Category Archives: Microbiome Clinical Trials

Rebiotix Reports Topline Results From a Controlled Open-label Phase 2 Trial of RBX2660 (PUNCH™ Open Label) For the Prevention of Recurrent Clostridium difficile (C. diff.) Infection (rCDI)

In The News

April 2017

 

 

Rebiotix Inc., a clinical-stage microbiome company focused on harnessing the power of the human microbiome to treat challenging diseases, today announced topline results from a controlled open-label Phase 2 trial of RBX2660 (PUNCH™ Open Label) for the prevention of recurrent Clostridium difficile (C. diff.) infection.

Data indicated that RBX2660 was well-tolerated and achieved the primary efficacy endpoint of preventing C. diff. recurrence; patients treated with RBX2660 exhibited a treatment success rate of 78.8% compared with a historical control of 51.8% (p<0.0001). RBX2660 is a broad-spectrum microbiota suspension that is designed to rehabilitate the human microbiome by delivering live microbes into a patient’s intestinal tract to treat disease.

Lee Jones, president and CEO of Rebiotix, stated, “The 78.8% treatment success achieved in this open label Phase 2 trial demonstrates the potential of RBX2660, a broad spectrum microbiota drug product, to rehabilitate the gut microbiome and break the cycle of C. diff. recurrence. These results, coupled with the safety and efficacy data observed in our prior Phase 2b and Phase 2 clinical trials, position Rebiotix to advance RBX2660 into Phase 3 clinical development, solidifying our standing as the most clinically advanced microbiome company in the industry.”

PUNCH™ Open Label was designed as a prospective, multicenter, open-label, controlled Phase 2 study to assess the efficacy and safety of RBX2660 for the prevention of recurrent C. diff.

The primary efficacy endpoint involved a comparison of patients treated with RBX2660 to a closely matched set of antibiotic only treated historical controls through 56 days. There were 31 active treatment sites and four control sites in the US and Canada. 132 RBX2660 and 110 historical control subjects were included in this topline analysis.

Actively treated patients, after determining eligibility, were administered two doses of RBX2660; the first at day one and the second at day seven. Patients were then monitored for eight weeks to determine whether there was a recurrence of C. diff.

Top line results from the trial, which examined responses from 132 patients versus a historical control of 110 patients, indicated a treatment success rate of 78.8% as compared to a historical control of 51.8% (p<0.0001). Overall, RBX2660 was generally well-tolerated with the most commonly reported adverse events being gastrointestinal, including diarrhea, abdominal pain, flatulence, constipation and distension.


About Rebiotix Inc.

Rebiotix Inc. is a clinical-stage microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix is the most clinically advanced microbiome company in the industry, with its lead drug candidate, RBX2660, expected to enter Phase 3 clinical development for the prevention of recurrent Clostridium difficile (C. diff.) infection. Previously, RBX2660 was the subject of three Phase 2 trials in recurrent C. diff, including a Phase 2b randomized, double-blind, placebo-controlled trial (PUNCH™ CD2), with data indicating the drug was well-tolerated and demonstrated statistically significant treatment efficacy. RBX2660 has been granted Orphan Drug status, Fast Track status and Breakthrough Therapy Designation from the FDA for its potential to prevent recurrent C. diff. infection.

Rebiotix’s development pipeline includes multiple formulations targeting several disease indications and is built around its pioneering Microbiota Restoration Therapy (MRT) platform. MRT is a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad spectrum of live microbes into a patient’s intestinal tract via a ready-to-use and easy-to-administer format.

For More Information About C. difficile Clinical Trials In Progress : 

https://cdifffoundation.org/clinical-trials-2/

 

For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit www.rebiotix.com

 

Source:  Rebiotix 4/17

Researchers Explore Effects of Probiotics Supplements on Intestinal Microbiota of Food Allergic Mice

Exploration of the effect of probiotics supplementation on intestinal microbiota of food allergic mice

Abstract

Environmental factor-induced alterations in intestinal microbiota have been demonstrated to be associated with increasing prevalence of food allergy. However, it is not clear to what extent oral administration of probiotics can affect gut microbiota composition, thus inhibiting food allergy development. Using ovalbumin (OVA)-sensitized murine model, it was demonstrated that probiotics ameliorated allergic symptoms, including reducing OVA specific-IgE, and -IgG1 levels in the serum, Th2 cytokines release in spleen, and occurrence of diarrhea. Moreover, 16S rRNA analysis showed that the probiotics-mediated protection was conferred by an enrichment of Coprococcus and Rikenella. The present study supports the theory that probiotics can treat food allergy by modulating specific genera of the gut microbiota.

Introduction

Food allergy is an adverse immune response to certain kinds of food. It is estimated that food allergy affects about 8% of children and 4% of adults [1,2]. The rapid increase in the prevalence of food allergy over past several decades cannot be explained by genetic variation alone. In current, avoidance of dietary allergens is the only proven remedy available for food allergic suffers.

Growing evidence suggests that gut microbiota exerts profound influence on immune system maturation and tolerance acquisition. Intestinal microflora alteration, caused by environmental factors (e.g., mode of birth, antibiotics, diet, vaccination, sanitation), has been observed to be associated with many gastrointestinal diseases, including food allergy [3], inflammatory bowel diseases [4], or colorectal cancer [58]. Of note, intestinal microflora has been demonstrated to play an important role in maintaining the Th1/Th2 balance [9], which is the key mechanism involved in allergic diseases.

