actoxumab/bezlotoxumab (MK-3415A) / Merck (MSD) - LARVOL DELTA

COMPARING EFFICACY OF BEZLOTOXUMAB, ORAL AND FECAL MICROBIOTA THERAPEUTICS, AND ANTIBIOTICS IN PREVENTING RECURRENT CLOSTRIDIUM DIFFICILE INFECTION: A NETWORK META-ANALYSIS (DDW 2025) - " We conducted a comprehensive search of electronic databases, including PubMed, Cochrane Library, and Embase, to identify Randomized Controlled Trials (RCTs) and Cohort studies from the last 10 years through October 2024 comparing the efficacy of Bezlotoxumab, Fecal Microbiota Transplant (Donor, RebyotaTM), Oral Microbiota Capsules (Donor, VowstTM, VE303TM), Vancomycin, Fidaxomicin, and Rifaximin in preventing recurrent Clostridium difficile infection...In the frequentist network meta-analysis, Actoxumab with Bezlotoxumab (RR=0.61 [0.37; 0.99]), Rebyota™ (RR=0.67 [0.45; 0.99]), VE303 (RR=0.30 [0.09; 0.97]), and Vowst™ (RR=0.29 [0.15; 0.56]) showed a statistically significant reduction in the rate of recurrent Clostridium difficile Infection (rCDI)... This review shows that Vowst™ effectively reduces recurrent Clostridium difficile infection (rCDI) rates compared to placebo and shows more consistent efficacy than other therapies. As an easy-to-use oral capsule, Vowst™ may..."

Retrospective data • Infectious Disease

Monoclonal antibody-mediated neutralization of Clostridioides difficile toxin does not diminish induction of the protective innate immune response to infection. (PubMed, Anaerobe) - "Monoclonal antibodies (mAbs) that neutralize Toxin A and Toxin B, actoxumab and bezlotoxumab, respectively, significantly reduce disease severity in a murine model of C. difficile infection...Interestingly, mAbs-treated mice exhibited increased infiltration of eosinophils in the intestinal lamina propria, which has been previously reported to promote a protective host response following C. difficile infection. These findings show that activation of host protective mechanisms remain intact in the context of monoclonal antibody-mediated toxin neutralization."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • IL22

Biofilm Formation of Clostridioides difficile, Toxin Production and Alternatives to Conventional Antibiotics in the Treatment of CDI. (PubMed, Microorganisms) - "Treatment of recurrent CDI (rCDI) with antibiotics, especially vancomycin (VAN) and metronidazole (MNZ), increases the risk of experiencing a relapse by as much as 70%. Fidaxomicin, on the other hand, proved more effective than VAN and MNZ by preventing the initial transcription of RNA toxin genes. Alternative forms of treatment include quorum quenching (QQ) that blocks toxin synthesis, binding of small anion molecules such as tolevamer to toxins, monoclonal antibodies, such as bezlotoxumab and actoxumab, bacteriophage therapy, probiotics, and fecal microbial transplants (FMTs). This review summarizes factors that affect the colonization of C. difficile and the pathogenicity of toxins TcdA and TcdB. The different approaches experimented with in the destruction of C. difficile and treatment of CDI are evaluated."

Journal • Review • Infectious Disease • Transplantation

Monoclonal anti-toxin therapy supports the protective innate immune response following Clostridioides difficile infection (P423) (IMMUNOLOGY 2023) - "Monoclonal antibodies (mAbs) that neutralize Toxin A and Toxin B, actoxumab and bezlotoxumab, respectively, significantly reduce disease severity in a murine model of C. difficile infection, however the impact of toxin neutralization on the induction of the innate immune response following infection is unknown...Further, no difference in neutrophil infiltration or production of IFNg or IL-17 from innate lymphoid cells (ILCs) was observed within the intestinal lamina propria following infection...Both IL-22+ ILCs and eosinophils promote protective host response following C. difficile infection. These findings indicate that activation of natural host protective mechanisms remain intact in the context of treatment that neutralizes toxin but does not alter C. difficile burden in the intestine."

Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • IFNG • IL17A • IL22

Add-on interventions for the prevention of recurrent Clostridioides Difficile infection: A systematic review and network meta-analysis. (PubMed, Anaerobe) - "Add-on treatment with oligofructose, NTCD-M3 spores, rifaximin, RBX2660, and bezlotoxumab likely reduces the risk of CDI. Evidence on probiotics and SER-109 are uncertain, thus adequately powered trials are warranted."

