Do data support the use of commercially available fecal microbiota transplantation products in managing recurrent Clostridioides difficile infection?

Introduction
The Centers for Disease Control and Prevention (CDC) has identified Clostridioides difficile (C. difficile) as one of 5 “urgent threats”, highlighting the need for immediate and aggressive action to prevent complications and recurrences of this infection.¹ Unfortunately, many patients who experience an initial episode of C. difficile infection (CDI) go on to develop recurrent CDI (rCDI), which is generally characterized as the reappearance of the disease (based on both clinical and laboratory evidence) within 8 weeks after completing antibiotic therapy.² Symptoms resurface in 20% to 35% of patients following standard of care (SOC) antibiotic treatments for CDI, often within 30 days. Additionally, approximately 60% of patients experiencing recurrences develop a pattern of chronic rCDI, with the risk of recurrence more than doubling after ≥2 episodes.

Since our Group’s previous FAQ on this topic, fecal microbiota transplantation (FMT) has emerged as an important therapeutic approach for rCDI.^3-7 Stool material used for FMT is conventionally obtained either from stool banks or made in hospital laboratories in accordance with Food and Drug Administration (FDA) guidance and applicable investigational new drug (IND) requirements.^8,9 More recently, the first 2 commercially available FMT products were approved by the FDA: Rebyota (fecal microbiota, live-jslm) in 2022 and Vowst (fecal microbiota spores, live–brpk) in 2023.^10,11 Characteristics of both products are summarized in Table 1. It is important to note that both products are approved for use in adults for the prevention of recurrence following SOC antibiotic treatment, and neither product should be used for the treatment of active CDI.

Role of FMT for rCDI
Several national guidelines for CDI recommend FMT as a treatment for rCDI.^4-7 However, there is somewhat a lack of consensus on the number of recurrences that warrant the use of this unique therapy. The Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) recommend FMT after trying SOC antibiotics for ≥2 recurrences (i.e., 3 CDI episodes). On the other hand, the American College of Gastroenterology (ACG) and American Society of Colon and Rectal Surgeons (ASCRS) suggest FMT earlier, for individuals experiencing their second or later recurrence of CDI (i.e., the third or later CDI episode), in an effort to prevent further recurrences. The ACG also recommends a repeat FMT for individuals experiencing rCDI within 8 weeks of an initial FMT.

The literature shows that FMT has a high success rate in patients with rCDI.¹² For instance, a 2023 Cochrane review found that when compared to control (vancomycin, fidaxomicin, rectal bacteriotherapy, placebo), FMT significantly increased the likelihood of resolution of rCDI (risk ratio, 1.92; 95% confidence interval [CI], 1.36 to 2.71), without increasing the risk of serious adverse events (AEs) (risk ratio, 0.73; 95% CI, 0.38 to 1.41) or mortality (risk ratio, 0.57; 95% CI, 0.22 to 1.45).

The subsequent sections of this summary will delve into the clinical data supporting the commercially available FMT products. As of the publication of this summary, the commercially available products have not been compared to non-commercial FMT products, such as those obtained from stool banks or made in hospital laboratories from donor stool.

Clinical efficacy of commercially available FMT products
Rectally administered live fecal microbiota spores
The approval of rectally administered live fecal microbiota spores was based on a phase 3 double-blind, placebo-controlled randomized controlled trial (RCT) (PUNCH CD3; N=289).¹³ The widespread availability and utilization of FMT during the study period posed challenges for enrolling participants into a placebo-controlled trial. Therefore, analysis of PUNCH CD3 was conducted using a Bayesian hierarchical model that borrowed data from a preceding phase 2b trial (PUNCH CD2; N=134).^13,14 Both trials enrolled adults with rCDI (PUNCH CD3: ≥1 recurrences; PUNCH CD2: ≥2 recurrences) or ≥2 severe CDI episodes within the preceding year that led to hospitalization. Exclusion criteria for both trials included presence of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), chronic diarrhea, celiac disease, colostomy, a compromised immune system, and a previous FMT prior to study enrollment.