The role of probiotics in allergic disease has been highlighted recently. Bifidobacteria and lactobacilli, which are common species of probiotics existing in most people, can affect immune function by various pathways. In many cases, probiotics supplementation was demonstrated to induce TGF-β expression, which ameliorates food allergy by suppressing Th2 response, and inducing Foxp3+ Treg production [1015]. A microarray analysis of intestinal epithelial cells from gnotobiotic mice revealed a mechanism that Clostridia facilitated immune cells to produce interleukin-22 (IL-22), regulated innate lymphoid cell function and intestinal epithelial permeability to protect against allergen sensitization [3]. Besides, the suppressive effect of probiotics on Th17 response has been shown both in murine asthma [16] and atopic dermatitis model [17]. However, whether probiotics treatment elicited changes in the composition of the intestinal microbiota, thereby regulating allergic disease remains poorly understood.

The current study investigated the beneficial effect of Bifidobacterium Infantis (BB) in a murine model of food allergy at the level of commensal microbiota. Sequencing of the V4-V5 regions of 16S rRNA genes revealed that BB could modulate specific genera of intestinal microbiota in mice, which may induce immune responses in gastrointestinal tract to defend against food allergens.

Materials and methods

Animals

All the animal experimental procedures were conducted according to the guidelines approved by the Experimental Animal Ethic Committee at Shenzhen University, and were carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 1996). 6-8 weeks old female Balb/c mice were housed in a SPF animal facility with a 12 h light-dark cycle and were free to access standard diet and water.

Food allergic animal model

Mice were intragastrically administered with 100 mg OVA plus 20 mg cholera toxin (CT) in a final volume of 300 ml using a ball-end mouse feeding tube once a week for 4 consecutive weeks. At the end of sensitization, mice were challenged with 5 mg OVA orally. After 24 h, the mice were killed and serum and splenocytes were collected for the following analysis as reported previously (referred to as FA group) [25].

BB preparation and supplementation

BB was kindly provided by Shenzhen Kexing Biotech CO., LTD (Shenzhen, China) as lyophilized powder and inoculated before giving to mice. From Day 15 to Day 28, sensitized mice were orally administered with 200 ml/mouse of normal saline containing 108 cfu/ml as previously described (referred to as FAPro group) [13]. On day 29, the mice were challenged as described above.

Serum immunoglobulin levels

Serum was collected, and OVA-specific IgE was detected by commercial ELISA kit (Biolegend, USA) according to the manufacturer’s instructions. OVA-specific IgG1 was measured by an in-house ELISA as previously described [26].

DNA extraction, amplification and sequencing

During the process of food allergy model establishment, fecal samples (up to ~1 g) were collected on Day 0, 7, 14, 28, 29, and stored at -80°C. The total DNA from fecal samples was extracted by reported method [27]. The 16S rRNA was amplified and sequenced on the Ion Torrent Personal Genome Machine as reported in previous study [28].

Bioinformatics analysis

The data was treated with in-house pipeline developed based on mothur v.1.33.3 [29]. The community structure was calculated based on the membership and relative abundance of taxonomic groups in the sample. In this study, the Permutational multivariate analysis of variance (PERMANOVA) was used to assess the effect of BB (covariate) on operational taxonomic units (OTUs) profiles. A two-tailed Wilcoxon rank-sum test was used in the profile to identify the different OTUs and KEGG Orthologs (KOs). In addition, we used PICRUSt [30] to produce predicted KOs from the 16S rRNA gene sequence data.

Statistical analysis

In Figure 1, all values are presented as the means ± SEM. Differences between two groups were evaluated with the Student t test, while data among three or more groups were evaluated with one-way ANOVA (Prism version 5, GraphPad Software; CA, USA). A P value less than 0.05 was considered to indicate significant differences.

Figure 1

Allergic reactions in the mouse intestine were attenuated by BB. Balb/c mice were treated with PBS (Naïve group), OVA/CT (FA group), OVA/CT+BB (FAPro group). The bars indicate the levels of serum OVA-specific IgE (A), -IgG1 (B), IL-4, -5, and

Results

BB showed significant protective effect on food allergic mice

Food allergic mice model was established using OVA as allergen, CT as adjuvant. As shown in Figure 1A and and1B,1B, treatment with BB for two weeks attenuated sIgE and sIgG1 by 33% and 32% respectively, when compared with FA group. Moreover, spleneocytes were harvested from all the three groups of mice and incubated with OVA for 3 days. The levels of typical Th2-type cytokines in supernatant were determined by commercial ELISA. Intragastrically administered with BB significantly reduced IL-4, -5, and -13 by 31%, 24%, and 50% respectively in FA mice (Figure 1C). In addition, after challenge with OVA, the FA mice showed significant diarrhea (Figure 1D), which could be ameliorated by BB.

BB-induced phenotypic improvement was associated with specific OTUs

Next, to investigate the effect of BB on gut microbiome, we carried out metagenomic sequencing of fecal samples from FA and FAPro mice. All sequencing reads were finally classified into 1195 operational taxonomic units (OTUs). The correlation between food allergic phenotypes and OTUs was calculated. It was found that 61 OTUs were significantly related to sIgE, sIgG1, IL-4, IL-5, and IL-13. Among them, 45 OTUs were positively correlated with these phenotypes and 16 OTUs were negatively correlated (Figure 2). For instance, Otu0724, annotated to the family S24-7, was significantly positive correlated with allergic phenotypes. On the contrary, Otu0543, annotated to the genus Bacteroides, was significantly negatively correlated. Upregulation or downregulation of the relative abundances of these OTUs could trigger certain immune responses. The results indicated that BB treatment may change immune indexes of food allergy through modulation of these OTUs.

Figure 2

The heatmap of correlation between five phenotypes and OTUs profile. Red means positive correlation, while blue represents negative correlation.

