We completed our Phase 1b clinical study for our UC drug candidate, SER-287, in subjects with active mild to moderate UC who were failing current therapies. The results of the SER-287 Phase 1b study, a randomized, double-blinded, placebo-controlled, multiple-dose, induction study enrolled patients with active mild-to-moderate UC, with Total Modified Mayo scores of 4 to 10 were positive. The study enrolled 58 subjects who exhibited pre-study disease activity despite treatment with standard-of-care therapeutics. SER-287 safety and tolerability was a primary study endpoint. The study showed no imbalance in adverse events in SER-287-treated patients as compared to patients treated with placebo and no drug-related serious adverse events were observed.
Analyses of microbiome data, a co-primary endpoint of the trial, showed that SER-287 induced regimen-dependent engraftment of SER-287 derived bacterial species into the colonic microbiome of patients treated with SER-287. Patients administered vancomycin pre-treatment followed by daily administration of SER-287 had the highest level of SER-287 engraftment, which was statistically significant. This patient cohort corresponded with the study arm where the most significant clinical benefits were observed, including clinical remission and endoscopic improvement. Differences in the composition of the microbiome post treatment were also associated with clinical remission. Bacterial engraftment signatures were durable throughout the dosing period of the trial and were also observed at four weeks post administration of the final SER-287 dose. The pharmacologic impact of the SER-287 engraftment was supported by metabolomic and transcriptomic data. Analysis of metabolites and gene expression signatures associated with inflammation and immune modulation, were observed to be correlated with remission in SER-287 treated subjects.
Based on these encouraging data from the Phase 1b trial, in December 2018, we initiated our Phase 2b trial, ECO-RESET, evaluating SER-287 in patients with active mild-to-moderate UC. Based on feedback obtained from the FDA on the SER-287 Phase 2b study design, we believe the study could serve as one of two required pivotal trials supporting potential future registration of SER-287. The Phase 2b study is a three-arm placebo-controlled trial of approximately 200 patients with active mild-to-moderate UC. Two groups of patients will receive different doses of SER-287, both following pretreatment with a short course of oral vancomycin. A third study arm will receive placebo. The study’s primary endpoint will evaluate clinical remission measured after 10 weeks of SER-287 administration. Endoscopic improvement will be measured as a secondary efficacy measure. We expect to complete trial enrollment by mid-2020.
Our Phase 3 clinical candidate, SER-109, is designed to rapidly and durably correct dysbiosis in the colonic microbiome in the setting of recurrent CDI. CDI is most often caused by the use of broad spectrum antibiotics which create a dysbiosis of the microbiome, thus increasing susceptibility to infection by Clostridium difficile, or C. difficile, a spore forming bacterium. C. difficile expresses toxins leading to debilitating diarrhea in affected individuals, and which can also cause more severe outcomes, such as inflammation of the colon (colitis), toxic megacolon and death. The U.S. Centers for Disease Control, or CDC, has identified CDI as one of the top three most urgent antibiotic-resistant bacterial threats in the United States. It is the most common cause of hospital acquired infection in the United States and has overtaken methicillin-resistant Staphylococcus aureus, or MRSA in incidence of disease. CDI is responsible for the deaths of approximately 29,000 Americans each year. Based on an epidemiological study conducted by the CDC, the incidence of CDI in the United States, was estimated to be 453,000 (95% confidence interval, 397,100 to 508,500) (Lessa et. al., Burden of Clostridium difficile Infection in the United States, New England J. of Medicine, 2015). While the epidemiological data are varied outside the United States due to the widespread use of antibiotics, CDI is a growing global disease. The standard of care for CDI is to treat with antibiotics. In many cases, antibiotic treatments may resolve the acute infection caused by C. difficile. However, these antibiotic treatments kill beneficial bacteria indiscriminately, inducing a dysbiosis of the microbiome and potentially making patients more susceptible to a recurrence of CDI. For those patients who experience a CDI recurrence, it is likely that dysbiosis of the microbiome is the proximal cause of disease. Published data suggests that the risk of recurrence is approximately 25% after the primary CDI, 40% after a first recurrence and as high as 60% for those experiencing two or more recurrences.
SER-109 is a donor-derived, purified bacterial spore-based microbiome therapeutic candidate consisting of an average of approximately 50 bacterial species purified from healthy donor stool. SER-109 is designed to prevent further recurrences of CDI in patients with recurrent CDI by restructuring the dysbiotic microbiome to a state that resists C. difficile growth and colonization. If approved by the FDA, SER-109 could be a first-in-field oral microbiome drug. We initiated a Phase 3 clinical study of SER-109 in approximately 320 patients with multiply recurrent CDI. The on-going study is designed to evaluate patients for 24 weeks with the primary endpoint of comparing the C. difficile recurrence rate in subjects who receive SER-109 verses placebo at up to eight weeks after dosing.
We continue to enroll the SER-109 Phase 3 study for patients with recurrent CDI despite the widespread use of FMT to treat CDI. As interference from this uncontrolled, understudied and unapproved product has impacted the enrollment rate of our SER-109 placebo-controlled clinical trial, we are evaluating modification of the study design to expedite clinical results.
Our SER-301 program is in preclinical discovery and bioprocess development. SER-301 is being rationally designed by utilizing our reverse translational microbiome therapeutics platform to incorporate learnings from our SER-287 and SER-262 clinical studies. We have identified specific bacterial species that engraft and are associated with clinical remission, and further we have identified metabolites made by these bacteria that correlate with clinical efficacy. We also have gene expression data from patient mucosal biopsies showing which genes and pathways are favorably altered by SER-287 treatment. All of these data are being leveraged in the design of SER-301.