zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva - LARVOL DELTA

Novel drugs approved by the EMA, the FDA and the MHRA in 2025: A year in review. (PubMed, Br J Pharmacol) - "Among the FIC drugs, it is worth mentioning the Nav1.8 channel inhibitor suzetrigine, the first non-opioid approved to palliate acute pain; the first positive allosteric modulator of transient receptor potential melastatin 8 (TRPM8), acoltremon, that increases basal tear production in dry eye disease, a globally common disorder; lerodalcibep, a 'third generation' adnectin inhibitor of the protease Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) to treat elevated LDL-c; and zoliflodacin and gepotidacin, both innovatively targeting bacterial topoisomerases to treat uncomplicated urinary tract infections. These approaches include: the combination of two FIC drugs, the RAF/MEK clamp avutometinib paired with the FAK/Pyk2 inhibitor defactinib, to block more efficiently the RAS-RAF-MEK-ERK/FAK oncogenic pathway in low-grade serous ovarian cancer; fitusiran, the first RNAi therapy for haemophilia, targeting for the first time the production of the natural..."

European regulatory • FDA event • Journal • Review • Bronchiectasis • Dry Eye Disease • Hematological Disorders • Hemophilia • Infectious Disease • Nephrology • Oncology • Ophthalmology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pain • Pulmonary Disease • Rare Diseases • Respiratory Diseases • Solid Tumor • NAV1 • TRPM8

Two new drugs for gonorrhea. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Infectious Disease

Evaluation of Drug-Drug Interaction Potential Between the Oral Antibiotic Zoliflodacin and the CYP3A4 Inhibitor Itraconazole: A Phase 1 Study in Healthy Participants. (PubMed, Clin Transl Sci) - "No clinically significant abnormal laboratory values, vital signs, or electrocardiogram findings were reported. In conclusion, the Cmax of zoliflodacin was essentially unchanged (1.03-fold higher) when co-administered with a strong CYP3A4 inhibitor, while AUC exposures increased by less than 1.5-fold, which, combined with an acceptable safety profile, indicate a low DDI potential between zoliflodacin and CYP3A4 inhibitors."

Journal • P1 data

Bacterial DNA topoisomerase IV and DNA gyrase inhibitors: history of the quinolones, their clinical usage and potential alternatives for the future. (PubMed, J Antimicrob Chemother) - "Fluoroquinolones such as levofloxacin and ciprofloxacin remain important and effective therapeutic options today due to their broad-spectrum antibacterial activity, chemical stability and high bioavailability. The clinical development of new non-quinolone bacterial topoisomerase inhibitors (for example, zoliflodacin, gepotidacin and fobrepodacin) offers a promising solution to these issues and has the potential to play a crucial role in combating the growing problem of antimicrobial resistance. This review article will discuss the evolution of quinolone and fluoroquinolone antibacterial agents as key topoisomerase inhibitors, examine their current clinical applications and challenges to future development, and explore the potential of new topoisomerase inhibitors."

Journal • Review • Infectious Disease

NUZOLVENCE (zoliflodacin). (PubMed, Clin Ther) - No abstract available

Journal

Microbiological analysis and whole-genome sequencing of Neisseria gonorrhoeae from the microbiological failures in the international, zoliflodacin, phase 3, clinical trial for treatment of uncomplicated urogenital gonorrhoea: a retrospective, genomic, observational study. (PubMed, Lancet Microbe) - "In the zoliflodacin phase 3, randomised controlled trial, 23% of the zoliflodacin microbiological failures and the single ceftriaxone and azithromycin microbiological failure had different gonococcal strains at TOC versus baseline, which suggests reinfections and not treatment failures. In addition, 59% of the zoliflodacin microbiological failures, all in anogenital sites, had no obvious microbiological explanation based on the low zoliflodacin MICs, previous pharmacodynamic studies, and no evidence of resistance selection after zoliflodacin therapy. A reinfection as the cause for these microbiological failures could not be excluded. We recommend that WGS is implemented in future randomised controlled trials for gonorrhoea treatment to further evaluate possible microbiological failures, exclude reinfections (to avoid underestimating the cure rates), and characterise antimicrobial resistance determinants."

Journal • Observational data • P3 data • Retrospective data • Infectious Disease

Development of an impedance-based fast antimicrobial susceptibility test for Neisseria gonorrhoeae. (PubMed, J Antimicrob Chemother) - "iFAST® AST results were concordant with the current clinical standards and measured in under 8 h. This method is therefore promising for the development of a rapid and accurate phenotypic N. gonorrhoeae antimicrobial susceptibility test."

