IASO Bio Presented Study Findings on the Impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma with Equecabtagene Autoleucel(FUCASO) Myeloma at 2024 ASH

On December 9, 2024 IASO Biotherapeutics ("IASO Bio"), a biopharmaceutical company focused on the discovery, development, manufacturing, and commercialization of innovative cell therapies and biologics, reported findings via a poster presentation of the results on the impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma(R/RMM) with Equecabtagene Autoleucel (Eque-cel, FUCASO) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, IASO Biotherapeutics, DEC 9, 2024, View Source [SID1234648947]). The results highlighted the importance of the efficacy-to-target ratio in the treatment of multiple myeloma, emphasizing the crucial role of sustained CAR T-cell persistence, unaffected by baseline soluble B-cell maturation antigen (sBCMA) levels, to achieve optimal disease control.

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Title: Impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma: Insights from the Phase 2 FUMANMA-1 Study
Publication Number: 4761
Presentation Time: 6:00 PM -8:00 PM, Monday, December 9, 2024(San Diego)

Conclusions

The efficacy-to-target ratio is a crucial determinant of clinical outcomes in patients treated with Eque-cel, underscoring the importance of CAR T-cell persistence.
This ratio may serve as a biomarker for future treatment planning, highlighting the need for sustained CAR T-cell persistence to achieve optimal disease control.
Baseline sBCMA levels do not negatively affect the persistence and efficacy of Eque-cel.
This post-hoc analysis of the Phase 2 study of FUMANBA-1 primarily investigated the relationship between CAR T-cell persistence and progression-free survival (PFS) as well as time to progression (TTP). It also examined the impact of sBCMA levels through the lens of the efficacy-to-target ratio, measured by the ratio of vector copy number (VCN) duration to baseline sBCMA levels. With a median follow-up of 24.67 months, 107 patients in 14 centers were treated with Eque-cel.

At the data cutoff, the ongoing remission group showed a longer median VCN duration than those with progression or relapse(12.52m vs 9.03m),as shown in Figure 1.The median efficacy-to- target ratio for the 107 subjects was 1.05 (days*mL/ng). As shown in Figure 2, those with a lower ratio had a significantly higher risk of disease progression, with a hazard ratio (HR) for TTP of 3.07 (95% CI: 1.51–6.24, p=0.0011) and for PFS of 2.3 (95% CI: 1.27–4.14, p=0.0045), both indicating a strong correlation between the efficacy-to-target ratio and the risk of disease progression.

Among baseline characteristics—including ECOG score, R-ISS and ISS disease stages, tumor BCMA expression, tumor burden, baseline sBCMA level, previous autologous stem cell transplantation (ASCT), triple-class exposure, bridging therapy, prior CAR-T treatment, and lymphodepleting conditioning—only previous ASCT (n=30) and ADA as post-infusion factors were significantly associated with Eque-cel persistence, with hazard ratios (HR) 0.35 and 5.79, respectively, as shown in Table 1.

Among the 107 subjects, only 14 exhibited an aplastic neutrophil recovery phenotype, characterized by persistent neutrophil counts below 500/μl for 14days or more. This phenotype did not significantly affect VCN duration compared to patients without the condition, indicating that the long-term persistence of Eque-cel does not increase hematological toxicity.

The principal investigator of this study, Professor Lugui Qiu, from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Professor Chunrui Li, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, stated:

"This post-hoc analysis explored the determinants of long-term efficacy after CAR-T treatment through the lens of the efficacy-to-target ratio (VCN persistence/sBCMA). It confirmed the significance of this ratio in achieving long-term control of multiple myeloma (PFS and TTP). The findings suggest that a CAR-T product with long-lasting efficacy, unaffected by the target, which means not affected by sBCMA levels, would be a more optimal choice in the treatment of MM.

The result further highlighted the crucial role of sustained persistence of CAR-T cells in improving the prognosis of patients with R/RMM. In our 2023 ASH (Free ASH Whitepaper) oral report, we previously confirmed a positive correlation between Eque-cel persistence and the maintenance of MRD negativity. The median duration time of CAR-T cells for Eque-cel was 419 days, which may be a key factor in achieving the high MRD negativity rate of 97.8% and the sustained MRD negativity rate of 81.7% at 12 months post-infusion.

Notably, only 14 of 107 subjects exhibited aplastic neutrophil recovery lasting 14 days or more. This finding indicates that the long-term persistence of Eque-cel does not increase hematological toxicity, further validating the safety of this therapy."

Dr. Jie Chen, Chief Medical Officer of IASO Bio, stated:
The outcomes presented by IASO Bio at the ASH (Free ASH Whitepaper) Annual Meeting highlighted the significant impact of the efficacy-to-target ratio on disease control in multiple myeloma. The data demonstrated that subjects with an efficacy-to-target ratio above the median value had a better prognosis in terms of PFS and TTP. These findings further confirmed the positive effect of long-term CAR-T cells persistence in achieving sustained remission. Eque-cel was deliberately selected in its early development to be a candidate molecule not influenced by sBCMA levels, offering patients deeper and more durable remission. Additionally, the study showed that only a small number of patients experienced neutropenia lasting more than 14 days after treatment with Eque-cel. The result affirmed that the long-term persistence of Eque-cel does not increase the hematological toxicity, further validating its safety profile.

We are fully confident in the outstanding efficacy and safety of Eque-cel. Currently, We have initiated and are rapidly advancing a randomized controlled Phase 3 clinical study of this therapy for second- and third-line multiple myeloma. We look forward to bringing this advanced therapy to a broader population of multiple myeloma patients both domestically and internationally as soon as possible."

About FUMANBA-1 Study
FUMANBA-1 is a single-arm, open-label phase 1b/2 registrational clinical study conducted in 14 Chinese centers to assess the efficacy and safety of the Equecabtagene Autoleucel in patients with R/RMM who have received ≥3 lines of prior therapies. The trial enrolled patients with RRMM who had previously received at least three lines of therapy, including proteasome inhibitors and immunomodulatory agents-based chemotherapy regimens, and had disease progression on their last line of therapy. Patients who had previously received BCMA CAR-T therapy were also eligible for enrollment.

IDEAYA Biosciences Announces Development Candidate Nomination of IDE892, a Potential Best-in-Class MTA-cooperative PRMT5 Inhibitor

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.

LOMOND THERAPEUTICS REPORTS RESULTS FROM ONGOING CLINICAL STUDIES OF LONITOCLAX, A SELECTIVE BCL-2 INHIBITOR WITH BEST-IN-CLASS SELECTIVITY VERSUS BCL-XL AND NO CYP 3A4 LIABILITY

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.

Faron presents BEXMAB data at ASH Annual Meeting

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.

Dizal Presents Latest Data of DZD8586, a LYN/BTK Dual Inhibitor, in B-cell Non-Hodgkin Lymphoma at the 2024 ASH Annual Meeting

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.