Pivotal Phase 3 Studies of Bezlotoxumab, Merck’s Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint
September 20, 2015 11:30 am ET
Company Plans to Submit New Drug Applications in U.S., EU and Canada in 2015
Results Presented for the First Time at ICAAC/ICC 2015 Annual Meeting
Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today 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 U.S., 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, Sept. 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, U.K., 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 neutralize 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, Ill., and a lead investigator for
About the pivotal Phase 3 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%, p=0.0003) and
(15.7%; p=0.0003), and the combination bezlotoxumab and actoxumab arms
(15.9%, p<0.0001) and (14.9%, p<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 (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%, 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.
About C. difficile infection
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 U.S. According to the U.S.
Centers for Disease Control and Prevention (CDC), C. difficile is
estimated to have caused almost half a million infections in the U.S. in
2011, with 29,000 deaths, often occurring within 30 days of initial
diagnosis. In the U.S., 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 percent of these patients having
further C. difficile recurrence.
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