Journal • Retrospective data • Review • Infectious Disease

AAV-mediated delivery of actoxumab and bezlotoxumab results in serum and mucosal antibody concentrations that provide protection from C. difficile toxin challenge. (PubMed, Gene Ther) - "Hundred percent of mice given AAV6.2FF-actoxumab survived a lethal dose of TcdA. This proof of concept study demonstrates that AAV-mediated expression of C. difficile toxin antibodies is a viable approach for the prevention of recurrent C. difficile infections."

Journal • Gene Therapies

HUMAN BIOPSY-DERIVED COLONOIDS ARE USEFUL TO STUDY LUMINAL C DIFFICILE INFECTION AND THE RELATIVE BENEFIT OF ACTOXUMAB OR BEZLOTOXUMAB. (DDW 2020) - "Human biopsy derived colonoids provide a useful pre-clinical model and closely mimic responses to C. difficile intoxication and therapeutic outcomes. We show a potential mechanistic difference between Actoxumab and Bezlotoxumab using human organoids."

Immunology • Oncology • Solid Tumor

EFFICACY AND SAFETY OF MONOCLONAL ANTIBODIES AGAINST CLOSTRIDIOIDES DIFFICILE TOXINS FOR PREVENTION OF RECURRENT CLOSTRIDIOIDES DIFFICILE INFECTION; A SYSTEMATIC REVIEW AND META-ANALYSIS (DDW 2020) - "Subgroup analysis showed that bezlotoxumab plus actoxumab was remarkably preventive for patients with the following high-risk features: inpatients, vancomycin treatment, and BI/NAP/027 strain. The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe CDI rather than mild cases."

Retrospective data • Review • Immunology

Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis. (PubMed, J Clin Gastroenterol) - "The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe C. difficile infection rather than mild cases."

Journal • Retrospective data • Review

Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II. (PubMed, Clin Infect Dis) - P3; "From Monoclonal Antibodies for C. difficile Therapy II, no participants (n = 0/69) with a sustained clinical cure through 12 weeks following bezlotoxumab infusion experienced recurrent Clostridioides difficile infection (rCDI) after 9 months (versus actoxumab + bezlotoxumab, n = 2/65; versus placebo, n = 1/34). Bezlotoxumab's efficacy appears to be due to prevention rather than delayed onset of rCDI. NCT01513239."

Clinical • Journal • Observational data • P3 data

Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. (PubMed, Clin Infect Dis) - P3; "Higher eAb titers against toxin B, but not toxin A, were associated with protection against rCDI. These data are consistent with the observed efficacy of bezlotoxumab, and lack of efficacy of actoxumab, in the MODIFY trials.High titers of endogenous antibodies to Clostridioides difficile toxin B, but not toxin A, were associated with reduced recurrence of C. difficile infection. These findings are consistent with efficacy data from the phase 3 MODIFY trials of bezlotoxumab and actoxumab."

Journal

Assessment of Bezlotoxumab Immunogenicity. (PubMed, Clin Pharmacol Drug Dev) - P2, P3; "Immunogenicity to bezlotoxumab was evaluated following a single intravenous dose (≤20 mg/kg) or 2 consecutive doses (10 mg/kg) given 84 days apart in healthy participants across 3 phase 1 trials (Protocol MK-3415A-004, N = 30; Protocol CA-GCDX-05-01, N = 54; Protocol MK-3415A-006, N = 12) and following a single 10 mg/kg dose in 1 phase 2 trial (Protocol CA-GCDX-06-02, ClinicalTrials.gov identifier: NCT00350298; N = 97) and 2 phase 3 trials (Protocols MK-3415A-001 and MK-3415A-002, ClinicalTrials.gov identifiers: NCT01241552 and NCT01513239; N = 1414). Nine participants tested non-treatment-emergent positive in phase 3 trials, 1 of whom was neutralizing antibody-positive. Overall, the immunogenicity potential of bezlotoxumab is considered to be low."

Journal

Adeno-Associated Virus-Mediated Expression of Monoclonal Antibodies against Healthcare-Acquired Bacterial Infections (ASGCT 2019) - "...Additionally, AAV6.2FF was re-engineered to express hIgG mAbs with variable heavy and light domains of MEDI3902 to target the type 3 secretion system (PcrV) and exopolysaccharide (Psl) of Pseudomonas aeruginosa...Intramuscular injection of 5x1010vg of both AAV6.2FF-Actoxumab and AAV6.2FF-Bezlotoxumab resulted in serum concentrations of human IgG over 250µg/ml by 28 days post-injection. This method of AAV-mediated gene delivery and vectored immunoprophylaxis offers advantages prophylactically or post-infection and shows promise in prolonging the therapeutic effect of recombinant mAb administration."