Brady, Kelly

6554 Background: SER-155 is an investigational, oral, live biotherapeutic product (LBP) comprised of 16 bacterial strains designed to decolonize gastrointestinal (GI) pathogens, improve epithelial barrier integrity, and modulate immune responses to prevent bloodstream infections (BSI). In the placebo-controlled cohort 2 of the phase 1b study, SER-155-001 (NCT04995653), SER-155 was generally well tolerated with a safety profile similar to placebo and the incidence of BSIs, a secondary endpoint, was significantly lower after treatment with SER-155 when compared to placebo. We report exploratory analyses of biomarkers of T cell expansion relevant for immune reconstitution after HCT. Methods: Participants were randomized 1:1 to receive 4 days of oral vancomycin (for microbiome conditioning) and 10 days of SER-155 or placebo/placebo administered pre-HCT (course 1) and post-neutrophil engraftment (course 2). Primary endpoints were safety and SER-155 strain engraftment (PK). Exploratory endpoints included plasma cytokine concentrations measured by ELISA and analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry. Results: Demographics were comparable across treatment arms. 34 of 45 randomized participants were treated and received allo-HCT (SER-155, 20; placebo, 14); 28 received course 2 (SER-155, 19; placebo, 9). SER-155 strain engraftment was observed in the peri-transplant period (median 11.5 strains after course 1) and post-HCT (median 11 strains after course 2 and HCT Day 100). Significant differences and trends in cytokines of systemic inflammation and immune homeostasis were observed relative to placebo prior to HCT Day 0 and post-HCT. On HCT Day 0, both arms had similar concentrations of IL7 and IL15 (Table 1). However, after course 2, and at HCT Day 100, significantly higher concentrations of IL7 were observed in the SER-155 arm relative to placebo (p=0.02, and p=0.003, respectively). In a preliminary analysis of PBMCs from a subset of participants, a high frequency of CD4+ T cells were observed in the SER-155 arm at the same timepoints. For homeostatic cytokine IL15, no significant differences were observed between arms. Conclusions: The significantly higher concentrations of IL7 with SER-155 treatment and observed frequency of CD4+ T cells support the potential role of the GI microbiome in promoting homeostatic expansion of peripheral T cells and immune reconstitution important for successful HCT. Clinical trial information: NCT04995653 . Median plasma IL7 and IL15 (pg/mL), SER-155 vs. placebo (generalized linear model). HCT Day or event SER-155 IL7 Placebo IL7 SER-155 IL15 Placebo IL15 D0 13.8 13.0 31.9 30.4 D7 15.1 14.6 50.9 62.6 D14 12.8 15.5 56.6 69.8 Post-neutrophil engraftment 13.4 9.0 16.3 15.4 Post-course 2 7.4* 3.9 6.2 9.1 D100 7.1** 3.5 6.2 6.2 *p<0.05, **p<0.01.

Background: In patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), low gastrointestinal (GI) microbial diversity is associated with risk of bloodstream infections (BSIs), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in allo-HCT patients by preventing pathogen domination, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a 2-part, Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing allo-HCT. Here, we present preliminary safety and tolerability data from the open-label Cohort 1 through Day 100 post HCT. Study Design and Methods: Adult recipients of allo-HCT were eligible for screening. Patients were excluded if they: a) were planned for umbilical cord blood or ex vivo T-cell depletion, b) had received a fecal microbiota transplant or any live biotherapeutic product within 3 months prior to screening, and/or c) had evidence of relapse or progression of hematologic malignancy (minimal residual disease was allowed). HCT conditioning and aGvHD prophylaxis were per investigator discretion. Following screening, patients received two treatment courses (before conditioning and after neutrophil engraftment) comprised of microbiome conditioning with 4 days of oral vancomycin (to facilitate engraftment of SER-155 strains) followed by 10 days of oral SER-155 (see study design schematic, Figure 1). The primary endpoint was the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), designated as invasive infection, BSI, and GI infection. Results: Fifteen adult patients were enrolled and 13 received study drug (safety population). Of these 13 patients, the median age was 67.0, all were White, and 54% were male. Underlying diseases included acute myeloid leukemia (6 patients [46.2%]); myelodysplastic syndromes and myeloproliferative neoplasms (2 patients each [15.4%]; and acute lymphoblastic leukemia, chronic myeloid leukemia, and classic Hodgkin's lymphoma (1 patient each [7.7%]). Ten patients (76.9%) received peripheral blood stem cells; 9 (69.2%) had an unrelated donor, 8 (61.5%) underwent a reduced-intensity conditioning regimen, and 3 (23.1%) received myeloablative conditioning. Eleven patients received allo-HCT, all patients had neutrophil engraftment within the expected timeframe and 10 had 100-day follow-up data available. Nine of these patients (81.8%) received tacrolimus/methotrexate-based GvHD prophylaxis. SER-155 was generally well-tolerated ( Table 1). Treatment-emergent AEs (TEAEs) were observed in all patients as is expected in this patient population. One TEAE considered unrelated to study drug, resulted in study discontinuation. Most AEs were gastrointestinal in nature with diarrhea being the most common AE. No SAEs were considered related to SER 155, and most SAEs and AESIs occurred after HCT and before starting the second course of SER-155. No deaths occurred prior to Day 100. Three deaths occurred after Day 100, all deemed to be unrelated to study drug by the investigators. No BSIs attributable to organisms in SER-155 occurred. Commencement of the double-blind, randomized, placebo-controlled Cohort 2 (n=60) was initiated following approval of the Data Safety Monitoring Committee. Conclusions: In patients enrolled in this open-label Cohort 1 of this Phase 1b study, SER-155 was well-tolerated through Day 100. Although sample size is limited, the observed safety and tolerability profile of SER-155 in this patient population is consistent with multiple preclinical assessments supporting the safety of SER-155 for therapeutic use. Enrollment in the double-blind, randomized, placebo-controlled second cohort to assess safety, efficacy, and changes in microbiome composition and function is ongoing.