Actoxumab Research Articles

Bezlotoxumab (BEZ) for Prevention of Clostridium difficile Infection (CDI) Recurrence (rCDI): Distinguishing Relapse from Reinfection with Whole Genome Sequencing (WGS)

BackgroundBezlotoxumab (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 an absolute 10% (relative ~40%) reduction in rCDI over 12-weeks compared with placebo (PBO). The addition of ACT did not improve efficacy. This post hoc analysis investigated whether BEZ prevented relapse with the same strain and/or reinfection with a new strain.Methods C. difficile strains isolated from patient stool samples were typed by PCR ribotyping, PCR free library construction and Illumina whole genome sequencing (WGS). rCDI was defined as diarrhea with toxigenic C. difficile in stool. Reinfection and relapse were differentiated by comparing ribotype (RT) and pair-wise single-nucleotide WGS variations (PWSNV). Relapse was assigned if the baseline RT and the RT isolated during rCDI were the same and PWSNVs were ≤2. Reinfection was defined as rCDI cases with a different RT compared with baseline or the same RT with >10 PWSNVs. Patients receiving BEZ or ACT+BEZ were pooled and patients receiving PBO or ACT were pooled. The effect of BEZ on the cumulative incidence of relapse and reinfection was estimated by Fine & Gray’s competing risks survival model.ResultsAmong 514 patients with rCDI in MODIFY I/II, 259 (50.4%) had a baseline and a post-baseline C. difficile isolate. There were 198 (76.4%) relapse and 50 (19.3%) reinfection cases (Table). Among rCDI cases, proportions of reinfection and relapse were similar between treatments. Proportion of relapses was higher for RT 027. Significant differences in crude cumulative incidence for relapse (P < 0.001) were observed for BEZ and ACT+BEZ groups compared with PBO and ACT groups. Similar changes were observed for reinfection but results were not significant. Cumulative incidence curves showed that relapses occurred earlier and at a higher rate than reinfections, but the reduction in rCDI was similar (Figure).ConclusionThe BEZ-induced reduction in rCDI observed in MODIFY I/II reflects the prevention of relapses due to the same strain. A reduction in reinfections was also observed, but likely due to a smaller number of reinfection cases, the difference was not significant.Disclosures M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company; Z. Zeng, Merck & Co., Inc.: Employee, May own stock/hold stock options in the Company ; M. Wilcox, Merck & Co., Inc.: Consultant, Consulting fee; Cubist: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium; Alere, Actelion Pharma, Astellas, Optimer, sanofi pasteur, Summit Pharma, bioMerieux, Da Volterra, Qiagen, Cerexa, Abbott, AstraZeneca, Pfizer, Durata Therapeutics, Seres Therapeutics, Valneva, Nabriva Therapeutics, Roche, The Medicines Company, Basilea P: Consultant, Consulting fee; Alere, Actelion Pharmaceuticals, Pharmaceuticals, Astellas, Optimer Pharmaceuticals, sanofi pasteur, Summit Pharmaceuticals, bioMerieux, Da Volterra, Qiagen, Cerexa, and Abbott: Grant Investigator, Grant recipient; J. Li, BGI-Shenzhen: Employee, Salary; H. Zhao, BGI-Shenzhen: Employee, Salary; X. Li, BGI-Shenzhen: Employee, Salary; D. Guris, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; P. Shaw, Merck & Co., Inc.: Employee, May own stock/hold stock options in Company

Genome Wide Analysis Reveals Host Genetic Variants that Associate with Reduction in Clostridium difficile Infection Recurrence (rCDI) in Patients Treated with Bezlotoxumab

BackgroundBezlotoxumab (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).MethodsDNA 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.ResultsAn 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.ConclusionAn 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

Endogenous Serum IgG Antibodies to Clostridium difficile Toxin B Are Associated with Protection against C. difficile Infection Recurrence

