Developing a new drug for Sexually Transmitted Infections Emilie Alirol, PhD Antimicrobial Chemotherapy Conference, 15 January 2019 Royal College of Physicians, London
Content Global burden of Sexually Transmitted Infections GARDP Research & Development strategy for STIs Zoliflodacin project Project timelines and partners
Global burden of STIs 357 million new cases every year Gonorrhea: 78 million cases Chlamydia: 131 million cases Trichomonas: 143 million cases Syphilis: 5.6 million cases STI manifestation and complications Pelvic inflammatory disease (PID); Chronic pelvic pain; Ectopic pregnancy; Spontaneous abortions and Stillbirth; Post-partum infections; Infertility; neonatal conjunctivitis and blindness; increase HIV transmission Infections due to Neisseria gonorrhoeae Leading cause of urethral discharche worldwide Highest prevalence and incidence in Western Pacific, Africa and South East Asia Infections in women mainly asymptomatic Indistiguishable from Chlamydia or Mycoplasma infections Remarkable capacity to acquire resistance; Listed as a priority pathogen in AMR lists by WHO, US, Canada and UK
Spread of gonococcal resistance All antibiotics used since the 30s have elicited resistance Resistance to ESC and azithromycin is on the rise; Multi-drug resistant strains are circulating globally; a few treatment failures linked to these strains have been reported. Neisseria gonorrhoeae is listed in several priority pathogens list (e.g. WHO, US CDC, Canada) Azithromycin Extended Spectrum Cephalosporin (ESC)
GARDP STI Research and Development strategy By 2023 MAIN GOALS Deliver 1 new treatment that: Works against drug-sensitive and drug-resistant forms of the disease Is suitable for integration into STI syndromic management Works in uro-genital and extra-genital infections Accelerate the development of one NCE Investigate combinations of existing AB Explore development of FDCs and co-packaged products Improve treatment guidelines and foster responsible use
TPP short-term IDEAL MINIMUM Indication Uncomplicated gonorrhea Uncomplicated gonorrhea In vitro activity against co-infecting Chlamydia trachomatis Chlamydia trachomatis pathogens Mycoplasma genitalium Patient population Adults and adolescents Adults and adolescents Clinical efficacy (Urogenital) 97% (95% CI, 95-100) 95% (95% CI, 90-100) Clinical efficacy (Extra-genital) Equivalent to current treatment regimens Equivalent to current treatment regimens Mechanism of action Bactericidal Bactericidal Intracellular activity - Activity against resistant strains Activity against ESC and macrolideresistant NG strains Activity against ESC and macrolideresistant NG strains No cross resistance with other Ab Limited cross-resistance with other Ab Safety and tolerability Safe in pregnancy and lactation - No patient monitoring required post treatment Minimal outpatient monitoring required post treatment Contra-indications None Pregnancy and lactation Drug-Drug Interaction profile None Minimal Route of Administration Oral Oral Dosing Schedule Single dose Single dose Treatment duration One day One day Stability Heat stable, 3-year shelf-life in region 4b Heat stable, 2-year shelf-life in controlled room temperature Time to patient availability 5 years 7 years
IDEAL MINIMUM Indication Uncomplicated / complicated gonorrhea Uncomplicated gonorrhea In vitro activity against co-infecting Chlamydia trachomatis Chlamydia trachomatis pathogens Mycoplasma genitalium Patient population Adults, children and adolescents Adults, children and adolescents Clinical efficacy (Urogenital) 97% (95% CI, 95-100) 95% (95% CI, 90-100) Clinical efficacy (Extra-genital) 97% (95% CI, 95-100) 95% (95% CI, 90-100) Mechanism of action Unique mechanism Bactericidal Bactericidal Intracellular activity - Activity against resistant strains Activity against ESC and macrolideresistant NG strains Activity against ESC and macrolideresistant NG strains No cross resistance with other Ab Limited cross-resistance with other Ab Safety and tolerability Safe in pregnancy and lactation - No patient monitoring required post treatment Minimal outpatient monitoring required post treatment Contra-indications None Pregnancy and lactation Drug-Drug Interaction profile None Minimal Route of Administration Oral Fixed Dose Combination Co-packaged loose oral combination Dosing Schedule Single dose Multiple dose Treatment duration Up to 3 days Up to 5 days Stability Heat stable, 3-year shelf-life in region 4b Heat stable, 2-year shelf-life in controlled room temperature Time to patient availability 7 years 10 years
Zoliflodacin (ETX0914) Mechanism of action First-in-class drug (spiropyrimidinetrione) Inhibits DNA biosynthesis by binding to topo II Mode of Action (MoA) differs from other topo II inhibitors Development history Phase I single-ascending dose (Astra Zeneca) Phase I Absorption, Distribution, Metabolism, Excretion (Astra Zeneca) Phase II trial on uncomplicated gonococcal infection (NIAID) Following Proof-of-Concept Entasis developed a new formulation (granules for oral suspension) Relative Bioavailability (rba) trial (NIAID) Food Effect trial (GARDP) Industrial partner Entasis Therapeutics Inc Current development plan Thorough QT (TQT) trial (NIAID) Phase III pivotal trial (GARDP)
