In the past 25 years, a steady increase in bacteria immune to antibiotics has become a serious threat to global public health.
With the rise of resistance to the most widely used treatments and few new antibiotics in development, experts have warned of a return to a pre-antibiotic era, where medical procedures will no longer be able to take place, and patients may routinely die from seemingly minor infections.
The antibiotics challenge
With rapid progress made over the past hundred years in our understanding of human disease, it might seem hard to believe that finding new antibiotics is proving so difficult. But this class of medicines brings with it such a complex set of challenges that only a handful of companies remain active in this area.
At GSK we have a long heritage and expertise in antibiotics going back 40 years, and we’re committed to continuing our research in this area. There are three main barriers we need to overcome in order to succeed at this:
The complexity of the science and clinical trials process
The complex structure of many bacteria means that developing new medicines capable of penetrating and killing them is proving exceptionally difficult.
Bacteria have highly effective defence mechanisms, giving them the ability to mutate over time and become resistant to many of the medicines available to treat them. Resistance has been fuelled by the widespread misuse of antibiotics – such as using them to treat viral infections like coughs and colds – which they are not able to cure.
Another significant obstacle to developing new antibiotics lies in the clinical trials process that is used to test new medicines. To prove the value of new antibiotics a we need to test them against bacterial infections that are resistant to the medicines that are typically prescribed. Finding patients with these specialized infections can be very challenging and current diagnostics can’t identify them quickly.
As a result, there are times when large number of patients need to be enrolled in a clinical trial to ensure the patients with resistant infections are captured. There are also situations where regulators require that testing run for extended periods of time, which delays getting new medicines to those who need them. Regulators are taking another look at the clinical trials process and have started to develop more streamlined approaches.
The need for transformational diagnostics
Because many bacterial infections are easily confused with other types of illness, identifying the right patients for a clinical trial for a new antibiotic can be particularly tricky. Also, as most infections are not long-term illnesses, patients have often either recovered or died from their illness by the time a reliable diagnosis has been reached. This means there is an urgent need for better diagnostics.
Developing new, quicker tests to diagnose bacterial infections will not only help make clinical trials more efficient. Fast diagnostics will also be a critical tool in the “real-world” setting, removing the need for doctors to make diagnoses based on patients’ symptoms alone. This will ensure that antibiotics are only prescribed to people with bacterial infections, and will help drive down antibiotic misuse. This is key to curbing the spread of resistance.
The challenging commercial environment
Because the science is so complex and the development process so lengthy, antibiotics cost a huge amount to research, and bringing them to market requires significant investment. According to the Association of the British Pharmaceutical Industry (ABPI), it can take over 12 years to discover and develop a new medicine and typically costs more than $1.5 billion to do all of the research necessary for a medicine to be licensed for use.
Yet despite this, these medicines don’t – and shouldn’t – get used very often. To help stave off resistance, new antibiotics created today will be used as little as possible. And when they are used, patients generally only need a short course of treatment for bacterial infections. This lies in stark contrast to the treatment of many chronic illnesses, for which patients often need to take medication for life.
This means that pharmaceutical companies don’t tend to recover their costs in researching and developing these medicines, which has led many companies to stop research in this area altogether. A new commercial model for antibiotics is therefore urgently needed, which “de-links” sales and returns on investment.
Our efforts to find new antibiotics
Tackling antibiotic resistance is a challenge we want to be part of solving, but one company cannot do it alone. Due to the various complexities of researching new antibiotics, we believe taking a more open-minded approach to sharing information is key.
One of the ways we are doing this is by engaging in public partnerships, enabling us to work with governments, scientific institutions and other companies, sharing our knowledge and expertise. In recent years, we have committed to two partnerships specifically aimed at accelerating the search for new antibiotics.
The Innovative Medicines Initiative (IMI) – New Drugs for Bad Bugs
IMI is Europe’s largest public-private partnership aiming to improve the drug development process. Acting as a neutral third party, the IMI has created a collaborative environment between pharmaceutical and biotech companies, universities and other scientific institutions, to facilitate more innovative drug discovery.
