EX-99.2 3 tm236663d1_ex99-2.htm EXHIBIT 99.2
Exhibit 99.2

| • SYN-004 is an orally administered, β-lactamase enzyme designed to preserve the intestinal microbiome in patients receiving IV β-lactam antibiotics. • A previous study among patients with lower respiratory tract infections receiving ceftriaxone plus SYN-004 vs. placebo found decreased risk of Clostridioides difficile infection (CDI) among the SYN-004 group.1 • Patients who received SYN-004 also had fewer alterations to the gut microbiome and resistome, including reductions in the frequency of β-lactamase and vancomycin resistance genes.2 • Published data suggest improved outcomes among HCT recipients with a healthier microbiome at engraftment, including less GVHD and improved survival • SYN-004 may improve outcomes after HCT through microbiome preservation during IV β-lactam antibiotic administration. • This study evaluates the safety, tolerability, and potential absorption of SYN-004 in HCT recipients. • Interim blinded analyses after the MER cohort suggest SYN-004 is well tolerated in HCT patients. • SYN-004 detection was uncommon by ECL. • Functional drug was not detected in blood; positive ECL may represent absorption of inactive SYN-004 fragments. • BSIs were common among HCT patients (47%); all but 1 BSI were the precipitating event for MER initiation. • The BSI that occurred after MER initiation was caused by a methicillin resistant S. epidermidis, resistant to MER. • This study is currently enrolling in the piperacillin-tazobactam cohort. • Adults undergoing allogeneic HCT with myeloablative conditioning • Preserved organ function and no known antibiotic allergy • Phase 1b/2a, triple-blinded, randomized controlled trial • Randomized 2 (SYN-004) : 1 (placebo) • 3 antibiotic cohorts: meropenem (MER), piperacillin-tazobactam, and cefepime • Cohort 1 MER was used for neutropenic fever coverage. • Study drug was started on HCT day +1 and continued until 72h after MER discontinuation. • Figure 1 provides an overview of study activities. • Schema will be the same for the PIP/TAZO and cefepime study arms. • Target enrollment per cohort = 12 participants completing at least two antibiotic PK blood draw periods. • Primary outcomes: assess potential SYN-004 systemic absorption via plasma levels; assess effects of SYN-004 on systemic antibiotic concentrations; assess incidence of BSIs and bacterial intestinal infections while receiving SYN-004; assess tolerability and grade 3 or 4 adverse events; and assess overall survival at 30 days after study drug dosing completed. Theriva Biologics, Inc. (formerly Synthetic Biologics, Inc.) • 19 patients started study drug; 12 had at least two MER PK blood draws and were considered evaluable (Table 1). • A total of 13 SAEs occurred among 10 patients (Table 2). • None were found to be related to study drug or study procedures. • 9/19 (47%) developed a BSI while on study drug (Table 3). • 8 BSIs were the precipitating event for MER initiation. • 1 patient developed methicillin-resistant Staphylococcus epidermidis BSI while receiving MER. BACKGROUND METHODS RESULTS CONCLUSIONS TABLE 3. Bloodstream infections among patients who received study drug or placebo (N=19) Variable N (%) BSIs before meropenem initiation 8 (42) a Staphylococcus epidermidis 4 (21) Escherichia coli 1 (5) Klebsiella pneumoniae 3 (15) Capnocytophaga sputigena 1 (5) Leptotrichia spp. 1 (5) Streptococcus bovis 1 (5) BSIs after meropenem initiation 1 (5) Staphylococcus epidermidis, methicillin resistant 1 (5) BSIs within 30 days after end of study drug/placebo and meropenem (n=14 patients enrolled) 2 (14) Escherichia coli 1 (7) Staphylococcus epidermidis, methicillin resistant b 1 (7) TABLE 2. Severe adverse events among study participants (N=19) Severe Adverse Event N Sepsisa 6 Acute kidney injury 2 Kidney infection (BK