Treatment with BB shows no effect on alpha-diversity of intestinal microflora

Chao [18] and ACE [19] are usually used to compute community richness; the higher score, the more richness. Shannon and Simpson metrics are commonly used to calculate community diversity [20]. The higher Shannon index indicates the greater community diversity, while the higher Simpson index indicates the lesser community diversity. We used these 4 kinds of alpha diversity parameters to describe the microbiologic species diversity changes between FA group and FAPro group (Figure 3). Student’s t-test showed that there were no significant differences of these four indexes (Figure 3). The results indicated that BB was not strong enough to change population diversity and richness of intestinal microbiota.

Figure 3

Boxplot of 4 kinds of alpha diversity between FA and FAPro group. Chao, ACE, Shannon, simpson are the four kinds of alpha diversity metrics. FA (n=27), FAPro (n=34). Mean values ± SEM are plotted.

BB didn’t alter intestinal microbiota compositon in mice

In order to investigate whether probiotics treatment change the composition of intestinal microbiota, we used principal coordinate analysis (PCoA) to compare FA and FAPro group. As shown in Figure 4, there was no significant difference between FA and FAPro group. Thus, it was implied that BB showed no effect on modulation of microbiota composition.

Figure 4

The PCoA of OTU profile between FA and FAPro mice. 16S rRNA gene surveys (analyzed by JSD-based PCoA) from mice fed PBS (red) or probiotics (blue) diets are presented in a different clustering pattern. Principal coordinate1 (PC)1 and PC2 are the x axis

The taxonomic classification of gut microbiota in mice

We found that Bacteroidetes and Firmicutes were two most prevalent phyla present in food allergic mice treated with or without probiotics, the same as that under physiological status [3]. Furthermore, Lachnospiraceae, S24-7, Rikenellaceae, and Ruminococcaceae accounted for four major components at family levels (Figure 5A). Further analysis revealed that 2-wk of BB treatment resulted in a significant change in fecal microbiota composition at genus level. As shown in Figure 5B, the levels of Coprococcus and Rikenella were significantly increased by 66% and 60% respectively, after BB treatment. Thus, the relative abundances of Coprococcus and Rikenella may be used as microbial biomarkers to diagnose food allergy.

Figure 5

A. Taxonomic distributions in gut communities. Values represent the relative abundance of bacteria at family level across all samples within FA group and FAPro group. A small amount of microorganism is unknown. B. Comparision of 12 major genera between

Comparison of OTUs levels between FA and FAPro mice

Next, Wilcoxon rank test showed that 92 OTUs were significantly different between FA group and FAPro group. Among them, 40 OTUs (43.5%) were enriched in FA group. 33 OTUs were picked out through a FDR adjust and make a heatmap with the OTU percentage profile (Figure 6). Moreover, we found that probiotics administration could enrich more bacteria assigned to Coprococcus, Rikenella and Bacteroides in the mice gut (Figure 6).

Figure 6

Heatmap of gut bacteria in FA and FAPro group at OTU level. Blue regions represent relatively low OUT abundance, while red regions means relatively high OTU abundance.

Mice gut microflora changed across time

In order to monitor the change of gut bacteria during the period of probiotics administration, we collected fecal samples at 5 time points: before oral treatment of probiotics (FAPro1), after one week’s probiotics administration (FAPro2), after two weeks’ administration (FAPro3), 1 h after allergen challenge (FAPro4), 24 h after allergen challenge (FAPro5). Intriguingly, we selected 12 most abundant genera and found that at least 6 genera of gut bacteria, including Odoribacter, Bacteroides, Coprococcus, Blautia, Eubacterium, Prevotella changed with time after probiotics treatment (Figure 7). For example, the levels of Odoribacter were significantly increased by 3.3 fold at the time point of 24 h after challenge compared to the time point of 1 h after challenge.

Figure 7

Time-dependent manner of gut bacteria changes at genus level. During the period of probiotics administration, we collected fecal samples at 5 time points: before oral treatment of probiotics (FAPro1), after one week’s probiotics administration

Metabolic pathways of gut microbiota was altered by BB supplementation

We used PICRUSt to produce predicted metagenomes from 16S rRNA gene sequence database. 143 KOs were found to be significantly different between FA and FAPro mice, using Wilcoxon rank test, p value < 0.05. Among them, only 4 KOs were enriched in FAPro group (Table 1). The results implied that BB supplementation significantly modified metabolic pathways of gut microbiota.

Table 1

Four KEGG Orthologs were enriched in FAPro group

Discussion

Gut microbiota plays an important role in the pathogenesis of food allergy. In this study, we found that oral administration of BB induced significant improvement on allergic symptoms in mice. Furthermore, the results demonstrated that BB conferred a protective effect on food allergic mice through up-regulation of the relative abundance of Coprococcus and Rikenella at genus level. Furthermore, the genera of gut microflora were presented in a time-dependent pattern after BB treatment.

Growing evidence suggests that the relationship among diet, probiotics, immune system and gut microbiota ecology determines the disease susceptibility to allergy [21]. Thus, it is very likely that intragastrical administration of probiotics may treat food allergy by restoring the unbalanced indigenous microbiota and controlling the inflammatory responses. Until now, there is no investigation targeting the direct effect of probiotic supplementation on intestinal microbiota. Although there are more than 1000 species of intestinal bacteria, most of them belong to just a few phyla. Bacteroidetes and Firmicutes phyla dominate the adult intestine. The intestinal microbiota is of high variation from people to people at species-level, but bifidobacteria and lactobacilli are common species existing in most people [22]. Thus, in the present study we chose BB to treat a classical animal model sensitized by OVA. In this study, animals treated with probiotics for two weeks showed improvement in all major indicators of experimental mucosal allergy, in line with the results previously reported [23].

