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Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence.

ABSTRACT: Background:Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods:The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results:The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions:The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration:NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

SUBMITTER: Gerding DN

PROVIDER: S-EPMC6093994 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.

Project description:IntroductionClostridium difficile infection (CDI) is the major cause of infectious nosocomial diarrhoea and is associated with considerable morbidity, mortality and economic impact. Bezlotoxumab administered in combination with standard of care (SoC) antibiotic therapy prevents recurrent CDI. This study assessed the cost-effectiveness of bezlotoxumab added to SoC, compared to SoC alone, to prevent the recurrence of CDI in high-risk patients from the Spanish National Health System perspective.MethodsA Markov model was used to simulate the natural history of CDI over a lifetime horizon in five populations of patients at high risk of CDI recurrence according to MODIFY trials: (1) ≥ 65 years old; (2) severe CDI; (3) immunocompromised; (4) ≥ 1 CDI episode in the previous 6 months; and (5) ≥ 65 years old and with ≥ 1 CDI episode in the previous 6 months. The incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed.ResultsIn all patient populations (from 1 to 5), bezlotoxumab added to SoC reduced CDI recurrence compared to SoC alone by 26.4, 19.5, 21.2, 26.6 and 39.7%, respectively. The resulting ICERs for the respective subgroups were €12,724, €17,495, €9545, €7386, and €4378. The model parameters with highest impact on the ICER were recurrence rate (first), mortality, and utility values. The probability that bezlotoxumab was cost-effective at a willingness-to-pay threshold of €21,000/QALY was 85.5%, 54.1%, 86.0%, 94.5%, 99.6%, respectively.ConclusionThe results suggest that bezlotoxumab added to SoC compared to SoC alone is a cost-effective treatment to prevent the recurrence of CDI in high-risk patients. The influence of changes in model parameters on DSA results was higher in patients ≥ 65 years old, with severe CDI and immunocompromised. Additionally, PSA estimated that the probability of cost-effectiveness exceeded 85% in most subgroups.FundingMerck Sharp & Dohme Corp.

Project description:Abstract Background Bezlotoxumab (BEZ) and actoxumab (ACT) are monoclonal antibodies against C. difficile toxins B and A, respectively. Patients receiving a single infusion of BEZ alone or with ACT in the MODIFY I/II trials showed a consistent reduction in the rate of rCDI over a 12-week period compared with a placebo (PBO) infusion. Exploratory genome wide analyses were conducted to determine whether genetic variants across the genome were associated with treatment response (rCDI). Methods DNA was extracted from blood obtained from patients who consented to genetic analysis (PGx population). Genetic data were generated on a commercial Axiom array platform (Affymetrix). Genotype imputation was performed using the 1000 Genomes Phase 3 reference data and Impute2 software after genetic quality control. Data from BEZ and ACT+BEZ arms were combined to provide increased power. The logistic regression with likelihood ratio test was used to search for single nucleotide polymorphisms (SNPs) that were strongly associated with a treatment effect on rCDI. Results An SNP rs2516513 located in the extended major histocompatibility complex (xMHC), region with a minor allele frequency of 25% in the general population, was associated with rCDI (P = 3.04E-08) (Figure 1). rCDI rates for the PGx population and in subgroups at high/low risk for rCDI stratified by SNP rs2516513 are shown in Table 1. Carriers of the T allele of SNP rs2516513 were associated with a statistically significant reduction in rCDI in BEZ-treated patients but not in PBO-treated patients (DrCDI = -21.5%). The magnitude of the effect of the T allele on rCDI is most prominent in patients who have ?1 risk factor for rCDI (DrCDI = -24.6%), but is also present in patients without risk factors (DrCDI = -10.6%). In CC homozygous patients, rCDI rates are similar in both treatment groups and in patients at high and low risk of rCDI. Conclusion An SNP variant rs2516513 is associated with a lower rate of rCDI recurrence in patients treated with BEZ. The location of the associated genetic variant on chromosome 6 within xMHC, suggests that a host driven, immunological mechanism may play a role in rCDI and may predict patients most likely to respond to BEZ. As this is an exploratory finding, the results should be replicated in an independent validation study. Disclosures P. Shaw, Merck & Co., Inc.: Employee, May own stock/hold stock options in Company; J. Shen, Merck & Co., Inc.: Employee, may hold stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company; J. Li, BGI-Shenzhen: Employee, Salary; R. Mogg, Merck & Co., Inc.: Employee, May hold stock/stock options in the Company; D. V. Mehrotra, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; R. L. Blanchard, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company

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Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence.

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