The last new class of antibiotics was discovered in 1984, ending the ‘golden era’ of antibiotics. Quite a few antimicrobial discovery programmes
have been abandoned since the early 1990s. This is largely because a new antibiotic requires decades of research, but will remain effective only for a few years, until the bacterium acquires resistance.
New treatments for bacterial infections caused by multidrug- or extensively drug-resistant Gram-negative pathogens continues to be an area of unmet need.
As of June 2019, approximately 42 new antibiotics with potential to treat serious bacterial infections are in clinical development, according to available data. Of this, the majority of candidates are targeted at Gram-positive bacteria.
Furthermore, a subset of these pathogens has shown increased resistance to carbapenems. Carbapenems are one of the antibiotics of last resort. The WHO has identified a critical need for R&D in carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRAB) and Pseudomonas aeruginosa (CRPA).
Just 18 of the 67 compounds in development have been found likely to have the potential to address at least 1 of these pathogens. Four of these have been discontinued. Of the remaining 14, the majority have potential activity against most CRE with Klebsiella pneumoniae carbapenemase
production, a study reviewing the pipeline found.
A few among them also showed potential to address CRAB and CRPA.
Acinetobacter and Pseudomonas pose major challenges to drug developers due to their particularly complex outer membrane structures, including penetration barriers, and a wide variety of efflux pumps. None of the ten approvals since 2014 are indicated against CRE, CRAB or CRPA on their FDA drug labels.
GARDP and ‘5 BY 25’ goal
To tackle AMR, the Global Antibiotic Research and Development Partnership (GARDP) has developed programmes in antimicrobial memory recovery and evaluation, discovery and exploratory research as well as REVIVE, an online space to educate and connect the antimicrobial R&D community.
Initiated by the WHO and the Drugs for Neglected Disease initiative (DNDi) in May 2016, the aim of the programme is to use innovative approaches to identify and validate a portfolio of antimicrobial candidates for future development as sustainable treatment options.
“No country, company or organization can tackle drug resistance alone. GARDP’s success is dependent on partnerships with governments, the private sector, academia and civil society,” says Dr Manica Balasegaram, Executive Director, GARDP.
Antimicrobial memory recovery and evaluation aims to recover the knowledge, data, and assets of forgotten, or abandoned antibiotics. GARDP works with the experts who investigated the molecules and training and supports a new generation of antibiotic discovery researchers and developers.
GARDP’s ‘5 BY 25’ goal targets the development and delivery of five new and improved treatments to address antibiotic-resistant infections that pose the greatest threat to health and development.
The five new treatments will focus on the priority pathogens identified by WHO.
“GARDP’s approach to prioritizing treatments for our 5 BY 25 goal encompasses pathogens, populations, and specific infections. What this means is we are focused on drug-resistant bacteria on the WHO priority pathogen list, and on diseases and populations disproportionately affected by drug resistance,” says Dr Balasegaram.
GARDP is currently working on treatments for neonatal sepsis, for use with children, for sexually transmitted infections and serious bacterial infections in hospitalized adults.
Zoliflodacin for resistant gonorrhoea
GARDP and Entasis Therapeutics, a clinical-stage biopharmaceutical company, started a global phase 3 pivotal trial of zoliflodacin for uncomplicated gonorrhoea in September.
Zoliflodacin is a novel, first-in-class oral antibiotic.
The trial is expected to enrol approximately 1,000 adults with urogenital gonorrhoea from clinical trial sites in the US, The Netherlands, Thailand and South Africa. Patients included in the trial will be randomized (2:1) to receive either zoliflodacin or a combination of ceftriaxone and azithromycin and will be assessed one week later for the persistence of the infection. Data from the phase 3 clinical trial is anticipated in 2021.
Under the partnership agreement, GARDP is responsible for the phase 3 trial, as well as pharmaceutical development activities for zoliflodacin to support regulatory approval and market access and availability. GARDP has commercial rights to zoliflodacin in up to 168 low- and select middle-income countries, while Entasis retains commercial rights in the rest of the world.
Fosfomycin to treat neonatal sepsis
In July 2018, a global observational study on neonatal sepsis began in Delhi, India. The study will collect clinical information on confirmed sepsis in up to 3,000 new-borns in hospitals and neonatal units in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Vietnam, and Uganda.
GARDP has also developed two target product profiles (TPPs). The first is to re-purpose the existing fosfomycin for use – in a combination regimen – for the treatment of clinically diagnosed neonatal sepsis. A clinical trial to determine the safety and appropriate dosing of fosfomycin is underway in Kenya.
The second TPP is for an antibiotic to treat confirmed or highly suspected neonatal sepsis resulting from multidrug-resistant Gram-negative infections.
Paediatric polymyxin B
GARDP is developing a paediatric investigation plan to facilitate the initial registration of polymyxin B in Europe, particularly in Italy and Greece, followed by other regions with a high burden of drug-resistance, including those in Africa and Asia.
A collaboration with Novartis’ generic division, Sandoz, is also underway to accelerate the development and availability of antibiotic treatments for children in low and middle-income settings.
GARDP is evaluating the late-stage clinical pipeline, as well as old antibiotics, to identify potential treatments. The focus is on clinically evaluating candidates against multidrug-resistant bacteria to support label extension and provide evidence for appropriate use with patients with serious multidrug-resistant infections. It is also working with partners to identify a new treatment for multidrug-resistant infections in hospitalized people.
According to Dr Balasegaram, across high-income countries, up to 10% of all hospital patients will contract some form of infection, a figure that rises for patients admitted to intensive care units. These levels are even higher in low- and middle-income countries, where medical procedures such as surgery, organ transplants, cancer chemotherapy and diabetes management are very high risk with health-care facilities facing significant constraints.
There is no ‘one-size-fits-all’ solution, adds Dr Balasegaram. GARDP’s approach to sustainable access means involvement across several areas, each requiring varying degrees of engagement, which may include advocating, facilitating and directly implementing.