Zoliflodacin project vision and objectives Aim: Register, launch and roll out Zoliflodacin in a selected number of high-burden countries Objectives 1) Develop a robust and affordable commercial product 2) Ensure registration by preparing submission-ready clinical and pre-clinical package 3) Support integration in policies and guidelines 4) Develop a stewardship and access strategy Regulatory Pathway Registration Public Health Pathway Integration in EML and WHO guidelines Sustainable access strategy Use in community STIs clinics
Pharmaceutical development plan : objective Pharmaceutical Development Objective Develop and commercialise a robust, stable and affordable product meeting the minimum acceptable requirements of the (quality) target product profile Priority focus areas Cost of goods reduction for commercial drug substance Stability and robustness of current drug product for Phase 3 Evaluation of alternative formulation options Pharmaceutical Development status Pharmaceutical development well advanced; Scale-up of manufacturing scheduled for Q3 2019 Cost-of-Goods reduction program almost completed Manufacturing of clinical supplies for phase 3 on-going
Microbiology Plan Microbiology Plan Objective Develop a product that is effective against recent, geographically diverse clinical isolates, further characterize resistance induction potential and inform selection of combinations and alternative dosing scheme for phase III b / IV trial Priority focus areas Update and expand susceptibility data Confirm activity against Chlamydia and Mycoplasma Evaluate combinations to inform phase 3b-phase 4 trial Microbiology plan status Initial data on combinations and resistance induction; work on set up of Hollow Fiber Model initiated Susceptibility testing of Thai and South African isolates on-going
Clinical Development Plan Clinical Development Plan Objective Develop a product that is safe and effective against uncomplicated, urogenital gonorrhea, explore efficacy against extra-genital infections and other STIs and generate necessary evidence to support integration in guidelines Priority focus areas Generate adequate PK/PD data Phase 3 pivotal trial to support registration Phase 3b-4 to support integration into relevant guidelines Clinical development status Food Effect trial completed; analysis on-going Phase III being planned
Pivotal phase III trial Design: An open-label, randomized, controlled, non-inferiority trial to evaluate the efficacy and safety of a single dose of zoliflodacin compared to a single 500 mg dose of Ceftriaxone + a single 1 g dose of Azithromycin in patients with uncomplicated gonorrhea 5 US sites 3 SA sites 1 EU site 4 Thailand sites
Partners Institution Department of Reproductive Health and Research, World Health Organisation (WHO) Foundation for Innovative Diagnostics (FIND) Entasis Therapeutics National Institute of Allergy and Infectious Diseases (NIAID) University of Birmingham, Alabama US Center for Disease Control (US CDC) Centre for HIV & STIs, National Institute for Communicable Diseases (NICD) Wits RHI, University of Witwatersrand University of KwaZulu Natal (UKZN) South Africa Medical Research Council (SA-MRC) Bureau of AIDS, TB, and STIs, Department of Disease Control, Thai Ministry of Public Health (MoPH) Thailand US CDC Collaboration (TUC) Thai Red Cross AIDS Research Center (TRCARC) University of Mahidol Tropical Medicine Hospital Country USA South Africa Thailand WHO Collaborating Center for STI, Orebro University Hospital University of Florida Sweden Department of Infectious Diseases, Public Health Service Amsterdam The Netherlands
GARDP/DNDi team Stephen Robinson Anthony Simon Jean-Yves Gillon Sophie Delhome Jessica Renaux Erika Correia Annick Janin Yann Ferrisse Seamus O Brien Laura Piddock
Thank you Global Antibiotic R&D Partnership (GARDP) Drugs for Neglected Diseases initiative 15 Chemin Louis-Dunant 1202 Geneva Switzerland gardp.org
Access and Stewardship The use of syndromic management is thought to be a driver of resistance. Over-prescription and easy access through over-the-counter sales lead to high antibiotics use especially in low and middle income countries (LMICs). Antimicrobial resistance strikes harder on the poor Repeated exposure of N. gonorrhoeae and other commensal Neisseria species to antibiotics given to treat gonorrhoea or other infections can select for resistance. The use of two drugs with different modes of action is thought to delay emergence of resistance. This has been successfully applied to treatment of HIV and tuberculosis. Whether this strategy also works in N. gonorrhoeae is not known.
Access and Stewardship What GARDP is doing Develop antibiotics with narrow indications (i.e. uncomplicated gonococcal infection) Investigate resistance emergence when new antibiotics are combined with different possible partner drugs Ensure new antibiotics are registered in LMICs as well as HICs Generate robust evidence to inform international and national guidelines change beyond supporting marketing authorization Conduct necessary pharmaceutical development to decrease the Cost-of-Goods of new antibiotics Work with WHO, FIND and diagnostics developers to define target characteristics of point-ofcare (POC) tests for gonorrhea identification and resistance/susceptibility detection Define the best diagnostic approach to detect emergence of resistance to newly developed antibiotics