ALPI

Interim blinded safety and pharmacokinetic data to be presented at the Congress of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Global) ROCKVILLE, MD, USA I April 10, 2025 I Theriva Biologics (NYSE American: TOVX), (“Theriva” or the “Company”), a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, today announced the presentation of the previously disclosed blinded safety and pharmacokinetic (PK) data from the ongoing Phase 1b/2a randomized, double-blinded, placebo-controlled clinical trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (HCT) recipients for the prevention of acute graft-versus-host-disease (aGVHD). These data will be featured in an ePoster Flash Session oral presentation at the Congress of the European Society of
 Clinical Microbiology and Infectious Diseases (ESCMID Global), taking place in Vienna, Austria from April 11-15, 2025. Details on ePoster number E0145 can be found below. About the Phase 1b/2a Clinical Trial The ongoing randomized, double-blinded, placebo-controlled Phase 1b/2a clinical trial is being conducted at Washington University School of Medicine in St. Louis. The trial is designed to evaluate the safety, tolerability, and potential absorption of oral SYN-004 (150 mg q.i.d. for a maximum of 28 days) into the systemic circulation of allogeneic HCT recipients who receive an IV antibiotic to treat fever. To mitigate risk, Cohort 1 of the study administered meropenem as the study-assigned antibiotic. Meropenem is a carbapenem antibiotic that is not metabolized by SYN-004. Patients in Cohort 2 were administered piperacillin/tazobactam as the study-assigned antibiotic and patients in Cohort 3 will receive cefepime. Piperacillin and cefepime can be metabolized by SYN-004. The trial is also designed to evaluate potential protective effects of SYN-004 on the gut microbiome as well as generate preliminary information on potential therapeutic benefits and patient outcomes of SYN-004 in allogeneic HCT recipients. The trial is expected to enroll up to 36 participants with three sequential cohorts, each evaluating a different study-assigned IV beta-lactam antibiotic. Safety and pharmacokinetic data for each cohort is reviewed by an independent Data and Safety Monitoring Committee that makes a recommendation on whether to proceed to the next IV beta-lactam antibiotic. More information on the study is available here ( NCT04692181 ). About SYN-004 (ribaxamase) SYN-004 (ribaxamase) is an oral prophylactic therapy designed to degrade certain IV beta-lactam antibiotics within the GI tract and maintain the natural balance of the gut microbiome for the prevention of Clostridioides difficile infection (CDI), overgrowth of pathogenic organisms, the emergence of antimicrobial resistance (AMR) and acute graft-versus-host-disease (aGVHD) in allogeneic hematopoietic cell transplant (HCT) recipients. Allogeneic HCT recipients routinely receive long courses of IV beta-lactam antibiotics to treat infection following conditioning therapy. Antibiotic-mediated damage of the gut microbiome in allogeneic HCT recipients may lead to adverse outcomes including CDI, VRE colonization and potentially fatal bacteremia and aGVHD. A previously completed placebo-controlled Phase 2b clinical trial of 412 patients demonstrated SYN-004 protected the gut microbiome from antibiotic-mediated dysbiosis. Patients who received SYN-004 also demonstrated significantly better maintenance and recovery of the gut microbiome as well as lower incidences of new colonization by opportunistic and potentially pathogenic microorganisms such as VRE. About Theriva™ Biologics, Inc. Theriva™ Biologics (NYSE American: TOVX), is a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need. The Company’s subsidiary Theriva Biologics, S.L. , has been developing a new oncolytic adenovirus platform designed for intravenous (IV), intravitreal and antitumoral delivery to trigger tumor cell death, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system. The Company’s lead clinical-stage candidates are: (1) VCN-01 (zabilugene almadenorepvec), an oncolytic adenovirus designed to replicate selectively and aggressively within tumor cells, and to degrade the tumor stroma barrier that serves as a significant physical and immunosuppressive barrier to cancer treatment; (2) SYN-004 (ribaxamase) which is designed to degrade certain commonly used IV beta-lactam antibiotics within the gastrointestinal (GI) tract to prevent microbiome damage, thereby limiting overgrowth of pathogenic organisms such as VRE (vancomycin resistant Enterococci) and reducing the incidence and severity of acute graft-versus-host-disease (aGVHD) in allogeneic hematopoietic cell transplant (HCT) recipients); and (3) SYN-020, a recombinant oral formulation of the enzyme intestinal alkaline phosphatase (IAP) produced under cGMP conditions and intended to treat both local GI and systemic diseases. For more information, please visit Theriva Biologics’ website at www.therivabio.com . SOURCE: Theriva Biologics

碱性磷酸酶(ALP）是一种普遍存在的膜结合糖蛋白，存在于从细菌到人类的许多生物体中。在大多数情况下，它们是同源二聚体酶，每个催化位点包含三个金属离子，即两个锌和一个镁。这些酶通过催化有机磷酸酯的水解或去除生物矿化的抑制剂无机焦磷酸(PPI)来催化水解。ALP由一组同工酶组成。每个同工酶都是由不同基因位点编码的糖蛋白。研究发现，人类所有的ALP基因都是从一个祖先基因进化而来的。图1显示了推导出的ALP进化树的大致轮廓。图1. 人类ALP基因的假定进化关系   ALP特征人碱性磷酸酶包括:肝/骨/肾碱性磷酸酶 (ALPL）、肠道碱性磷酸酶 (ALPI）、胎盘碱性磷酸酶 （ALPP）和生殖细胞碱性磷酸酶 (ALPPL2/ALPG）。ALPPL2和ALPP在氨基酸序列上几乎相同(同源性98%)，两者与ALPI具有高度同源性(87%同源性)，与ALPL具有一定的同源性(57%同源性)。ALPL在肾等组织广泛表达；ALPI主要在十二指肠表达；ALPP和ALPPL2在正常组织中几乎不表达，仅在胎盘和生殖组织和肺组织中的低表达。图2. ALPP/ALPPL2在正常组织表达高度受限除正常细胞外，ALPP/ALPPL2的表达与某些类型的癌症(如结肠癌、胃癌、卵巢癌、乳腺癌、骨肉瘤、神经母细胞瘤和白血病)的进展有关，使其成为这些癌细胞的临床标志物。研究表明，ALPP和ALPPL2在多种实体瘤表达增加，如卵巢癌、睾丸癌、子宫内膜癌、非小细胞肺癌、膀胱癌、胃癌等。图3. ALPP/ALPPL2在多种实体瘤中的表达临床主要进展ALPP/ALPPL2在正常组织几乎不表达或低表达，而在多种实体瘤中高表达，因此是一个肿瘤特异性较好的靶点，其具有ADC、双抗及CAR-T等药物形式开发的潜力。目前，ALPP和ALPPL2现有3个项目临床在研，最快进展到临床2期。表3. 主要临床进展SGN-ALPVSGN-ALPV是由Seagen 研发的一款靶向ALPPL2和ALPP的ADC药物，在研适应症主要针对实体瘤。该药物经过内吞作用进入细胞，在溶酶体中裂解出MMAE后杀伤细胞，在过表达ALPPL2的细胞系中杀伤活性可达到ng级别，也可产生部分ADCC/ADCP效应。在胃癌、胰腺癌、卵巢癌中能起到明显的抑制作用。图4. SGN-ALPV作用机制SGN-ALPV于2022年4月进入临床I期研究，用于探索其在卵巢癌、子宫内膜癌、NSCLC、胃癌等多种实体瘤中的疗效。2023年3月13日,辉瑞拟430亿美元收购Seagen，押注抗癌“导弹”药物；12月12日，宣布将于12月14日完成对Seagen的收购。12月13日，clinicaltrials显示，SGN-ALPV临床研究因投资组合优先次序而终止。TC-A101TC-A101是TCRCure的特异性靶向ALPP的CAR-T细胞治疗法，目前已进入临床1/2期，主要是评估TC-A101治疗 ALPP阳性转移性卵巢癌和子宫内膜癌患者的安全性和有效性。目前暂无详细的数据披露。AB-1015AB-1015 是 ArsenalBio 公司首个进入临床开发阶段的内部发现的 T 细胞药物，是ArsenalBio产品管线AB-X的一员。AB-X由ArsenalBio独有的编程细胞技术平台ICT打造，以期能以较低剂量的T细胞达到治疗效果。AB-1015可同时识别ALPG/P和MSLN，双靶标的设计有助于T细胞更精准地识别和杀死癌细胞，同时保护正常健康组织免受毒害。2023 年 1月 5 日,ArsenalBio 宣布，作为卵巢癌治疗药物开发的 AB-1015 1 期临床试验的首例患者给药成功。目前仍处于对耐药/难治性上皮性卵巢癌的1期临床研究中。小结ALPP/ALPPL2的潜在适应症包括卵巢癌、子宫内膜癌、胃癌等实体瘤，这些癌种均具有较大未满足的临床需求；且目前临床在研的项目尚处于早期，布局的公司较少，竞争也相对较小。参考资料【1】https://doi.org/10.3390/cells10123338【2】https://doi: 10.1007/978-1-62703-562-0_3.【3】2022 AACR Abstract No. 1766

