On December 09, 2024 InnoCare reported latest data of orelabrutinib were presented at the ongoing 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, InnoCare Pharma, DEC 9, 2024, View Source [SID1234648962]).

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Poster Presentation

1. Orelabrutinib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Who Are Intolerant to Prior Bruton Tyrosine Kinase Inhibitors (BTKi): Updated Results from a Phase 2 Study (Abstract No.: 4399)

Orelabrutinib improved outcomes of prior BTKi-intolerant adverse events (AEs), particularly the off-target toxicities. Patients who switched experienced minimal and low levels of intolerance recurrences and all achieved disease control. These updated results show promising efficacy and safety data of orelabrutinib in prior BTKi-intolerant iNHL patients.

As data cutoff (July 9, 2024), 66 patients were enrolled and 64 patients were available for AE and efficacy analysis. At a median follow-up of 6.8 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Both PFS and OS rates remained 100%.

2. Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 Study) (Abstract No.: 3244)

This is a multicenter, open-label, non-randomized phase II study for previously untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without restriction by del(17p)/TP53 aberrations and/or immunoglobulin heavy⁃chain variable region gene (IGHV) mutation status. The Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab regimen leads to a rapid and deep molecular remission with a manageable safety profile in previously untreated CLL patients including those with unfavorable characteristics.

After cycle 6, the rates of peripheral blood (PB) undetectable minimal residual disease (uMRD) and bone marrow (BM) uMRD by flow cytometry (FCM) were 95% and 86%, respectively, and the rate of complete response (CR)/CR with incomplete hematologic recovery (CRi ) was 59%. After cycle 12, the rates of PB-uMRD by FCM, BM-uMRD by FCM, and CR/CRi were 95%, 91% and 77% respectively.

3. A Prospective, Multicenter, Single-Arm Study on the Combination of Orelabrutinib and Rituximab in the Second-Line Treatment of Relapsed/Refractory Marginal Zone Lymphoma (Abstract No.: 4391)

This is a prospective, multicenter, single-arm, phase II clinical trial, aiming to evaluate the efficacy and safety of orelabrutinib in combination with rituximab in patients with relapsed or refractory Marginal Zone Lymphoma (MZL). The preliminary results of this study suggest that the combination therapy of orelabrutinib and rituximab is effective in patients with rrMZL and has manageable safety, with tolerable maintenance therapy.

Of the 12 enrolled patients, 6 have completed the interim efficacy assessment, achieving an overall response rate (ORR) of 100%. 3 patients completed the combination therapy and entered the maintenance phase, keeping the ORR at 100%. All patients chose orelabrutinib for maintenance therapy.

4. Orelabrutinib, Rituximab, and Thiotepa (ORT) in Combination with or without High-Dose Methotrexate in Untreated Primary Central Nervous System Lymphoma (Abstract No.: 4487)

The orelabrutinib, rituximab, and thiotepa (ORT) regimen, with or without high-dose methotrexate (HD-MTX), has shown initial efficacy and a manageable safety profile in treating Primary Central Nervous System Lymphoma (PCNSL), particularly in elderly patients with MCD subtypes. Autologous stem cell transplantation (ASCT) following ORT with or without HD-MTX induction therapy further improves patient response. Patients with complete response (CR) did not relapse and were well-tolerated on orelabrutinib maintenance therapy.

The median follow-up was 8.27 months. The best CR rate was 85.71%, and the longest CR duration was 22.53 months. The objective response rate (ORR) was 85.71%.

5. Preliminary Data of a Single-Arm, Phase II Study of Orelabrutinib with/without Rituximab in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma after BTK Inhibitor Therapy (Abstract No.: 3240)

Despite the currently limited follow-up period, orelabrutinib combined with or without rituximab, demonstrated favorable efficacy in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients with detectable MRD post-BTK inhibitor treatment, and MRD decreased significantly after 9 months. This treatment holds the potential to emerge as a new therapeutic option for CLL/SLL patients.