When use traditional culture based techniques to determine the composition of the gut microbiota, there are only ~10% of gut bacteria possibly to be studied since others are not culturable [24]. Therefore, in order to further determine the different components of intestinal microbiota caused by probiotics, we chose state-of-the-art next-generation sequencing method to detect the 16S rRNA of faces samples and determine the frequency of microbes and its metabolic pathway in gastrointestinal tract. We found that there were 12 genera of gut bacteria existing in both FA and FAPro groups. After supplementation with BB for two weeks, each genus changed periodically. Based on their relative abundances, BB administration could up-regulate Rikenlla and down-regulate Eubacterium. These two genera of bacteria have never been highlighted by other related researches. Instead, Stefka [3] et al demonstrated that a Clostridia-containing microbiota was associated with innate lymphoid cell function and intestinal epithelial permeability. The divergence may be attributed to that they didn’t use a kind of probiotics to treat allergic mice.

In conclusion, this is the first study to explore microbial population changes in food allergic animal model, in case of probiotics administration. Likely, specific gut bacterial changes contributed to disease process altered by probiotics. Still, patients study are warranted in the future to determine whether the findings herein reported can be validated and correlated with the clinical features.

Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (No. 81300292 to B.Y., No. 81271950 to Q.M.J., and 81460252 to X.Y.L.), Guangdong Foreign Scientific Technology Cooperative Project (No. 2013B051000088 to Z.G.L.), Shenzhen Scientific Technology Basic Research Projects (No. 005177 to Q.M.J., JCYJ20140418095735538 to Z.G.L., and JCYJ20130402151227168 to S.G.H.).

Disclosure of conflict of interest

None.

Authors’ contribution

B.Y., L.X. and S.L. performed experiments and analyzed data. B.Y. wrote the manuscript. X.Y.L. and Y.L. performed experiments. Q.M.J, P.C.Y. and Z.G.L. organized the project and supervised the experiments. P.C.Y. revised the manuscript.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340674/

Seres Therapeutics Announces a New SER-109 Phase 2 Clinical Study (ECOSPOR III) For Patients With Multiple Recurrent C. diff. Infections (CDI’s)

Seres Therapeutics Inc. a leading microbiome therapeutics platform company, announced on March 16th, 2017 plans to initiate a new SER-109 Phase 2 clinical study (ECOSPOR III) in patients with multiply recurrent Clostridium difficile (C. difficile) infection. The ECOSPOR III study design was finalized following a positive Type B meeting with the U.S. Food and Drug Administration (FDA). In a separate announcement today, Seres reported fourth quarter and full year 2016 financial results and provided an update on multiple ongoing microbiome clinical programs.

Seres plans to initiate a new SER-109 clinical study in approximately 320 patients with multiply recurrent C. difficile infection. Study participants will be randomized 1:1 between SER-109 and placebo. To ensure accurate measurement of C. difficile infection, diagnosis of recurrent C. difficile infection for both study entry and for endpoint analysis will be confirmed by C. difficile cytotoxin assay. Patients in the SER-109 arm will receive a total SER-109 dose, administered over three days, approximately 10-fold higher than the dose used in the prior ECOSPOR study. ECOSPOR III will evaluate patients for 24 weeks and the primary endpoint will compare the C. difficile recurrence rate in subjects who receive SER-109 verses placebo at up to eight weeks after dosing. The FDA has agreed that this new trial may qualify as a pivotal study with achievement of a persuasive clinical effect and addressing FDA requirements, including clinical and statistical factors, an adequately sized safety database, and certain CMC parameters.

“We are pleased to have received highly constructive guidance from the FDA regarding further SER-109 clinical development and we plan to initiate a new clinical study as soon as possible,” said Roger J. Pomerantz, M.D., President, CEO and Chairman of Seres. “Our prior SER-109 studies provided important new biological and clinical data that have advanced our pioneering microbiome therapeutic efforts. Based on our learnings and dialogue with the FDA, we believe that we are now positioned to initiate a robust clinical study that may provide the basis for SER-109 approval. There is an urgent need for improved treatments for C. difficile infection, and we believe SER-109 has great potential to address the underlying cause of the disease and become the first approved microbiome therapeutic in this new field of medicine.”

About SER-109

SER-109, an oral capsule, is Seres’ lead Ecobiotic® microbiome therapeutic for the treatment of multiply recurrent C. difficile infection. SER-109 is a biologically sourced consortium of bacterial spores designed to catalyze a shift in a dysbiotic gastrointestinal microbiome to a healthier state.

About Seres Therapeutics

Seres Therapeutics, Inc. is a leading microbiome therapeutics platform company developing a novel class of biological drugs that are designed to treat disease by restoring the function of a dysbiotic microbiome, where the natural state of bacterial diversity and function is imbalanced. The Phase 2 study of Seres’ program SER-109 has been completed in multiply recurrent Clostridium difficile infection. Seres’ second clinical candidate, SER-287, is being evaluated in a Phase 1b study in patients with mild-to-moderate ulcerative colitis (UC). Seres is also developing SER-262, the first ever synthetic microbiome therapeutic candidate, in a Phase 1b study in patients with primary CDI. For more information, please visit www.serestherapeutics.com. Follow us on Twitter @SeresTx.

Forward-looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding SER-109 development plans, the timing, design, and results of the ECOSPOR III study , the potential for ECOSPOR III to provide different results than the previous ECOSPOR study, the impact analysis of prior clinical studies may have on clinical outcomes, the potential for ECOSPOR III to qualify as a Pivotal Study, dysbiosis as an underlying cause of C. difficile and other diseases.

