Spero Therapeutics (United States)

Abstract Background Management of complicated urinary tract infections (cUTIs) is increasingly difficult due to rising antimicrobial resistance. There is an unmet need for oral treatment options for antimicrobial-resistant cUTIs. Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an investigational oral carbapenem with activity against antimicrobial-resistant Enterobacterales, including extended-spectrum β-lactamase–positive (ESBL+) pathogens. Methods PIVOT-PO (NCT06059846) was a global, randomized, double-blind, non-inferiority (10% margin) Phase 3 study comparing the efficacy and safety of oral TBP-PI-HBr with intravenous (IV) imipenem-cilastatin (IMI-CIL) in hospitalized adult patients with cUTI or acute pyelonephritis (AP) (Figure 1). The primary endpoint of overall response (clinical cure plus microbiological eradication) at test-of-cure (TOC) was assessed in the microbiological intent-to-treat (micro-ITT) population. An interim analysis to assess efficacy and futility was reviewed by an Independent Data Monitoring Committee and the study was stopped for efficacy. Results Baseline characteristics were balanced between treatment groups (Table 1). Overall response at TOC was 58.5% in 261/446 participants who received TBP-PI-HBr versus 60.2% in 291/483 participants who received IMI-CIL (adjusted treatment difference: −1.3%; 95% CI: −7.5%, 4.8%). Treatment effects were comparable in participants with ESBL+ Enterobacterales (Table 2). The safety profile of TBP-PI-HBr was overall consistent with IMI-CIL; the two most frequent treatment-emergent adverse events were diarrhea and headache (Table 3). Conclusion Oral TBP-PI-HBr was non-inferior to IV IMI-CIL in the treatment of cUTI or AP and showed comparable efficacy in participants with ESBL+ Enterobacterales. No new safety signals were identified. TBP-PI-HBr may provide an effective oral treatment option for cUTI or AP. Funding: PIVOT-PO was funded by Spero Therapeutics, Inc. The development of TBP-PI-HBr is supported in part with federal funds from the U.S. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under contract number HHSO100201800015C. Disclosures All Authors: No reported disclosures

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long‐term prophylaxis of hereditary angioedema. Here, we report the results from a two‐part, phase 1, open‐label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight‐matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow‐up for safety was over 84 days post‐dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow‐up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post‐dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC), increased less than 3‐fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose‐proportional manner. Inhibition of FXIIa‐mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti‐drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.

Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered β-lactam-β-lactam inhibitor combination widely used in clinical practice). We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and β diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554). The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in βdiversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events. The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease. Spero Therapeutics.

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy.

BackgroundAntimicrobial resistance (AMR) is a growing threat. ESBL-producing Enterobacterales infections are rising, especially within the community setting. Patients requiring OPAT services will increase based on AMR to oral antibiotic (ABX) options. OPAT adverse events (AEs) are linked to the use of IV catheters, followed by adverse drug events. Complications that arise from OPAT, often necessitate acute care services. We sought to quantify costs associated with OPAT AEs.MethodsA multicenter retrospective claims analysis from the state of Utah’s (UT) Public IBIS database was performed for 2020. OPAT AEs as described in the literature were used to query charges. All UT hospitals and common OPAT AE principal diagnosis (PDx) codes were included in the analysis. Estimated inpatient (IP) costs associated with common OPAT AEs were calculated from a charge-to-cost ratio (22.5%) using publicly available data from the Centers for Medicare & Medicaid Services. Event counts reported for UT were scaled proportionally to estimate total events for the U.S. population. Emergency department (ED) incidence rates for OPAT AEs from 2016 to 2020 were also examined.ResultsDuring the study period, 248,843 patients met study inclusion for an OPAT AE PDx. Among IV-related complications, catheter phlebitis accounted for highest median cost per IP event at $14,051. Other PDx, included catheter blockage and central line-associated bloodstream infections at $11,237 and $10,103, respectively, followed by $9,371 for complications post injection. Thrombotic events equated to total of $11,915 for the combined costs of deep venous thrombosis and pulmonary embolism. Lastly, C. difficile infections accounted for a median cost of $5,284 (Figure 1). Age-adjusted rates of ED activity related to AEs rose to 17.6 per 10,000 in 2020; this marked an 18% increase from 2016 (Figure 2).Figure 1.Figure 2.ConclusionGive that viable oral ABX treatment options in the community setting are limited, patients will require additional OPAT services as AMR rates continue to escalate. OPAT services are not without added risks of complications, as the average median cost for an OPAT AE was $8,852. These costs may be minimized by the addition of new oral ABXs that overcome AMR, thus improving patient outcomes.DisclosuresMauricio Rodriguez, PharmD, MS-HEOR, BCPS, BCCCP, BCIDP, Spero Therapeutics: Employee Georgia Buscaglia, PhD, Spero Therapeutics: Advisor/Consultant Steven Tolle, BFA, Spero Therapeutics: Advisor/Consultant Darren Michael, PhD, CC, SC, Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Grant/Research Support.