Enrolled participants received SOC antibiotic therapy and had improvement in CDI symptoms.^13,14 In PUNCH CD3, participants were randomized 2:1 to receive a single dose of rectally administered live fecal microbiota spores or placebo following a 24- to 72-hour washout period after SOC antibiotic therapy.¹³ In PUNCH CD2, participants were randomized 1:1:1 to receive either 2 doses of rectally administered live fecal microbiota spores, 2 doses of placebo, or 1 dose of each, administered approximately 1 week apart, following a 24- to 48-hour washout period after SOC antibiotic therapy.¹⁴

Treatment success, defined as the absence of CDI within 8 weeks of study treatment, was the primary outcome of the trials.^13,14 A preliminary 8-week analysis of PUNCH CD2 demonstrated that 1, but not 2, doses of rectally administered live fecal microbiota spores were superior to placebo for the outcome of treatment success.¹⁵ Success rates were 67%, 61%, and 45% for the groups that received 1 dose of active treatment followed by 1 dose of placebo, 2 doses of active treatment, and 2 doses of placebo, respectively (p=0.049 for the comparison of groups that received 1 dose of active treatment followed by 1 dose of placebo vs 2 doses of placebo). Based on these results, the 1-dose active treatment group was chosen for further study, and the Bayesian analysis used in PUNCH CD3 only incorporated data from the 1-dose active treatment group and the placebo control group of the PUNCH CD2 study.¹³ In a 24-month final efficacy and safety analysis from PUNCH CD2, success rates in the intention-to-treat population were 56.8%, 55.6%, and 43.2%  for the groups that received 1 dose of active treatment followed by 1 dose of placebo, 2 doses of active treatment, and 2 doses of placebo, respectively; in the per-protocol population, success rates were 87.5%, 75%, and 58.1%, respectively.¹⁴

In PUNCH CD3, initial predictions from the Bayesian hierarchical model showed success rates of 70.4% and 58.1% in the active treatment and placebo groups, respectively.¹³ However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-calculated treatment success rates for active and placebo treatment groups were 70.6% and 57.5%, respectively (treatment effect, 13.1%; 95% confidence interval [CI], 2.3 to 24.0). Furthermore, the posterior probability of superiority was 0.991 in favor of the active treatment group. Among those participants who achieved treatment success at 8 weeks, more than 90% remained free of rCDI through 6 months.

Additionally, 65 participants in PUNCH CD3 who experienced treatment failure received a second treatment course, which consisted of open-label rectally administered live fecal microbiota spores.¹³ Among 24 participants initially treated with a blinded placebo and later given open-label treatment, 15 (62.5%) achieved treatment success within 8 weeks and all remained free of rCDI through 6 months. Among 41 participants initially treated with blinded live fecal microbiota spores and subsequently treated with open-label treatment, 22 (53.7%) achieved treatment success within 8 weeks, with 86% remaining free of rCDI through 6 months.

Across both studies, AEs were mostly mild-to-moderate in severity and related to gastrointestinal issues.^13,14 In the final analysis of PUNCH CD2, treatment-related AEs occurred in 28.9% of participants.¹⁴ PUNCH CD3 did not report the rate of treatment-related AEs, but gastrointestinal disorders were the only AEs reported in ≥5% of participants in all treatment groups.¹³

Orally administered live fecal microbiota spores
The approval of orally administered live fecal microbiota spores was based on the ECOSPOR III trial.¹⁶ In this trial, 182 adults with ≥3 episodes (ie, ≥2 recurrences) of CDI in the previous 12 months who received 10 to 21 consecutive days of SOC antibiotic therapy with improvement in CDI symptoms were randomized to receive 4 orally administered capsules containing live fecal microbiota spores or placebo once daily for 3 consecutive days. Exclusion criteria in this trial were similar to the PUNCH CD trials.

The primary outcome of the trial was the rate of rCDI within 8 weeks of study treatment, which was reduced in the group that received active treatment as compared to placebo (12% vs 40%; relative risk, 0.32; 95% CI, 0.18 to 0.58).¹⁶ These findings remained consistent in subgroup analyses based on participant age (<65 years vs. ≥65 years) and previous antibiotic treatment (vancomycin vs. fidaxomicin). In a subsequent publication evaluating the durability of response, the rate of rCDI after 24 weeks of follow-up was 21.3% following active treatment and 47.3% following placebo (relative risk, 0.46; 95% CI, 0.30 to 0.73); the median (range) time to recurrence was 3.3 (0.6 to 23.4) weeks and 1.6 (0.6 to 18.1) weeks, respectively.¹⁷ The incidence of AEs was similar between treatment groups and most were mild-to-moderate in severity. Treatment-emergent AEs that occurred in ≥5% of participants, and more frequently with active treatment vs placebo included abdominal distension, constipation, diarrhea, and urinary tract infection.