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Seres Therapeutics Share Key Findings From Earlier Reported SER-109 Phase 2 Clinical Study Outcome

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As published in Seres Therapeutics Press Release  January 31, 2017

 

Findings suggest that both misdiagnosis of C. difficile recurrent infection in some patients, and dosing that may have been suboptimal in certain patients, contributed to the previously reported SER-109 Phase 2 study outcome –

FDA discussions are ongoing regarding a new, redesigned clinical study for SER-109

CAMBRIDGE, Mass., On January 31, 2017 —Seres Therapeutics Inc., a leading microbiome
therapeutics platform company, reported that it has completed in-depth analyses of the previously reported SER-109 Phase 2, eight-week clinical study data in patients with multiply recurrent Clostridium difficile infection.

The company also reported the full, 24-week SER-109 Phase 2 study results and open label extension study data.

“Since obtaining the unexpected SER-109 clinical study results last summer, we have undertaken a comprehensive assessment of the program to understand the reasons for the results,” said Roger J. Pomerantz, M.D., President, CEO and Chairman of Seres.

“We have now identified specific factors that we believe contributed to the Phase 2 results, including issues related to both the accurate diagnosis of C. difficile recurrent infection, and potential suboptimal dosing of certain subjects in the trial. The SER-109 analyses were recently shared with the FDA, and we are actively discussing the design of a new clinical trial for SER-109. There remains a compelling need for an effective, safe, and convenient FDA approved therapy for patients with recurrent C. difficile infection, and this investigation provides insights to guide further clinical development of SER-109.”

Investigation Summary: C. difficile Diagnosis: Analysis was conducted to evaluate both the role of C. difficile diagnostic testing in defining the correct SER-109 Phase 2 study entry population, and in the proper diagnosis of C. difficile recurrences during the study. In the Phase 2 study, 81% of study subjects (72 of 89 subjects) were enrolled based on polymerase chain reaction (PCR) based testing for C. difficile, as well as clinical evaluation. An important and increasingly well-appreciated limitation of PCR testing is that while a positive result indicates that C. difficile cytotoxin genes are present, a positive PCR test does not necessarily indicate thatthe organism is viable and producing disease causing cytotoxins, nor that
C. difficile is the source of clinical symptoms.1

Two separate observations were made pertaining to the effects of discordant results from PCR and cytotoxin assay on the SER-109 trial. The qualifying stool samples evaluated for Phase 2 study entry were not available for retesting for cytotoxin, however, the company was able to retest the samples associated with patients entering the open label extension trial for the presence of the C. difficile cytotoxin and determined that only 44% of samples (15 of 31 subjects) that tested positive by PCR testing also tested positive based on C. difficile cytotoxin assay. These results suggest that a substantial proportion of patients who entered the SER-109 Phase 2 study may have been C. difficile carriers and, therefore, C. difficile infection may not have been the source of the clinical symptoms. In addition, data from this analysis suggest that the use of PCR to measure C. difficile may have overestimated study recurrences in both treatment arms of the Phase 2 trial, further complicating interpretation of study results. This was shown by reanalysis of samples with cytotoxin assay, from patients diagnosed as recurrent in the Phase 2 study. In this retesting, between one quarter andone half of presumed study recurrences may not have been true C. difficile infections leading to pathology.

From the analyses described above, the company believes that misdiagnoses may have occurred both in some patients entering the SER-109 trial, as well as for recurrences diagnosed during the trial.

SER-109 Pharmacokinetics, Pharmacodynamics, & Dosing

The company performed an in-depth analysis to examine SER-109 biological activity in the Phase 2 trial, as measured by microbiome changes in patients and downstream biological effects in the gastrointestinal tract. Results demonstrated a statistically significant increase in the richness of commensal spore-forming bacterial species in patients treated with SER-109, as compared to those receiving placebo. These data demonstrate that SER-109 successfully engrafted and was biologically active in the Phase 2 study. In addition, among those patients with an increased prevalence of specific SER-109 associated bacterial species, a decreasedrate of high confidence recurrences (i.e., recurrences confirmed by C. difficile cytotoxin assay) was demonstrated.

The company also assessed whether the SER-109 dose impacted the degree of microbiome changes observed. All Phase 2 patients received 1 X 10 8 bacterial spores, whereas patients in the prior SER-109 Phase 1b open label study received doses ranging approximately 700-fold, from 3 X 107 to 2 X 109 spores. The company also performed high-resolution whole metagenomics sequencing of stool samples collected from patients in both the SER-109 Phase 1b, as well as the Phase 2 trial as part of this analysis. The analysis indicated that subjects in the open-label Phase 1b study who received a higher dose achieved a significantly greater increase in diversity of commensal spore-former bacteria by 1 week post-treatment, as compared to both Phase 1b and Phase 2 subjects treated with lower doses. These results suggest that the dose used in the SER-109 Phase 2 study may have been suboptimal in certain patients, and may have resulted in a less robust drug effect, contributing to decreased efficacy in Phase 2, as compared to the Phase 1b study.

Much of the SER-109 Phase 2 microbiome-related learnings are based on advancements in the computational analytics and higher resolution whole metagenomics sequencing techniques that Seres is pioneering, and several of these methods were developed after the SER-109 Phase 2 study was designed. Insights obtained from this work may also
benefit Seres’ broad preclinical and clinical microbiome development pipeline.

Analysis of SER-109 Phase 2 Study Clinical Drug Product

The company also conducted a thorough and detailed investigation of the potential impacts of manufacturing and formulation changes implemented in the Phase 2 study. No issues regarding product quality or formulation were identified which would have impacted the Phase 2 study results.

