Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details

Figures & data

Table 1 Live Biotherapeutic Products Approved or in Clinical Trials for Preventing Recurrent Clostridioides Difficile Infection

Product Type	Product name; Company	Composition And Storage Administration Parameters	Current Status
Donor-derived enema	REBYOTA (RBX2660)^Citation11 Rebiotix, Ferring Pharmaceuticals	● Fecal microbiota, live-jslm ● Rectal suspension containing between 1×10^8 and 5×10^10 CFU per mL of fecal microbes including >1x10^5 CFU/mL of Bacteroides ● Requires storage at −80°C and is then thawed and administered via retention enema Dose: 150 mL rectal suspension one time	FDA Approved
Donor- derived oral capsule	VOWST (SER-109);^Citation15,Citation91,Citation118 Seres Therapeutics	● Fecal microbiota spores, live-brpk ● Narrow consortium or Firmicutes spores derived from donated stool suspension which is treated with ethanol to kill living organisms and the slurry is then filtered to remove solids and isolate spores from the Firmicutes phyla ● Formulated into capsules each containing 1×10^6 - 3×10^7 Firmicutes spore CFU ● Requires 10 ounces of magnesium citrate as a bowel washout preparation ● Dose: four capsules orally once daily on an empty stomach for three days	FDA Approved
	RBX7455^Citation12 Rebiotix, Ferring Pharmaceuticals	● Fecal microbiota, live-jslm ● Derived from RBX2660 suspension containing ≥10^7 live bacteria / mL and treated with a proprietary formulation of lyoprotectant and cryoprotectant excipients to stabilize the lyophilized bacteria at room temperature and against gastric acid in capsule form. ● Delivered as doubly encapsulated V-caps^® stored at 2 to 8°C until dispensing.	Phase 2 trial complete, halted further development
	CP-101^Citation94,Citation119 Finch Therapeutics	● Oral Full-Spectrum MicrobiotaTM (broad consortium) ● Lyophilized capsule of, full-spectrum microbiota containing diverse microorganisms	Further development halted
Designed oral capsules	VE-303;^Citation103,Citation104 Vendanta Biosciences	● A defined consortium of 8 commensal strains of clonally derived and distinct Clostridium species (5 strains from Clostridia cluster XIVa, 2 from cluster IV, and 1 from cluster XVII) ● Enteric capsules each containing 1×10^8 CFU of lyophilized bacteria from each species for a total 8×10^8 CFU of bacteria in 400mg combined with sucrose, histidine, yeast extract, cysteine, and other excipients	Phase 2 trial complete
	NTCD-M3 (VP20621);^Citation105,Citation120 Shire pharmaceuticals	● Enteric capsules containing a non-toxigenic C. difficile strain M3	Phase 2 trial complete
	MET-2;^Citation93 Microbial Ecosystem Therapeutics	● A proprietary consortium of 40 commensal bacterial species from strains which are then purified and combined as a lyophilized product into capsules for oral delivery	Phase 1 trial complete
	ART24 (ADS024)^Citation9 Adiso Therapeutics	● A single-strain of Bacillus velezensis lyophilized and administered via capsule	Phase 1
	DSM33864 DifProtec(TM)^Citation117 Novozymes A/S	● A single strain probiotic dietary supplement capsule containing Bacillus velezensis	Phase = N/A
	SER-262^Citation121Seres Therapeutics	● Cultivated Eubacterial Spore Suspension, Encapsulated Ecobiotic^® ● A rationally designed, multi-strain microbiome therapeutic produced synthetically by in vitro anaerobic fermentation to produce commensal bacteria in spore form	Phase 1 complete

Abbreviation: CFU, colony-forming units.

Table 2 Clinical Trial Data for REBYOTA and VOWST

Trial Name (Drug)	Number of Prior CDI Episodes	Prior CDI Treatment	Diagnostic Test Used to Identify CDI	Antibiotic Use Through The Follow-Up Period (8 weeks)	Surgical and ICU Exclusions	Immunologic and Medical Exclusions
PUNCH CD3 (REBYOTA)	● Required ≥ 1 recurrence after a primary episode or ≥ 2 severe episodes within the last 1 year	● Standard-of-care antibiotic therapy (defined as 10 to 21 days of treatment with vancomycin [125 mg QID] and/or fidaxomicin [200 mg BID])	● Any positive stool test for the presence of toxigenic C. difficile within 30 days prior to enrollment	● Did not allow oral vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide or IVIG through the 8-week follow-up unless prescribed by a treating investigator during the study as a result of recurrent CDI diagnosis	● Excluded intra-abdominal surgery within the prior 60 days ● Did not exclude patients in the ICU	● Excluded patients with high medical risks and clinically significant co-morbid disease per the opinion of the investigator ● Excluded patients with ANC<1000 cells/ml^3
ECOSPOR III (VOWST)	● Required ≥ 3 episodes of CDI within the previous 9 months, inclusive of the current episode	● Standard-of-care antibiotic therapy (defined as 10 to 21 days of treatment with vancomycin [125 mg QID] and/or fidaxomicin [200 mg BID])	● Positive C. difficile stool sample tested by a toxin assay preferably performed by the central laboratory	● Allowed antibiotic treatment. Patients were excluded at study start if projected to receive antibiotics during the 8-week period post-randomization	● Excluded major gastrointestinal surgery (eg Bowel resection /diversion) within 3 months prior to enrollment ● Excluded prior total colectomy or bariatric surgery (Prior appendectomy or cholecystectomy allowed) ● Excluded patients admitted or expected to be admitted to ICU	● Excluded patients with high medical risks and clinically significant co-morbid disease per the opinion of the investigator ● Excluded patients with ANC<500 cells/ml^3

Note: [a] This table only includes key inclusion/exclusion criteria that were determined to be different between the two trials. For full inclusion/exclusion criteria, please refer to the respective protocols of the trials.

Abbreviations: CDI, Clostridioides difficile Infection; ICU, Intensive Care Unit.

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