Is SER-109 effective in reducing the risk of Clostridioides difficile (C. difficile) infection recurrence up to 8 weeks after treatment with fidaxomicin or vancomycin?

Comment by InpharmD Researcher

A phase 3, double-blind, randomized, controlled trial (ECOSPOR III) showed that oral administration of SER-109 was superior to placebo in reducing the risk of recurrent C.difficile infection up to 8 weeks after treatment with either vancomycin or fidoxomicin.
Background

The Infectious Diseases Society of America (IDSA) recommends the following for C.difficile infection (CDI) in adults:

For patients with an initial CDI episode, fidaxomicin, given its beneficial effects and safety profile, is suggested rather than a standard course of vancomycin. Vancomycin may be considered an effective alternative.

For patients with recurrent CDI episodes, fidaxomicin (standard or extended-pulsed regimen) is suggested rather than a standard course of vancomycin.

For patients with a recurrent CDI episode within the last 6 months, using bezlotoxumab as a co-intervention along with standard-of-care (SOC) antibiotics is suggested, rather than SOC antibiotics alone.

Metronidazole has been removed as a first-line treatment, with the use of oral vancomycin or fidaxomicin recommended instead. When vancomycin or fidaxomicin is contraindicated or are not available, metronidazole can be considered only in initial, non-severe CDI episodes. If used, length of treatment should be limited to 10 days, with a maximum of 14 days in those patients without full response. [1,2]

Promising agents for C.difficile infection, currently in phase 3 trials, include the antibiotic ridinilazole, the microbiome products SER-109 and RBX2660, and a vaccine. SER-109 (manufactured by Seres therapeutics) is a donor stool-derived microbiota-based product with purified spores from ethanol-treated stool and contains approximately 50 species of Firmicutes spores. Ethanol treatment of stool minimizes the risk of pathogen transmission due to inactivation of viruses and vegetative bacteria along with fungal and parasitic organisms. Administered orally, SER-109 is indicated for the prevention of recurrent C. difficile infections in patients who have experienced multiple recurrent infections. It is composed of a biologically sourced group of spore-based bacteria designed to create a new, healthy microbiome in patients whose natural microbiome has been damaged or is imbalanced. It has been granted orphan drug and breakthrough therapy designations by the FDA.

A phase I, open-label, dose-ranging study including 30 patients with multiply recurrent CDI demonstrated that 86.7% met the primary efficacy end-point in the absence of CDI compared with 96.7% achieving clinical resolution at 8 weeks. There were no safety concerns seen. An increase in microbial diversity after SER-109 treatment was observed.

A phase II, randomized, double-blinded, placebo-controlled trial of 89 patients with 3 or more episodes of CDI randomized patients 2:1 to receive SER-109 (single dose of ~108 spores) or placebo. Recurrent CDI rates were not different between SER-109 and placebo, except in a subgroup analysis of those aged 65 or older where SER-109 demonstrated a significant reduction in CDI recurrence compared with placebo. [2,3]

References:

1. 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. Clinical Infectious Diseases. 2021;73(5):e1029-e1044.

2. Durham SH, Le P, Cassano AT. Navigating changes in Clostridioides difficile prevention and treatment. J Manag Care Spec Pharm. 2020 Dec;26(12-a Suppl):S3-S23. doi: 10.18553/jmcp.2020.26.12-a.s3. PMID: 33533699.

3. Khanna S. Microbiota restoration for recurrent Clostridioides difficile: Getting one step closer every day! J Intern Med. 2021 Aug;290(2):294-309. doi: 10.1111/joim.13290. Epub 2021 Apr 15. PMID: 33856727.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is SER-109 effective in reducing the risk of Clostridioides difficile (C. difficile) infection recurrence up to 8 weeks after treatment with fidaxomicin or vancomycin?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Table 1 for your response.


 

SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection

ECOSPOR III (SER-109 versus Placebo in the Treatment of Adults with Recurrent Clostridium difficile Infection)

Design

Phase 3, double-blind, randomized, placebo-controlled trial

N= 182

Objective

To show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment

Study Groups

SER-109 group: N= 89

Placebo group: N= 93

Inclusion Criteria

Patients 18 years of age or older who had had three or more episodes of C. difficile infection within 12 months, inclusive of the qualifying acute episode, which was defined as three or more unformed bowel movements over 2 consecutive days, a positive C. difficile toxin test, and resolution of symptoms while receiving 10 to 21 days of standard-of-care antibiotic therapy

Methods

SER-109 is an investigational oral microbiome therapeutic composed of live purified Firmicutes bacterial spores. The authors hypothesized that the Firmicutes spore-forming bacteria would compete metabolically with C. difficile for essential nutrients, modulate bile-acid profiles to reestablish resistance to colonization.

