Genital tract infection with Neisseria gonorrhoeae does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. TherapyX, Inc. is advancing GneX12, a novel immune therapeutic that is designed to enhance antibiotic-mediated clearance of persistent Neisseria gonorrhoeae infection and induce long-term protection against subsequent exposure, i.e. a therapeutic vaccine. Specifically, GneX12 is the canonical type 1 cytokine interleukin-12 (IL-12) encapsulated in proprietary biodegradable sustained-release microparticles. Phase I studies in a murine model of gonoccal infection demonstrated that intra-vaginal administration of GneX12 achieved rapid disease clearance and induced the development of long-term protective immunity. Phase II work optimized treatment schedule; demonstrated the critical role of Th1 immunity in disease clearance; revealed that long-term protection was mediated by an anti-gonoccocal humoral response; that the antibodies were cross- protective; and that co-administration with antibiotics did not interfere with the induction of long-term protection. Additional Phase II work established scale-up manufacturing processes and completed a type C meeting with the FDA, garnering agency agreement with our single species primate toxicology plan to support an investigative new drug application (IND).
The aims of the current Phase IIb application are based on agency recommendations communicated during that meeting. Specifically, Aim 1 studies will complete additional toxicology, including reproductive toxicology, assessment in rodents as recommend by FDA.
In Aim 2, a large-batch ?GMP-like? GneX12 drug product is manufactured in compliance with FDA drug substance and drug product release recommendations for use in IND-enabling, non-human primate toxicology studies. A meeting request and package, including final CMC and pre-clinical toxicology questions and finalized clinical protocols, will then be prepared and submitted for a Type B meeting with the FDA (Aim 3). Lastly, based on the FDA guidance obtained in Aim 3, initial tolerability and pK of GneX12 in non-human primates is established and IND readiness is assessed (Aim 4) in preparation for an open IND and first-in-man clinical trials. The long-term goal of this project is to develop a biologic, which when administered in conjunction with antibiotics, will not only enhance disease clearance but will also induce long-term protective immunity. No similar product currently exists.
) Gonorrhea is the second-most-frequent, notifiable infectious disease in the United States; the Centers for Disease Control report >300,000 cases annually, and world-wide incidence is estimated at >100 million new infections per year. No vaccine is available and the emergence of multiple-drug-resistant strains now raises serious and urgent concerns over future treatment options. This proposal seeks to develop a novel strategy of immune intervention against gonorrhea, by redirecting the host?s immune response to generate effective immunity that eliminates an existing infection and protects against re-infection.
| Liu, Yingru; Perez, Julianny; Hammer, Laura A et al. (2018) Intravaginal Administration of Interleukin 12 during Genital Gonococcal Infection in Mice Induces Immunity to Heterologous Strains of Neisseria gonorrhoeae. mSphere 3: |
| Russell, Michael W (2015) Thinking globally, acting locally: harnessing the immune system to deal with recalcitrant pathogens. MBio 6:e00382-15 |
| Liu, Yingru; Egilmez, Nejat K; Russell, Michael W (2013) Enhancement of adaptive immunity to Neisseria gonorrhoeae by local intravaginal administration of microencapsulated interleukin 12. J Infect Dis 208:1821-9 |
