FDA panel votes in favor of fecal transplant therapy for recurrent C. difficile infection
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An FDA advisory committee recently voted there was adequate data to support the safety and efficacy of fecal microbiota transplant therapy Rebyota for the treatment of adult patients with recurrent Clostridioides difficile infection.
Following a full day of discussion and presentations on the epidemiology of C. difficile infection (CDI) in the U.S. and available data on Rebyota (RBX2660, Rebiotix Inc.), the Vaccines and Related Biological Products Advisory Committee voted 13-4 in favor of the availability of adequate data supporting effectiveness and 12-4, with one abstention, in favor of the availability of adequate data supporting safety.
“Despite the decrease in incidence of CDI, the overall burden of incident recurrent CDI is still substantial and associated with high morbidity and costs,” Alice Y. Guh, MD, MPH, a medical officer in the CDC’s Division of Health Care Quality Promotion, said. “An increasing proportion of CDI are now community-associated with a large portion of cases requiring hospitalization, which could be contributing to transmission within the hospital setting.”
She added, “A majority of patients have had recent antibiotic and outpatient health care exposures, indicating that prevention efforts focused on health care delivery might still be effective.”
Evidence in favor of the decision was presented by representatives from Rebiotix who reported on data from 978 individuals exposed to at least one dose of Rebyota across six clinical trials. They highlighted results from phase 2 and phase 3 randomized, double-blind, placebo-controlled trials (2014-01, 2017-01) to support its efficacy.
In the phase 2 trial, 128 individuals received blinded treatment of two enema doses of RBX2660, two enema doses of placebo or a combination of RBX2660 and placebo. The primary efficacy endpoint was treatment success, defined as the absence of CDI-associated diarrhea without need for retreatment with anti-infective therapy or fecal transplant 56 days following the last enema.
Results showed a 56.8% (25/44 individuals) success rate among patients in the combined RBX2660 and placebo group, a 55.6% (25/45 individuals) success rate among patients in the RBX2660 two-dose group and a 43.2% (19/44 individuals) success rate among patients in the placebo two-dose group, a difference that was not statistically significant.
In the phase 3 trial, researchers evaluated the safety and efficacy of RBX2660 in the prevention of recurrent CDI among 289 individuals. They defined treatment success as the absence of CDI diarrhea through 8 weeks following blinded study treatment.
Results from the intent-to-treat analysis demonstrated a success rate of 70% among individuals dosed with RBX2660 vs. 60.9% among individuals given placebo. Results from the modified intent-to-treat analysis demonstrated a sustained clinical response (up to 6 months follow-up) of 65.5% vs. 56.5%, respectively, with an insignificant difference (9.1%).
The integrated summary of safety included data from pooled analyses of all individuals exposed to at least one study treatment. Adverse events occurred in 66.4% of individuals (285/429) who received one dose of RBX2660, 80.3% (236/294) who received two doses, 78.6% (11/14) who received three doses, 91.7% (11/12) who received four doses and 72.5% (543/749) who received any dose of RBX2660. Treatment-emergent adverse events occurred in 61.8% (265), 79.6% (234), 78.6% (11), 91.7% (11) and 69.6% (521), respectively.
Despite presented evidence, some committee members found the data inadequate for the proposed voting questions.
“I voted no on both counts and find it impossible to disentangle the safety and efficacy, which are inextricably linked, and need to be balanced against one another,” Holly Janes, PhD, professor and associate head of the biostatistics, bioinformatics and epidemiology program at Fred Hutchinson Cancer Center, said. “I found the package to be relatively weak in terms of the level of statistical evidence, generalizability of the study populations and robustness of these analyses. ... I was not fully convinced that we could not have been presented with a stronger package of data.”
Others, however, said the critical need for treatment outweighed inadequacies in data and study enrollment.
“Having reviewed all the materials before the meeting, I was leaning toward two [no votes],” Henry Bernstein, DO, MHCM, FAAP, professor of pediatrics at Hofstra University and Cohen Children’s Medical Center, said. “But ultimately, listening to both the presentations made, as well as the conversations around the table, it swayed me that although there is a modest benefit in safety there is a real need for patients to have this option.”
Perspective
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Brian B. Baggott, MD, FACG
The FDA Advisory Committee generates independent advice and recommendations to the FDA on scientific and technical aspects of products being evaluated by the agency. The committee’s report on the safety and effectiveness of RBX2660 is good news for our patients with rCDI.
There are more than 500,000 cases of CDI per year in the United States, of which 25% will have a course of recurrent disease. It is now appreciated that repeated treatment of CDI with antibiotics — as recommended by ACG (5/2021) and Infectious Diseases Society of America (6/2021) practice guidelines — will most often control the active infection but may not rid the host of C. difficile spores that can activate when antibiotics are discontinued. We have all cared for many patients who are dependent on vancomycin suppression therapy.
Microbiome restorative therapy offers a promising way to break the cycle of rCDI. RBX2660 has undergone rigorous and formal phase 1, 2 and 3 trials, which have repeatedly demonstrated the safety and effectiveness of this product.
We are entering an exciting era of microbiome therapeutics for many disorders. Hopefully these products will break the cycle of recurrent infection and alleviate the significant suffering these patients endure.
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FDA. Vaccines and Related Biological Products Advisory Committee Sept. 22, 2022 meeting announcement. Available at: https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-september-22-2022-meeting-announcement. Accessed: Sept. 27, 2022.
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