Background: Antibiotics alone are often insufficient to treat recurrent C. difficile infection (rCDI) because they have no activity against C. difficile spores that germinate within a disrupted microbiome. SER-109, an investigational, oral, microbiome therapeutic comprised of purified Firmicutes spores, was designed to reduce rCDI through microbiome repair. We report an integrated efficacy analysis through week 24 for SER-109 from phase 3 studies, ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a randomized, placebo-controlled phase 3 trial conducted at 56 US or Canadian sites that included 182 participants with ≥2 CDI recurrences, confirmed via toxin EIA testing. Participants were stratified by age (<65 years or ≥65 years) and antibiotic regimen (vancomycin, fidaxomicin) and were randomized 1:1 to placebo or SER-109 groups. ECOSPOR IV was an open-label, single-arm study conducted at 72 US or Canadian sites including 263 participants with rCDI enrolled in 2 cohorts: (1) rollover participants from ECOSPOR III who experienced on-study recurrence diagnosed by toxin EIA (n = 29) and (2) participants with ≥1 CDI recurrence (diagnosed by PCR or toxin EIA), inclusive of the current episode (n = 234). In both studies, the investigational product was administered orally as 4 capsules over 3 consecutive days following symptom resolution after standard-of-care antibiotics. The primary efficacy end point was rCDI (recurrent toxin-positive diarrhea requiring treatment) through week 8. Other end points included CDI recurrence rates and safety through 24 weeks. Results: These 349 participants received at least 1 dose of SER-109 in ECOSPOR III or ECOSPOR IV (mean age 64.2; 68.8% female). Overall, 77 participants (22.1%) enrolled with their first CDI recurrence. Four participants received blinded SER-109 in ECOSPOR III followed by a second dose of open-label SER-109 in ECOSPOR IV. Overall, the proportion of participants who received any dose of SER-109 with rCDI at week 8 was 9.5% (33 of 349; 95% CI, 6.6 %–13.0%), and the CDI recurrence rate remained low through 24 weeks (15.2%, 53 of 349; 95% CI, 11.6%–19.4%), corresponding to sustained clinical response rates of 90.5% (95% CI, 87.0%–93.4%) and 84.8% (95% CI, 80.6%–88.4%), respectively (Fig. 1). Most rollover participants (25 of 29, 86.2%) were from the placebo arm; 13.8% had rCDI by week 8. Conclusions: In this integrated analysis, the rates of rCDI were low and durable in participants who received the investigational microbiome therapeutic SER-109, with sustained clinical response rates of 90.5% and 84.8% at weeks 8 and 24, respectively. These data further support the potential benefit of microbiome repair with SER-109 following antibiotics for rCDI to prevent recurrence in high-risk patients.

Financial support: This study was funded by Seres Therapeutics.

Disclosure: None

Background: Clostridioides difficile infection (CDI) often recurs in patients aged ≥65 years and those with comorbidities. Clinical trials often exclude patients with history of immunosuppression, malignancy, renal insufficiency, or other comorbidities. In a phase 3 trial (ECOSPOR III), SER-109 was superior to placebo in reducing recurrent CDI (rCDI) risk at week 8 and was well tolerated. We report integrated safety data for SER-109 in a broad patient population through week 24 from phase 3 studies: ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a double-blind, placebo-controlled trial conducted in participants with ≥2 CDI recurrences randomized 1:1 to placebo or SER-109. ECOSPOR IV was an open-label, single-arm study conducted in 263 patients with rCDI enrolled in 2 cohorts: (1) rollover participants from ECOSPOR III with on-study recurrence and (2) participants with ≥1 CDI recurrence, inclusive of the current episode. In both studies, the investigational product was administered as 4 oral capsules over 3 days. Treatment-emergent adverse events (TEAEs) were collected through week 8; serious TEAEs and TEAEs of special interest (ie, bacteremia, abscess, meningitis) were collected through week 24. Results: In total, 349 participants received SER-109 in ECOSPOR III and/or ECOSPOR IV (mean age 64.2; 68.8% female). Chronic diseases included cardiac disease (31.2%), immunocompromised or immunosuppressed (21.2%), diabetes (18.9% ), and renal impairment or failure (13.2%). Overall, 221 (63.3%) of 349 participants who received SER-109 experienced TEAEs through week 24. Most were mild to moderate and gastrointestinal. The most common (>5% of participants) treatment related TEAEs were flatulence, abdominal pain and distension, decreased appetite, constipation, nausea, fatigue, and diarrhea. No participants experienced a treatment-related TEAE leading to study withdrawal. Invasive infections were observed in 28 participants (8%); those with identified pathogens were unrelated to SER-109 species, and all were deemed unrelated to treatment by the investigators. There were 11 deaths (3.2%) and 48 participants (13.8%) with serious TEAEs, none of which were deemed treatment related. There were no clinically important differences in the safety profile across subgroups of sex, race, prior antibiotic regimen, or number of CDI recurrences. No safety signals were observed in participants with renal impairment or failure, diabetes, cardiac disease, or immunocompromised or immunosuppressed individuals. Conclusions: In this integrated analysis of phase 3 trials, SER-109, an investigational microbiome therapeutic, was well tolerated in this vulnerable patient population with prevalent comorbidities. No infections, nor those with identified pathogens, were attributed to SER-109 or product species. This safety profile might be expected because this purified product is composed of spore-forming Firmicutes normally abundant in the healthy microbiome.

Financial support: This study was funded by Seres Therapeutics.

Disclosures: None

Depictions of mythical beings appear in many different forms of art world-wide, including rock art of various ages. In this paper we explore a particular type of imagery, back-to-back figures, consisting of two human-like figures or animals of the same species next to each other and facing in opposite directions. Some human-like doubles were joined at the back rather than side-by-side, but also face opposite directions. In this paper, we report on new research on rock art, bark paintings and recent paintings on paper and chart a 9000-year history of making aesthetically, symbolically and spiritually powerful back-to-back figures in Arnhem Land, Northern Territory, Australia.

Enrichment of the heavy rare earth elements (HREE) in carbonatites is rare as carbonatite petrogenesis favours the light (L)REE. We describe HREE enrichment in fenitized phonolite breccia, focusing on small satellite occurrences 1–2 km from the Songwe Hill carbonatite, Malawi. Within the breccia groundmass, a HREE-bearing mineral assemblage comprises xenotime, zircon, anatase/rutile and minor huttonite/thorite, as well as fluorite and apatite.

A genetic link between HREE mineralization and carbonatite emplacement is indicated by the presence of Sr-bearing carbonate veins, carbonatite xenoliths and extensive fenitization. We propose that the HREE are retained in hydrothermal fluids which are residually derived from a carbonatite after precipitation of LREE minerals. Brecciation provides a focusing conduit for such fluids, enabling HREE transport and xenotime precipitation in the fenite. Continued fluid–rock interaction leads to dissolution of HREE-bearing minerals and further precipitation of xenotime and huttonite/thorite.

At a maximum Y content of 3100 µg g−1, HREE concentrations in the presented example are not sufficient to constitute ore, but the similar composition and texture of these rocks to other cases of carbonatite-related HREE enrichment suggests that all form via a common mechanism linked to fenitization. Precipitation of HREE minerals only occurs where a pre-existing structure provides a focusing conduit for fenitizing fluids, reducing fluid – country-rock interaction. Enrichment of HREE and Th in fenite breccia serves as an indicator of fluid expulsion from a carbonatite, and may indicate the presence of LREE mineralization within the source carbonatite body at depth.