Journal • Infectious Disease

In Vitro Activity of Zoliflodacin Against Neisseria gonorrhoeae Isolates from Shanghai, China (2020-2023). (PubMed, Antibiotics (Basel)) - "In vitro susceptibilities to zoliflodacin and six conventional antibiotics (penicillin, tetracycline, ciprofloxacin, azithromycin, ceftriaxone, and spectinomycin) were determined using the agar dilution method. These findings demonstrate that zoliflodacin possesses robust activity against circulating multidrug-resistant N. gonorrhoeae lineages in Shanghai and support its potential clinical use for the treatment of gonorrhea. Continued genomic and phenotypic surveillance is warranted to preserve the long-term efficacy of this novel agent."

Journal • Preclinical • Infectious Disease • MTRR

Enzyme-DNA Interactions Affect the Catalytic Inhibition of Mycobacterial Gyrases by Antibacterial Drugs. (PubMed, ACS Infect Dis) - "Therefore, we examined the effects of moxifloxacin and ciprofloxacin (fluoroquinolones) and zoliflodacin (spiropyrimidinetrione) on the three catalytic activities presumably carried out by gyrase in mycobacteria: decatenation of tangled DNA, negative supercoiling of relaxed DNA, and relaxation of positive supercoils. Rather, results suggest that the potency of gyrase inhibition by interfacial antibacterials is modulated by the topological state of the DNA and its specific interactions with gyrase. Whereas most studies focus on DNA cleavage induced by gyrase-targeted antibacterials, this study provides mechanistic insights into how antibacterials rob replicating cells of essential gyrase functions."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Zoliflodacin inhibits Streptococcus mutans biofilms. (PubMed, Front Cell Infect Microbiol) - "Indifferent effects were found when ZFD was combined with NaF or CHX on S. mutans growth and biofilm formation. In summary, ZFD is a potential antibacterial agent for caries control because of its antibiofilm effects, inconspicuous cytotoxicity, low risk of resistance induction and antibacterial activity against S. mutans."

Journal

Gyrase and Topoisomerase IV as Antibacterial Targets for Gepotidacin and Zoliflodacin: Teaching Old Enzymes New Tricks. (PubMed, Int J Mol Sci) - "The first-in-class agents gepotidacin and zoliflodacin, respectively, were approved for human use in 2025, representing the first new antibacterial classes targeting these enzymes in decades. This commentary examines the mechanisms of action of these agents, contrasts their interactions with gyrase and topoisomerase IV relative to fluoroquinolones, and considers their potential to address resistance while preserving the long-term clinical viability of therapy directed against the bacterial type II topoisomerases."

Journal • Review

Comparing Strategies to Introduce Two New Antibiotics for Gonorrhea: A Modeling Study. (PubMed, Clin Infect Dis) - "In a model of US MSM, the equal allocation strategy for introducing new drugs for gonorrhea matched or outperformed the strategy of sequential introduction in terms of resistance prevalence."

Clinical • Journal • Infectious Disease

Combatting antimicrobial-resistant Neisseria gonorrhoeae: new antibiotics and the pipeline of antigonococcal therapeutics. (PubMed, Curr Opin Infect Dis) - "Recent advances in the development of antibiotics, biologics and small molecules against gonorrhea provide optimism against the stark background of multidrug-resistant gonorrhea. Ongoing surveillance remains critical to evaluate the efficacy of newly introduced treatments."

Journal • Review • Infectious Disease

Zoliflodacin and gepotidacin cross-resistance in Neisseria gonorrhoeae. (PubMed, bioRxiv) - "Here, we show that gyrB D429N confers cross-resistance to gepotidacin in some clinical isolates and that its fitness effect varies with strain back-ground. These findings inform strategies for introducing the new topoisomerase inhibitors into clinical use and for surveillance of resistance."

Journal • Infectious Disease

Zoliflodacin shows benefit as an oral treatment for uncomplicated gonorrhoea. (PubMed, Lancet) - No abstract available

Journal • Infectious Disease

Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial. (PubMed, Lancet) - P3 | "Zoliflodacin was non-inferior to ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhoea and had a similar safety profile. These data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea."

Head-to-Head • Journal • P3 data • Hematological Disorders • Human Immunodeficiency Virus • Infectious Disease • Leukopenia • Neutropenia • Pain

Global genomic and antimicrobial resistance profiling of Neisseria gonorrhoeae: Insights from whole genome sequencing and minimum inhibitory concentration analysis. (PubMed, PLoS Negl Trop Dis) - "Efflux pump systems are key to N. gonorrhoeae resistance and adaptability. Regional MIC variations indicate that local antibiotic use shapes resistance patterns. The high resistance to penicillin and spectinomycin highlights the need for alternative treatments, whereas zoliflodacin and fluoroquinolones remain effective but require monitoring. This study emphasizes global AMR surveillance, novel therapies, and targeted antimicrobial stewardship to address multidrug-resistant infections."

