Merck, a global healthcare leader, announced that the two pivotal phase 3 clinical studies for bezlotoxumab, its investigational antitoxin for prevention of Clostridium difficile (C. 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 these results, the company plans to submit new drug applications seeking regulatory approval of bezlotoxumab in the US, EU and Canada in 2015. Currently, there are no therapies approved for the prevention of recurrent disease caused by C. difficile.

Results from the studies were presented for the first time at the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and International Congress of Chemotherapy and Infection (ICC) joint meeting in San Diego, September 17-21.

“Results of these studies showed that a single, one-time infusion of the antitoxin bezlotoxumab given with standard of care C. difficile antibiotic treatment significantly reduced the recurrence of C. difficile infection compared to standard of care alone, and demonstrated this benefit over a 12-week period,” said Dr. Mark Wilcox, Leeds Teaching Hospitals and University of Leeds, UK, and a lead investigator for the studies.

“These results were also demonstrated in patient subgroups known to be at high risk for C. difficile recurrence.”

Bezlotoxumab is not an antibiotic. It is a selective, fully-human, monoclonal antibody designed to neutralise C. difficile toxin B, a toxin that can damage the gut wall and cause inflammation, leading to the symptoms of C. difficile enteritis, which include abdominal pain and watery diarrhea. Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and licensed to Merck in 2009 for development as a potential therapeutic for C. difficile infection.

“Recurrence is a major challenge with C. difficile infection, and novel approaches are needed to help prevent the cycle of C. difficile recurrence,” said Dr. Dale Gerding, professor of medicine, Loyola University Chicago Stritch School of Medicine, Maywood, and a lead investigator for the studies.

Two global, phase 3, double-blind studies were conducted to evaluate 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 1452 patients (median age 65 years) in 19 countries and the MODIFY II study enrolled 1203 patients (median age 67 years) in 17 countries. The studies were conducted in both hospital and outpatient settings, and the primary endpoint for each study was evaluated through 12 weeks following study drug administration.

In the MODIFY I study, 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 the MODIFY II study, 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 per cent, p=0.0003) and (15.7 per cent; p=0.0003), and the combination bezlotoxumab and actoxumab arms (15.9 per cent, p<0.0001) and (14.9 per cent, p<0.0001), compared to the placebo arms (27.6 per cent) and (25.7 per cent), respectively. In MODIFY I and MODIFY II, 1396 and 1163 patients were evaluated in the full analysis sets, 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 episode(s) 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 = 2), patients 65 years of age or older, and patients with compromised immunity. These subpopulation analyses were pre-specified in the protocol for each study.

In the studies, 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 per cent, 6.7 per cent and 5.6 per cent) and the placebo group (6.5 per cent, 5.0 per cent and 2.8 per cent). 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 per cent, 5.3 per cent and 4.5 per cent) and the placebo group (3.4 per cent, 6.6 per cent and 4.2 per cent). 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. Furthermore, 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 authorisation application.

The incidence of C. difficile infection has risen sharply over the last two decades and today is a leading cause of healthcare-acquired infections in community hospitals in the US. According to the US Centers for Disease Control and Prevention (CDC), C. difficile is estimated to have caused almost half a million infections in the US in 2011, with 29,000 deaths, often occurring within 30 days of initial diagnosis. In the US, 8 out of 10 deaths related to C. difficile infection occur in patients 65 years of age or older.

C. difficile infection occurs most often in patients staying in healthcare settings, especially hospitals or nursing homes, who recently took certain antibiotics or other medications. The incidence of C. difficile infection is higher in certain patient populations, including people 65 years of age or older, and in patients with compromised immune systems due to an underlying disease or from treatment. Recurrence is a major challenge in C. difficile infection, with approximately one-in-four patients experiencing a recurrence after the initial episode, and more than 40 per cent of these patients having further C. difficile recurrence.