SYN004 / Synermore - LARVOL DELTA

Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody. (PubMed, Molecules) - "Autoradiography and NanoSPECT/CT confirmed the sustained retention of I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development."

Journal • PK/PD data • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR

SYN-004 Safety and Tolerability in Allo-HCT Subjects (clinicaltrials.gov) - P1b/2a | N=36 | Recruiting | Sponsor: Theriva Biologics, Inc. | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Transplantation

A Study to Find the MTD of SYN125 in People With Solid Tumors and the MTD of SYN125 With a Fixed Dose of SYN004 in People in Patients With Epithelial Cancers With EGFR Expressions (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: Synermore Biologics Co., Ltd. | Recruiting ➔ Active, not recruiting | N=36 ➔ 22 | Trial completion date: May 2022 ➔ Sep 2023 | Trial primary completion date: Feb 2022 ➔ Jul 2023

Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • EGFR

Interim analysis of SYN-004 phase 1b/2a trial in haematopoietic cell transplant (HCT) recipients (ECCMID 2023) - No abstract available

P1/2 data • Transplantation

The Urgent Threat of Clostridioides difficile Infection: A Glimpse of the Drugs of the Future, with Related Patents and Prospects. (PubMed, Biomedicines) - "Many possible drugs of the future for CDI, with diverse mechanisms of action, are in development in the form of microbiota-modulating agents (e.g., ADS024, CP101, RBX2660, RBX7455, SYN-004, SER-109, VE303, DAV132, MET-2, and BB128), small molecules (e.g., ridinilazole, ibezapolstat, CRS3123, DNV3837, MGB-BP-3, alanyl-L-glutamine, and TNP-2198), antibodies (e.g., IM-01 and LMN-201), and non-toxic strains of CD (e.g., NTCD-M3). The development of some therapeutic agents (e.g., DS-2969b, OPS-2071, cadazolid, misoprostol, ramoplanin, KB109, LFF571, and Ramizol) stopped due to failed clinical trials or unknown reasons...The current pipeline of anti-CDI medications appears promising. However, it will be fascinating to see how many of the cited are successful in gaining approval from drug regulators such as the US FDA and becoming medicines for CDI and r-CDI."

Journal • Review • Developmental Disorders • Infectious Disease

Interim Analysis of Syn-004 Phase 1b/2a Trial in Hematopoietic Cell Transplant (HCT) Recipients (TCT-ASTCT-CIBMTR 2023) - "This study evaluates the safety, tolerability, and potential absorption of SYN-004 in HCT recipients, divided into three cohorts (meropenem (MER), piperacillin-tazobactam, and cefepime). Interim blinded analyses after the MER cohort suggest SYN-004 is well-tolerated with HCT. SYN-004 detection was uncommon by ECL; functional drug was not detected in blood."

Late-breaking abstract • P1/2 data • Bone Marrow Transplantation • Infectious Disease • Transplantation

Rational Design and Systemic Appraisal of an EGFR-Targeting Antibody-Drug Conjugate LR-DM1 for Pancreatic Cancer. (PubMed, J Med Chem) - "By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6...Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • EGFR

SYN-004 Safety and Tolerability in Allo-HCT Subjects (clinicaltrials.gov) - P1b/2a | N=36 | Recruiting | Sponsor: Synthetic Biologics Inc. | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Transplantation

Excellent effects and possible mechanisms of action of a new antibody-drug conjugate against EGFR-positive triple-negative breast cancer. (PubMed, Mil Med Res) - "LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes. It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR • KLF4 • POU5F1 • SOX2

SYN-004 Safety and Tolerability in Allo-HCT Subjects (clinicaltrials.gov) - P1b/2a; N=36; Recruiting; Sponsor: Synthetic Biologics Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Graft versus Host Disease • Immunology • Transplantation

A Study to Find the Maximum Tolerated Dose (MTD) of SYN125 in People With Solid Tumors and the MTD of SYN125 With a Fixed Dose of SYN004 in People With Cancer of the Internal or External Lining of the Body. (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Synermore Biologics Co., Ltd.; Trial completion date: Dec 2021 ➔ May 2022; Trial primary completion date: Sep 2021 ➔ Feb 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • EGFR