ROCKVILLE, Md., Jan. 09, 2023 (GLOBE NEWSWIRE) -- Theriva Biologics (NYSE American: TOVX), (“Theriva” or the “Company”), a clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, today announced that the first patient has been dosed in the Phase 1 investigator sponsored clinical trial of VCN-01, an intravenous oncolytic adenovirus, for patients with high-grade brain tumors who are scheduled for surgical resection. “We are pleased to dose the first patient and evaluate the ability of our lead oncolytic adenovirus, VCN-01, to enter brain tumors following systemic administration,” said Steven A. Shallcross, Chief Executive Officer of Theriva Biologics. “This design builds on the data that we obtained from previous trials of systemically delivered VCN-01 for treating metastatic pancreatic cancer, another difficult to treat disease. If the results show that VCN-01 gains entry to brain tumors that are otherwise only accessible through surgery, this could be transformative for patients by enabling multiple treatments with VCN-01 without the complications of brain surgery. We look forward to driving this program forward and addressing the unmet need for the thousands of patients with primary or metastatic brain tumors who could potentially benefit from this novel oncolytic therapy.” Trial Design: The Phase 1, open-label, non-randomized trial is designed to evaluate the safety, tolerability and intratumoral presence of VCN-01 administered intravenously at a single dose of 1 x 1013 vp (virus particles) in up to 12 patients with recurrent high-grade glioma or brain metastases, prior to planned surgery. All patients will undergo surgical resection of their tumors between eight and 15 days following VCN-01 infusion, allowing for assessment of any toxicities and their resolution. More information about the trial is available here. The clinical trial is being led by Dr. Adel Samson, an expert in clinical immunotherapy and Head of the Translational Cancer Immunotherapy Group at the University of Leeds, as well as Professor Susan Short of Clinical Oncology and Neuro-oncology and Head of the Brain Cancer Research Section at Leeds Institute of Cancer and Pathology. The trial is funded by The Brain Tumour Charity and Cancer Research UK. Dr. Samson commented, “Patients with recurrent high-grade primary brain tumors typically have a poor prognosis, and often have to undergo one or more surgical interventions to remove their tumors. The leaky vasculature of many brain tumors may provide an excellent opportunity for systemically administered VCN-01 to enter the tumor, where it can replicate and initiate tumor cell killing, immune stimulation and destruction of tumor stroma. This could provide a more effective and less invasive therapeutic option for these patients.” About Theriva Biologics, Inc. Theriva Biologics (NYSE American: TOVX), is a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need. The Company’s subsidiary Theriva Biologics, S.L., has been developing a new oncolytic adenovirus platform designed for intravenous (IV), intravitreal and antitumoral delivery to trigger tumor cell death, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system. The Company’s lead clinical-stage candidates are: (1) VCN-01, an oncolytic adenovirus designed to replicate selectively and aggressively within tumor cells, and to degrade the tumor stroma barrier that serves as a significant physical and immunosuppressive barrier to cancer treatment; (2) SYN-004 (ribaxamase) which is designed to degrade certain commonly used IV beta-lactam antibiotics within the gastrointestinal (GI) tract to prevent microbiome damage, thereby limiting overgrowth of pathogenic organisms such as VRE (vancomycin resistant Enterococci) and reducing the incidence and severity of acute graft-versus-host-disease (aGVHD) in allogeneic hematopoietic cell transplant (HCT) recipients); and (3) SYN-020, a recombinant oral formulation of the enzyme intestinal alkaline phosphatase (IAP) produced under cGMP conditions and intended to treat both local GI and systemic diseases. For more information, please visit Theriva Biologics’ website at www.therivabio.com.