The Antimicrobial Drugs Advisory Committee of the FDA ( Food and Drug Administration ) has discussed Zinplava ( Bezlotoxumab ), an investigational agent for prevention of Clostridium difficile ( C. difficile ) infection recurrence.
The Advisory Committee agreed, with a vote of 10 to 5 with one abstention, that there is substantial evidence of the safety and effectiveness of Bezlotoxumab for the prevention of Clostridium difficile infection recurrence in patients aged 18 years and older.
Bezlotoxumab is an investigational antitoxin given in conjunction with standard of care antibiotics that are used in the treatment of C. difficile infection. Bezlotoxumab is designed to neutralize C. difficile toxin B, a toxin that can damage the gut wall and cause inflammation, leading to C. difficile-associated diarrhea.
The application for Bezlotoxumab is based in part on data from the pivotal MODIFY I and MODIFY II clinical trials. Data from these trials were previously presented at the Interscience Conference of Antimicrobial Agents and Chemotherapy ( ICAAC ) and International Congress of Chemotherapy and Infection ( ICC ) 2015 joint meeting.
Two global, phase III, 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 ( Monoclonal 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%, p=0.0003 ) and ( 15.7%; p=0.0003 ), and the combination Bezlotoxumab and Actoxumab arms ( 15.9%, p less than 0.0001 ) and ( 14.9%, p less than 0.0001 ), compared to the placebo arms ( 27.6% ) and ( 25.7% ), 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, 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%, 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. 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 authorization application. ( Xagena )
Source: Merck, 2016