FDA Panel Backs Bezlotoxumab for C diff  Recurrence Prevention

Troy Brown, RN

June 09, 2016

The US Food and Drug Administration's (FDA's) Antimicrobial Drugs Advisory Committee voted 10 to 5, with 1 abstention, today to recommend bezlotoxumab injection (Merck & Company, Inc) for the prevention of Clostridium difficile infection (CDI) recurrence in patients aged 18 years or older.

Bezlotoxumab is a fully human monoclonal immmunoobulin G1/kappa antibody that binds to and neutralizes C difficile toxin B, likely by preventing it from binding to colonic cells and causing their inflammation. Bezlotoxumab is administered intravenously (IV) as a single dose of 10 mg/kg over 1 hour.

"I think these were well-done studies that were very detailed and provided us with a tremendous amount of data; we know the severity of recurrence of C diff and its impact. I believe that the sponsors showed that it was efficacious and overall very safe," said temporary voting member Christina Surawicz, MD, professor of medicine, Division of Gastroenterology, associate dean for faculty development, University of Washington School of Medicine, Seattle.

Phase 3 Trials

The decision follows a discussion of data from several trials including two phase 3 trials (Studies P001 and P002). Both studies were randomized, multicenter, double-blind, placebo-controlled trials of patients aged at least 18 years with a confirmed diagnosis of CDI. The clinical trial process was complicated by the fact that early in the development process, the company hypothesized that actoxumab, an antitoxin A antibody, would also prevent recurrence of CDI, and that the two drugs together might be even more effective.

Also, because the drugs were given along with standard of care (SOC) antimicrobial medications, researchers possibly underestimated the number of patients who experienced CDI recurrence because the patients had failed to respond to the antimicrobial. Thus, the FDA voiced a number of concerns and recommendations throughout the phase 2 and phase 3 trial processes.

Study P001 was an adaptive, four-group, factorial trial that evaluated the efficacy, safety, and pharmacokinetics of a single intravenous infusion of actoxumab (n = 232), bezlotoxumab (n = 386), or actoxumab + bezlotoxumab (n = 383) vs placebo (0.9% sodium chloride (n = 395) for prevention of CDI recurrence in patients who were also receiving antibacterials for treatment of CDI. The researchers randomly assigned 1452 patients in a 1:1:1:1 ratio to each of the treatment and placebo groups and followed up the patients for 12 weeks. An independent data monitoring committee halted enrollment in the actoxumab group because of safety concerns of actoxumab relative to the placebo group and low efficacy relative to the combination group. The trial continued to enroll patients in the remaining three treatment groups until study completion.

The design of Study P002 was identical to that of Study P001, except that the study did not include an actoxumab group alone, the researchers did not plan an interim analysis, and in Study P002, a subset of patients underwent an extended follow-up period through 12 months to assess for CDI recurrence and colonization with toxigenic C difficile. The researchers randomly assigned patients in the 1:1:1 ratio to one of the three treatment or placebo groups: actoxumab plus bezlotoxumab (n = 390), bezlotoxumab (n = 395), and placebo (n = 378).

The primary efficacy objective in both studies was whether or not treatment with a single infusion of one or both of the individual monoclonal antibodies given in addition to the SOC antimicrobials decreased CDI recurrence when compared with placebo and SOC therapy alone during the 12-week study period.

An additional primary objective in Study P001 and secondary objective in Study P002 was to determine whether or not treatment with actoxumab plus bezlotoxumab with SOC therapy decreased the proportion of patients with CDI recurrence over a period of 12 weeks when compared with treatment with a single monoclonal antibody (actoxumab or bezlotoxumab) with SOC therapy.

A secondary objective for both trials was to ascertain the proportion of patients who achieved global cure (defined as a subject who had clinical cure of the baseline CDI episode and no CDI recurrence) in each treatment group compared with placebo. An exploratory objective of the trials was to assess the proportion of patients in each treatment and placebo group who achieved clinical cure as compared with placebo.

Efficacy

In Study P001, the proportion of patients who experienced CDI recurrence was significantly lower in the actoxumab plus bezlotoxumab group (15.9%) when compared with placebo (27.6%). The adjusted differences in CDI recurrence between actoxumab plus bezlotoxumab and placebo were −11.6% (95% confidence interval [CI], −17.3% to −5.9%) and −10.1% (95% CI, −15.9% to −4.3%) between bezlotoxumab and placebo. The proportion of patients who had CDI recurrence in the actoxumab plus bezlotoxumab group compared with the bezlotoxumab group was slightly lower but was not statistically significant (two-sided P-value = .5944).

The proportion of patients who experienced global cure was higher in patients who took actoxumab plus bezlotoxumab (58.7%) and bezlotoxumab (60.1%) compared with placebo (55.2%), but these differences were not statistically significant. The adjusted differences in global cure between actoxumab plus bezlotoxumab and placebo were 3.5% (95% CI, −3.4% to 10.4%) and 4.8% (95% CI, −2.1% to 11.7%) between bezlotoxumab and placebo.

In Study P002, the proportion of patients who experienced CDI recurrence was significantly lower in the actoxumab plus bezlotoxumab group (14.9%) and the bezlotoxumab group (15.7%) when compared with placebo (25.7%). The adjusted differences in CDI recurrence between actoxumab plus bezlotoxumab and placebo was −10.7% (95% CI, −16.3% to -5.1%), and −9.9% (95% CI, −15.5% to −4.2%) between bezlotoxumab and placebo. The proportion of patients who experienced CDI recurrence was slightly lower in the actoxumab plus bezlotoxumab group compared with in the bezlotoxumab group, but the difference was not statistically significant (two-sided P-value = .7483).

The proportion of patients who experienced global cure was higher in the actoxumab plus bezlotoxumab group (57.4%) compared with placebo (52.1%), but the adjusted difference (5.2%; 95% CI, −1.7% to 12.2%) was not statistically significant (two-sided P = .1386).

The proportion of patients who experienced global cure was significantly higher (66.8%) (two-sided P < .001) compared with placebo, with an adjusted difference of 14.6% (95% CI, 7.8% to 21.4%). "The significance of this difference should be interpreted with caution given the predefined testing strategy in which the actoxumab plus bezlotoxumab vs placebo comparison was to be tested first," the FDA explained in a briefing.

"I was driven particularly by the urgent need for targeted therapy in people with C diff. I also hope these are used primarily in high-risk [patients], I hope that follow-up studies are done to help further clarify its role in people who are not high-risk...safety effects in [congestive heart failure (CHF)] and other cardiac disease," said voting committee member Jonathan Honegger, MD, assistant professor of pediatrics, Ohio State University College of Medicine, and Division of Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio.

Safety

When administered as a single IV infusion, the overall safety profile of bezlotoxumab was favorable, with similar rates of treatment-emergent adverse events, serious adverse events, and deaths compared with placebo. Patients treated with bezlotoxumab experience no increase in adverse events related to potential immune-mediated reactions compared with patients who received placebo. There was a numerically higher number of serious adverse events and deaths in patients with baseline CHF treated with bezlotoxumab compared with patients with baseline CHF who received placebo.

"I think it's really critical if this [drug] does proceed, that there are more phase 4 studies done to really see what's happening with the drug [in isolation]...from the perspective of safety. The CHF and death signal, I think, is actually significant," said voting committee member Demetre C. Daskalakis, MD, assistant commissioner, Bureau of HIV Prevention and Control, New York Department of Health and Mental Hygiene.

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