In rare, positive news in the field of antibiotics, Merck recently announced the approval of Zerbaxa to combat two types of pneumonia commonly found in hospitals. The drug – which consists of ‘one-two punch’ of the cephalosporin, ceftolozane, and the β-lactamase inhibitor tazobactamto limit resistance – has garnered weak sales since its initial 2014 approval for complicated intra-abdominal infections and complicated urinary tract infections post Merck’s $9.5bn 2014 acquisition of Cubist Pharma.
Antimicrobial drug discovery was once the backbone of the pharmaceutical industry, but the last two decades has seen a string of divestments and shutdowns, culminating in Novartis’ announcement last year that it would cease its R&D activities in antibiotic exploration, making it the latest in a long list of pharma giants to stop work in this field. Add to this Achaogen’s bankruptcy earlier this year, and the constant threat of antimicrobial resistance (AMR) and it's difficult to see how the antibiotic pipeline will be filled.
This makes Merck’s announcement welcome reading, as the approval connects Zerbaxa with a patient base in need of new treatments. However, while it offers renewed hopes of reasonable investment returns in this therapy area, challenges with antibiotic R&D remain. The pipeline is still reliant on old science, weighted towards molecules that are structurally based on antibiotic classes currently being used in the hospital setting, meaning the threat of resistance will continue to remain a close concern. Add to this the long development and approval process, limited product exclusivity window with which to recoup investment, slow uptake, and the big pharma exodus becomes clear.
To drive volume towards new treatments, new diagnostics are urgently needed to increase accuracy in detecting infection pathogens. Clinical and regulatory pathways are also a major challenge; approval pathways are supposed to readily match appropriate solution to unmet medical need(s), but they are slow and ineffective in dealing with the evolutionary arms-race that is AMR. As such, antibiotics are frequently used off-label for the treatment of hospital-acquired infections as physicians focus on eliminating the infecting pathogen, while regulatory approval is often based on infection site indication. Clinically, it is also difficult to mobilize a clinical study in time to encompass patients in outbreaks of resistant pathogens on a large enough scale to demonstrate superiority over the supposed standard of care. Additionally, patients with serious infections are often acutely ill and that makes consenting for enrollment difficult.
Some practical solutions offer potential. Clinical trial networks with protocols in place could have a major positive impact in identifying and enrolling patients infected with resistant pathogens.
However, effective research into new antibiotics still requires a different funding model. The reservation of new, improved therapies to later lines is certainly a major cause – but confounding this small, limited access to hard-to-treat patients, is the strong downward price pressure given the typical low costs payers are familiar with in this space.
So what is being done to revitalize R&D in AMR? New paradigms are being put forward, with intrepid biotechs leading the charge; microbiome solutions, monoclonal antibodies, bacteriophages and vaccines have all been put forth as commercially viable options to explore. The big change though will be from greater collaboration across global healthcare stakeholders to ensure co-created solutions that drive towards the main unmet treatment needs, e.g. new, efficacious options to treat critical ESKAPE pathogens. It will take regulators, payors, and healthcare systems working with manufacturers to de-risk and incentivize this vital effort – something that may need coordination at the governmental and international level.
Pneumonia in ventilated patients remains a significant clinical challenge and is associated with substantial morbidity and mortality ... The need to cover diverse pathogens including Pseudomonas aeruginosa and certain Enterobacteriaceae adds to the challenge