Limitations
The pivotal trials for the commercially available FMT products demonstrate that these treatments are safe and effective in reducing the risk of rCDI in patients with risk factors for recurrence of this infection.^13-17 However, a few key limitations should be taken into consideration when making clinical decisions regarding these treatments. First, PUNCH CD3 included patients with ≥1 recurrence, which does not align with guideline recommendations that call for use of SOC antibiotics for ≥2 or ≥3 recurrences before FMT is considered.^4-7,13 Importantly, one-third of study participants in PUNCH CD3 were enrolled after only 1 recurrence.¹³ The risk of recurrence increases with each subsequent infection, therefore, participants with fewer recurrences had a lower baseline risk of rCDI, which may have impacted outcomes.^2,13 Furthermore, the placebo response rate in PUNCH CD3 was high, potentially attributed to the use of PCR assays to confirm CDI, which could lead to false-positive cases.^6,7,13 Additionally, all trials excluded patients with IBD, IBS, and immunosuppressive conditions, and they had a predominantly White participant population (≥90%), which limits the generalizability of their findings. Importantly, IBD or immunosuppressive conditions have been shown to increase the risk for rCDI.²

Conclusion
The efficacy and safety of the commercially available orally and rectally administered FMT products are supported by data from RCTs with up to 6 months follow up.^13-17 The rectal product is administered as a single dose but come with relatively cumbersome storage requirements. In contrast, the orally administered therapy is a 3-day course and requires bowel preparation.^10,11 Overall, both products are well-tolerated with most AEs mild to moderate in severity and primarily related to gastrointestinal issues.

References

1. Antibiotic resistance threats in the United States, 2019. Centers for Disease Control and Prevention. Published December 2019. Accessed September 12, 2023. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
2. Feuerstadt P, Theriault N, Tillotson G. The burden of CDI in the United States: a multifactorial challenge. BMC Infect Dis. 2023;23(1):132. doi:10.1186/s12879-023-08096-
3. Can patients with recurrent C difficile infection be treated with a prepared fecal microbiota product? University of Illinois at Chicago Drug Information Group. July 2014. Accessed September 12, 2023. https://dig.pharmacy.uic.edu/faqs/2014-2/july-2014-faqs/
4. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
5. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused update guidelines on management of clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
6. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
7. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
8. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridioides difficile Infection Not Responsive to Standard Therapies – Guidance for Industry. Food and Drug Administration. Published November 2022. Accessed September 12, 2023. https://www.fda.gov/vaccines-blood-biologics/guidance-complianceregulatory-information-biologics/biologics-guidances.
9. Fecal Microbiota Transplantation (FMT), Bacteriotherapy. American College of Gastroenterology. June 2022. Accessed September 12, 2023. https://gi.org/topics/fecal-microbiota-transplantation-fmt-bacteriotherapy/#:~:text=What%20is%20FMT%3F,that%20of%20a%20heathy%20donor
10. Rebyota. Package insert. Ferring Pharmaceuticals Inc. November 2022.
11. Vowst. Package insert. Aimmune Therapeutics, Inc. April 2023.
12. Minkoff NZ, Aslam S, Medina M, et al. Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile). Cochrane Database Syst Rev. 2023;4(4):CD013871. doi:10.1002/14651858.CD013871.pub2
13. Khanna S, Assi M, Lee C, et al. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs. 2022;82(15):1527-1538. doi:10.1007/s40265-022-01797-x
14. Dubberke ER, Orenstein R, Khanna S, Guthmueller B, Lee C. Final results from a phase 2b randomized, placebo-controlled clinical trial of rbx2660: a microbiota-based drug for the prevention of recurrent clostridioides difficile infection. Infect Dis Ther. 2023;12(2):703-709. doi:10.1007/s40121-022-00744-3
15. Dubberke ER, Lee CH, Orenstein R, Khanna S, Hecht G, Gerding DN. Results from a randomized, placebo-controlled clinical trial of a RBX2660-A microbiota-based drug for the prevention of recurrent clostridium difficile infection. Clin Infect Dis. 2018;67(8):1198-1204. doi:10.1093/cid/ciy259
16. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficileN Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516
17. Cohen SH, Louie TJ, Sims M, et al. Extended follow-up of microbiome therapeutic SER-109 Through 24 Weeks for recurrent Clostridioides difficile Infection in a randomized clinical trial. JAMA. 2022;328(20):2062-2064. doi:10.1001/jama.2022.16476

Prepared by:
Kathy Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2023

The information presented is current as September 10, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.