A pair of posters presented at Digestive Disease Week 2022 showed the efficacy of an investigational biotherapeutic in preventing Clostridioides difficile infection recurrence and restoring the microbiome.
A pair of posters presented at Digestive Disease Week 2022 showed the efficacy of an investigational biotherapeutic in preventing Clostridioides difficile infection (CDI) recurrence and restoring the microbiome.
The first abstract provided results of an analysis of the multicenter, randomized controlled phase 3 trial PUNCH CD3, which enrolled adult patients with recurrent CDI.1 All 262 patients in this analysis had received standard-of-care antibiotic treatment before being randomized to receive either placebo or the investigational microbiota-based drug, RBX2660. Treatment success was defined by patients remaining free of any CDI recurrence for 8 weeks after treatment, and they were monitored for recurrence and treatment-emergent adverse events (TEAEs) for up to 6 months after treatment.
Because comorbidities are thought to play a role in CDI recurrence, investigators stratified patients into 3 groups by their underlying health conditions as determined by baseline Charlson Comorbidity Index scores: mild (score, 0-2), moderate (3-4), and severe (≥5). Most patients (n = 107) were in the mild comorbidity subgroup; 71 and 84 were in the moderate and severe subgroups, respectively. Those with mild comorbidities had fewer episodes of CDI before treatment compared with those with moderate or severe comorbidity burden.
In each subgroup, those receiving RBX2660 were more likely to achieve treatment success than those who received placebo: 76.5% vs 71.8% in the mild group, 68.0% vs 57.1% in the moderate group, and 67.8% vs 52.0% in the severe group. Although those in the mild group were most likely to see treatment success, the absolute difference between the placebo and intervention groups increased as comorbidity burden increased.
The abstract authors noted that most TEAEs were mild and moderate, and serious AEs were uncommon and occurred at similar rates between patients regardless of comorbidity burden or receipt of placebo vs RBX2660. There were no deaths or potentially fatal TEAEs related to the investigational drug or its administration.
Paul Feuerstadt, MD, of Yale University School of Medicine and PACT Gastroenterology Center, and an author of this poster, said in an interview with The American Journal of Managed Care® (AJMC®) that “it’s truly an exciting time in this space,” considering that clinicians across disciplines have struggled to manage CDI for decades.
“We’ve really been hamstrung for years with just having a standard-of-care antimicrobial to treat this infection resulting in recurrences and a huge patient burden,” Feuerstadt explained. “As we start to embark on the future here and we see a potential FDA approval of a product, this is really exciting, because we can see that end of the tunnel and we can see a broader application of a treatment that we know works.”
In the second poster, which was designated a Poster of Distinction at the conference, investigators assessed the restoration of the microbiome and bile acid composition after treatment with RBX2660 or placebo across 2 randomized, controlled, blinded trials—PUNCH CD2 (n = 153) and PUNCH CD3 (n = 887)—and the open label PUNCH OLS trial.2 Participants with a history of CDI provided stool samples at baseline and 1, 4, and 8 weeks after blinded treatment.
Among those who responded to treatment, defined by their lack of CDI recurrence at 8 weeks after treatment, the diversity and composition of the microbiome shifted significantly, and greater shifts were seen among responders who received RBX2660 than placebo. Investigators noted that Bacteroidia and Clostridia became more abundant whereas Gammaproteobacteria and Bacilli decreased after treatment, and this shift was observed as early as 1 week after treatment.
When using the Microbiome Health Index (MHI-A) biomarker of dysbiosis and restoration, investigators noted that this measure was restored from dysbiotic to healthy levels across all 3 trials, with a less pronounced improvement among responders to placebo.
Finally, analyses of PUNCH CD2 and PUNCH CD3 revealed that bile acid composition shifted from primary bile acid predominance before treatment to secondary bile acid predominance after treatment. Primary bile acids stimulate C difficile to grow, whereas healthy microbiota metabolize them to secondary bile acids, which repress C difficile from growing, Ken Blount, PhD, chief scientific officer of Rebiotix and lead author on that poster, told AJMC®.
“Collectively, these results indicate a totality of evidence that RBX2660 restored microbiome and bile acid compositions concurrent with clinical response, and the restorative changes are characteristic of shifts from a postantibiotic dysbiosis state to a healthier state,” the poster concluded.
Blount told AJMC® that this is “the largest study of its kind looking at that kind of microbiome and bile acid change for an investigational live biotherapeutic product.”
The take-home, Blount summarized, is that “the microbiome and the bile acid data are really supportive of why this may be working and showing the superior benefit to placebo in the clinic.”
1. Tillotson GS, Ando M, Ng S, Feuerstadt P. Treatment success of RBX2660 in reducing recurrent Clostridioides difficile infection in patients with underlying comorbidities. Presented at: Digestive Disease Week; May 21-24, 2022; San Diego, CA. Abstract Su1600.
2. Blount K, Hau H, Papzyan R, Fuchs B, Shannon B, Gonzalez C. Microbiome and bile acid restoration was consistent across three clinical trials of RBX2660 for recurrent Clostridioides difficile infection: a combined analysis. Presented at: Digestive Disease Week; May 21-24, 2022; San Diego, CA. Abstract Su1596.