VenatoRx Pharmaceuticals (United States)

BackgroundMycobacterium abscessus (Mabs) causes respiratory tract infections in cystic fibrosis patients, systemic infections in immunocompromised patients, and soft tissue abscesses. Treatment is problematic due to the innate resistance of this organism to most drugs. Amoxicillin (AMX) and tebipenem (TBP), are ineffective due to the presence of a β-lactamase, BLAMab. Ledaborbactam (LED), a broad-spectrum boronic acid β-lactamase inhibitor being developed as an orally bioavailable etzadroxil prodrug, inhibits this β-lactamase. The in vitro activities of LED in combination with AMX or TBP against Mabs were evaluated by microtiter broth dilution.MIC50 and MIC90 of amoxicillin and tebipenem with and without the addition of ledaborbactam against 22 isolates of M. abscessusMethodsClinical isolates were provided by Barbara Brown Elliott, Barbara Body, Jeffrey Starke, and CDC. ATCC 19977 was purchased from ATCC. AMX, TBP, LED, and the control drug, omadacycline (OMC) were dissolved in DMSO and frozen. MIC testing was accomplished using a modified CLSI method. Briefly, drugs were diluted in cation-adjusted Mueller Hinton broth (CAMHB). Polystyrene 96-well round-bottom plates were prepared with CAMHB and the drugs were added to the first well prior to being serially 2-fold diluted. Mabs isolates (21 clinical isolates and ATCC 19977) were diluted in CAMHB with or without 4 or 0.5 µg/mL of LED (final concentration of approximately 1.25 x 105 CFU/mL). The cell suspension was added to each well. Plates were incubated at 37 °C in ambient air for 5 days prior to reading. The MIC assays were run in duplicate with QC strains run in parallel to confirm expected activities of all compounds. The MIC50 and MIC90 are defined as the concentration at which 50% and 90% of the 22 isolates were inhibited.ResultsThe MIC50 / MIC90 of AMX and TBP were >256 / >256 µg/mL, and 64 / >64 µg/mL respectively. LED markedly enhanced the activities of each of these agents. The MIC50 / MIC90 of AMX and TBP in combination with LED 0.5 µg/mL was 8 / 8 µg/mL and 4 / 4 µg/mL, respectively. LED at 4 µg/mL in combination with AMX or TBP yielded similar results.ConclusionThe addition of LED to both AMX and TBP dramatically improved the in vitro activities of these compounds against Mabs. Evaluating these combinations in animal models of Mabs infection will provide a better understanding of their potential to treat human disease.DisclosuresDavid A. Six, PhD, Venatorx Pharmaceuticals, Inc.: Employee Michael H. Cynamon, MD, Paratek: use of omadacycline for M. abscessus infections

Taniborbactam is a novel cyclic boronate β-lactamase inhibitor that potentiates the in vitro activity of cefepime against Enterobacterales and Pseudomonas aeruginosa strains harboring serine and metallo-β-lactamases. Taniborbactam lacks intrinsic antibacterial activity. An in vitro hollow fiber infection model (HFIM) was used to evaluate bacterial kill and the potential for treatment-emergent resistance associated with the clinical cefepime-taniborbactam dose of 2-0.5 g every 8 h, administered as a 2 h infusion, for 7 days. Nine cefepime-resistant bacterial strains were studied among one Escherichia coli, five Klebsiella pneumoniae, and three P. aeruginosa that harbored a variety of cephalosporinases, extended-spectrum β-lactamases, and carbapenemases with cefepime-taniborbactam MIC values that ranged from 0.25 to 8 µg/mL. All nine strains grew rapidly when treated with cefepime alone, consistent with phenotypic resistance. Human plasma concentration-time profiles for cefepime and taniborbactam were simulated in the HFIM systems and resulted in bactericidal activity (≥3 log10 CFU/mL reduction) against eight of nine strains when assessed 8 h after initiation of the first dose, and against all nine strains by day 7. Treatment-emergent resistance, defined as bacterial subpopulations with ≥4 times the baseline MIC, was not detected in any cefepime-taniborbactam model from days 1 to 7. Therefore, human cefepime-taniborbactam exposures demonstrated sustained bactericidal activity and suppressed the emergence of resistance in a 7-day HFIM among serine and metallo-β-lactamase-positive Enterobacterales and P. aeruginosa strains. These observations support the clinical development of cefepime-taniborbactam and inform understanding of its potential role in treating serine and/or metallo-β-lactamase-positive Gram-negative bacterial infections.