At 9 months, 66.7% achieved undetectable peripheral blood MRD, with a 9-month complete response rate (CRR) of 77.8% and a 1-year overall survival (OS) of 100%, and no patient has progressed thus far.

6. Preliminary Data on the Efficacy and Safety of Orelabrutinib Combined with Rituximab and Methotrexate (ORM Regimen) As First-Line Treatment for Primary Central Nervous System Lymphoma, and the Exploration of Cerebrospinal Fluid ctDNA Dynamic Monitoring (Abstract No.: 4500)

The Orelabrutinib Combined with Rituximab and Methotrexate regimen demonstrates high overall response rate (ORR) and complete response (CR) in the treatment of Primary Central Nervous System Lymphoma (PCNSL), with acceptable safety. Our results suggest that dynamic monitoring of cerebrospinal fluid circulating tumor DNA (ctDNA) is of significant importance for the early evaluation of therapeutic efficacy and prognosis prediction in PCNSL.

During treatment the best response evaluation showed an ORR of 86.4% and a disease control rate (DCR) of 100%; Among the 21 patients who completed all induction therapies, the ORR was 85.71% with a CR rate of 76.19%.

Among 19 patients with detectable ctDNA in baseline CSF, 13 patients had undetectable ctDNA in C5D1 CSF, of which 12 patients achieved CR. Patients with undetectable CSF ctDNA at C5D1 showed longer progression-free survival (PFS), indicating that early clearance of CSF ctDNA can predict favorable prognosis.

7. Preliminary Efficacy of Orelabrutinib Targeted Therapy in Induction Therapy of Primary Central Nervous System Diffuse B-Cell Lymphoma (Abstract No.: 4496)

The Orelabrutinib, Rituximab and High-dose MTX regimen is an effective and safe induction therapy for primary central nervous system diffuse B-cell lymphoma, with a total response rate of 83.3% and a median onset time of 1 course for partial response (PR) and 2 courses for complete response (CR). It is a promising induction therapy for primary central nervous system diffuse B-cell lymphoma.

8. The Primary Results of R-MTO Regimen (Rituximab, Methotrexate, Thiotepa, and Orelabrutinib) As the First-Line Induction Therapy Followed By Autologous Stem Cell Transplantation in Newly Diagnosed Primary Central Nervous System Lymphoma (Abstract No.: 1742)

This is a prospective designed, ongoing, single-center, single-arm, open-label study. The Rituximab, Methotrexate, Thiotepa, and Orelabrutinib induction treatment has demonstrated notable efficacy in achieving higher response rates among patients with newly diagnosed Primary Central Nervous System Lymphoma (PCNSL), and a tolerable safety profile.

A total of 26 patients with newly diagnosed PCNSL were enrolled in this study. The overall response rate (ORR) was 96.15%, and the complete response (CR) rate was 92.30% after 4 cycles of treatment. Among ten patients who underwent autologous hematopoietic stem cell transplantation (HSCT), all of them (100%) remained in CR. The progression-free survival (PFS) and overall survival (OS) rate at 12 months were 82.24%, and 87.00% respectively.

9. Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Idiopathic Multicentric Castleman Disease: A Single-Center, Retrospective Study (Abstract No.: 1656)

Orelabrutinib, with its high response rate, durable response time, and improved safety profile can be a viable alternative for the treatment of patients with relapsed/refractory (r/r) idiopathic multicentric Castleman disease (iMCD).

Ten patients with r/r iMCD were included in the study, Seven patients (70%) were assessed as responders, two of whom achieved complete response. The median time to remission for responders was 9.8 months (range: 5.9–20.5 months). In the non-responder group, despite not achieving response criteria, these patients still showed a continuous improvement in median hemoglobin, albumin, C-reactive protein (CRP) and creatine levels with treatment at month 12. No grade 3 or above adverse reactions occurred.

