients, EGFR Exon20ins mutations have been difficult to treat due to their unique spatial conformation, diverse mutation subtypes, and high heterogeneity. There has been a persistent lack of safe and effective targeted treatment options for this mutation, leading to limited survival benefits for patients.

Sunvozertinib’s innovative molecular structure enables it to overcome the inherent difficulties of targeting EGFR Exon20ins mutations, offering improved efficacy, safety, and ease of administration. Supported by findings yielded in the multicenter phase 2 pivotal study WU-KONG6, sunvozertinib was approved in China for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or following platinum-based chemotherapy, validating its potent and well-tolerated profile in previously treated NSCLC patients with EGFR Exon20ins mutations.

About Breakthrough Therapy Designation

The FDA’s Breakthrough Therapy Designation is intended to expedite the development and regulatory review of drugs for serious or life-threatening conditions. To qualify, new drugs must demonstrate promising preliminary clinical results indicating substantial improvement on clinically significant endpoints over existing treatments. Drugs designated as breakthrough therapies benefit from a suite of accelerated development policies, including close guidance by FDA experts throughout the clinical development process, significantly improving communication efficiency. Upon submission of a marketing application, such drugs may also be eligible for priority review if they meet relevant criteria.

About sunvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA for the treatment of advanced NSCLC with EGFR exon20ins mutations after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins mutations. The primary endpoint of the study, which was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins mutations.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug related TEAEs (treatment emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 PART B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR Exon20ins mutations.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).