Pseudomonas aeruginosa is a major gram-negative pathogen responsible for a variety of infections and possessing an array of both intrinsic and acquired resistance mechanisms, including β-lactamases, like the chromosomal Pseudomonas-derived cephalosporinase (PDC). β-Lactams are the most widely prescribed class of antibiotics in the United States, and antipseudomonal cephalosporins (including cefepime) are important therapies (alone or combined with β-lactamase inhibitors) for P. aeruginosa infections. Taniborbactam is a novel, bicyclic boronate β-lactamase inhibitor with activity against all β-lactamase classes and is being developed in combination with cefepime. PDC-88 is an R2-loop deletion variant conferring resistance to cefepime and ceftazidime and elevating ceftolozane/tazobactam minimum inhibitory concentration (MIC). Herein, we elucidated PDC-88 resistance mechanisms and compared inhibition by taniborbactam and avibactam. In an isogenic background, PDC-88 increased cefepime MICs by 16-fold compared to PDC-3. In vitro, compared to PDC-3, PDC-88 had 8.3-fold higher catalytic efficiency for cefepime achieved by decreasing KM 12.8-fold and decreasing kcat 1.6-fold. This is supported by our crystallographic observation that the PDC-88 deletion enlarged the active site in the vicinity of the R2-loop, likely better accommodating cefepime. Taniborbactam and avibactam restored cefepime activity by inhibiting PDC-88. Compared to avibactam, taniborbactam had 4.1- and 9-fold lower Ki app values for PDC-3 and PDC-88, respectively, with higher kon (k2/K) and similar koff for both enzymes. Structurally, taniborbactam positioned very similarly in the PDC-3 and PDC-88 active sites, interacting with many nearby residues. Based upon these data, cefepime-taniborbactam may represent an important alternative to ceftazidime-avibactam and ceftolozane-tazobactam for P. aeruginosa infections.

Abstract Background Cefepime-taniborbactam (FTB) is an investigational β-lactam/β-lactamase inhibitor combination that is active against carbapenem-resistant Enterobacterales and multidrug resistant Pseudomonas aeruginosa expressing serine and metallo-β-lactamases. CERTAIN-1 (Cefepime Rescue with Taniborbactam in cUTI) demonstrated that FTB was superior to meropenem (MEM) for the treatment of cUTI. Subgroup analyses were performed to determine the consistency of response, including for subgroups potentially more challenging to treat (e.g., bacteremia). Methods CERTAIN-1 was a randomized, double blind, double dummy, Phase 3 study comparing FTB to MEM in adults hospitalized with cUTI or Acute Pyelonephritis (AP). The primary endpoint was the composite (microbiologic and clinical) response at the test of cure (TOC) visit in the microITT population. A pre-specified test for superiority for the primary endpoint was performed following confirmation of non-inferiority. Patient demographic and baseline characteristics were analyzed for composite success. Treatment difference in success rate and corresponding 95% CI were calculated. Results 661 patients were randomized and 436 patients (66.0%) were included in the microITT population; 38.1% of patients were ≥ 65 years of age and 13.1% had baseline bacteremia. Composite success rates were 70.6% and 58.0% for FTB and MEM groups, respectively for the primary endpoint at the TOC visit and FTB was superior to MEM (treatment difference [FTB-MEM], 12.6%; 95% CI, 3.1 to 22.2; p=0.0088). Composite success rates were consistent with the primary analysis for subgroups, including BMI and renal impairment, in patients with potentially more serious infections (e.g., bacteremia, sepsis), and in at-risk patient subgroups (e.g., age ≥ 65, diabetes mellitus) (Table). No subgroup appears to have driven the overall result of superiority of FTB compared to MEM for the composite success rate. Conclusion FTB was superior to MEM for the primary endpoint at TOC and composite response rates were numerically higher in all subgroups, consistent with the primary efficacy response. Disclosures Mary Beth Dorr, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Merck and Co.: Shareholder|Pfizer: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Leanne Gasink, MD, MSCE, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|CSL Behring: Advisor/Consultant|CSL Behring: Consulting fees|Everest Medicines: Grant/Research Support|Evopint Biosciences: Advisor/Consultant|Evopint Biosciences: Consulting fees|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|LBG Consulting, LLC: Principal|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees|Vera Therapeutics: Advisor/Consultant|Vera Therapeutics: Consulting fees Tim Henkel, MD, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Employee, consulting fees, shareholder Greg Moeck, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Hongzi Chen, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds Scott A. McConnell, PharmD, Venatorx: employee|Venatorx: Stocks/Bonds Paul McGovern, MD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Paratek Pharmaceuticals: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder

ABSTRACTA novel approach to immunotherapy is the activation of toll-like receptor 8 (TLR8). Motolimod, a selective TLR8 agonist can act in concert with approved immunotherapies to sensitize T cells and augment natural killer (NK) cell function. Despite treatment with chemotherapeutic agents and advance disease, cancer patients remain sensitive to motolimod.