Vedanta Phase II Data Position It To Chase Seres In C. Difficile Recurrence
Executive Summary
Vedanta thinks its live biotherapeutic sourced from clonal cell banking could offer strong prevention against C. difficile infections after antibiotics have cleared an initial infection.
Chasing Seres Therapeutics, Inc. for the first microbiome product approval, Vedanta Biosciences, Inc. reported on 5 October that its live biotherapeutic product VE303 has succeeded in a Phase II study preventing recurrence of Clostridium difficile infections and is ready to move into Phase III in 2022. On the news of the successful Phase II study, the US Biomedical Advanced Research and Development Authority (BARDA) exercised a contract option to provide $23.8m to fund the Phase III study.
After clinical setbacks in 2017, Seres rebounded in 2020 with positive Phase III data for SER-109 –comprised of highly purified bacterial spores from multiple Firmicute species derived from the stool of healthy donors – to prevent C. diff infection recurrence. (Also see "Seres Aims To File C. Diff Microbiome Drug On Single Pivotal Trial" - Scrip, 10 Aug, 2020.) Seres is expected to file a new drug application for SER-109 with the US Food and Drug Administration in mid-2022.
In topline data from Vedanta’s 79-patient CONSORTIUM study, VE303 met its primary endpoint of preventing disease recurrence through eight weeks of treatment with the higher of two doses used in the trial. Vedanta, a privately held biotech founded by PureTech Health plc, did not provide numerical data on how the lower dose of VE303 fared in the study. In an interview, CEO Bernat Olle told Scrip that one of the goals for the Phase II study was to choose a dose to take into Phase III and with an across-the-board clean safety profile, it makes sense to take the higher and more efficacious dose into a pivotal study.
The high dose of VE303 yielded a 31.7% placebo-adjusted reduction (45.5% versus 13.8%) in recurrence rate (p=0.0077), which Vedanta says equates to a greater than 80% reduction in the odds of recurrence. The endpoint was measured either by toxin and PCR testing or, when no patient stool sample was available for testing, by clinician’s diagnosis and treatment for recurrence. Vedanta said full results of the study are still being compiled and will be presented at a future medical conference.
Vedanta now needs to have an end-of-Phase II meeting with the FDA to plan the Phase III program, Olle said. In CONSORTIUM, 29 patients were randomized to the high dose of VE303, 27 to the lower dose and 22 to placebo. Olle said he expects the Phase III study, by contrast, will enroll several hundred patients. The money from BARDA, under a 2020 contract with the agency that could bring Vedanta $76.9m in total, will help fund the Phase III study, although the biotech also raised a $68m series D financing in July, led by Magnetar Capital. (Also see "Finance Watch: $135m In Venture Capital Will Fund Amylyx’s Late-Stage ALS Drug" - Scrip, 21 Jul, 2021.)
VE303 differs from Seres’s SER-109 and other gut microbiome-derived therapeutic candidates in that it is not a fecal transplant but an oral capsule comprising eight strains of live bacteria manufactured at pharmaceutical-grade consistency from clonal bacterial cell banks. Vedanta says these “defined bacterial consortia” therapeutics may offer a more consistent and safer therapeutic benefit along with a scalable production model.
The cell banks Vedanta uses are from a large library the firm has gathered from human volunteers across four continents, Olle said, comprising roughly 100,000 isolates of gut bacteria. Vedanta studies responses and non-responses from clinical studies of other microbiome therapy candidates, he explained, to “generate a hypothesis for which types of bacteria may be associated with cure.” It follows up that research with animal modeling to determine causation by introducing or subtracting various isolates to see if a phenotype of interest is gained or lost, he said.
“For example, the ability of an animal to resist infection against Clostridium difficile is abrogated or reconstituted when you introduce certain material,” the exec said. Ultimately, Vedanta looks for bacteria that offer pharmacological properties of benefit as well as genomic characteristics that indicate they won’t lead to antibiotic resistance, he added.
Adding To The Standard Of Care
Because antibiotics used to treat C. difficile infections – such as vancomycin and fidaxomicin – are effective at treating an initial infection but not at preventing a recurrence, Vedanta hopes that if VE303 is approved, it will be broadly adopted for administration to C. diff-infected patients immediately after their round of antibiotic therapy, Olle said. The company also anticipates that BARDA may want to stockpile VE303 if it obtains FDA approval.
“An antibiotic puts the current episode under control, but, unfortunately, a collateral consequence of antibiotic use is that your microbial flora, your microbiome, is disrupted by the antibiotic,” Olle explained. “The spores of C. difficile that are not killed by the antibiotic can come back with a vengeance and cause a recurrence. So antibiotics are okay to manage the current episode, but they sort of paradoxically make you susceptible to experiencing a recurrence.”
Beyond VE303, Vedanta’s VE202 has completed Phase I studies for inflammatory bowel disease and is slated to move into a Phase II trial in ulcerative colitis. It has three other clinical candidates across both company-sponsored and investigator-initiated studies, Olle added, for food allergies, hepatic encephalopathy and cancer. The firm’s preclinical program targeting Gram-negative pathogens is nearing the declaration of a candidate as well, he said.