A Single Dose Therapy to Treat Drug Resistant Gonorrhea

PROJECT SUMMARY / ABSTRACT Gonorrhea is a sexually transmitted infection caused by N. gonorrhoeae. In recent years, the number of people with gonorrhea infections in the US has steadily increased, with more than 700,000 infections reported in 2021. N. gonorrhoeae has proven adept at acquiring resistance to every single antimicrobial therapy used for its treatment in history, starting with the sulfonamides in the 1930s and then penicillin, tetracyclines, fluoroquinolones, oral cephalosporins, and macrolides. In the past decade, there have been reports of strains resistant to the last remaining recommended treatment, ceftriaxone. Thus, we are on the precipice of returning to a pre-antibiotic era of untreatable gonorrhea. Left untreated, gonorrhea infections can cause serious or life- threatening sequelae including infertility and ectopic pregnancy in women, and, if disseminated to the blood, may lead to complicated infections resulting in cardiovascular and neurological problems. Further, vertical transmission to neonates can lead to blindness or life-threatening bloodstream infections if not promptly treated. In this Fast Track SBIR grant, we propose to develop an intramuscular (IM) injection formulation of an innovative antibiotic, AMX-2005, as a first-in-class, single dose therapy for the treatment of drug-resistant gonorrhea. A single dose regimen is currently the preferred therapeutic paradigm to treat gonorrhea by the treating physicians and public health organizations such as the World Health Organization due to concerns surrounding dosing compliance in some patients and the threat this poses to on-therapy resistance emergence and continued spread of infection in the community. We believe that a single dose therapy is most likely achieved with a non-oral antibiotic based on PK-PD considerations. AMX-2005 possesses numerous microbiological attributes that are desirable as an antibiotic for the treatment of drug-resistant gonorrhea such as lack of cross-resistance to other antibiotics (including high-level ceftriaxone- and azithromycin-resistant strains), low potential for resistance development (spontaneous mutation frequencies <5.6x10-10 CFU/mL), and rapid bactericidal activity, including against intracellular N. gonorrhoeae. A single IM injection of a protype formulation of AMX-2005 has demonstrated efficacy in a vaginal model of gonorrhea infection in mice comparable to the current gold standard ceftriaxone. These proof-of-concept data highlight the potential of AMX-2005 to address the urgent threat posed by the possible dissemination of strains resistant to all currently available antibiotics and advocate for rapid development of injectable AMX-2005. In this grant, we plan to optimize/manufacture the IM formulation, perform IND-enabling safety evaluations, and obtain necessary pharmacokinetic data leading to an IND application for IM AMX-2005 to commence the first human clinical trial.