Except poster presentation, more than 10 studies were also selected as online publications at the meeting. For more detailed clinical data, please refer to ASH (Free ASH Whitepaper) website.

On December 09, 2024 AngioDynamics, Inc. (NASDAQ: ANGO), a leading and transformative medical technology company focused on restoring healthy blood flow in the body’s vascular system, expanding cancer treatment options and improving patient quality of life, reported it received U.S. Food and Drug Administration (FDA) 510(k) clearance for the NanoKnife System for prostate tissue ablation (Press release, AngioDynamics, DEC 9, 2024, View Source [SID1234648961]).

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"These efforts are designed to accelerate the adoption of the NanoKnife System, redefine the standard of care for prostate health, and deliver treatment outcomes that patients and physicians need. AngioDynamics is committed to driving meaningful impact through this revolutionary technology, providing new hope to patients and improved quality of life."

The Company received clearance for the NanoKnife System for prostate tissue ablation following the completion of the pivotal PRESERVE clinical study and submission of results to the FDA in September. The study evaluated the safety and effectiveness of the system for ablating prostate tissue in patients with intermediate-risk prostate cancer (PCa). Conducted in collaboration with the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC), PRESERVE enrolled 121 patients across 17 clinical sites.

"We are incredibly proud to receive FDA clearance for the NanoKnife System’s use in prostate tissue," said Jim Clemmer, President and Chief Executive Officer of AngioDynamics. "This milestone is the first step in recognizing our vision to become the standard, function-preserving treatment for men with prostate tumors. The NanoKnife System minimizes the life-altering complications often associated with traditional treatments by selectively targeting prostate tissue while preserving critical functions. As we expand our global footprint and increase access to our technology, we are launching comprehensive education and awareness campaigns to empower physicians with hands-on training and clinical support while engaging patients through innovative outreach initiatives."

Mr. Clemmer added, "These efforts are designed to accelerate the adoption of the NanoKnife System, redefine the standard of care for prostate health, and deliver treatment outcomes that patients and physicians need. AngioDynamics is committed to driving meaningful impact through this revolutionary technology, providing new hope to patients and improved quality of life."

The PRESERVE clinical study met its primary effectiveness endpoint demonstrating the performance of the NanoKnife System for the ablation of prostate tissue in patients with intermediate-risk PCa. At 12-months post-procedure, 84.0% of men were free from in-field, clinically significant disease. In addition, the study demonstrated strong quality of life outcomes with short-term urinary continence being preserved (96.6% at baseline, 95.4% at 12-months) and the ability to maintain erections sufficient for intercourse only decreasing 9% compared to baseline (80.7% to 71.7%).1

The study’s results validated the robust safety and clinical efficacy profile of the NanoKnife System, reinforcing findings from more than 32 clinical studies performed around the world involving over 2,600 patients.1

Prostate cancer is the second most common cancer in men worldwide, with approximately 1.5 million new cases diagnosed annually.2 Many of these patients seek alternatives to radical procedures that can lead to significant, long-term urological side effects.3 The NanoKnife System is the first and only non-thermal, radiation-free, ablation technology designed to treat prostate tissue by using IRE technology, offering patients a minimally invasive option for prostate treatment.

The NanoKnife System delivers an innovative alternative to conventional radical surgery or radiotherapy, which often results in significant dysfunction in urinary continence and erectile potency.4 With its non-thermal approach, the system is engineered to preserve vital structures inside and outside the prostate, offering patients improved outcomes, reduced recovery times, and enhanced quality of life.5

For important risk information, visit View Source

About the NanoKnife System

The NanoKnife System utilizes Irreversible Electroporation (IRE) technology to effectively destroy targeted cells without the use of thermal energy by delivering high-voltage pulses, creating permanent nanopores within the cell membrane. This stimulus induces an apoptotic-like cellular death in the targeted tissue, resulting in a complete ablation of the targeted tissue.6 Visit nanoknife.com for full product information.

