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SER-109, a potential first-in-class oral investigational microbiome therapeutic, was granted Breakthrough Therapy and Orphan Drug designations by the FDA for the treatment of recurrent CDI following standard-of-care antibiotics. SER-109 comprises live purified Firmicutes spores on the basis of their modulatory role in the life cycle of C. difficile and disease pathogenesis. Preclinical data demonstrated the efficacy of Firmicutes spores in reducing CDI recurrence, which led to the hypothesis that spore-forming bacteria may compete metabolically with C. difficile for essential nutrients and/or modulate bile acid profiles to re-establish colonization resistance.
- Clostridioides difficile infection (CDI)
- SER-109
- microbiome therapeutics
1. Manufacturing and Characterization of SER-109
A schematic of the manufacturing steps of SER-109 is shown in Figure 1. Manufacturing and quality systems for SER-109 are state-of-the-art, and were designed to deliver the microbial components that facilitate potency while mitigating the risk of pathogen transmission and significantly reducing the impurities associated with donor materials. The resilience of Firmicutes spores permits their enrichment through an ethanol-based purification process. Unlike most vegetative commensal organisms, spores are resistant to gastric acid, heat, and a range of chemical and physical changes, exhibiting exceptional stability during manufacturing and drug product storage, and allowing for oral delivery via capsules with a low pill burden.
Figure 1. SER-109 Manufacturing processes mitigate risk.
Comprehensive donor screening and subsequent monitoring are essential first steps in producing the purified SER-109 product. Once a donor clears a thorough health history, physical examination, and full array of laboratory testing, stool is processed in a controlled bioprocessing environment through a proprietary, rigorous process designed to remove vegetative bacteria, fungi, parasites, and viruses via solvent inactivation and purification steps in compliance with current good manufacturing process regulations. The inactivation and clearance processes were further validated by challenge studies using model organisms of various pathogens. These studies confirmed the process’ capability to reduce potential pathogenic bacteria, fungi, parasites, and viruses to undetectable levels. Product release testing for SER-109 ensures conformance to microbiological purity standards [1][2].
This rigorous approach to drug manufacturing represents a philosophy of necessary redundancy to mitigate the risk to patients beyond donor screening alone, while enriching for a final product of highly purified Firmicutes spores in a convenient oral formulation with a low pill burden.
2. Efficacy and Safety
SER-109 efficacy and safety were evaluated in Phase 1b, 2b, and 3 trials. While the Phase 1b study provided proof-of-concept supporting the efficacy of a targeted, purified spore-based approach in patients with rCDI, the primary efficacy endpoint (reduction in CDI recurrence at Week 8 in SER-109 vs. placebo) in the Phase 2b trial was not achieved. An indepth investigation comparing the discordant results from the Phase 1b and 2 trials demonstrated that dosing in the Phase 2 study was suboptimal. In addition, the use of PCR diagnostic testing, which is less specific, may have resulted in the inclusion of colonized patients without active infection or may have led to a diagnosis of on-study recurrence in patients only colonized with C. difficile. Compared with subjects who had recurred, SER-109 species engraftment in the GI tract was significantly greater in subjects with a sustained clinical response (p < 0.05), affirming the association of engraftment with clinical outcome [1]. This analysis informed the design of the Phase 3 ECOSPOR-III trial, including a ~10-fold higher dose selection, and the requirement for diagnostic toxin testing at study entry and at suspected recurrence to ensure the enrollment of subjects with active CDI and confirm the accuracy of the endpoint.
ECOSPOR III was a double-blind placebo-controlled trial of 182 adults with three or more CDI episodes who were randomized to receive either SER-109 or placebo (4 oral capsules daily for three days) following standard-of-care (SOC) antibiotic treatment (vancomycin or fidaxomicin per investigator discretion). SER-109 was superior to the placebo in reducing CDI recurrence at Week 8, the primary endpoint (12% vs. 40%, respectively; relative risk (RR), 0.32 (95% CI, 0.18–0.58; p < 0.001 for RR < 1.0; p < 0.001 for RR < 0.833)) [3]. Of the SER-109 subjects, 88% met the alternative metric of a sustained clinical response compared with 60% of the placebo subjects [3].
Among subjects without a sustained clinical response, the time to recurrence was rapid, with the majority experiencing recurrence within the first month after dosing. There was also a significant treatment difference between the two arms in time to recurrence, showing an early clinical benefit of SER-109 compared with SOC antibiotics alone, which was maintained over 24 weeks [4].
The benefit of SER-109 over placebo was also consistently observed in analyses of subgroups of subjects with risk factors for recurrence. Regardless of age (<65 or ≥65 years), antibiotic received (vancomycin or fidaxomicin), or Charlson comorbidity score category, SER-109 following SOC antibiotics led to lower CDI recurrence rates compared with SOC antibiotics alone [5][6][7]. The efficacy of SER-109 was unaffected by the use of proton-pump inhibitors and H2-blockers, which are often discontinued in patients with CDI with subsequent risk of gastritis or other complications [8].
