Bezlotoxumab reduced rates of recurrent Clostridium difficile infection in high-risk patients, reported the latest analysis of the MODIFY I and II trials. The pre-specified subgroup analysis was presented at Digestive Diseases Week, held 21-24 May in San Diego, CA.

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Bezlotoxumab was found to reduce CDI recurrence in two new trials.

Each year, C. difficile infection (CDI) is estimated to cause 172,000 infections across 27 countries in the European Union.

Although antibiotic treatment of primary infection is often successful, up to 35 percent of patients experience recurrence. Furthermore, following a first recurrence, patients have a 45 percent probability of a second recurrence, with risk increasing for subsequent recurrences.

Bezlotoxumab (Zinplava) is a selective, fully human, monoclonal antibody designed to provide passive immunity by neutralizing CDI toxin B – a toxin that damages the gut wall and causes inflammation leading to symptoms, including abdominal pain and watery diarrhea.

A key factor in CDI colonization is disruption of the gut microbiome by antibiotics. Treating CDI infections with additional antibiotics, explained study presenter Ciaran Kelly, opens the way for re-infection once the course of antibiotics has been completed.

“The neutralization of CDI toxin B by bezlotoxumab prevents signs and symptoms of CDI, hence additional CDI directed antibiotics are not needed if relapse or re-infection occurs. This allows the normal gut microbiome to restore itself,” said Prof. Kelly, from Harvard Medical School in Boston, MA.

MODIFY I and II were two phase III trials of bezlotoxumab in patients with CDI treated with standard-of-care antibiotics. In the studies, 781 patients were randomized to receive bezlotoxumab, while 773 received a placebo.

Bezlotoxumab, which has a systemic half-life of around 20 days, allowing circulation of antibodies for up to 3 months, was administered as a single, intravenous infusion (10 milligrams per kilogram) at any stage during the 10-14-day course of standard CDI-directed antibiotics.

Results showed the primary endpoint CDI recurrence – defined as a new episode of diarrhea (more than three loose stools in less than 24 hours) following clinical cure (initial clinical response of the baseline CDI episode) – occurred in 27 percent of patients receiving placebo vs. 17 percent receiving bezlotoxumab (P=.0003, relative risk reduction 37 percent).

The current presentation was a sub-analysis of MODIFY I and II data in patients considered at high risk for CDI recurrence, including those with severe CDI (Zar score higher than 2), those who are immune compromised, aged 65 years and older, infected with “hyper-virulent” strains (027, 078, or 244), who had prior recurrence (more than one CDI episode in the past 6 months) and prior recurrences (more than two previous CDI episodes ever).

Overall, 75 percent of patients in MODIFY I and II had at least one risk factor for CDI recurrence.

Results of the latest analysis are as follows:

  • For those with severe CDI (Zar score higher than 2), CDI recurred in 22 percent taking placebo vs. 11 percent taking bezlotoxumab (RR 50percent)
  • For the immune compromised, CDI recurred in 28 percent taking placebo vs. 15 percent taking bezlotoxumab (RR 46 percent)
  • For those older than 65 years, CDI recurred in 31 percent taking placebo vs. 15 percent taking bezlotoxumab (RR 52 percent)
  • For those with a hyper-virulent strain, CDI recurred in 32 percent taking placebo vs. 22 percent taking bezlotoxumab (RR 41 percent)
  • For those with less than one CDI episode in the past 6 months, CDI recurred in 41 percent taking placebo vs. 25 percent taking bezlotoxumab (RR 39 percent)
  • For those with fewer than two previous CDI episodes, CDI occurred in 42 percent taking placebo versus 29 percent taking bezlotoxumab (RR 31 percent).
  • Taking into consideration that many risk factors occur together, the investigators also explored the effects of multiple risk factors. In one analysis, they showed that for elderly people with prior CDI, recurrence was 43 percent for those randomized to placebo vs. 20 percent for those receiving bezlotoxumab (RR 57 percent).

    “The results demonstrated that certain CDI high-risk groups are at increased risk for recurrent CDI and therefore more likely to benefit from bezlotoxumab therapy for recurrence prevention,” said Prof. Kelly.

    The analysis, he added, showed that the beneficial effects of bezlotoxumab were maintained irrespective of baseline characteristics, and that they were not diminished in patients with multiple risk factors.