United States: The NanoKnife System with six outputs is indicated for surgical ablation of soft tissue, including prostate tissue.

Canada: The NanoKnife System is a medical device for cell membrane electroporation. Electroporation is a phenomenon that occurs in cell membranes as cells are exposed to an electrical field of sufficiently high intensity. The electric field acts as a physical stimulus, bringing about alterations in cell membranes that result in increased permeability.

European Union: The NanoKnife System is indicated for the ablation of prostate tissue in patients with intermediate risk prostate cancer.

On December 09, 2024 Molecular Targeting Technologies, Inc. (MTTI) reported preclinical study results for their proprietary 225Ac-EBTATE against SSTR2 NET cancers online in the European Journal of Nuclear Medicine. ("Long acting 225Ac-EBTATE is highly efficacious against somatostatin receptor-2-positive neuroendocrine tumors" (View Source) (Press release, Molecular Targeting Technologies, DEC 9, 2024, View Source [SID1234648960]).

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Professor Humphrey Fonge of the Université de Laval and lead author commented, "At just 40% of the administered dose reported for 225Ac-DOTATATE, 225Ac-EBTATE produces enhanced anti-tumor efficacy in Small Cell lung cancer (SCLC) and Pan-neuroendocrine tumor (NET) models as shown with complete tumor remissions. At a therapeutic dose of 2x 34 kBq, 225Ac-EBTATE showed general safety for 28 days after blood biochemistry analysis, CBC, and histopathological examination of major organs and tissues. We demonstrated that 225Ac-EBTATE was effective against human small-cell lung cancer (SCLC) with 80% complete remission and 100% survival in preclinical models."

MTTI has licensed commercial use rights for the patented Evans blue (EB) technology from the National Institute of Biomedical Imaging and Bioengineering ("NIBIB"), part of the National Institutes of Health ("NIH"). This platform is the basis for the best-in-class, new generation, collection of targeted radiopharmaceuticals (TRP). EB binds to serum albumin, extending in vivo circulatory half-life and tumor residence time, enhancing up to 30-fold uptake at a tumor and enabling good efficacy with significantly lower radiopharmaceutical activity and fewer dosing cycles vs. the current standard of care. Our 3-year follow up of 177Lu-EBTATE in patients* (N=30) with metastatic neuroendocrine tumors, demonstrated good safety with no nephro- or hepatoxicity and 86% disease control rate using only 40% of the administered dose of 177Lu-DOTATATE.

Dr. Jean-Mathieu Beauregard, MD, Associate Professor of Department of Radiology of Université Laval, said, "I am encouraged to see the positive results of 225Ac-EBTATE in treating small cell lung cancer and Pan-neuroendocrine tumor (NET) in preclinical studies. I look forward to working with MTTI and Professor Fonge to translate this into the clinic."

Dr. Chris Pak, President & CEO of MTTI commented "225Ac-EBTATE effectiveness was encouraging, paralleling the clinical superiority of 177Lu-EBTATE. We look forward to collaborating with Professors Beauregard and Fonge to drive 225Ac-EBTATE into clinical trials in 2025."

On December 09, 2024 TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics ("BBOT" or the "Company"), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, reported the publication of preclinical data supporting the hypothesis that targeting both "ON" and "OFF" forms of KRASG12C results in greater potency, deeper responses, and slowed development of resistance leading to significant benefits over "OFF" only KRASG12C inhibitors approved in non-small cell lung cancer (NSCLC) (Press release, BridgeBio, DEC 9, 2024, View Source [SID1234648959]). The publication, titled "Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C" was published in the peer-reviewed journal Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Current KRASG12C inhibitors work by binding to the inactive guanosine diphosphate (GDP)-bound "OFF" form of the protein, preventing its oncogenic activation. However, they do not directly target or inhibit the active guanosine triphosphate (GTP)-bound "ON" form. This limitation leaves KRASG12C "ON" unaddressed, leading to adaptive resistance characterized by increased expression and activity of the active KRASG12C "ON" state. The data in this manuscript demonstrate that BBO-8520, a first-in-class direct dual inhibitor, directly binds to both the "ON" and "OFF" states of KRASG12C in the Switch-II/Helix3 pocket. There, it covalently modifies the target cysteine to disable effector binding to the "ON" state of KRASG12C. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of downstream signaling, resulting in durable tumor regression in multiple tumor models, including those resistant to KRASG12C "OFF" only inhibitors.

