VNRX-7145 / VenatoRx - LARVOL DELTA

Safety and pharmacokinetics of single and multiple doses of ledaborbactam etzadroxil with or without ceftibuten in healthy volunteers. (PubMed, Antimicrob Agents Chemother) - P1 | "No clinically relevant CTB and LED PK interactions occurred with the CTB + LED-E combination. These results support further development of the CTB + LED-E combination for the treatment of complicated urinary tract infections caused by drug-resistant Enterobacterales.CLINICAL TRIALSThese studies are registered with ClinicalTrials.gov as NCT04243863 and NCT04877379."

Journal • PK/PD data • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Nephrology

ARGONAUT-IV: susceptibility of carbapenemase-producing Klebsiella pneumoniae to the oral bicyclic boronate β-lactamase inhibitor ledaborbactam combined with ceftibuten. (PubMed, Antimicrob Agents Chemother) - "Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone."

Journal • Infectious Disease • Nephrology • Pneumonia

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection. (PubMed, Antimicrob Agents Chemother) - "In vivo, ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236)...At ≤1 μg/mL, ceftibuten-ledaborbactam (MIC, 0.25 μg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 μg/mL), and 54.1% of carbapenem-nonsusceptible isolates...Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC, 2 μg/mL) and 82.9% of OXA-48-group-positive (MIC, 2 μg/mL) isolates at ≤1 μg/mL. Continued development of ceftibuten-ledaborbactam appears warranted."

Journal • Infectious Disease • Nephrology

Innovative β-lactam/β-lactamase inhibitor combinations for carbapenem-resistant Gram-negative bacteria. (PubMed, Future Microbiol) - No abstract available

Journal • Infectious Disease

VNRX-7145-102: VNRX-7145 Drug-Drug Interaction in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=53; Completed; Sponsor: Venatorx Pharmaceuticals, Inc.; Recruiting ➔ Completed

Clinical • Trial completion

In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes. (PubMed, J Antimicrob Chemother) - "VNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common serine β-lactamases, including ESBL, AmpC and the KPC and OXA-48-like carbapenemases. Ceftibuten/VNRX-5236 may have potential as an oral treatment for infections caused by resistant Enterobacterales, while sparing carbapenems."

Journal • Preclinical • Infectious Disease

[VIRTUAL] ARGONAUT-IV: Susceptibility of Carbapenem-resistant Klebsiellae to Ceftibuten/VNRX-5236 (IDWeek 2021) - "AMK, amikacin; CST, colistin; CAZ, ceftazidime; CZA, ceftazidime-avibactam; FEP, cefepime; MEM, meropenem; MVB, meropenem-vaborbactam; CTB, ceftibuten; TGC, tigecycline. The addition of VNRX-5236 enhanced the activity of CTB against the 200 Klebsiella isolates tested, reaching a total of 92.5% susceptibility. The prodrug (VNRX-7145) allows for oral administration, making it a potential option for step-down therapy. Importantly, VNRX-5236 has a broader spectrum of activity than existing oral BLIs, opening new treatment options for resistant infections as a key addition to the existing antibiotic arsenal."

Infectious Disease

[VIRTUAL] In vitro Activity of Ceftibuten in Combination with VNRX-5236 against Clinical Isolates of Enterobacterales from Urinary Tract Infections Collected in 2018-2020 (IDWeek 2021) - "Ceftibuten in combination with VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases... A substantial percentage of isolates were non-susceptible to extended-spectrum β-lactams, levofloxacin (LVX), trimethoprim-sulfamethoxazole (SXT), and amoxicillin-clavulanate (AMC) (Table)... Ceftibuten/VNRX-5236 exhibited promising in vitro activity against recent Enterobacterales from UTIs, and may have potential as an oral treatment option for complicated urinary tract infections, including those caused by serine β-lactamase-expressing Enterobacterales (ESBL, KPC, OXA-48/OXA-48-like) for which there are currently few oral treatment options available."

Combination therapy • Preclinical • Infectious Disease

VNRX-7145-102: VNRX-7145 Drug-Drug Interaction in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=54; Recruiting; Sponsor: Venatorx Pharmaceuticals, Inc.; Trial completion date: Aug 2021 ➔ Nov 2021; Trial primary completion date: Aug 2021 ➔ Nov 2021

Clinical • Trial completion date • Trial primary completion date

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections. (PubMed, Infect Dis Ther) - "Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/β-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI...The β-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins...Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/ARX1796, have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy."

Clinical • Journal • Infectious Disease • Nephrology • Pneumonia

Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes. (PubMed, J Med Chem) - "Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases."

Journal • Complement-mediated Rare Disorders • Infectious Disease

VNRX-7145 SAD/MAD Safety and PK in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=83; Completed; Sponsor: Venatorx Pharmaceuticals, Inc.; Recruiting ➔ Completed

Clinical • Trial completion

VNRX-7145 Drug-Drug Interaction in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Venatorx Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open

VNRX-7145 Drug-Drug Interaction in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=42; Not yet recruiting; Sponsor: Venatorx Pharmaceuticals, Inc.

Clinical • New P1 trial

VNRX-7145 SAD/MAD Safety and PK in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=96; Recruiting; Sponsor: VenatoRx Pharmaceuticals, Inc.; Trial completion date: Jun 2020 ➔ Feb 2021; Trial primary completion date: Jun 2020 ➔ Feb 2021

Clinical • Trial completion date • Trial primary completion date

VNRX-7145 SAD/MAD Safety and PK in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=96; Recruiting; Sponsor: VenatoRx Pharmaceuticals, Inc.; Suspended ➔ Recruiting

Clinical • Enrollment open

VNRX-7145 SAD/MAD Safety and PK in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=96; Suspended; Sponsor: VenatoRx Pharmaceuticals, Inc.; Recruiting ➔ Suspended

Clinical • Trial suspension

VNRX-7145 SAD/MAD Safety and PK in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=96; Recruiting; Sponsor: VenatoRx Pharmaceuticals, Inc.

New P1 trial

In Vivo Pharmacodynamics of VNRX-7145 in the Neutropenic Murine Thigh Infection Model when Administered in Combination with Humanized Exposures of Twice Daily Ceftibuten (CTB) against Serine β-Lactamase-Producing Enterobacteriaceae (SBL-EB) (IDWeek 2019) - "A composite assessment of exposure-responses indicated a fAUC0-24/MIC of 9.0 (R2 0.70) was associated with stasis.Conclusion : Against CTB-resistant SBL-EB, inclusive of OXA-48- and KPC-producing strains, VNRX-5236 potentiated the in vivo activity of the CTB human-simulated exposure. The identified fAUC0-24/MIC target associated with bacterial stasis should be considered when selecting VNRX-7145 doses for clinical studies."

Combination therapy • PK/PD data • Preclinical