3. Safety Profile
Safety data from 231 patients treated with at least one dose of SER-109 across four clinical trials (SERES-001, SERES-004, SERES-005, and SERES-012) showed SER-109 to be well-tolerated. Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in intensity and resolved without sequelae. The most common TEAEs in subjects who had received either SER-109 or the placebo were gastrointestinal in nature (e.g., flatulence, abdominal pain, abdominal distention, diarrhea, constipation). The most common TEAEs occurring at higher rates in SER-109 treated subjects compared to placebo-treated subjects were abdominal distension, constipation, diarrhea, and urinary tract infection. No urinary tract infections were related to SER-109, and available culture data showed expected uropathogens, unrelated to SER-109 dose species. In the placebo-controlled studies, the incidence of SAEs was similar between the SER-109 and placebo arms. No serious drug-related TEAEs were observed. Across these four clinical studies of 231 subjects who had received SER-109, there were 8 deaths (3.5%). This rate compares favorably to reported mortality rates in other treatment trials of patients with primary and recurrent CDI with rates up to 8.7% [9][10][11][12]. No deaths were considered to be related to SER-109. Fatalities were due to a range of causes, including those due to pre-existing conditions, with no detectable patterns. The observed safety profile of SER-109 might be anticipated since Firmicutes normally reside within the healthy microbiome.
4. Pharmacology of SER-109
Treatment with SER-109 leads to the engraftment of drug product species, driving compositional and functional changes in the microbiome thought to be critical to a sustained clinical response. These compositional and functional changes characterize the pharmacokinetics and pharmacodynamics of this unique microbiome therapeutic.
SER-109 Firmicutes spores germinate into metabolically active vegetative bacteria that colonize and replicate in the colon, a process referred to as engraftment, a measure of the pharmacokinetics of a microbiome drug. The engraftment of SER-109 dose species within the gastrointestinal tract leads to compositional changes in and the restructuring of the microbiome with reciprocal loss of proinflammatory Gram-negative Proteobacteria [13][14] as the abundance of Gram-positive Firmicutes increases. The engraftment of SER-109 dose species can be specifically tracked and quantified by examining the number of SER-109 dose species in post-treatment fecal samples, which were not present pretreatment using highly sensitive and specific genetic markers [1][2][3].
5. Additional Potential Benefits of Restructuring the Gastrointestinal Microbiome
Patients with recurrent CDI often have a history of exposure to numerous courses of antibiotics, which puts them at risk of carrying antibiotic resistance genes (ARGs). The exposure to broad-spectrum antibiotics can lead to antimicrobial drug resistance, which can limit therapeutic options when infections arise. Drug-resistant bacteria can rapidly proliferate and become dominant in the gastrointestinal tract, particularly when the expansion of Gram-negative bacteria occurs in a vacuum of low microbial diversity. The researchers hypothesized that restructuring the microbiome with SER-109 may have ancillary benefits on the prevalence and abundance of ARGs post treatment in stool samples of the study participants as compared to those who were randomized to placebo.
In fact, in this post hoc analysis of ECOSPOR III, ARGs were highly prevalent and abundant at the baseline among subjects in both arms, noted in multiple drug classes including fluoroquinolones, tetracyclines, and aminoglycosides [15].
However, SER-109 led to a restructuring of the microbiome, which was associated with changes in the prevalence and abundance of ARGs. SER-109 treatment was associated with a significant and rapid decline in ARGs as early as Week 1 compared to the placebo, with a sustained decline through Week 8 post-treatment [15]. A reduction in ARGs was associated with a marked decline in the relative abundance of the Proteobacteria phylum and an increase in Firmicutes. The analysis of the various bacterial families present revealed a marked decline in Enterobacteriaceae, which were positively associated with an abundance of ARGs. Non-spore-forming Firmicutes such as Enterococcus were also positively associated with ARGs. Conversely, the relative abundance of spore-forming Firmicutes found in SER-109 was negatively associated with ARG abundance, highlighting the potential advantage of this novel microbiome therapeutic over other “complete communities” that harbor both Proteobacteria and non-spore-forming Firmicutes [15].
The manufacturing process for SER-109 specifically retains spore-forming Firmicutes and excludes other organisms, including Enterococcus and Enterobacteriaceae. The effects of decreasing the reservoir of pathobionts that harbor clinically relevant ARGs may potentially minimize the horizontal gene transfer of ARGs to pathogens within host microbiomes, lower the shedding of ARGs into the environment, and reduce the risk of antibiotic drug-resistant bacterial infections. Further research into these potential benefits is warranted in light of the limited pipeline of drugs for antibiotic-resistant infections.
This entry is adapted from the peer-reviewed paper 10.3390/antibiotics11091234
References
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