Summary of SER-109 24-Week and Open Label Extension Study Results

The full, 24-week Phase 2 study results continue to demonstrate that SER-109 was generally well tolerated. The most common adverse events associated with SER-109 included diarrhea, abdominal pain and flatulence. The Phase 2 study population represented older individuals, many in poor health, and a high rate of serious adverse events (SAEs) was reported in both study arms. A numerically higher rate of SAEs was observed in the SER-109 arm (15.0% versus 10.3% for placebo), however there was no detectable pattern in the SAEs observed, and none of these were considered to be SER-109 drug-related by the study investigators.

As expected with recurrent C. difficile infection, relatively few additional recurrences occurred beyond 8 weeks, and the 24-week data provides relatively little new information regarding efficacy. Based on 24-week data, five further patients recurred in the SER-109 arm, but three of the five recurrences (60%) were in patients who terminated the trial early, resulting in an imputed recurrence. In the placebo arm, one patient also terminated the trial early, resulting in an imputed recurrence. Early terminations, and loss of patients to follow-up, are common in the long safety follow-up portions of clinical trials.

Phase 2 study subjects who experienced a C. difficile recurrence had the option to enroll in an open label extension study, where they were treated with SER-109 and were followed for an additional 24 weeks. In total, 34 patients entered the open label extension study and 11 patients recurred during the initial 8-week study period, a 32% recurrence rate.

Source:

About Seres Therapeutics:  Seres Therapeutics, Inc. is a leading microbiome therapeutics platform company developing a novel class of biological drugs that are designed to treat disease by restoring the function of a dysbiotic microbiome, where the natural state of bacterial diversity and function is imbalanced. The Phase 2 study of Seres’ program SER-109 has been completed in multiply recurrent C. difficile infection. Seres’ second clinical candidate, SER-287, is being evaluated in a Phase 1b study in patients with mild-to-moderate ulcerative colitis (UC). Seres is also developing SER-262, the first ever synthetic microbiome therapeutic candidate, in a Phase 1b study in patients with primary C. difficile infection. For more information, please visit http://www.serestherapeutics.com. Follow us on Twitter @SeresTx.

Forward-looking Statements:  This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our SER-109 development plans, the timing, design, and potential results of a new clinical study for SER-109, the potential for a redesigned trial to provide different results, and the impact any analysis may have on clinical outcomes.

These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: we have incurred significant losses, are not currently profitable and may never become profitable; our need for additional funding, which may not be available; our limited operating history; the unpredictable nature of our early stage development efforts for marketable drugs; the unproven approach to therapeutic intervention of our microbiome therapeutics; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; potential delays in enrollment of patients which could affect the receipt of necessary regulatory approvals; potential delays in regulatory approval, which would impact the ability to commercialize our product candidates and affect our ability to generate revenue; any fast track or Breakthrough Therapy designation may not lead to faster development, regulatory approval or marketing approval; our possible inability to receive orphan drug designation should we choose to seek it; our reliance on third parties to conduct our clinical trials and the potential for those third parties to not perform satisfactorily; our reliance on third parties to manufacture our product candidates, which may delay, prevent or impair our development and commercialization efforts; our lack of experience in manufacturing our product candidates; the potential failure of our product candidates to be accepted on the market by the medical community; our lack of experience selling, marketing and distributing products and our lack of internal capability to do so; failure to compete successfully against other drug companies; potential competition from biosimilars; failure to obtain marketing approval internationally; post-marketing restrictions or withdrawal from the market; anti-kickback, fraud, abuse, and other healthcare laws and regulations exposing us to potential criminal sanctions; recently enacted or future legislation; compliance with environmental, health, and safety laws and regulations; protection of our proprietary technology; protection of the confidentiality of our trade secrets; changes in United States patent law; potential lawsuits for infringement of third-party intellectual property; our patents being found invalid or unenforceable; compliance with patent regulations; claims challenging the inventorship or ownership of our patents and other intellectual property; claims asserting that we or our employees misappropriated a third-party’s intellectual property or otherwise claiming ownership of what we regard as our intellectual property; adequate protection of our trademarks; ability to attract and retain key executives; managing our growth could result in difficulties; risks associated with international operations; potential system failures; the price of our common stock may fluctuate substantially; our executive officers, directors, and principal stockholders have the ability to control all matters submitted to the stockholders; a significant portion of our total outstanding shares are eligible to be sold into the market; unfavorable or lacking analyst research or reports; and we are currently subject to securities class action litigation. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission, or SEC, on November 10, 2016 and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.

Reference:

  1. Polage, C. R., et al. (2015). Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Internal Medicine, 175(11), 1792–1801.

IR or PR Contact:

Carlo Tanzi, Ph.D., Seres Therapeutics, 617-203-3467

Head of Investor Relations and Corporate Communications

Ctanzi@serestherapeutics.com

U.Va.’s Division of Infectious Diseases and International Health Could Lead To a New Treatment For C. diff. Infection (CDI)

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Every year, about half a million patients are infected by Clostridium difficile, an otherwise harmless bacterium that can multiply out of control when the use of antibiotics upsets the balance of microorganisms in the gut. In 2011, about 15,000 deaths were directly attributable to the infection, according to a recent study by the federal Centers for Disease Control and Prevention (CDC).

Current probiotic treatments, which promote the growth of helpful bacteria, have been ineffective against the infection, also known as C. diff.

But work being done at U.Va.’s Division of Infectious Diseases and International Health could lead to a new treatment by the end of the calendar year, according to Dr. Bill Petri, chief of the division. That’s an unusually optimistic estimate in medical research, where scientific breakthroughs predate new treatments by several years.