The research program New Drugs for Bad Bugs (ND4BB), which was launched in May in 2012, is a key part of the IMI and the European Commission’s “action plan against the rising threats from antimicrobial resistance.” It aims to address all of the key issues associated with the development of new antibiotics, with projects focusing on:
- improving the underlying scientific understanding of antibiotic resistance
- designing and implementing efficient clinical trials
- taking novel drug candidates through clinical development
The first projects in this programme have been funded jointly by the IMI and five pharmaceutical and biotechnology companies, including GSK. At present, the following three projects are underway:
COMBACTE (Combatting Bacterial Resistance in Europe)
Clinical trials for antibiotics can be more difficult to conduct than those for other medicines because the illnesses they are designed to treat are generally short-lived, making it difficult to find appropriate patients for enrollment. Drawing conclusive results for regulatory approval can therefore be a challenge, which can slow the progress of new medicines being made available to patients.
The work of COMBACTE focuses on the design and implementation of more efficient clinical trials through the development of a clinical trial network (COMBACTE CLIN-Net), a European laboratory surveillance network (COMBACTE LAB-Net), pioneering statistical methods and innovative clinical trial designs (COMBACTE STAT-NET).
TRANSLOCATION (Molecular basis of the bacterial cell wall permeability)
The TRANSLOCATION project has two significant goals. First, it aims to increase our overall understanding of the complex science behind bacterial systems, including how to get antibiotics into bacteria and how to stop multi-resistant bacteria from ejecting the drug.
By combining expertise from a range of fields and in sharing the knowledge and data discovered, TRANSLOCATION will strive to develop useful guidelines for the discovery of new drugs for AMR bacteria. Secondly, TRANSLOCATION will create a data-sharing tool, the ND4BB Information Centre, which will be a repository of legacy and ongoing antibacterial data. This tool will be used across the ND4BB programme to address key questions and to establish best practice in AMR drug discovery and development.
ENABLE (European Gram-negative Antibacterial Engine)
A particular challenge in antibiotics development is a class of bacteria known as gram-negative. These bacteria, which are responsible for many hospital-acquired infections, have an additional protective layer that interferes with the penetration of a medicine into the cell. This makes it it especially difficult to find new treatments for these types of infection, and the development process can take years longer than for many other types of medicine.
Launched by the IMI in February 2014, the European Gram-negative Antibacterial Engine (ENABLE) is a six-year project aiming to accelerate progress in the development of anti-bacterials for gram-negative infections. Bringing together scientists from 13 countries and 32 partners from academia, small-medium enterprises (SMEs) and pharmaceutical companies, this project aims to create a drug discovery engine through which partners can combine their knowledge, expertise and data to fast-track the development of agents that show potential in fighting these infections.
This project is currently evaluating a series of proposals in order to ensure that a robust pipeline of new compounds will be taken forward. New partners are invited to join throughout its course and this will in turn encourage more scientists to take part in the combat against antibiotic resistant bugs, pooling further expertise and knowledge to create even more innovative solutions.
Biomedical Advanced Research and Development Authority (BARDA)
In May 2013, we entered a partnership with the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS), to support the development of new antibiotics.
This partnership is unique, as it provides us with the flexibility to work both on studies that were already underway within GSK and on new research across multiple assets in our portfolio, rather than on the development of one specific medicine. This means that if a molecule fails – as often happens in drug development – we can switch our focus to a different asset without having to establish a new contract – an approach that we hope will accelerate the overall development process.
We are already seeing evidence that this collaborative approach is working. One of the investigational antibiotics we are developing as part of this partnership is due to enter the final stage of clinical trials (phase III) in 2014/2015.
Incentivizing antibiotic research
We believe that if we’re to succeed in tackling the problem of antibiotic resistance, we need to encourage more investment in this area of research. Here, our President of Pharmaceuticals R&D, Patrick Vallance, discusses how this could be achieved.
