Bezlotoxumab Improves Standard Care in Recurrent C diff

Veronica Hackethal, MD

January 25, 2017

Bezlotoxumab has a similar safety profile and significantly lower rate of recurrent Clostridium difficile infection than placebo among patients receiving standard-of-care antibiotics, according to data from the phase 3 trials MODIFY I and MODIFY II. Results were published online January 25 in the New England Journal of Medicine.

The study also showed that adding actoxumab to bezlotoxumab did not improve efficacy.

"Bezlotoxumab was associated with a rate of recurrent infection that was 38% (10 percentage points) lower than that associated with standard-of-care therapy alone," write Mark Wilcox, MD, from the University of Leeds, United Kingdom, and colleagues.

"Actoxumab was not efficacious when given alone and provided no additional benefit when given with bezlotoxumab," they add.

C difficile is the most common cause of hospital-acquired infectious diarrhea. Patients often experience recurrences, which are more difficult to treat, result in more severe outcomes, and contribute to burgeoning healthcare costs.

Actoxumab and bezlotoxumab are human monoclonal antibodies to C difficile toxins A and B, respectively. These antibodies have been linked to protection against C difficile infection.

In October 2016, the US Food and Drug Administration (FDA) approved bezlotoxumab to decrease recurrent C difficile infection, based in part on the results from the MODIFY I and MODIFY II trials (previously called Study P001 and Study P002).

Both studies were double-blind, randomized, placebo-controlled trials that took place at 322 sites in 30 countries between November 2011 and May 2015. The studies included 2655 adults who were receiving standard-of-care oral antibiotics (vancomycin, metronidazole, or fidaxomicin) for C difficile infection.

Researchers randomly assigned patients to an infusion of bezlotoxumab (10 mg/kg), actoxumab plus bezlotoxumab (10 mg/kg each), or placebo (0.9% saline). Patients in the MODIFY I trial also received actoxumab monotherapy (10 mg/kg), but this regimen was discontinued after a planned interim analysis showed its lack of efficacy. The modified intention-to-treat population was 2559 (96%), of whom 85% completed the trial through 12 weeks.

The primary endpoint was recurrent infection within 12 weeks after receipt of the infusion.

In MODIFY I, patients experienced recurrent C difficile infection at significantly lower rates with bezlotoxumab alone compared with placebo (17% vs 28%, respectively; adjusted difference, –10.1 percentage points; 95% CI, –15.9 to –4.3 percentage points; P < .001). Recurrent infection was also significantly lower with actoxumab plus bezlotoxumab than with placebo (16% vs 28%, respectively; adjusted difference, –11.6 percentage points; 95% CI, –17.4 to –5.9 percentage points; P < .001). However, the rate of recurrent infection did not differ significantly between actoxumab and placebo (26% vs 28%, respectively; P = .64).

Likewise, in MODIFY II the rate of recurrent C difficile infection was significantly lower with bezlotoxumab alone compared with placebo (16% vs 26%, respectively; adjusted difference, –9.9 percentage points; 95% CI, –15.5 to –4.3 percentage points; P < .001). Recurrent infection was also significantly lower with actoxumab plus bezlotoxumab than with placebo (15% vs 26%, respectively; adjusted difference, –10.7 percentage points; 95% CI, –16.4 to –5.1 percentage points; P < .001).

In a pooled analysis, rates of sustained cure (initial clinical cure without recurrent infection over 12 weeks) were 64% with bezlotoxumab alone, 58% with actoxumab plus bezlotoxumab, and 54% with placebo.

Subgroup analyses of the pooled data set also showed that patients at high risk for recurrent infection or adverse outcomes had lower rates of recurrent infection with bezlotoxumab and actoxumab plus bezlotoxumab compared with placebo.

All groups had similar rates of adverse events, though these were slightly higher with actoxumab (bezlotoxumab, 61.7%; actoxumab plus bezlotoxumab, 58.6%; actoxumab, 67.2%; placebo, 61.2%). The most common adverse events included diarrhea and nausea.

In a linked editorial, John Bartlett, MD, from Johns Hopkins University School of Medicine, Baltimore, Maryland, notes that the relative risk and cost of bezlotoxumab will need to be evaluated in comparison to alternative options, including fidaxomicin, which is already in use and has been linked to lower relapse rates. Other options in development include several new drugs now in clinical trials (ridinilazole, surotomycin, cadazolid, RBX2660, and SER-109). Trials are also evaluating three vaccines as well as oral administration of nontoxigenic C difficile organisms.

"[B]ezlotoxumab is a new, now-FDA-approved anti–C. difficile agent that has proved effective in reducing the rate of first post-treatment relapses of C. difficile infection; however, uptake by clinicians will vary on the basis of cost and assessments of relapse risk in association with this drug as compared with the alternative options," he concludes.

The study was funded by Merck. Several authors report being employees of and holding stock in Merck. Other company ties exist for multiple authors. Study author Dr Gerding holds patents related to the treatment and prevention of C difficile infection. Dr Bartlett has disclosed no relevant financial relationships.

N Engl J Med. 2017;376:381-382, 305-31. Abstract, Editorial

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