Microbiome-based therapy for recurrent CDI hits mark in patients with comorbidities

The investigational microbiota-based live biotherapeutic RBX2660 is safe and averts repeat episodes of Clostridioides difficile infection (CDI) across patient populations with comorbid conditions, as shown in a study presented at Digestive Disease Week (DDW) 2022.

In an analysis involving 262 recurrent CDI patients who were included in the modified intent-to-treat population of the phase III PUNCH CD3 trial, RBX2660 consistently and safely reduced CDI recurrence in adults, regardless of baseline comorbidities, according to the study’s lead author Glenn Tillotson, a partner at GST Micro LLC, Richmond, Virginia, US.

Based on Charlson Comorbidity Index (CCI) scores at screening, the severity of comorbidity was mild in 107 patients, moderate in 71, and severe in 84. Mean participant age increased with increased comorbidities, and the mild group had fewer CDI episodes than the severe group. Despite these differences, RBX2660-treated patients across all CCI subgroups were more likely to remain recurrence-free for 8 weeks after treatment compared with those who received placebo. [DDW 2022, abstract Su1600]

The absolute difference in treatment success rates between RBX2660 and placebo increased in parallel with comorbidity burden: 5 percent in the mild group, 11 percent in the moderate group, and 16 percent in the severe group.

Across all CCI subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate and serious AEs were uncommon, Tillotson noted. One RBX2660-treated patient in the severe group had an AE that led to death, but no deaths or potentially life-threatening TEAEs were deemed related to the investigational drug or its administration.

Intestinal microbiota restoration

Antibiotics is the standard first-line therapy for CDI, but these drugs can induce unfavourable gut microbiota alterations, decreasing colonization resistance against other pathogens. This resulting microbiome disruption, or dysbiosis, is said to be the key pathogenic driver of CDI recurrence. [Rev Esp Quimioter 2019;32:47-54; J Antimicrob Chemother 2017;72:128-136]

On the other hand, the potential first-in-class microbiota-based live biotherapeutic RBX2660 is designed to deliver a broad consortium of diverse microbes to the gut to reduce recurrent CDI episodes after antibiotic treatment.

A separate study presented at DDW 2022 has shown that RBX2660 is indeed able to restore microbiome diversity and bile acid compositions concurrent with clinical response. In a combined microbiome and metabolomic analysis of participants in three trials of RBX2660 (PUNCH CD2, n=153; PUNCH CD3, n=887; and the open label PUNCH OLS, n=653), treatment responders exhibited significant recovery in both the diversity and the composition of microbiome, with more extensive changes among RBX2660- vs placebo-treated responders.

Specifically, the healthy commensals Bacteroidia and Clostridia classes increased in abundance, while the Gammaproteobacteria and Bacilli decreased. Moreover, the Microbiome Health Index (MHI-A), a biomarker of postantibiotic dysbiosis and restoration, shifted from dysbiotic to healthy levels. Finally, bile acid compositions were restored from primary predominance to secondary predominance—a composition more resistant to C. difficile colonization and infection. [DDW 2022, abstract Su1596]

These changes were observed as early as 1 week after treatment across the three trials and were maintained to the 8-week efficacy endpoint as well as to the end of the follow-up (6 months for CD2 and CD3, 24 months for OLS), said principal investigator Ken Blount, chief scientific officer at Rebiotix Inc in Roseville, Minnesota, US.

“Both the microbiome data and the bile acids data are highly consistent with a shift from an antibiotic-induced dysbiosis towards a healthier state, and this is in line with the clinical outcome in which RBX2660 across the three trials was shown to be superior to placebo for reducing recurrent CDI,” Blount added.