“Some of these advanced probiotics are actually being tested today in the clinic for their role,” Petri said. “We’re actually participating in advanced clinical trials at U.Va.”

Immunologist Erica L. Buonomo was the driving force behind the new discovery, Petri said, which has to do with the role of white blood cells in protecting against C. diff.

Buonomo found that a particular type of white blood cells, called eosinophils, act as a barrier against the infection, which breaks down the lining of the gut. These eosinophils are recruited by a protein called IL-25. A serious C. diff infection kills eosinophils, allowing the bacteria to enter the gut.

The researchers found that gut bacteria stimulate the production of IL-25, so the right probiotic could help with the production of protective eosinophils.

“We identified a pathway in the immune response that reduces the severity of an infection,” Buonomo said. “When we activate this pathway, we find mice are a lot less sick.”

The discovery would be especially helpful for elderly patients, who are most at risk. It also could have larger implications in the world of microbiology.

Eosinophils are best known for their role in allergic reactions and asthma attacks, when a high number of eosinophils cause inflammation.

The function of these cells was not entirely clear before Buonomo’s discovery. She believes this knowledge could help doctors fight other types of gastrointestinal disorders, such as irritable bowel syndrome.

U.Va. is now working on a probiotic with a Boston-based firm called Seres Therapeutics 

The finished product will be tested in Charlottesville, Petri said.

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Seres Therapeutics, Inc. Announced That It Has Initiated a Phase 1b Clinical Trial Evaluating SER-262 In Patients With Primary C. diff. Infection (CDI)

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Seres Therapeutics Inc.  a leading microbiome therapeutics company, announced today that it has initiated a Phase 1b clinical trial evaluating SER-262 in patients with primary Clostridium difficile infection (CDI).

SER-262 is an Ecobiotic® rationally-designed, fermented microbiome therapeutic derived by a manufacturing process that does not require human donor material. SER-262 is the first synthetically-derived and designed microbiome therapeutic ever to reach clinical-stage development.

“We intend to continue to utilize our platform technology and unique knowledge of bioinformatics, microbiology, manufacturing and regulatory requirements to develop additional rationally designed microbiome therapeutics for serious diseases in each of our three therapeutic franchises: infectious disease, immunology and metabolic disease.”

SER-262, an oral capsule, contains a consortium of twelve bacterial strains in spore form. The strains included in SER-262 were selected based on multiple criteria including analysis of human microbiome data, efficacy in animal models of CDI, and bacterial strain level characterization.1 The composition of SER-262 was selected among Seres’ field-leading human microbiome library containing over 14,000 well-characterized strains of bacteria.

The SER-262 Phase 1b study, a 24-week randomized, placebo-controlled, dose escalation study is expected to enroll approximately 60 patients who have experienced a first episode of CDI. The primary endpoint of the study will compare the CDI recurrence rate between the SER-262 and placebo groups at up to 8 weeks after dosing.

Approximately 640,000 and 820,000 individuals in U.S. each year experience a primary occurrence of CDI, and about 25 percent will suffer from a subsequent recurrence.

“Advancing SER-262 to the clinic is a landmark event for Seres and the microbiome field in general. The SER-262 program has demonstrated our ability to rapidly develop a new class of synthetic microbiome therapeutics comprised of rationally designed bacterial compositions,” said Roger Pomerantz, M.D., President, Chief Executive Officer and Chairman of Seres. “We intend to continue to utilize our platform technology and unique knowledge of bioinformatics, microbiology, manufacturing and regulatory requirements to develop additional rationally designed microbiome therapeutics for serious diseases in each of our three therapeutic franchises: infectious disease, immunology and metabolic disease.

With the initiation of the SER-262 Phase 1b study in primary CDI, and the ongoing SER-109 Phase 2 study in multiply recurrent CDI, Seres now has ongoing microbiome clinical programs across the entire CDI population. Initial study results from the SER-109 Phase 2 study are expected in mid-2016.

About Seres Therapeutics
Seres Therapeutics, Inc. is a leading microbiome therapeutics platform company developing a novel class of biological drugs that are designed to treat disease by restoring the function of a dysbiotic microbiome, where the natural state of bacterial diversity and function is imbalanced. Seres’ most advanced program, SER-109, has successfully completed a Phase 1b/2 study demonstrating a clinical benefit in patients with recurring Clostridium difficile infection (CDI) and is currently being evaluated in a Phase 2 study in recurring CDI.

The FDA has granted SER-109 Orphan Drug, as well as Breakthrough Therapy, designations. Seres’ second clinical candidate,

SER-287, is being evaluated in a Phase 1b study in patients with mild-to-moderate ulcerative colitis (UC).

For more information, please visit www.serestherapeutics.com.

Follow Seres Therapeutics  on Twitter @SeresTx.

 

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Microbiome – C. diff. Treatments On The Horizon

NewsUpdate

 

 

 

PROBIOTICS:

Pick a disease or disorder, and somebody, somewhere, has said that a probiotic supplement—an over-the-counter, unregulated pill usually filled with a single strain of friendly gut bacteria—might cure it, whether it’s cancer, obsessive-compulsive disorder, or a yeast infection.

But there’s very little evidence that probiotic supplements do any good. “There’s a lot of promise here but not a lot of proof yet,” said Cliff McDonald, associate director for science at the Centers for Disease Control and Prevention’s Division of Healthcare Quality Promotion.

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CDC Reports:

Half a million people a year are infected with C. diff in the U.S., the CDC estimates, with 29,000 annual deaths related to the diarrheic bacterium. More than 65 percent of C. diff infections involve exposure in a health-care facility, according to a 2015 study, creating more than $4.8 billion in excess health-care costs at acute-care facilities alone.

