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Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: a Phase 2, Randomized, Dose- XX Ranging, Single-Oral Dose Evaluation Stephanie N

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Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: a Phase 2, Randomized, Dose- XX Ranging, Single-Oral Dose Evaluation Stephanie N View metadata, citation and similar papers at core.ac.uk brought to you by CORE Clinical Infectious Diseases provided by IUPUIScholarWorks MAJOR ARTICLE Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose- XX Ranging, Single-Oral Dose Evaluation Stephanie N. Taylor,1 David H. Morris,2 Ann K. Avery,3 Kimberly A. Workowski,4 Byron E. Batteiger,5 Courtney A. Tiffany,6 XXXX Caroline R. Perry,6 Aparna Raychaudhuri,6 Nicole E. Scangarella-Oman,6 Mohammad Hossain,6 and Etienne F. Dumont6 1Section of Infectious Disease, Louisiana State University Health Sciences Center, New Orleans; 2Desert AIDS Project, Palm Springs, California; 3Department of Medicine, Division of Infectious Diseases, MetroHealth Medical Center, Cleveland, Ohio; 4Department of Medicine, Division of Infectious Diseases, Emory University Department of Medicine, Atlanta, Georgia; 5Department of Medicine, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis; and 6Research & Development, GlaxoSmithKline, Collegeville, Pennsylvania Background. In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacter- ial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea. Methods. Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4–8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and sus- ceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin. Results. The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of partic- ipants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose. Conclusions. This study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea. Clinical Trials Registration. NCT02294682. Keywords. gepotidacin; urogenital; gonorrhea; Neisseria gonorrhoeae. Gonorrhea is a sexually transmitted infection caused by Neisseria gonorrhea in the future [8–10]. The Centers for Disease Control OA-CC-BY gonorrhoeae (NG), with 78 million infections reported globally in and Prevention and the World Health Organization have labe- 2012 [1]. In the United States, approximately 468 500 gonococcal led drug-resistant NG with threat levels of urgent and high, infections were reported in 2016, an 18.5% increase from 2015 [2], respectively, and identified a critical need for new antibiotic while in Europe, approximately 66 000 gonococcal infections were treatments [11–14]. Current guidelines recommend first-line reported in 2014, a 25% increase from 2013 [3]. Consequences of dual antibiotic therapy that consists of intramuscular ceftriax- untreated gonococcal infections include pelvic inflammatory dis- one combined with oral azithromycin [1, 15, 16]. Although this ease, infertility in women and men, ectopic pregnancy, tubo-ovarian approach may delay the emergence of cephalosporin-resistant abscess, neonatal conjunctivitis, and disseminated gonorrhea [4]. NG, the impending threat remains. Surveillance data demon- Over the past few decades, NG has demonstrated the ability strate increasing minimum inhibitory concentrations (MICs) to develop resistance to most antibiotics recommended or used for NG to third-generation extended-spectrum cephalosporins for treatment [5–7], suggesting the possibility of untreatable and azithromycin in the United States, Canada, and Europe [13, 17–20]. Several therapeutic options are being evaluated for the treatment of gonorrhea, including dual combinations of estab- Received 12 December 2017; editorial decision 4 February 2018; accepted 23 March 2018; published online April 2, 2018. lished and novel antibiotics [5, 14, 21–23]. Correspondence: S. N. Taylor, LSU Health Sciences Center, Section of Infectious Diseases, Gepotidacin (GSK2140944) is a novel triazaacenaphthylene 3308 Tulane Ave., 5th Floor, New Orleans, Louisiana 70119 ([email protected]). bacterial type II topoisomerase inhibitor that is currently in Clinical Infectious Diseases® 2018;67(4):504–12 © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society development [24–29]. Gepotidacin selectively inhibits bacterial of America. This is an Open Access article distributed under the terms of the Creative Commons DNA replication by interacting in a unique way on the GyrA Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. subunit of bacterial DNA gyrase and the ParC subunit of bac- DOI: 10.1093/cid/ciy145 terial topoisomerase IV. Gepotidacin has in vitro activity against 504 • CID 2018:67 (15 August) • Taylor et al pathogens resistant to established antibacterials, including cip- Exclusion criteria included a body mass index ≥40.0 kg/m2; rofloxacin-resistant and -susceptible strains of NG [30, 31]. In hysterectomized women without a cervix; men diagnosed with this study, we evaluated the efficacy of single, oral doses of gepo- epididymitis or orchitis; a medical condition or required medica- tidacin for treatment of uncomplicated urogenital gonorrhea. tion that may have been aggravated by acetylcholinesterase inhibi- tion; diagnosis of Clostridium difficile (CD) infection; liver disease; METHODS prespecified baseline electrocardiogram (ECG) abnormalities and Study Design cardiovascular conditions; disseminated gonococcal infections; This phase 2, randomized, multicenter, open-label, dose-rang- antibiotic treatment within 14 days; or taking medications with a ing study was conducted at 12 sites (11 US sites and 1 UK site) known risk of torsades de pointes. Participants agreed to abstain from April 2015 to August 2016 to evaluate the efficacy, safety, from or to use a male condom for any sexual activity from baseline tolerability, and plasma exposures of 2 single oral doses of gepo- through test-of-cure (TOC) to prevent reinfection. tidacin in uncomplicated urogenital gonorrhea. Throughout the study, real-time sponsor-blinded reviews of safety data and NG Participant Evaluation and Therapy isolate identification and susceptibilities by GlaxoSmithKline The total study duration was approximately 1 week with 2 study review teams were conducted. Additionally, an independent visits: baseline (day 1) and TOC (days 4–8). At baseline, a physi- review team had the authority to recommend discontinuation cal examination, assessment of vital signs, clinical laboratory tests, of a dose, continue randomization as planned, or end the trial and ECGs were performed. Baseline microbiology procedures due to success or futility (Figure 1). The study was conducted in included collection of pretreatment urogenital swab specimens for accordance with the International Council for Harmonisation NG culture from all participants; a Gram stain was performed on of Technical Requirements for Pharmaceuticals for Human Use, male urogenital specimens. From areas of known exposure, pre- Good Clinical Practice, and applicable country-specific require- treatment pharyngeal and rectal swab specimens for NG culture ments, including institutional review board and ethics commit- were collected. Pretreatment urogenital swab or urine specimens tee approvals. Participants provided written, informed consent for detection of NG and Chlamydia trachomatis (CT) by NAAT before any study procedures were performed. assay were obtained at baseline only. Eligible participants were stratified by gender and randomized 1:1 to receive a 1500-mg Participants (3 × 500-mg capsules) or 3000-mg (6 × 500-mg capsules) single Men and nonpregnant, nonlactating women aged ≥18 years who oral dose of gepotidacin administered open label with food at the had suspected uncomplicated urogenital gonorrhea, defined clinic (Figure 1). Dose selection was based on in vitro and in vivo as the presence of purulent urethral or cervical discharge upon data and pharmacokinetic modeling, which indicated the low and physical examination and a prior culture or nucleic acid amp- high doses would provide systemic exposures to cover urogenital lification test (NAAT) positive for NG, a Gram stain positive NG isolates with gepotidacin MICs of 0.5 µg/mL and 1 µg/mL, for gram-negative diplococci from male urethral specimens, or respectively. At 2 hours postdose, ECG and blood pharmacokinetic reported sexual contact with a partner diagnosed with gonorrhea sample collection were performed. Based on blinded, real-time within the past 14 days were enrolled. assessment of systemic
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