The FDA has requested the submission of new data and analyses from the MODIFY I and MODIFY II clinical trials previously submitted with the pending biologics license application (BLA) for bezlotoxumab, an investigational agent for the prevention of Clostridium difficile infection (CDI) recurrence. The additional data and analyses constitute a major amendment to the BLA, resulting in an extension of the Prescription Drug User Fee Act (PDUFA) goal date by three months. The new goal date is October 23, 2016.

The FDA had granted a priority review designation to the bezlotoxumab BLA, with an original PDUFA goal date of July 23, 2016. On June 9, the agency’s Antimicrobial Drugs Advisory Committee voted 10-to-5, with one abstention, in support of the efficacy and safety of bezlotoxumab in preventing CDI recurrence.

C. difficile produces two exotoxins, A and B. Bezlotoxumab is a monoclonal antibody that inhibits the binding of toxin B to mammalian cells, preventing the intracellular entry of this exotoxin, including the enzymatic components that are responsible for the toxin’s pathogenic effects. Toxins A and B contribute to the persistence of the tissue damage and immune-system effects that underlie the symptoms of CDI. Bezlotoxumab does not bind to toxin A.

The bezlotoxumab development program included two phase 3, randomized, multicenter, double-blind, placebo-controlled trials (P001 and P002). In study P001, 1,396 subjects were randomly assigned to receive a single intravenous infusion of actoxumab, bezlotoxumab, actoxumab plus bezlotoxumab, or placebo. The study’s primary efficacy objective was to determine whether treatment with a single infusion of actoxumab plus bezlotoxumab or with the individual monoclonal antibodies (actoxumab and/or bezlotoxumab) given in addition to standard-of-care (SOC) therapy reduced the proportion of subjects with CDI recurrence over 12 weeks compared with treatment with a single infusion of placebo with SOC therapy. Study P002 (N = 1,163) was basically identical in design to study P001 except that the actoxumab monotherapy arm was not included.

In study P001, a significantly lower proportion of subjects experienced CDI recurrence in the actoxumab/bezlotoxumab group (15.9%; P < 0.0001) and in the bezlotoxumab group (17.4%; P = 0.0006) compared with the placebo group (27.6%). Clinical cure of the initial CDI episode, however, was lower for both actoxumab/bezlotoxumab (74.7%; P = 0.0057) and bezlotoxumab (77.5%; P = 0.0622) compared with placebo (82.8%).

In study P002, a significantly lower proportion of subjects experienced CDI recurrence in the actoxumab/bezlotoxumab arm (14.9%; P = 0.0002) and in the bezlotoxumab arm (15.7%; P = 0.0006) compared with the placebo arm (25.7%). Clinical cure of the initial CDI episode was numerically lower for actoxumab/bezlotoxumab (72.3%) compared with placebo (77.8%). However, clinical cure was numerically higher for bezlotoxumab (82.5%) compared with placebo. Neither of these comparisons was statistically significant (P = 0.0801 and P = 0.0973, respectively).

Sources: Merck; July 21, 2016; and FDA Briefing Document; July 7, 2016.

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