Background & AimsEfruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1–F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis.MethodsPatients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy.ResultsEfruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] −9 μg/L efruxifermin vs. −3.4 μg/L placebo; p = 0.0130) and ELF score (−0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB −5.7 kPa efruxifermin vs. −1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients.ConclusionsEfruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies.Lay summaryCirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH.Clinical Trial NumberNCT03976401

BackgroundLimited data are available in the United States on the 12-month epidemiology, outpatient (OP) antibiotic treatment patterns, outcomes, and costs associated with complicated urinary tract infections (cUTIs) in adult patients.MethodsA retrospective observational cohort study of adult patients with incident cUTIs in IBM MarketScan Databases between 2017 and 2019 was performed. Patients were categorized as OP or inpatient (IP) based on initial setting of care for index cUTI and were stratified by age (<65 years vs ≥65 years). OP antibiotic treatment patterns, outcomes, and costs associated with cUTIs among adult patients over a 12-month follow-up period were examined.ResultsDuring the study period, 95 322 patients met inclusion criteria. Most patients were OPs (84%) and age <65 years (87%). Treatment failure (receipt of new unique OP antibiotic or cUTI-related ED visit/IP admission) occurred in 23% and 34% of OPs aged <65 years and ≥65 years, respectively. Treatment failure was observed in >38% of IPs, irrespective of age. Across both cohorts and age strata, >78% received ≥2 unique OP antibiotics, >34% received ≥4 unique OP antibiotics, >16% received repeat OP antibiotics, and >33% received ≥1 intravenous (IV) OP antibiotics. The mean 12-month cUTI-related total health care costs were $4697 for OPs age <65 years, $8924 for OPs age >65 years, $15 401 for IPs age <65 years, and $17 431 for IPs age ≥65 years.ConclusionsThese findings highlight the substantial 12-month health care burden associated with cUTIs and underscore the need for new outpatient treatment approaches that reduce the persistent or recurrent nature of many cUTIs.

Tebipenem pivoxil is the first orally available carbapenem antibiotic and has been approved in Japan for treating ear, nose, and throat and respiratory infections in pediatric patients. Its active moiety, tebipenem, has shown potent antimicrobial activity in vitro against clinical isolates of Enterobacterales species from patients with urinary tract infections (UTIs), including those producing extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamase. In the present study, tebipenem was tested for stability to hydrolysis by a set of clinically relevant β-lactamases, including TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 enzymes. In addition, hydrolysis rates of other carbapenems, including imipenem, meropenem, and ertapenem, were determined for comparison. It was found that, similar to other carbapenems, tebipenem was resistant to hydrolysis by TEM-1, CTX-M, and AmpC β-lactamases but was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes with catalytic efficiency values (kcat/Km) ranging from 0.1 to 2 × 106 M-1s-1. This supports the reported results of antimicrobial activity of tebipenem against ESBL- and AmpC-producing but not carbapenemase-producing Enterobacterales isolates. Considering that CTX-M and AmpC β-lactamases represent the primary determinants of multidrug-resistant complicated UTIs (cUTIs), the stability of tebipenem to hydrolysis by these enzymes supports the utility of its prodrug tebipenem, tebipenem pivoxil hydrobromide (TBP-PI-HBr), as an oral therapy for adult cUTIs.

Introduction: Scant data are available on the 30-day financial burden associated with incident complicated urinary tract infections (cUTIs) in a cohort of predominately elderly patients. This study sought to examine total and cUTI-related 30-day Medicare spending (MS), a proxy for healthcare costs, among Medicare fee-for-service (FFS) beneficiaries who resided in the community with newly diagnosed cUTIs. Methods: A retrospective multicenter cohort study of adult beneficiaries in the Medicare FFS database with a cUTI between 2017 and 2018 was performed. Patients were included if they were enrolled in Medicare FFS and Medicare Part D from 2016 to 2019, had a cUTI first diagnosis in 2017–2018, no evidence of any UTI diagnoses in 2016, and residence in the community between 2016 and 2018. Results: During the study period, 723,324 cases occurred in Medicare beneficiaries who met the study criteria. Overall and cUTI-related 30-day MS were $7.6 and $4.5 billion, respectively. The average overall and cUTI-related 30-day MS per beneficiary were $10,527 and $6181, respectively. The major driver of cUTI-related 30-day MS was acute care hospitalizations ($3.2 billion) and the average overall and cUTI-related 30-day MS per hospitalizations were $16,431 and $15,438, respectively. Conclusion: Overall 30-day MS for Medicare FSS patients who resided in the community with incident cUTIs was substantial, with cUTI-related MS accounting for 59%. As the major driver of cUTI-related 30-day MS was acute care hospitalizations, healthcare systems should develop well-defined criteria for hospital admissions that aim to avert hospitalizations in clinically stable patients and expedite the transition of patients to the outpatient setting to complete their care.