Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (n = 22) were confined to the clinic at baseline, received oral gepotidacin at 1,500 mg twice daily for 5 days (on-therapy period; days 1 to 5), and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits.


Inclusion Criteria
Otherwise healthy participants were eligible to be included in the study only if all of the following criteria applied: Age 1. Participant must have been ≥18 to 65 years of age, inclusive, at the time of signing the informed consent.

Type of Participant and Disease Characteristics
2. The participant had 2 or more of the following clinical signs and symptoms of acute cystitis with onset ≤72 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain.
3. The participant had pyuria (≥10 white blood cells/mm 3 or the presence of leukocyte esterase) and/or nitrite from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
Note: Repeat baseline urine samples were allowed if contamination, defined as ≥10 squamous epithelial cells, was observed under microscopic evaluation.

Sex
4. The participant was female. A female participant was eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: • Not a woman of childbearing potential (WOCBP)

OR
• A WOCBP who agrees to follow the contraceptive guidance from baseline through completion of test-of-cure (TOC).

Informed Consent
5. The participant was capable of giving signed informed consent, which included compliance with the requirements and restrictions listed in the informed consent form and in the protocol.

Exclusion Criteria
Participants were excluded from the study if any of the following criteria apply:

Medical Conditions
1. The participant resided in a nursing home or dependent care-type facility.
2. The participant had a body mass index ≥40.0 kg/m 2 or a body mass index ≥35.0 kg/m 2 with obesity-related health conditions such as high blood pressure or uncontrolled diabetes. • Any surgical or medical condition (active or chronic) that may have interfered with drug absorption, distribution, metabolism, or excretion of the study drug (e.g., ileostomy or malabsorption syndrome). Participants who had a gastric bypass or a cholecystectomy were excluded from the study.

OR
• Hemoglobin value <12 g/dL or a known uncorrected iron deficiency.
7. The participant, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete study follow-up.
8. The participant had a serious underlying disease that could have been imminently life threatening, or the participant was unlikely to survive for the duration of the study period.

9.
The participant had acute cystitis that was known or suspected to be due to fungal, parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas aeruginosa or Enterobacteriaceae (other than Escherichia coli) as the contributing pathogen.
10. The participant had symptoms known or suspected to be caused by another disease process such as asymptomatic bacteriuria or chronic interstitial cystitis.
11. The participant had an anatomical or physiological anomaly that predisposed the participant to urinary tract infections (UTIs) or may have been a source of persistent bacterial colonization, including calculi, obstruction or stricture of the urinary tract, primary renal disease (e.g., polycystic renal disease), or neurogenic bladder, or the participant had a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesico-ureteral reflux, detrusor insufficiency).
12. The participant had an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract.
13. The participant who, in the opinion of the investigator, had an otherwise complicated UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptoms onset ≥96 hours before the screening assessment, or a temperature ≥101°F, flank pain, chills, or any other manifestations suggestive of upper UTI.
14. The participant had anuria, oliguria, or significant impairment of renal function (creatinine clearance <30 ml/min or clinically significant elevated serum creatinine).
15. The participant presented with vaginal discharge at baseline (e.g., suspected sexually transmitted disease). 25. The participant had a current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), including symptomatic viral hepatitis or moderate-to-severe liver insufficiency (Child Pugh class B or C). Note: Participants with asymptomatic viral hepatitis were eligible for study participation.

Prior Antibiotic/Antifungal Use Exclusion
26. The participant received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.

Concomitant Medication Use Exclusion
27. The participant must have agreed not to use the medications or nondrug therapies from baseline through TOC (as described in the protocol).

Prior/Concurrent Clinical Study Experience
28. The participant was previously enrolled in this study or has previously been treated with gepotidacin.
29. The participant participated in a clinical trial and received an investigational product within 30 days or 5 half-lives, whichever is longer.
a Serial blood PK sampling was performed for the first dose of gepotidacin on Day 1 and for the time-matched dose on Day 4. Blood samples were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose. Optional cervical, rectal, and pharyngeal swab PK specimens were collected on Day 4 at predose and 2 hours postdose. b Serial urine PK sampling was performed for the first dose of gepotidacin on Day 1 and for the time-matched dose on Day 4. Urine samples were collected predose and at intervals of 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours postdose. c Predose PK blood samples were collected before each time-matched dose on Days 1 through 5. Predose PK urine samples were collected 0 to 2 hours before each time-matched dose on Days 1 through 5. d Participants checked-out of the clinic after all study procedures were performed, including a predose clean-catch midstream urine sample for Gram stain, quantitative bacteriology culture, and antimicrobial susceptibility testing, predose PK sample collections, and safety assessments. Participants should have remained in the clinic to complete a total of 10 doses. Participants were instructed to return for the TOC (Day 10 to 13) and follow-up (Day 28±3) Visits. BID, twice daily; PK, pharmacokinetic; TOC, test-of-cure; WBC, white blood cells.     Baseline       Summarizing disposition, baseline and demographic characteristics, reduction in susceptibility to gepotidacin, clinical symptom score, outcome and response, and clinical cure micro-ITT Participants in the ITT population, received at least 1 dose of gepotidacin, and had a qualifying baseline uropathogen from a quantitative bacteriological culture of a pretreatment clean-catch midstream urine specimen 8 Summarizing bacteriology results, susceptibility and MIC results, microbiological outcome and response, and PK/PD assessment PKPD Participants in both the PK parameter population and the micro-ITT population 8 None (data were summarized using the micro-ITT population) Abbreviations: BID, twice daily; ITT, Intent-to-Treat; micro, microbiological; PD, pharmacodynamic; PK, pharmacokinetic.