"The aspiration to design a first-in-class, direct, dual inhibitor of the GTP-bound ‘ON’ and GDP-bound ‘OFF’ forms of KRASG12C has been achieved," said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. "BBO-8520 is a dual inhibitor of KRASG12C that provides optimal target coverage with exquisite potency, overcoming key deficiencies of ‘OFF’ only inhibitors, and represents a novel mechanism of action because it is the only direct inhibitor that actually blocks effector binding. Preclinical data shows that this novel mechanism delays the emergence of adaptive resistance seen with ‘OFF’ only inhibitors in the clinic. The potential of this approach holds significant promise for delivering enhanced clinical outcomes in patients with NSCLC."

"Using nuclear magnetic resonance (NMR) and X-ray crystallography, as well as biochemical and cell-based assays, we’ve been able to decipher the mechanism of action of this potent dual inhibitor," said lead author Anna Maciag, PhD, Principal Scientist at Frederick National Laboratory for Cancer Research (FNLCR). "Our ability to apply the multitude of high throughput screens and assays available at FNLCR allowed for quick structure activity relationship (SAR) determination and progress."

Resistance to KRASG12C "OFF" inhibitors primarily arises from increased KRASG12C activity in its "ON" state. This can occur through mutant allele amplification or activation of receptor tyrosine kinases (RTKs) by growth factors. Newly synthesized KRAS is likely to bind GTP, as intracellular GTP concentrations are roughly ten times higher than GDP. As a result, upregulating the mutant protein’s transcription offers an efficient escape mechanism for cells to bypass the effects of "OFF" inhibitors. Similarly, receptor tyrosine kinase (RTK) activation can effectively overcome "OFF" only inhibitors by maintaining a high level of KRASG12C in its "ON" state. This study shows that the presence of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) significantly impairs the potency of "OFF" inhibitors in vitro, while amplification of KRASG12C is also detrimental in vivo. In contrast, BBO-8520 maintains exquisite potency in the presence of growth factors, mutant allele amplification, as well as when mutations are engineered to maintain KRASG12C in the "ON" form.

BBO-8520 is currently being evaluated in a Phase 1 study (NCT06343402) of KRASG12C NSCLC patients pre-treated with first generation KRASG12C "OFF" inhibitors or with no prior KRASG12C targeted therapy experience. The discovery of BBO-8520 was the result of a collaboration between the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Lawrence Livermore National Laboratory, and BBOT.

On December 09, 2024 Synthekine Inc., an engineered cytokine therapeutics company, reported positive initial results from a first-in-human Phase 1 study (NCT05665062) of SYNCAR-001 + STK-009 for the treatment of relapsed or refractory CD19+ hematologic malignancies (Press release, Synthekine, DEC 9, 2024, View Source [SID1234648958]). In the results presented from 8 patients treated in the dose escalation portion of the study with a fixed SYNCAR-001 infusion of 30M cells and STK-009 doses ranging from 1.5 to 6 mg, this combination therapy was well tolerated with no dose-limiting toxicities (DLTs) or IL-2-related toxicities observed. This regimen also demonstrated durable responses, including complete responses in all 4 patients with non-Hodgkin lymphoma (NHL).

