FDA Advisory Committee Gives Positive Vote for Microbiota-based C. Diff Therapy

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) issued a positive vote on Sept. 22, 2022, for Ferring Pharmaceuticals’ RBX2660 (now with the brand name Rebyota) to reduce recurrence of C. difficile infection (CDI) after antibiotic treatment. RBX2660 is microbiota-based live biotherapeutic that contains live microorganisms that are used as active substances. RBX2660 is a fecal microbiota transplantation therapy that was developed by Rebiotix, a Ferring company.

The committee voted 13 to 4 indicating that the data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults 18 years of age and older following antibiotic treatment. The committee also voted 12 to 4 with one abstention that the data were adequate to support the safety of RBX2660.

“Patients with recurrent C. difficile infection currently have limited treatment options,” Paul Feuerstadt, M.D., Yale University School of Medicine, said in a press release. “The committee’s vote is a step toward potentially addressing the debilitating cycle of recurrence and the suffering faced by these patients.”

Committee member David Kim, M.D., director, Division of Vaccines Office of Infectious Disease and HIV/AIDS Policy, at the U.S. Department of Health and Human Services, voted yes. “The current standard of care is not ideal for recurrent CDI, wiping out the gut biome to get rid of the ‘weeds,’ to use the garden analogy, only to see that there is weed overgrowth before the normal bioflora come back. The product is safe and easy to administer and can be beneficial for many patients with CDI.”

Committee Chair Hana El Sahly, M.D., professor, Department of Molecular Virology, Microbiology and Infectious Diseases Baylor College of Medicine, voted no for several reasons. After the vote, she said didn’t think the data was adequate to support efficacy. “One of the statistical bars was not met, and a key secondary endpoint was not met either,” she said. “When we put this in the context of the literature of how FMT (fecal microbiota transplantation) has evolved, one of the most rigorous RCT with vancomycin, it had to be stopped because FMT was inferior to standard of care in recurrent C. diff.”

She abstained from voting on the safety question because she felt there was not enough data to comment on.

The human microbiome is a complex community of microorganisms in and on the body. In the gut, if a microbial imbalance occurs, this can lead to C. diff, irritable bowel syndrome or even diabetes. C. diff is a serious disease that causes severe diarrhea, fever, stomach tenderness or pain, loss of appetite, nausea, and colitis. It has been estimated that up to 35% of cases recur after initial diagnosis and people who have had a recurrence are at significantly higher risk of further infection.

Data from the Ferring’s PUNCH program studying RBX2660 were released in May 2022. A subgroup analysis of integrated data from randomized participants who received one dose of blinded treatment of RBX2660 or placebo in the PUNCH CD2 and PUNCH CD3 trials. In the analysis, participants who received RBX2660 demonstrated greater treatment success compared with placebo. Treatment success was defined as remaining recurrence-free for eight weeks after treatment.

The FDA’s presentation at the advisory committee meeting pointed out, however, that one study (Study 2014-01) did not demonstrate definitive evidence of effectiveness for a single dose of RBX2660. Additionally, the phase 3 Study 2017-01 experienced recruitment difficulties and the agency agreed to modify the design and borrow data from Study 2014-01.

On the safety analysis, the FDA’s presentation indicated that most adverse events were mild but there was small placebo comparator group. There were 18 deaths in the treatment group, but they were not considered related to RBX2660.