The oral beta-lactamase SYN-007 protects the gut microbiome from damage caused by oral amoxicillin /clavulanate without interfering with amoxicillin systemic absorption in dogs (ECCMID 2019) - "SYN-004 (ribaxamase) is an oral beta-lactamase intended to degrade selected IV beta-lactam antibiotics in the GI tract to protect the microbiome. A Phase 2b clinical study in patients receiving IV ceftriaxone significantly reduced C. difficile infection... SYN-007 protected the gut microbiome from damaged caused by oral administration of amoxicillin/clavulanate without affecting antibiotic systemic absorption. Notably, clavulanate did not interfere with SYN-007-mediated protection of the gut microbiome indicating that clavulanate did not inhibit beta-lactamase activity within the dog GI tract. These data demonstrate that the dual enteric coating formulation of SYN-007 prevented premature release of the beta-lactamase in the upper small intestine while allowing enzyme release soon enough to protect the colonic microbiota."

Gastrointestinal Disorder

Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial. (PubMed, Lancet Infect Dis) - P2 | "In patients treated with intravenous ceftriaxone for lower respiratory tract infections, oral ribaxamase reduced the incidence of C difficile infections compared with placebo. The imbalance in deaths between the groups appeared to be related to the underlying health of the patients. Ribaxamase has the potential to prevent C difficile infection in patients treated with intravenous β-lactam antibiotics, and our findings support continued clinical development of ribaxamase to prevent C difficile infection."

Clinical • Journal • P2b data • Infectious Disease • Pneumonia • Respiratory Diseases

The current novel therapeutic regimens for Clostridium difficile infection (CDI) and the potentials of Traditional Chinese Medicine in treatment of CDI. (PubMed, Crit Rev Microbiol) - "Currently, to address the relapse of CDI, several novel therapeutic approaches have emerged, including Bezlotoxumab, SYN-004 (Ribaxamase), RBX2660, and faecal microbial transplant. However, more rigorously designed basic researches and randomised controlled trials need to conduct to appraise the function mechanisms and effects of TCM. Finally, it is concluded that the combined therapeutic potentials of TCM and western medicine could be harness to resolve the recurrence and improve the outcome of CDI."

Journal

A Study to Find the Maximum Tolerated Dose of SYN125 in People With Advanced Colorectal and Head and Neck Cancer (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Synermore Biologics Co., Ltd.

Clinical • Combination therapy • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs. (PubMed, Microorganisms) - "Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioidesdifficile disease and attenuated emergence of antibiotic resistant organisms...Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically."

Journal

Low dose oral beta-lactamase protects the gut microbiome from oral beta-lactam-mediated damage in dogs. (PubMed, AIMS Public Health) - "Clinical proof of concept was achieved with SYN-004 (ribaxamase), a beta-lactamase enzyme formulated for oral delivery with intravenous penicillins and cephalosporins. Ribaxamase inactivated intestinal ceftriaxone, protected the gut microbiome, and significantly reduced the incidence of Clostridioides difficile disease...In dogs that received oral amoxicillin, SYN-007 reduced microbiome disruption without interfering with amoxicillin systemic absorption...These data demonstrate that effective SYN-007 doses can be reduced at least 10-fold while maintaining gut microbiome preservation. The potential to employ low SYN-007 doses to protect the gut microbiota has important implications for enhancing therapeutic outcomes for patients receiving oral beta-lactam antibiotics while simultaneously reducing cost per dose and ultimately, healthcare expenses."

Journal

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage. (PubMed, Microorganisms) - "...SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract...Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance...These data demonstrate that SYN-007 diminishes amoxicillin-mediated microbiome disruption and mitigates emergence and propagation of antibiotic resistance genes without interfering with antibiotic systemic absorption. Thus, SYN-007 has the potential to protect the gut microbiome by inactivation of beta-lactam antibiotics when administered by both oral and parenteral routes and to reduce emergence of antibiotic-resistant pathogens."

Journal

Syn-007, an Oral Beta-Lactamase Prevents Gut Microbime Dysbiosis Caused by Oral Amoxicillin and Oral Amoxicillin/Clavulanate Without Affecting Amoxicillin Systemic Absorption in Dogs (DDW 2019) - "SYN-004 (ribaxamase) is a clinical-stage, oral beta-lactamase for use with selected IV beta-lactam antibiotics intended to preserve the gut microbiome by inactivating residual antibiotics in the intestine. Antibiotic inactivation represents a potential new treatment paradigm for preservation of the gut microbiome and reduction of antibiotic resistance. SYN-007 has the potential to expand beta-lactamase-mediated microbiome protection to oral as well as IV beta-lactam anti- biotics."