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Merck Drug Reduces C. Difficile Recurrence in Two Pivotal Trials

Company plans NDA this year; bezlotoxumab would be first to market

The two pivotal phase III clinical studies for bezlotoxumab, Merck’s investigational antitoxin for prevention of Clostridium difficile infection recurrence, met their primary efficacy endpoint: the reduction in C. difficile recurrence through week 12 compared to placebo when used in conjunction with standard-of-care antibiotics for the treatment of C. difficile.

Based on the results, Merck plans to submit new drug applications seeking regulatory approval of bezlotoxumab in 2015. Currently, no therapies are approved for the prevention of recurrent disease caused by C. difficile.

Results from the studies were presented at the Interscience Conference of Antimicrobial Agents and Chemotherapy and International Congress of Chemotherapy and Infection joint meeting in San Diego from September 17 to 21.

Bezlotoxumab is not an antibiotic. It is a selective, fully human monoclonal antibody designed to neutralize C. difficile toxin B, which can damage the gut wall and cause inflammation, leading to the symptoms of C. difficile enteritis, including abdominal pain and watery diarrhea.

Two global, phase III, double-blind studies evaluated bezlotoxumab, either alone or in combination with actoxumab (a fully human monoclonal antibody against C. difficile toxin A), compared to placebo for the prevention of recurrent C. difficile infection in patients on standard-of care-antibiotics for a primary or recurrent C. difficile infection.

The MODIFY I study (Monocolonal Antibodies for C. Difficile Therapy) enrolled 1,452 patients (median age, 65 years) in 19 countries, while the MODIFY II study enrolled 1,203 patients (median age, 67 years) in 17 countries. The studies were conducted in hospital and outpatient settings, and the primary endpoint for each study was evaluated through 12 weeks following study drug administration.

In MODIFY I, patients receiving standard-of-care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg, n = 403), actoxumab (10 mg/kg, n = 242), the combination of bezlotoxumab and actoxumab (10 mg/kg each, n = 403), or placebo (n = 404). The actoxumab arm was stopped for efficacy and safety reasons after an interim analysis.

In MODIFY II, patients receiving standard-of-care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg, n = 407), bezlotoxumab and actoxumab (10 mg/kg each, n = 397), or placebo (n=399).

In both MODIFY I and MODIFY II, the rate of C. difficile infection recurrence through week 12, the primary efficacy endpoint, was significantly lower in the bezlotoxumab arms (17.4%, P = 0.0003, and 15.7%, P = 0.0003, respectively, and the combination bezlotoxumab/actoxumab arms (15.9%, P < 0.0001, and 14.9%, P < 0.0001, respectively) compared with the placebo arms (27.6% and 25.7%, respectively).

In both studies, the rate of C. difficile infection recurrence was lower in the bezlotoxumab arms compared to the placebo arms in patient subgroups known to be at high risk for C. difficile recurrence, including patients with any prior episodes of C. difficile infection within the previous six months, patients infected with the BI/NAP1/027 strain, patients with severe C. difficile infection (Zar score of 2 or more), patients 65 years of age or older, and patients with compromised immunity. These subpopulation analyses were prespecified in study protocols.

The adverse reaction rates were comparable across the bezlotoxumab and placebo arms. In MODIFY I, the most common adverse reactions through four weeks after infusion (nausea, diarrhea, and pyrexia) occurred at similar rates in the bezlotoxumab group (7.4%, 6.7%, and 5.6%) and the placebo group (6.5%, 5.0%, and 2.8%). In MODIFY II, the most common adverse reactions through four weeks after infusion (nausea, diarrhea, and urinary tract infection) occurred at similar rates in the bezlotoxumab group (5.8%, 5.3%, and 4.5%) and the placebo group (3.4%, 6.6%, and 4.2%). Additionally, rates of serious adverse reactions and deaths assessed through 12 weeks after infusion were comparable across these treatment arms.

Treatment with the combination of bezlotoxumab and actoxumab did not provide added efficacy over bezlotoxumab alone. Actoxumab alone provided no benefit in the prevention of C. difficile recurrence compared with placebo. Based on these results, bezlotoxumab alone was selected for the marketing authorization application.

Source: Merck, September 20, 2015.

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