Novel alternative to fecal microbiota therapy prevents recurrent CDI in study

Key takeaways:

• High-dose VE303 prevented more cases of recurrentC. difficileinfection compared with a lower dose medication or placebo.
• Most participants experienced treatment-emergent adverse events.

A novel oral microbiome-directed therapy called VE303 successfully prevented recurrentClostridioidesdifficileinfection in adults at high risk for recurrence, researchers found.

“C. difficileis a leading nosocomial pathogen, with considerable morbidity and mortality,”JeffreyLSilber, MD,chief medical officer of Vedanta Biosciences, told Healio.

“维espite initial improvement with a course of antibiotics, at least 20% of patients with [C. difficileinfection (CDI)] suffer a recurrence within a few weeks. Once someone suffers a recurrence, the probability of additional recurrences is 40% or higher,” he said.

Silber added that where available,fecal microbiota transplantation(FMT) has been successful in treating CDI, and more recently, companies have developed products based on FMT, or spore fractions thereof, such as REBYOTA, which was approved in late 2022, andSER-109, which has an FDA action date scheduled for the end of April.

Unfortunately, Silber said these approaches have “significant logistical and safety limitations.”

“They are inherently variable in composition and quality since they rely on stool donations that vary across donors and within a donor over time, they are not easily scalable for broad clinical use, and they carry the risk of transmitting an undetected pathogen or antibiotic resistance factor from donor to recipient,” Silber said. “Thus, a significant unmet medical need remains and alternatives are needed.”

He added, however, that in contrast to those approaches, Vedanta’s platform is built on rationally defined bacterial consortia, which contain a standardized set of commensalClostridiastrains at a standard potency.

“The composition of each consortium is based on extensive preclinical testing, to identify the right mix based on strain- and consortium-specific characteristics,” he explained. "The strains are grown from pure clonal cell banks, akin to monoclonal antibody production, and thereby avoid the variability and potential risks associated with using material from human donors.”

After a phase 1 study demonstrated that following a course of antibiotics, VE303 led to “durable colonization of consortia strains in a dose- and duration-dependent way” while also enhancing synthesis of short-chain fatty acids, increasing conversion of primary bile acids to secondary bile acids, and led to early recovery of a beneficial microbial community.

“For these reasons, the Vedanta team thought that a course of VE303 might be effective in reducing the risk of CDI recurrence in patients at high risk for recurrence,” Silber said.

To assess this, Silber and colleagues conducted a double-blind, placebo-controlled study, the results of which were presented at The European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) and inJAMA．

The study was conducted between February 2019 and September 2021 and evaluated a low and high dose of VE303, each of which was given to study participants at high risk for CDI recurrence once daily by capsule for 14 days.

According to the study, 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with one or more prior episodes in the last 6 months were included in the study and treated at 27 sites across the U.S. and Canada. The primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks.

Overall, 29 patients were given the high-dose VE303, 27 the low-dose VE303 and 22 a placebo. Through week 8 of the study, CDI recurrence was reported in 13.8% of patients treated with high-dose VE303, 37% of patients given low-dose VE303 and 45.5% of patients given a placebo.

The treatment was well tolerated across the study population. According to the study, 96.2% of participants experienced one or more adverse events, with patients in the high-dose group reporting more than the low-dose group and placebo group (53.3% vs. 29.6% vs. 31.8%). Silber added the adverse events were primarily gastrointestinal in nature and classified as mild or moderate.

“This study is the first demonstration in a randomized, double-blind, placebo-controlled trial that a defined bacterial consortium can be effective in reducing the probability of CDI recurrence in patients at risk,” Silber said. “If these findings are replicated in phase 3 and VE303 were to be approved by regulators, it would provide a scalable, consistent, well-tolerated and safe pharmaceutical-grade therapeutic alternative to approaches derived from human stool.”

Additional data were presented at ECCMID from patients followed for 24 weeks, and fecal calprotectin was measured on days 1, 14, 28, 56 and 168 following the start of treatment. The data showed that, in general, VE303 was associated with reduced inflammation — determined by lower fecal calprotectin.

Researchers found that increased fecal calprotectin indicated higher inflammation in participants with an “on-studyrecurrence” compared with nonrecurrent participants across treatment groups (P< .05)．Additionally, fecal calprotectin increased over time from day 1 in nonrecurrent placebo recipients (P< .05) but not in nonrecurrent patients receiving eitherdose of VE303 (P> .2).

The researchers wrote that VE303 “may provide benefit beyond microbiome restoration in patients with CDI by limiting pathological inflammation.”

Louie T, et al.JAMA．2023年,doi: 10.1001 / jama.2023.4314.

References:

• Crossette E, et al.An 8-strain defined bacterial consortium promotes microbiota restoration and limits inflammation in patients with recurrentClostridioidesdifficileinfection (rCDI). Presented at: European Congress of Clinical Microbiology & Infectious Diseases; April 15-18, 2023; Copenhagen, Denmark.