On December 9, 2024 IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported development candidate nomination of IDE892, a potential best-in-class MTA-cooperative PMRT5 inhibitor (Press release, Ideaya Biosciences, DEC 9, 2024, View Source [SID1234648946]).

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"We continue to expand our precision medicine oncology pipeline and are excited to nominate our 7th development candidate in IDE892, a potential best-in-class MTA-cooperative PMRT5 inhibitor. IDE892 advances our strategic objective to enable a wholly owned combination between the PRMT5 and MAT2A mechanisms, to deliver potentially greater efficacy in MTAP-deletion solids tumors through this rational combination approach," said Yujiro S. Hata, President and Chief Executive Officer of IDEAYA Biosciences. "Following extensive structure-based design and lead optimization, we have achieved our target product profile for the PRMT5 program with IDE892, including favorable potency, selectivity, and synergistic combination potential with MAT2A inhibitor IDE397," said Michael White, Ph.D., Chief Scientific Officer, IDEAYA Biosciences.

IDE892 was discovered through IDEAYA’s iterative physics-based ligand design and optimization platform, and is a highly potent and selective MTA-cooperative PRMT5 inhibitor with best-in-class potential and favorable drug-like properties. IDE892 has demonstrated exceptionally selective antiproliferative activity in MTAP-deleted tumor cell models and durable complete responses in combination with MAT2A inhibitor IDE397 in challenging MTAP-deletion preclinical models. IND-enabling studies for IDE892 are ongoing to support an Investigational New Drug (IND) filing to the U.S. Food and Drug Administration (FDA) in mid-2025, subject to satisfactory completion of ongoing preclinical and IND-enabling studies.

On December 9, 2024 Lomond Therapeutics, a spin-out of Eilean Therapeutics LLC, a precision oncology-focused discovery and development platform, reported results from single ascending dose Phase 1 clinical studies of oral once-daily lonitoclax (Press release, Lomond Therapeutics, DEC 9, 2024, View Source [SID1234648945]). In this series of healthy volunteer studies, no significant safety signals were observed at exposures where robust inhibition of BCL-2 was achieved, as measured via ex vivo activation of caspase in CLL primary cells. Furthermore, administration of itraconazole, a strong inhibitor of cytochrome P450 3A4 metabolism, did not significantly alter lonitoclax exposures. These results emphasize important advantages over venetoclax and venetoclax-like molecules in safety, tolerability, and feasibility of outpatient treatment, enabling lonitoclax to be used to safely treat CLL and AML patients.

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"The positive PK, PD, and safety findings from our Phase 1 trial mark the first clinical data that underscores the differentiated profile and promising potential of lonitoclax compared to venetoclax and venetoclax-like molecules for AML, CLL, and potentially other oncology indications patients," said Dr. Iain Dukes, Chief Executive Officer of Lomond Therapeutics. "We are excited to embark on the next phase of development for lonitoclax with an ongoing CLL study."

About Lonitoclax
Lonitoclax is a next generation BCL-2 inhibitor that has demonstrated best-in-class molecular pharmacology with the highest selectivity against BCL2, a key pro-survival protein that is overexpressed in many cancers. To mitigate the hematologic and immune toxicities observed with venetoclax, lonitoclax was designed with a unique binding mode to improve selectivity for Bcl-2 over Bcl-xL. In addition, a shorter half-life and reduced P4503A4 inhibition properties were built into the molecule to mitigate tumor lysis syndrome and drug accumulation risk, respectively. Lonitoclax has demonstrated monotherapy activity in pre-clinical models, as well as synergistic activity when combined with azacitidine, FLT3 inhibitors, and menin inhibitors in AML xenograft models. Unlike venetoclax, lonitoclax had minimal immunosuppressive activity on B cells, CD8 T cells, and NK cells in preclinical models.

On December 10, 2024 Faron Pharmaceuticals Ltd., a clinical-stage biopharmaceutical company focused on tackling cancers via novel immunotherapies, reported full analysis of the positive Phase 2 interim readout presented at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Faron Pharmaceuticals, DEC 9, 2024, View Source [SID1234648944]).

