What is gepotodacin used for?

Gepotidacin: A Novel Antibiotic for Urinary Tract Infections and Gonorrhea

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic primarily being developed for the treatment of uncomplicated urinary tract infections (UTIs) and urogenital gonorrhea, with promising efficacy against drug-resistant strains. 1

Mechanism of Action

• Gepotidacin works through a unique mechanism of action that inhibits bacterial DNA replication by:
  • Selectively inhibiting bacterial DNA gyrase (GyrA) and topoisomerase IV (ParC) 2
  • Binding to a distinct site on these enzymes, different from other antibiotics 3
  • Providing balanced inhibition of these two type II topoisomerase enzymes 3

This novel mechanism allows gepotidacin to maintain activity against many bacteria that have developed resistance to other antibiotics.

Clinical Applications

Uncomplicated Urinary Tract Infections (UTIs)

Gepotidacin has demonstrated significant efficacy in treating UTIs:

• Recently completed Phase III clinical trials (EAGLE-2 and EAGLE-3) showed:
  • Non-inferiority to nitrofurantoin in both trials
  • Superior efficacy compared to nitrofurantoin in the EAGLE-3 trial 3
  • Therapeutic success rates of 50.6% and 58.5% in the gepotidacin groups compared to 47.0% and 43.6% in the nitrofurantoin groups 3
• Dosage used in Phase III trials: 1500 mg orally twice daily for 5 days 3, 4

Neisseria gonorrhoeae Infections

Gepotidacin shows promise for treating gonorrhea, including drug-resistant strains:

• In Phase II studies for urogenital gonorrhea, gepotidacin successfully treated 66 (96%) of 69 patients with uncomplicated urogenital infections 5
• However, concerns exist regarding:
  • Limited efficacy for pharyngeal gonorrhea (only 1 of 2 patients with pharyngeal infection was cured in early trials) 5
  • Development of resistance during treatment in Phase II trials, with MICs increasing from 1 μg/mL to ≥32 μg/mL between enrollment and test-of-cure in two cases 5
  • To address resistance concerns, Phase III trials for gonorrhea are using a two-dose regimen 5

Acute Bacterial Skin and Skin Structure Infections (ABSSSIs)

• Phase II trials evaluated gepotidacin for Gram-positive ABSSSIs at various dosing regimens:
  • 750 mg q12h and 1,000 mg q8h groups met success criteria
  • 1,000 mg q12h group showed lower efficacy rates 6

Safety Profile

Gepotidacin has demonstrated an acceptable safety profile in clinical trials:

• Most common adverse events in UTI trials:
  • Diarrhea (14-18% of patients)
  • Nausea (less frequent than with nitrofurantoin) 3
• Most adverse events were mild to moderate in severity
• No life-threatening or fatal events were reported in Phase III UTI trials 3
• In ABSSSI trials, the most common adverse events were also nausea (20%) and diarrhea (13%) 6

Clinical Significance

Gepotidacin represents an important advancement in antimicrobial therapy for several reasons:

1. Novel mechanism of action: Provides activity against resistant pathogens where current therapies are failing 1

2. Oral formulation: Offers convenience for outpatient treatment of infections that increasingly face resistance issues 1

3. Activity against resistant strains: Particularly valuable for treating gonorrhea, which has developed resistance to multiple antibiotic classes 7

4. First new oral antibiotic for UTIs in over 20 years: Addresses a significant unmet need in clinical practice 1

Limitations and Concerns

• Resistance development: Emergence of resistance was observed in Phase II gonorrhea trials, requiring modification to a two-dose regimen for Phase III studies 5

• Limited pharyngeal efficacy: Early data suggests potentially lower efficacy for pharyngeal gonorrhea compared to urogenital infections 5

• Need for further pharmacokinetic studies: Additional research is needed to characterize the pharmacokinetics of gepotidacin in the pharynx and other tissues 5

Gepotidacin represents a promising new antibiotic option that could help address the growing challenge of antimicrobial resistance, particularly for UTIs and gonorrhea, though careful monitoring for resistance development will be essential if it receives regulatory approval.