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The data were presented by Lia Palomba, M.D., Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego. The poster will also be part of the ASH (Free ASH Whitepaper) Poster Walk on Blood Immunology & Cellular Therapy: Advancing Innovations and Translational Insights hosted by Blood Immunology & Cellular Therapy today from 7:30 a.m. to 8:30 a.m. PT.

"Enhancing CAR-T cells with consistent cytokine support, particularly IL-2, has the potential to significantly improve their therapeutic effect. However, prolonged wild-type IL-2 administration is currently not feasible due to severe toxicities like capillary leak syndrome (CLS)," said Dr. Palomba. "SYNCAR-001 + STK-009 represents an innovative solution, enabling the targeted delivery of a potent and durable IL-2 signal specifically to CAR-T cells in vivo and avoiding activation and proliferation of native lymphocytes that can cause CLS. Based on the data presented at ASH (Free ASH Whitepaper), we are encouraged by SYNCAR-001 + STK-009’s favorable safety and efficacy profile and its potential to treat patients with relapsed or refractory B cell malignancies."

SYNCAR-001 + STK-009 is a cytokine-enabled cell therapy regimen based on Synthekine’s proprietary orthogonal IL-2 technology. It is a two-component therapy consisting of SYNCAR-001, an autologous CD19-targeting chimeric antigen receptor T (CAR-T) cell which expresses an engineered IL-2 receptor, and STK-009, an engineered pegylated IL-2 cytokine that selectively signals through the engineered IL-2 receptor.

"The data presented at ASH (Free ASH Whitepaper) is important validation of our orthogonal IL-2 technology. Consistent with our preclinical observations, the combination of STK-009 and a low dose of SYNCAR-001 cells demonstrates robust cell expansion and persistence, potent cytotoxic activity, and durable cell fitness," said Debanjan Ray, chief executive officer of Synthekine. "We are excited to report that STK-009 selectively delivered IL-2’s proliferation and activation signal to SYNCAR-001 cells without the toxicities, including CLS, that are typically associated with wild-type IL-2 treatment. Furthermore, the ability of STK-009 to provide an IL-2 signal exclusively to SYNCAR-001 cells may allow us to bypass the need for potentially toxic lymphodepleting chemotherapy (LDC). We are now enrolling patients to this trial without LDC and have recently opened a trial in autoimmune diseases also without LDC."

SYNCAR-001 + STK-009 INITIAL PHASE 1 DOSE ESCALATION DATA IN CD19+ HEMATOLOGIC MALIGNANCIES

As of the October 8, 2024, data cutoff, 8 patients have been treated in the dose escalation portion of the study. Following a standard regimen of cyclophosphamide/fludarabine (cy/flu), patients received a fixed dose of 30 million SYNCAR-001 cells and doses of STK-009 at 1.5 mg (n=3), 3 mg (n=3) and 6 mg (n=2)
All patients were CAR-T naïve. Four patients had non-Hodgkin lymphoma (NHL) and four patients had chronic lymphocytic leukemia (CLL)
Complete response (CR) was observed in all 4 patients with NHL, and 1 patient with CLL had stable disease (SD) as best overall response
Responses were durable and ongoing in all 4 patients with NHL who exhibited CRs, with the longest duration of CR extending beyond 480 days
Majority of adverse events (AEs) were Grade 1 or 2; the most common AEs were cytopenias expected to occur with cy/flu treatment
Limited, mild-moderate cytokine release syndrome (CRS) was observed in 4 patients (maximum Grade 2); Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 1 patient
A high proportion of SYNCAR-001 cells sustain a long-lasting central memory phenotype on STK-009 treatment
Only minimal exhaustion and senescence of SYNCAR-001 cells was observed throughout the course of STK-009 treatment
In addition to this trial, a Phase 1 study (NCT06544330) of SYNCAR-001 + STK-009 in non-renal systemic lupus erythematosus and lupus nephritis is enrolling subjects, and received Fast Track designation from the U.S. Food and Drug Administration (FDA) in September 2024.