BackgroundMODIFY I/II were global trials of the efficacy and safety of bezlotoxumab (BEZ), a monoclonal antibody (mAb) against C. difficile toxin B, alone and with actoxumab (ACT), a mAb against C. difficile toxin A. BEZ was superior to placebo (PBO) at preventing recurrent CDI (rCDI) in patients (patients) receiving antibacterials for CDI. The addition of ACT did not improve efficacy. The aims were to explore potential biomarkers for rCDI risk in the patients receiving PBO by measuring endogenous IgG Abs against Cd toxins A and B (eAb-A and eAb-B); it was expected that patients with low eAb levels might be at increased risk of rCDI.MethodsSerum samples were collected pre-dose (PRE), at Week 4, and Week 12 postdose. eAb titers were measured using an electrochemiluminescence immunoassay. Results were reported as <1:1000, 1:1000, 1:5000, 1:25000, and ≥1:125000. As there is no clearly defined immunological surrogate of efficacy for rCDI tied to a specific eAb-A or eAb-B level, eAb levels were arbitrarily categorized as low (≤1:1,000), medium (1:5000), or high (≥1:25000). The rCDI rate was summarized by eAb category at each time point.ResultsThe proportion of patients with higher eAb-A and eAb-B titers increased following the initial CDI episode (Tables 1 and 2). There was no evident correlation between eAb-A titers and the rCDI rate at any time point. The proportion of patients who experienced rCDI within 12 weeks after randomization was highest in patients with low eAb-B titers PRE and at Week 4. rCDI rate in those with low eAb-B titer at all timepoints and in patients who had low titer only at PRE was similar.ConclusionThe rise in eAb-A and eAb-B titers over time is consistent with a convalescent humoral immune response to toxins A and B following CDI. The lack of correlation between eAb-A titers and rCDI is consistent with the lack of efficacy of ACT in prevention of rCDI. Conversely, higher eAb-B titers are associated with lower risk for rCDI, consistent with the efficacy of BEZ. 22.1% of patients with high eAb-B titers at PRE experienced rCDI. Therefore, eAb-B titers may have marginal utility as a biomarker for rCDI risk and are not likely to improve predictive value over clinical and demographic characteristics such as advanced age, compromised immunity, and CDI history.Disclosures C. P. Kelly, TBD: Investigator, Speaker honorarium; J. Shen, Merck & Co., Inc.: Employee, may hold stock/hold stock options in the Company; R. Railkar, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; D. Guris, Merck & Co., Inc.: Employee, may own 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

Bezlotoxumab Alone and With Actoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients on Standard of Care Antibiotics: Integrated Results of 2 Phase 3 Studies (MODIFY I and MODIFY II)

Background. Actoxumab ((ACT) MK-3415) and bezlotoxumab ((BEZ) MK- 6072) are human monoclonal antibodies against Clostridium difficile toxins A and B, respectively. Methods. Combined data from 2 double-blind, randomized, phase 3 studies in adult patients receiving oral standard of care (SoC) (metronidazole, vancomycin, or fidaxomi- cin) for primary or recurrent Cd ifficile infection (rCDI), including multiple rCDI. In MODIFY I, patients received a single infusion of ACT + BEZ 10 mg/kg each (MK- 3415A), ACT 10 mg/kg alone, BEZ 10 mg/kg alone, or placebo. In MODIFY II, patients received a single infusion of ACT + BEZ, BEZ alone, or placebo. Entry criteria, study visits/ procedures, and efficacy/safety endpoints were the same for both studies. The rCDI (new episode ofdiarrhea andpositive stooltest fortoxigenic Cd ifficile afterclinical cure ofbase- line CDI episode) was the primary endpoint, and global cure (clinical cure of initial epi- sode and no rCDI) was a secondary endpoint; both were evaluated through week 12. Results. A total of 2655 patients (median age 66 years, 57% female) enrolled in 30 countries and 2580 (97%) received the study infusion. Baseline characteristics were ba- lanced across treatment groups. In MODIFY I, the ACT alone group was stopped for ef- ficacy and safety reasons after interim analysis, based on a predefined adaptive plan. In the full analysis set (N = 2327, ACT alone excluded), 53% of patients were ≥65 years of age, 27% had prior CDI, 17% had severe CDI, and 11% were infected with 027 ribotype. The rCDI rates were significantly lower for ACT+BEZ (15.4%) and for BEZ alone (16.5%) versus placebo (26.6%, both 1-sided, P<.0001) and were reduced relative to placebo in subgroups with risk factors for rCDI, including age ≥65 years, history of CDI, infected with 027 ribotype, and severe CDI. Global cure was superior for BEZ alone (63.5%, 1- sided P=.0001) versus placebo and higher for ACT+BEZ (58.1%, 1-sided P=0.0426) versus placebo (53.7%). Safety endpoints were comparable for ACT + BEZ and BEZ alone versus placebo. The most common adverse events were diarrhea (5.9%), nausea (5.9%), and CDI (4.2%) (table).