Journal • Infectious Disease

Noncytotoxic polymyxin derivatives enhance antibiotic action against multidrug-resistant Gram-negative bacteria. (PubMed, Antimicrob Agents Chemother) - "Compound 1 extended the activity spectrum of rifampicin, zoliflodacin, and pristinamycin by lowering the minimum inhibitory concentrations of these antibiotics below their interpretative susceptibility breakpoints in MDR Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound 1 exhibited potent bactericidal activity in MDR P. aeruginosa and A. baumannii."

Journal • Infectious Disease • Pneumonia

In Vitro Activity of Zoliflodacin against Neisseria gonorrhoeae Isolates Collected in 2022 from The United States (IDWeek 2025) - No abstract available

Preclinical • Infectious Disease

Subgroup Analyses of Microbiological Cure Rates by Baseline Zoliflodacin MIC and Susceptibility to Ciprofloxacin in Participants from the Global Zoliflodacin Phase 3 Randomized Controlled Trial (IDWeek 2025) - No abstract available

Clinical • P3 data • Infectious Disease

Association of Sex Assigned at Birth and Sexual Orientation with Antimicrobial Susceptibility of Baseline Neisseria gonorrhoeae Isolates from Participants Recruited in the Global Zoliflodacin Phase 3 Randomized Controlled Trial (IDWeek 2025) - No abstract available

Clinical • P3 data • Infectious Disease

Antimicrobial resistance in Neisseria gonorrhoeae in nine sentinel countries within the World Health Organization Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP), 2023: a retrospective observational study. (PubMed, Lancet Reg Health West Pac) - "Minimum inhibitory concentrations (MICs, mg/L) values were determined for ceftriaxone, cefixime, azithromycin, gentamicin, and ciprofloxacin using Etest (bioMérieux). Novel antimicrobials for gonorrhoea treatment are critical; zoliflodacin and gepotidacin are promising. WHO, Global Fund."

Journal • Observational data • Retrospective data • Infectious Disease

Susceptibility of Neisseria gonorrhoeae to Zoliflodacin and Quinolones in Hyogo Prefecture, Japan. (PubMed, Pathogens) - "In addition to ZFD, we investigated the susceptibility of N. gonorrhoeae strains to ceftriaxone (CTRX), ciprofloxacin (CPFX), garenoxacin (GRNX), and sitafloxacin (STFX). ZFD showed potent antimicrobial activity against N. gonorrhoeae strains that are highly resistant to quinolones. It may become a new option in the treatment of gonococcal infections."

Journal • Infectious Disease

TXA15054 - A Novel Narrow Spectrum Oral Antibiotic Against Neisseria Gonorrhoeae (ASM Microbe 2025) - "In this context, TAXIS Pharmaceuticals has successfully developed novel narrow spectrum inhibitors that specifically target bacterial dihydrofolate reductase (DHFR) while avoiding any significant engagement with human-DHFR (3).While inactive against other Gram-positive and Gram-negative pathogens, TXA15054 is potent against multiple Neisseria gonorrhoeae (Ng) strains, including ceftriaxone-resistant strains (WHO-X, WHO-Y, WHO-Z), azithromycin-, ciprofloxacin-, and tetracycline-resistant CDC isolates, with impressive low MIC values ranging from 0.031 to 0.004 μg/mL...TXA15054 showed minimal impact against Lactobacillus species in the urogenital tract unlike ceftriaxone, azithromycin and clinical trial candidates, zoliflodacin and gepotidacin...Cell. 2020 Jun 25; 181(7):1518-1532."

Infectious Disease • Vaginitis • DHFR

Potential of Established and Novel Antibacterials Against Acinetobacter baumannii Gyrase and Topoisomerase IV (ASM Microbe 2025) - "Thus, we assessed the effects of two novel antibacterials, gepotidacin (a triazaacenaphthelene, TAA) and zoliflodacin (a spiropyrimidinetrione, SPT), on the activities of the A. baumannii type II topoisomerases. Finally, gepotidacin displayed potent inhibition of the catalytic activity of both WT and mutant gyrase/topoisomerase IV (IC50: WT gyrase ≈ 0.9 µM, GyrAS80L ≈ 0.3 µM, WT topo IV ≈ 0.4 µM; ParCS84L ≈ 0.06 µM). Results suggest that these new classes of antibacterials maybe useful for treating FQ-resistant A. baumannii infections."

Infectious Disease