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C. diff. Treatments On The Horizon:

To Learn More About ALL C. diff. Clinical Trials In Progress Click On The Following Link:

https://cdifffoundation.org/clinical-trials-2/

 

Seres Therapeutics, a microbiome-based biopharmaceutical company in Cambridge, Mass., is developing a pill, subject to a rigorous approval process under the Food and Drug Administration, to tackle recurrent Clostridium difficile. (The digestive system’s microbiome is the community of healthy gut bacteria that normally reside in the body.)

Seres aims to put the science behind a proven treatment of recurrent C. diff, fecal transplants, in a pill, which wouldn’t require a colonoscopy. Like probiotic supplements, it’s a gut bacteria product. Unlike the supplements, by the time it’s available it will have gone through the FDA wringer. It will contain about 50 strains of bacteria proven effective in treating C. diff and will require a doctor’s prescription.

Recurrent C. diff is an obvious entry point for Seres, said Chief Executive Officer Roger Pomerantz. “We asked, what is the lowest-hanging fruit?” But it’s hardly the end. The company has built a microbiome library of 14,000 strains of human bacteria it hopes will help it treat a range of diseases, eventually without needing feces at all.   Seres has embarked on the research with some pretty lofty goals, including finding treatments for obesity, liver disease, and cancer. It has partnerships with Massachusetts General Hospital, the Mayo Clinic, Memorial Sloan Kettering Cancer Center, and other respected medical institutions.  “We will figure out exactly what’s wrong with the microbiome, design a drug, and then pull the organisms out with our library, never touching a human donation,” Pomerantz said.    Seres’s lead product candidate, SER-109, will treat recurrent C. diff with four capsules taken orally instead of with transplants. While fecal matter is the raw material for the pills, the final product consists only of the spores necessary to treat the infection, which will have been extracted and purified.  SER-109 is expected to become the first oral microbiome therapy approved by the FDA, though Seres declined to predict exactly when it will arrive. Results from the latest trials are due by midyear, and Phase 3 trials are scheduled to follow later in the year. Seres hopes to follow up quickly with SER-287, a drug to treat ulcerative colitis, which could be the first microbiome drug to treat a chronic disease, and SER-262, to treat primary C. diff before it turns into the recurrent kind.

Other companies are racing to collect enough data for FDA approval, but right now Seres, which is publicly traded, looks to be the one to beat. “Seres is probably going to be the first one that’s going to knock at the FDA’s door,” said Mohan Iyer, chief business officer at Second Genome, a microbiome company studying how to treat disease with the compounds produced by gut bacteria instead of the gut bacteria themselves.

“SER-109 is poised to be first-in-class among fecal microbiota transplant-derived drugs,” Joseph Schwartz, an analyst at Leerink Partners, wrote in a May report. The report says the latest trial results “wowed the Street” but warns that the company could still be held back by “disappointing clinical data” and obstacles in the regulatory process.

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Another top contender is Rebiotix. Its RBX2660 is also designed to treat recurrent C. diff but, unlike SER-109, is administered with an enema; an oral version is in development. The treatment also differs significantly from Seres’s in formulation, including thousands of kinds of microbes from the donor’s stool, compared with SER-109’s 50 or so, as many as could be preserved and some of which haven’t even been identified.

“We make sure we have a minimum concentration of certain kinds that we know the patients lack,” CEO Lee Jones said. “But we don’t identify all of them. There’s no way to do that.” A recent study estimated that 1014 bacteria are in the human gut, most of which have never been isolated. Jones said the drug could hit the market by 2018.

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  • UPDATES:

The medications have been shown to be similarly effective—with no C. diff-associated diarrhea for 29 of 30 of Seres’s patients  and  27 of 31 of Rebiotix’s, in the companies’ latest results—and equally safe. Adverse reactions for both are limited to such problems as moderate diarrhea and abdominal cramping, which could be from the C. diff itself. Both have been designated as “breakthrough therapies” by the FDA, allowing for an expedited approval process, and both are likely soon to provide an at-home alternative to fecal transplants.

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Point Of View:

“I don’t know who is going to make it across the line first,” said Gail Hecht, director of gastroenterology and nutrition at Loyola University Medical Center and chairwoman of the American Gastroenterological Association for Gut Microbiome Research & Education. Hecht has attended a Seres advisory board meeting but doesn’t have a financial interest in the company. “It is indeed a race,” she said.

Seres does have at least one distinct market advantage. “Patients have different preferences,” Hecht observes, but “in general, people don’t particularly like enemas.”

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Human Fecal Transplants:

For nearly two thousand years, doctors have looked to this unlikeliest of places for medicine. One of the earliest documented applications is from the fourth-century Chinese medical doctor Ge Hong, whose “yellow soup” recipe to treat diarrhea included a healthy person’s dried or fermented feces. Sixteen hundred years later, in 1958, patients infected with C. diff received the first known human fecal transplants.

Stool Bank Information: 

Today the effectiveness of fecal transplants (formally known as fecal microbiota transplants) to treat recurrent C. diff is supported by a long list of studies, with researchers attributing the results to the restoration of the microbiome. OpenBiome, a nonprofit stool bank, shipped 1,828 treatments in 2014, a number that ballooned to 7,140 treatments in 2015 and looks to be eclipsed this year, with 4,323 treatments shipped to its clinical partners through May 31. And these numbers don’t take into account the transplants performed through directed fecal donations.

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To read article in its entirety:

http://www.bloomberg.com/news/articles/2016-06-30/coming-soon-gut-bacteria-that-actually-cure-your-disease