virus)a 1 GI bleed 1 Anorexia 1 Endocarditisa, b 1 Vomiting 1 Interim Safety Analysis of SYN-004 Phase 1b/2a Trial in Hematopoietic Cell Transplant (HCT) Recipients Mark A. Schroeder, MD1 , Hailey Sappington, MPH1 , Jeremy Eisele 1 , Elijah Martin 1 , Gabbie Lampen 1 , Kimberly A. Reske, MPH2 , Tiffany Hink, MT, ASCP 2 , Victoria Teuscher 2 , Matthew R. Keller, MS3 , Andrew Bristol, PhD4 , Charles Le, PhD4 , Sheila Connelly, PhD4 , Michael Moenk, PhD5 , Vince Wacher, PhD4 , Michael Kaleko, MD, PhD4 , Joseph L. Kuti, PharmD, FIDP, FCCP6 , Margaret A. Olsen, PhD, MPH2 and Erik R. Dubberke, MD, MSPH2 1Bone Marrow Transplantation & Leukemia Section, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; 2Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO; 3 Institute for Informatics, Washington University School of Medicine, Saint Louis, MO; 4Theriva Biologics, Inc., Rockville, MD; 5Charles River Laboratories, Skokie, IL; 6Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT Abstract #LBA6 aThree BSIs were polymicrobial, so total organisms adds up to more than 9. Polymicrobial BSIs included: S. epidermidis / K. pneumoniae; K. pneumoniae / S. bovis; S. epidermidis / C. sputigena. One patient had two separate BSIs: S. epidermidis and then E. coli. bCase of endocarditis reported as SAE a Infectious SAE; 1 sepsis event resulted in death (not related to study drug). bS. epidermidis; occurred after completion of study drug/placebo and meropenem. REFERENCES 1. Kokai-Kun JF et al. Lancet Infect Dis. 2019; 19 (5):487-496. 2. Kokai-Kun JF et al. Infect Drug Resist. 2020; 13:2521-2535. Results of PK analyses: •SYN-004 was detected in 3/137 (2.2%) specimens by ECL. •Patient A: 2/10 specimens positive: •9.45 ng/ml on day 2-3 after MER start •0.98 ng/ml on MER day 7. •Patient B: 1/4 specimens positive: 1.15 ng/ml within 72h of study drug start. •All were functional assay negative and SYN-004 absorption was adjudicated as indeterminate. •Meropenem concentrations best fitted a two-compartment model with CrCL proportional to CL. •Mean (SD) area under the curve for MER = 257mg*hr/L(159) (Table 4). Erik Dubberke, MD, MSPH Washington University School of Medicine Box 8051; 4523 Clayton Ave edubberk@wustl.edu St. Louis, MO 63110 TABLE 1. Demographics of study population Variable N (%) or median (range) Total enrollment 19 Number evaluable (at least 2 MER PK blood draws) 12 (63) Female 6 (32) White race 19 (100) Underlying malignancy AML 7 (37) MDS 8 (42) Other: Lymphoma, lymphoproliferative disease, PCL, CMML 4 (21) Time since diagnosis of hematologic malignancy (months) 10 (5-16) Transplant characteristics Peripheral blood stem cell 19 (100) Matched sibling 6 (32) Matched unrelated 12 (63) Haploidentical 1 (5) Match grade not 10/10 2 (11) Myeloablative conditioning 19 (100) FUNDING TABLE 4. Summary of meropenem pharmacokinetic and pharmacodynamic exposure parameters for the 12 patients on Day 2 and Day 7 of meropenema Parameter Day 2 Day 7 Cmax (µg/mL) 54.67 (51.69) 44.20 (23.42) Cmin (µg/mL) 1.46 (3.76) 0.91 (1.97) AUC24 (µg*h/mL) b 256.79 (159.48) Same as Day 2 fT>MIC Enterobacterales (%) c 69% (20) Same as Day 2 fT>MIC P. aeruginosa (%) d 58% (19) Same as Day 2 a Results presented as mean (standard deviation) total drug concentrations (Cmax, Cmin, AUC24 ) or free drug exposures (fT>MIC), corrected for protein binding of 2% b AUC24 calculated as the total dose received on day of therapy divided by the individual CL c Simulated exposure at the Enterobacterales susceptibility breakpoint (1 µg/mL) based on individual posterior PK parameters and actual dosing regimen received d Simulated exposure at the P. aeruginosa susceptibility breakpoint (2 µg/mL) based on individual posterior PK parameters and actual dosing regimen received NOTE: Target T>MIC is 40%. 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