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"The BEXMAB results continue to improve over time showing a remarkable 80% ORR in r/r MDS patients," said Dr. Juho Jalkanen, Chief Executive Officer of Faron. "The combination is well-tolerated and generates strong and durable cancer blast reduction and hematological improvements. This solidifies bexmarilimab’s unique and leading mechanism of action for the treatment of MDS and in the field of myeloid cell re-programming. With this compelling evidence, we are well positioned to advance to the full Phase 2 efficacy readout and actively pursue further regulatory interactions to navigate and refine the pivotal pathway for BLA filing."

Dr. Mika Kontro, MD, PhD, Associate Professor at the Helsinki University Hospital Comprehensive Cancer Center and Principal Investigator of the BEXMAB trial, said: "Addressing MDS remains a considerable therapeutic challenge due to the limited efficacy of the current standard of care, particularly in TP53 mutated and HMA-failed MDS patient populations. The data presented at ASH (Free ASH Whitepaper) are highly promising, showing notable improvements in overall response rate and overall survival. These findings highlight the meaningful strides Faron is making in improving treatment outcomes for r/r MDS."

The BEXMAB study is a multicenter study, taking place in Finland, UK and the U.S., evaluating the safety and efficacy of bexmarilimab, a novel anti-Clever-1 humanized antibody, with standard of care in patients with aggressive myeloid leukemias.

Faron will host a virtual webinar to discuss the full analysis of data today, 10 December 2024 at 16.00 EET/9am ET/6am PT.

To register for the event visit: BEXMAB Study Update

The ASH (Free ASH Whitepaper) Annual Meeting takes place from 7-10 December 2024, in San Diego, California and virtually.

ASH Poster presentation details:

Title: Encouraging Efficacy of Bexmarilimab with Azacitidine in Relapsed or Refractory MDS in Bexmab Ph1/2 Study

Session Time: Monday, 9 December 2024, 6:00 PM – 8:00 PM PT

Session Title: Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III

Location: San Diego Convention Center, Halls G-H

Lead Authors: Dr. Mika Kontro, MD, PhD, Associate Professor at the University of Helsinki; Dr. Naval Daver, MD, Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center

Abstract Number: 4265

The full Poster is available on the Company’s website at View Source and contains updated clinical data from the BEXMAB trial.

On December 9, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported the latest data from a pooled safety and efficacy analysis of DZD8586, a non-covalent blood-brain barrier (BBB) penetrant LYN/BTK dual inhibitor, in B-cell non-Hodgkin lymphoma (B-NHL) (Press release, Dizal Pharma, DEC 9, 2024, View Source [SID1234648943]). The data were presented at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The analysis pooled data from ongoing phase 1/2 clinical studies evaluating DZD8586 in patients with B-NHL who had progressed following, or were intolerant to, prior systemic therapies. As of October 20, 2024, 61 patients were included in the efficacy analysis and 84 patients were included in the safety set.

Anti-tumor efficacy:

In chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), the overall response rate (ORR) was 57.9% (≥ 50 mg) by data cutoff. Tumor response was observed in patients with prior treatment of covalent and non-covalent BTKi, and Bcl-2i. Tumor responses were observed in patients with classic BTK resistance mutations (C481X) as well as BTK "dead" mutations. Preliminary anti-tumor activity was observed in patients pre-treated by pirtobrutinib, with T474I mutation as well.
Significant tumor response was also observed in other B-NHL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), and central nervous system lymphoma (CNSL).
Safety:

Dose-dependent thrombocytopenia and neutropenia were the most common ≥grade 3 TEAEs, which could be well managed in the clinic.
PK and pharmacodynamic biomarker

Dose-proportional PK profile and dose-dependent modulation of pharmacodynamic biomarkers were observed.
In patients with CNSL, the Kpuu,CSF at steady state were 1.21 and 0.98, suggesting high CNS penetration of DZD8586 in human.
"A significant proportion of B-NHL patients treated with BTK inhibitors will eventually relapse and develop drug-resistant mutations. Two primary types of clinical resistance mutations have been identified: C481X mutation and BTK loss-of-activity mutations," said Xiaolin Zhang, PhD, CEO of Dizal. "DZD8586, as a non-covalent dual inhibitor targeting both BTK-dependent and -independent pathways, has demonstrated promising antitumor activity and safety profile in patients who did not respond to or develop resistance to both covalent and non-covalent BTK inhibitors, including those with CLL/SLL and other B-NHL. With multiple clinical development programs ongoing or under planning, DZD8586 is expected to bring significant clinical benefit to patients with relapsed or refractory B-NHL."

