Restoring Hope by Restoring Gut Flora: Rebyota and the Future of Combating Recurrent CDI

Clostridioides difficile infection (CDI), both initial and recurrent episodes of infection, is debilitating to those affected by it. After initial infection, as many as 20% to 25% of patients experience recurrent infection,1-3 which is defined as another episode of infection within 2 to 8 weeks after the initial episode.^4,5

After an initial recurrent episode, the risk of subsequent recurrent CDI episodes remains, and these episodes may vary in severity.⁶ Ultimately, recurrent CDIs can lead to complications that may require hospital readmission, surgical management, and increased costs to both the health care system and to the affected patients—as well as to mortality.^6-9

Current recommendations for the management of recurrent CDI are limited due to a lack of alternative therapies.^4,5 Preventing CDI recurrence is crucial and has become an outcome of interest in clinical research for newer agents active against CDI.^2,10-12 However, recurrent infection after antimicrobial therapy for both initial and recurrent CDI still affects patients and has led to the investigational use of alternative therapies such as fecal microbiota transplantation (FMT).

FMT involves using stool samples from healthy donors to hopefully replace the gastrointestinal microbiota makeup of the patient affected by recurrent CDI.¹³ It is available in a variety of delivery methods, including oral capsules, rectal enemas, and slurries delivered via colonoscopy.¹⁴ FMT is listed as a recommended therapeutic option in national CDI guidelines, typically for those who have experienced numerous episodes of recurrent infection after trialing (and failing) other recommended therapies.^4,5

FMT has shown promise in terms of preventing recurrent episodes of infection, and it is evident that fecal microbiota– based remedies are the future of treating CDI.^{15, 16} Manipulating the gastrointestinal microbiota makeup of those affected by CDI has led to an ever-expanding pipeline of potential microbiota-based remedies for CDI—and now a first-ever FDA-approved therapy.

Fecal microbiota, live-jslm (Rebyota) is the first formulation of fecal microbiota from human donors to be approved by the FDA.¹⁷ It was approved on November 30, 2022, for the prevention of recurrent CDI in adults aged 18 years and older after receiving antibiotic therapy for recurrent infection. It is administered as a 150-mL suspension via a rectal enema and done as an outpatient in a provider’s office within 24 to 72 hours of completion of an antibiotic course for the recurrent CDI episode.¹⁸

The purpose of fecal microbiota, live-jslm, as with FMT, is to restore the gastrointestinal flora makeup that was decimated by prior antibiotic use for the treatment of CDI to mitigate overgrowth of C difficile and ultimately prevent future infection. Significant advances have been made with the approval of fecal microbiota, live-jslm because safety standards have now taken precedence with the use of fecal microbiota products in humans. In fact, just prior to the approval of fecal microbiota, live-jslm, the FDA released a finalized guidance document related to its enforcement of the investigational new drug requirements for the use of FMT to treat CDI when FMT products are not obtained from a stool bank.¹⁹

Given the known risks of infection after FMT,²⁰ the enforcement of these safety standards going forward will improve patient care. The approval of fecal microbiota, live-jslm was contingent on the FDA’s Vaccines and Related Biological Products Advisory Committee’s review of 6 studies, with the efficacy data stemming from a combined analysis of a phase 2b and phase 3 study. The phase 3 PUNCHCD3 trial (NCT03244644), which was a randomized, double-blind, placebo-controlled study, incorporated outcomes data from a prior phase 2b study so that investigators could perform a Bayesian analysis to model estimates of treatment success—the primary outcome— and overall product efficacy. This method of outcome analysis was pursued because of challenges with patient enrollment and was recommended by the FDA.

The patient population used for the primary outcome analysis consisted of modified intention-to-treat populations from the phase 2b and 3 studies—defined as all patients who completed treatment and did not discontinue the trial within the first 8 weeks for reasons unrelated to CDI. Treatment success was defined as absence of CDI-associated diarrhea within 8 weeks of receipt of randomized treatment. The study enrolled patients 18 years and older with documented recurrent CDI who completed a course of standard-ofcare antibiotics or had 2 or more episodes of severe CDI that resulted in hospitalization within the past year.

Interestingly, an open-label portion of the study was reserved for those who did not respond to assigned blinded therapy within the first 8 weeks, enabling patients to receive open-label study drug.²¹ A total of 289 patients were randomly assigned in a 2:1 fashion to the study drug and a placebo, respectively. Overall, 267 patients received their allocated treatment, with 180 patients receiving the study drug and 87 the placebo. Most patients (n = 235; 88%) had received vancomycin for recurrent CDIs prior to study enrollment. Only 17 (6.4%) patients had received fidaxomicin. Those who had received bezlotoxumab as part of a treatment regimen for recurrent CDI were excluded from study enrollment.

Notably, 170 patients (63.7%) had experienced 3 or fewer recurrent CDI episodes. The study authors noted that roughly one-third of the patients enrolled had previously experienced only 1 recurrent episode of CDI.²¹ Treatment success was estimated to be 70.6% with the study drug vs 57.5% with placebo. This resulted in a treatment difference of 13.1% and posterior probability of superiority of 0.991, which exceeded a predetermined threshold (> 0.975), indicating potential statistical significance, according to the authors. Of note, 65 patients received a second dose of open-label study drug after treatment failure was confirmed; 41 of these patients were from the study drug cohort itself. In terms of safety data, the study drug was well tolerated overall, with most adverse effects being gastrointestinal related.²¹

There are certainly limitations with fecal microbiota, live-jslm that warrant cautious optimism. First, data are lacking for those who are immunocompromised because this population was excluded from study enrollment. There may be reservations with using an agent like fecal microbiota, live-jslm in this high-risk population because the FDA-approved agent bezlotoxumab indicated for secondary CDI prevention could be trialed first.^12,22 Future trials comparing the 2 agents, in conjunction with standard-of-care antimicrobials, would be beneficial to conduct. In addition, although the route of administration of fecal microbiota, live-jslm may not be an outright limitation, per se, it is certainly not the most desirable, and its use may be limited if patients remain hospitalized for more than 72 hours after completion of antibiotics for recurrent CDI.