 Prior to randomization, patients were stratified according to age and antibiotic received (vancomycin or fidaxomicin). After stratification, patients were randomized in a 1:1 ratio to receive either SER-109 or placebo, administered as four matching oral capsules, administered once daily over a period of three days. Ten ounces of magnesium citrate was administered the night before treatment to limit inactivation of SER-109 dose species.

Patients were monitored for eight weeks for recurrence, which was defined as onset of three or more unformed bowel movements per day over 2 consecutive days, a positive C. difficile stool toxin assay, an assessment by the investigator that treatment was warranted, and persistence of diarrhea until antibiotic treatment was initiated.

Patients reported solicited adverse events using diary cards for 7 days after completion of the course of SER-109 or placebo.

Stool specimens for whole metagenomic sequencing and targeted bile-acid analyses were obtained at baseline (within 3 days after completion of the antibiotic regimen) and at weeks 1, 2, and 8.

Duration

July 2017 to September 2020

Screening period: 3 weeks

Efficacy period: 8 weeks

Follow-up period: 16 weeks

Outcome Measures

Primary efficacy endpoint:

Superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after dosing. Patients whose condition did not meet the criteria for recurrent C. difficile infection were considered to have a sustained clinical response:

Overall recurrence

Sustained clinical response

Recurrence according to age

Recurrence according to previous antibiotic

 

Baseline characteristics

Characteristic

SER-109 (N= 89)

Placebo (N= 93)

Age–yr

65.6±16.5

65.5±16.7

Age <65 – no. (%)

41 (46)

38 (41)

Age >65 – no. (%)

48 (54)

55 (59)

Female sex – no. (%)

60 (67)

49 (53)

Race or ethnic group – no. (%)

Asian

1 (1)

0

Black

4 (4)

4 (4)

White

82 (92)

88 (95)

Other

2 (2)

1 (1)

Hispanic or Latino

5 (6)

6 (6)

Non Hispanic or Latino

84 (94)

87 (94)

Episodes of C.diff infection including qualifying episode – no. (%)

3

49 (55)

61 (66)

>4

39 (44)

32 (34)

Missing data

1 (1)

0

Previous antibiotic regimen – no. (%)

Vancomycin

64 (72)

69 (74)

Fidaxomicin

25 (28)

24 (26)

Results

 Overall Recurrence:

 

SER-109

N= 89

Placebo

N= 93

Relative risk (RR), 95% CI

P-value

Recurrence % in overall population

12

40

0.32 [0.18-0.58]

<0.001

Sustained response %

88

60

 

 

 

Recurrence According to Stratification:

 

< 65 years of age

RR, 95% CI

>65 years of age

RR, 95% CI

 

SER-109

N=41

Placebo

N=39

0.24 [0.07–0.78]

SER-109

N= 48

N= 54

0.36 [0.18–0.72]

Recurrence %

7

31

17

46

 

Vancomycin

0.41 [0.22–0.79]

Fidaxomicin

0.09 [0.01–0.63]

Recurrence %

16

38

4

46

 

Safety 

 

Adverse event

SER-109 (N= 90)

No. of Patients (%)

Placebo (N= 92)

No. of Patients (%)

Any adverse event

84 (93)

84 (91)

Adverse event related or possibly related to SER-109 or placebo

45 (51)

48 (52)

Serious adverse event

7 (8)

15 (16)

Adverse event of special interest that occurred or worsened after initiation of SER-109 or placebo

1 (1)

1 (1)

Serious adverse event leading to withdrawal from the trial

0

1 (1)

Adverse event leading to death

2 (2)

0

Study Author Conclusions

In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo.

InpharmDTM Researcher Critique

A reduction in the risk of recurrence among patients 65 years of age or older could be clinically important, as this age group is at increased risk for recurrent disease and hospital readmission. Given the stringent diagnostic testing prior to enrollment, effective follow-up period, and results, this could be a promising new therapy for recurrent CDI. 

However, there was low representation of minority populations in the recruited participants. Additionally, the absence of a stool specimen before antibiotic treatment limits the understanding of the full effect of SER-109 on the pre-antibiotic microbiome. 

 

 



References:

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.