Bruton’s Tyrosine Kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. However, resistance can arise through multiple mechanisms, compromising the treatment outcome and posing an urgent clinical challenge. The C481X mutation disrupts covalent BTK inhibitors binding to BTK enzyme and leads to treatment failure. Additionally, BTK-independent resistance mechanism due to loss of or much diminished BTK enzyme activity was also identified in the clinic. Currently, there is no targeted therapy available to address both resistance mechanisms.

DZD8586 was designed as a LYN/BTK dual inhibitor with high selectivity against other TEC family kinases (TEC, ITK, TXK and BMX), as well as full BBB penetration. By targeting BTK and LYN, it blocks both BTK-dependent and -independent BCR-signaling pathways, which may potentially overcome resistance to approved covalent and non-covalent BTK inhibitors.

On December 9, 2024 Solu Therapeutics, a biotechnology company pioneering therapies to eliminate disease-driving cells in cancer, immunology, and other therapeutic areas, reported positive preclinical data on STX-0712, its novel CCR2-CyTAC (Cytotoxicity Targeting Chimera), for the treatment of chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) (Press release, Solu Therapeutics, DEC 9, 2024, View Source [SID1234648942]). Results were presented over the weekend in two poster sessions at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held December 7-10, 2024, in San Diego, California.

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"The encouraging results from our preclinical studies in CMML and AML highlight the unique power of our CyTAC platform to precisely target and eliminate disease-driving cells," said Sergio Santillana, Chief Medical Officer of Solu. "STX-0712’s ability to selectively target CCR2-positive malignant monocytes in these two challenging blood cancers showcases the platform’s potential to support the development of transformative treatments for different types of cancer and other diseases. We look forward to advancing STX-0712 into clinical trials and continuing to leverage our platform for other high-need diseases."

Preclinical Results for STX-0712 in CMML
Key Findings:

CCR2 was highly expressed in >98% of malignant monocytes in peripheral blood and in a subset of CD34+ progenitors in the bone marrow of CMML patients, while minimal or no CCR2 expression was observed in CD34+ progenitor healthy controls.

In all patient samples tested, STX-0712 effectively depleted CD14+CCR2+ monocytes, achieving 66–91% cancer cell elimination with an average potency of 3nM.

In non-human primates (NHPs), STX-0712 demonstrated potent dose-dependent activity, effectively depleting more than 95% of CCR2-positive monocytes.

STX-0712 exhibited favorable pharmacokinetics in NHPs and was well tolerated, with no adverse effects observed.
To access the full abstract, click here.

Preclinical Results for STX-0712 in AML
Key Findings:

CCR2 was highly expressed on malignant monocytes from AML patient samples, with cases of acute monocytic leukemia (M5) and acute myelomonocytic leukemia (M4), showing the highest levels of expression.

STX-0712 successfully eliminated CCR2-positive malignant monocytes in 80% of patient samples, with up to 74% of cancer cells depleted and an average potency of 3nM.

When combined with venetoclax and azacitidine (standard-of-care treatments for AML), STX-0712 improved therapeutic efficacy in 60% of patient samples by differential targeting both CCR2-positive monocytes and undifferentiated blasts.

Minimal effects were observed on non-target populations such as lymphocytes and CCR2-negative CD34+ blasts, demonstrating the high selectivity of STX-0712.
To access the full abstract, click here.

"The results from these studies represent a significant milestone for Solu, as they reinforce the potential of STX-0712 in the treatment CMML and AML, two diseases with limited targeted therapies available," said Brandon Turunen, Co-founder, Chief Technology Officer, and Head of Drug Discovery at Solu. "By targeting the underlying drivers of these diseases, STX-0712 could offer a highly targeted approach to treatment while maintaining a strong safety profile. We look forward to advancing this promising program to clinical-stage research in 2025."

About STX-0712

STX-0712 is a CyTAC targeting the G-Protein Coupled Receptor (GPCR) CCR2, a selective marker expressed at high levels on malignant monocytes that are key drivers in certain hematologic cancers. By targeting CCR2, STX-0712 is designed to selectively eliminate these malignant cells.