Current therapies for recurrent
infection do not address the disrupted microbiome, which supports
spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic ...composed of purified Firmicutes spores for the treatment of recurrent
infection.
We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of
infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of
infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed.
Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of
infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval CI, 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 95% CI, 0.07 to 0.78 for patients <65 years of age and 0.36 95% CI, 0.18 to 0.72 for those ≥65 years) and antibiotic received (relative risk, 0.41 95% CI, 0.22 to 0.79 with vancomycin and 0.09 95% CI, 0.01 to 0.63 with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit
spore germination.
In patients with symptom resolution of
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. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).
Abstract
Background
Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination ...and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.
Methods
In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.
Results
89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.
Conclusions
Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.
Clinical Trials Registration
NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
In a phase 2 trial, SER-109, an investigational microbiome drug, did not reduce rates of recurrent CDI, despite a previously successful open-label study. Key contributing factors, which led to a redesign of the currently enrolling phase 3 trial, are highlighted.
The structural changes of chicken feather fibers (CFF) were investigated during pyrolysis by thermal analysis techniques coupled with mass spectrometry, solubility tests and gel permeation ...chromatography. The experimental data showed simultaneous disulfide bond cleavage and peptide crosslinking reactions, and suggested the dependency of crystalline melting on disulfide bond cleavage. The variation in the kinetics of these reactions played an important role in the melting transition and stability. Thus, careful tuning of the pyrolysis thermal profile provided conditions to obtain useful fibrous material at high temperatures. For instance, long-time heat treatments below the melting point provided sufficient crosslinks in the protein matrix to keep the fibrous structure intact. The protein matrix went through a series of transformations including cyclization and aromatization reactions above the melting point. Degradation of the matrix and liberation of aromatic carbons and cyclic amines were observed during these transformations. These pyrolysis mechanisms can serve as a guide for producing materials with desired properties from CFF and other keratin fibers, particularly in textile, high performance composite and catalyst applications.
Bacterial synthesis of PHA block copolymers Pederson, Erik N; McChalicher, Christopher W J; Srienc, Friedrich
Biomacromolecules,
06/2006, Volume:
7, Issue:
6
Journal Article
Peer reviewed
Polyhydroxyalkanoates (PHA) containing block copolymers were synthesized in Cupriavidus necator using periodic substrate addition. Poly(3-hydroxybutyrate) (PHB) segments were formed during fructose ...utilization. Pulse feeds of pentanoic acid resulted in the synthesis of 3-hydroxyvalerate monomers, forming poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) random copolymer. PHA synthesis was controlled using analysis of oxygen uptake and carbon evolution rates from the bioreactor off-gas. A combination of characterization techniques applied to the polymer batches strongly suggests the presence of block copolymers: (i) Thermodynamically stable polymer samples obtained by fractionation and analyzed by differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (NMR) indicate that some fractions, representing approximately 30% of the total polymer sample, exhibit melting characteristics and nearest-neighbor statistics indicative of block copolymers, (ii) preliminary rheology experiments indicate additional mesophase transitions only found in block copolymer materials, (iii) dynamic mechanical analysis shows extension of the rubbery plateaus in block copolymer samples, and (iv) uniaxial extension tests result in differences in mechanical properties (modulus and elongation at failure) expected of similarly prepared block copolymer and single polymer type materials.
Mechanical testing of solvent cast films consisting of short-chain-length (SCL) polyhydroxyalkanoate (PHA) films suggested that films consisting of block copolymers retained more elasticity over time ...with respect to films of similar random copolymers of comparable composition. Two experimental techniques, wide angle X-ray scattering (WAXS) and uniaxial extension, were used to quantitatively investigate the structure–property relationship of bacterially synthesized PHA block copolymers of poly(3-hydroxybutyrate) (PHB) homopolymer and poly(3-hydroxybutyrate-
co-3-hydroxyvalerate) random copolymer (PHBV) segments. Uniaxial testing experiments yielded the Young's modulus, ultimate tensile strength, and the elongation until fracture of the films. Percent crystallinity was determined by deconvolution of amorphous and crystalline scattering peaks obtained from WAXS. Two PHBV films containing either 8% 3-hydroxyvalerate monomer (3HV) or 29% 3HV exhibited a quick transition to brittle behavior, decreasing to less than 20% percent elongation at fracture within a few days after annealing. Conversely, the block copolymer samples remained higher than 100% elongation at fracture a full 3 months after annealing. Because block copolymers covalently link polymers that would otherwise form thermodynamically separate phases, the rates and degrees of crystallization of the block copolymers are less than the random copolymer samples. These differences translate into materials that extend the property space of biologically synthesized SCL PHA.
Abstract
Background
Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety ...risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores.
Methods
Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates.
Results
Bacterial log reduction factors ranged from 6.5 log10 to 7.4 log10 and lysis of spiked organisms occurred rapidly within 30 seconds.
Conclusions
These experiments demonstrate substantial and rapid inactivation of representative organisms, supporting the potential benefit of VOS manufacturing processes to mitigate risk.
Research leading to characterization, quantification, and functional attribution of the microbes throughout the human body has led to many drug-development programs. These programs aim to manipulate ...a patient’s microbiome through the addition of new strains or functions, the subtraction of deleterious microbes, or the rebalancing of the existing population through various drug modalities. Here, we present a general overview of those modalities with a specific focus on bacterial live biotherapeutic products (LBPs). The bacterial LBP modality has unique concerns to ensure product quality, thus, topics related to manufacturing, quality control, and regulation are addressed.
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•Microbiomes represent new drug targets for pharmaceutical development.•‘Dysbiosis’ describes poor composition or species balance, contributing to disease.•Live biotherapeutic products (LBPs) are an enriching class of microbiome therapies.•Manufacture leverages vaccine experience but must be adapted for commensal strains.•Variety of LBPs require per-product assessment of required quality elements.
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