Lastly, it is yet to be determined how much therapy with fecal microbiota, livejslm will cost patients and insurance companies. Although fecal microbiota, livejslm is the first fecal microbiota product approved by the FDA, there are other microbiota-based agents in the pipeline, particularly SER-109. SER-109 is derived from donor stool samples and consists of live, purified, gastrointestinal tract commensal bacterial spores manufactured into oral capsules.²³

This agent recently was evaluated in a phase 3 trial and found to be superior to placebo in reducing risk of CDI recurrence in patients who had received standard-of-care antibiotics.²⁴ More recently, additional phase 3 data from the ECOSPOR IV study (NCT03183141) was presented at IDWeek 2022.²⁵ The developer of SER-109, Seres Therapeutics, Inc, is gearing up because its biologics license application was accepted by the FDA for priority review.²⁶ If SER-109 becomes FDA approved, it would be the first oral fecal microbiota biologic therapy available for patients. There is no doubt that with the approval of fecal microbiota, live-jslm, a new standard has been set for future approval of FMT therapies.

Fecal microbiota, live-jslm is a promising therapy and an additional agent in the armamentarium to prevent recurrent CDI that will now be accessible to patients suffering from the debilitating effects of this disease. Although the FDA approval of fecal microbiota, live-jslm is a milestone, future trials of the agent against FDA-approved therapeutic options and other potential microbiota-based therapies are indeed warranted. Regardless, it is obvious that the once-distant future of fecal microbiota therapeutics for CDI is now here with the approval of fecal microbiota, live-jslm.

References

1. Fekety R, McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Mulligan ME. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis. 1997;24(3):324-333. doi:10.1093/clinids/24.3.324
2. Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012;55(suppl 2):S154-S161. doi:10.1093/cid/cis462
3. Reveles KR, Lawson KA, Mortensen EM, et al. National epidemiology of initial and recurrent Clostridium difficile infection in the Veterans Health Administration from 2003 to 2014. PLoS One. 2017;12(12):e0189227. doi:10.1371/journal.pone.0189227
4. 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
5. Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
6. Sheitoyan-Pesant C, Abou Chakra CN, Pépin J, Marcil-Héguy A, Nault V, Valiquette L. Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection. Clin Infect Dis. 2016;62(5):574-580. doi:10.1093/cid/civ958
7. Feuerstadt P, Boules M, Stong L, et al. Clinical complications in patients with primary and recurrent Clostridioides difficile infection: a real-world data analysis. SAGE Open Med. 2021;9:2050312120986733. doi:10.1177/2050312120986733
8. Nelson WW, Scott TA, Boules M, et al. Health care resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis. J Manag Care Spec Pharm. 2021;27(7):828-838. doi:10.18553/jmcp.2021.20395
9. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect. 2015;21(2):164-170. doi:10.1016/j.cmi.2014.08.017
10. Guery B, Menichetti F, Anttila VJ, et al; EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307. doi:10.1016/S1473-3099(17)30751-X
11. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615
12. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656. doi:10.1093/cid/ciy171
13. Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc. 2013;78(2):240-249. doi:10.1016/j.gie.2013.03.1329
14. Kim KO, Gluck M. Fecal microbiota transplantation: an update on clinical practice. Clin Endosc. 2019;52(2):137-143. doi:10.5946/ce.2019.009
15. El Halabi J, Palmer N, Fox K, Kohane I, Farhat MR. Fecal microbiota transplantation and Clostridioides difficile infection among privately insured patients in the United States. J Gastroenterol. 2022;57(1):10-18. doi:10.1007/s00535-021-01822-y
16. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(7):1079-1087. doi:10.1038/ajg.2012.60
17. FDA approves first fecal microbiota product. News release. FDA. November 30, 2022. Accessed December 18, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product#:~:text=%E2%80%9CToday's%20approval%20of%20Rebyota%20is,also%20potentially%20be%20life%2Dthreatening
18. Rebyota. Prescribing information. Ferring Pharmaceuticals Inc; 2022. https://www.fda.gov/media/163587/download
19. US Department of Health & Human Services, FDA, Center for Biologics Evaluation and Research. Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. November 2022. Accessed December 20, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota
20. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381(21):2043-2050. doi:10.1056/NEJMoa1910437
21. 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
22. Zinplava. Prescribing information. Merck & Co Inc; 2016. https://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf
23. McGovern BH, Ford CB, Henn MR, et al. SER-109, an investigational microbiome drug to reduce recurrence after Clostridioides difficile infection: lessons learned from a phase 2 trial. Clin Infect Dis. 2021;72(12):2132-2140. doi:10.1093/cid/ciaa387
24. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516
25. Seres Therapeutics presents SER-109 ECOSPOR IV study data at IDWeek and American College of Gastroenterology (ACG) 2022 annual meetings. News release. Seres Therapeutics Inc. October 23, 2022. Accessed December 22, 2022. https://ir.serestherapeutics.com/news-releases/news-release-details/seres-therapeutics-presents-ser-109-ecospor-iv-study-data-idweek
26. Seres Therapeutics to host investor webcast on December 8, 2022 to discuss SER-109 commercial strategy. News release. Seres Therapeutics Inc. November 22, 2022. Accessed December 22, 2022. https://ir.serestherapeutics.com/news-releases/news-release-details/seres-therapeutics-host-investor-webcast-december-8-2022-discuss