We should all be encouraged by the emerging global response to antibiotic resistance. This issue has, quite rightly, climbed the political agenda and recognition has increased across the globe of the potential debilitating consequences if we don’t act now. The notion of reverting to a pre-antibiotic era is truly alarming.
There is already a significant focus on encouraging responsible prescribing of antibiotics. This is key. Along with this, generous levels of public funding – from the EU’s Innovative Medicines Initiative, the US Biomedical Advanced Research Development Authority (BARDA) and others – have created research partnerships that are enhancing understanding of bacteria and antibiotics and supporting the development of new tools to tackle resistance.
These efforts have also created a momentum that’s inspiring other novel ways of fostering innovation and incentivizing the scientific community. But despite all this, we need to do more to ensure a long term and sustainable supply of new medicines to fight bacterial infections.
First, we need to encourage more investment in research directed towards therapeutics. GSK continues to be active in this field: in the past decade we’ve spent around $1bn on research to discover new antibiotics, and we’ve worked alongside other research bodies in the key research partnerships mentioned above. But overall, the number of large pharmaceutical companies doing antibiotics R&D has dwindled.
Why is this? Simply put, it’s because developing new antibiotics is very challenging, both scientifically and financially. Bacteria have evolved over millions of years to avoid attacks by chemicals. They live in hostile environments and have mastered the art of evasion and resistance. It’s little surprise, then, that failure rates are higher in antibiotics R&D than in most other areas. Often very large doses of antibiotics are required and that in turn brings problems for the host being treated (us!). Discovering and developing any medicine or vaccine is tough, but antibiotics is a phenomenally difficult area to be involved in.
Even when a company succeeds in bringing a new antibiotic to patients, a thorny question remains. How will that company be rewarded for its innovation and recoup the hundreds of millions of pounds it invested? Antibiotics present an unusual commercial conundrum.
New antibiotics shouldn’t be used widely; they should be used sparingly to avoid resistance. So sometimes the new antibiotic might sit on the shelf, only to be used as a last resort. But how can companies be encouraged to invest if the ideal scenario is that these medicines should be very inexpensive and not used much? This is an economic model that needs a rethink.
We need to create a model that encourages investment in research while discouraging unnecessary use of new antibiotics. It makes no sense for anybody to have incentives to use more of an antibiotic when, to protect future health, we should be trying to use less.
But what should a new economic model look like? There are various different ways that antibiotic R&D could be incentivized, the most obvious being simply pushing up the price of these medicines, to compensate for low volumes of sales, and to encourage sensible prescribing. This seems unlikely to work globally.
I favour a different approach. What if governments committed to a series of guaranteed payments to the company developing the medicine over a period of years once the medicine was made? These purchase agreements wouldn’t be linked to the volume of antibiotic sold, they would be paid to recognise the companies’ innovation and investment in the area of antibiotic development.
This would be like an insurance system where new, effective antibiotics would be available for patients if needed, but wouldn’t necessarily be used. And it would stop any commercial incentive to promote the use of large quantities of antibiotics.
There is a clear need for high-level discussion, on a global scale, to flesh out how such a scheme – or other similar proposals – would work in practice. But promising progress has recently been made towards this. With the establishment of expert groups in both the UK and US tasked with addressing the economics of antibiotics, and the development of a World Health Organization global action plan currently underway, the problem of antibiotic resistance has been elevated to the global political stage. I hope that here, it will continue to receive the focus it deserves.
At GSK we’ve a long heritage in anti-infectives and it’s an area where I want us to remain. We first began our research over 40 years ago and I’m proud that today we still have a dedicated R&D unit working to discover the next generation of medicines to treat bacterial infections. This isn’t just about developing conventional antibiotics – we also need to explore new ways of killing bugs, including boosting the body’s own defence mechanisms.
The world now has an opportunity to redesign the economics of antibiotics – a crucial step in ensuring the continued development of these important medicines. This is a tough challenge but it’s one that industry must become actively involved in.
This piece first appeared on the Longitude Prize blog site in December 2014