Peter Jackson, Executive Director, the AMR Centre
Public health leaders have long warned that the advances of modern medicine will soon be reversed by the world’s dwindling supply of effective antibiotics.
As we approach a new decade, it’s fallen to Dr Robert Redfield, Director to the Centers for Disease Control in the United States, to say that we have already crossed the line.
In the forward of the 2019 CDC report on the threat posed by antimicrobial resistance he said simply: ‘We need stop referring to a coming post-antibiotic era – it’s already here. You and I are living in a time when some miracle drugs no longer perform miracles and families are being ripped apart by a microscopic enemy.’
The dwindling number of research scientists around the world actually focused on developing new antibiotics are acutely aware of the gravity of the situation – and frustrated by the slow progress of market reform to address the payment problem at the heart of the AMR sector.
Existing reimbursement mechanisms and valuation metrics fail to address the fundamental challenge: balancing the need to reward innovators for their much-needed endeavours yet at the same time only using life-saving AMR drugs sparingly to avoid widespread emergence of new drug-resistant infections.
In other words, we need to ‘de-link’ the reward for innovation from the commercial pressure to prescribe more drugs. New antibiotics should be seen as a necessary last resort in hospitals in case of serious infections that can’t be treated in any other way.
One of the best analogies here comes from Kevin Outterson, the director of CARB-X, a global non-profit partnership dedicated to accelerating AMR research. He used the example of fire safety equipment.
“The optimal number of fires in this room is zero but there is fancy equipment in the ceiling to prevent fires – and you wouldn’t make the people who install that wait until there is a fire before they get a pay cheque.”
The World Economic Forum (WEF) recently joined the chorus of industry voices calling for the creation of new ‘pull’ incentives such as market entry rewards. To date, we have mostly seen ‘push’ incentives such as research grants – directed mainly towards small and medium-sized biotech companies.
These grants are not enough in themselves to tackle the core problem of major pharmaceutical companies withdrawing from R&D in this area. Big pharma needs to be an essential part of the AMR ecosystem, with its commercial, regulatory, supply-chain and stewardship expertise combined with global reach.
That is not the case currently. Most have abandoned the infectious disease sector because of market failure, the inability to achieve a return on the required R&D investment, compared with other therapeutic areas such as cancer, diabetes and cardiovascular disease.
The WEF says it’s time for governments and pharmaceutical companies to collaborate to make “tangible, incremental progress” on designing and implementing pull incentives to demonstrate the viability of the approach.
Its report, published in June 2019 in collaboration with the Wellcome Trust, also noted that only 16 new drug candidates targeting high- priority pathogens are now in development, and almost all are modifications of existing drugs.
Resistant bacteria are already causing more than 700,000 deaths globally every year. According to the 2019 CDC report, over 2.8 million US patients contracted a drug-resistant infection in 2017, and over 35,000 died as a result. At the same time, bacterial strains resistant to older drugs are growing more prevalent.
According to estimates by the UK government’s AMR Review, conducted by economist Lord O’Neill, AMR could kill 10 million people every year by 2050 unless urgent action is taken.
Given this very serious prognosis, there is a critical need for innovation in drug technology, clinical trial design and valuation of new treatments that take us towards a new marketplace for AMR drugs. Thankfully, there are some positive developments which need to be acknowledged.
In the UK, NHS England is collaborating with the National Institute for Health and Care Excellence (NICE) on a pilot project under which NHS England will evaluate and procure two AMR drugs on a trial basis – de-linking the valuation and reward payments from the medicines’ usage.
It will test a ‘subscription’ style model that pays pharmaceutical companies upfront for access to drugs based on their usefulness and value to the NHS and wider society.
The project is part of the UK government’s five-year, multi-agency action plan that includes improved stewardship to minimise the chances of resistant strains emerging. The plan is the latest step towards the government’s broader 20-year vision, and includes the targets to halve health associated gram-negative bloodstream infections and further reduce antimicrobial use by 15%
by 2024.
The plan also supports increased use of a ‘precision medicines’ approach increasing the percentage of prescriptions informed by diagnostics and decision support tools.
This welcome move by the UK will make it more attractive for companies to invest in AMR R&D, and their shareholders to support them, sending a strong signal that the UK Government is serious about fixing the broken market for the long term.
The NICE project is an important initiative but, needless to say, the global market failure will only be addressed if other countries act on market reforms.
The WEF says that to create and implement effective ‘pull’ mechanisms, we need international commitment to cross-departmental action, including health and finance functions of governments worldwide.
We also need to share best practice between governments as new valuation metrics and market reform mechanisms are rolled out and tested in action.
Well-defined eligibility criteria and visible Target Product Profiles for new AMR drugs to fill gaps in the pharmacy will also give clear signals to early-stage investors and biotech companies that their targeted innovations will be properly valued and rewarded.
A much-talked-about initiative in the United States is the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act which advocates hope to get through the US Congress in 2020.
It seeks to incentivise drug developers by changing the way Medicare reimburses hospitals for treating patients with bacterial infections. This is a very welcome step forward and should be widely supported but, to my mind, does not provide a de-linked mechanism to separate value for innovators from the number of prescriptions written.
I believe there is still plenty of scope for further innovation in the AMR market, in particular to encourage a vibrant drug development ecosystem. The average new drug in other therapeutic areas passes through four or five owners on its journey from discovery to commercialisation – from universities and research institutes, through small and medium-sized biotech companies to global pharma majors.
We need to encourage more transactions along the development pathway for new AMR drugs. It is essential that large pharma companies are an active and growing part of that network.
The UK’s AMR Centre (AMRC) is an important element within this emerging AMR ecosystem, providing an alternative pathway for drug developers to progress their projects into clinical trials, by offering in-kind preclinical and clinical development capacity in return for a share of future commercial revenues.
July 2019 saw us take forward an anti- virulence programme from the Japanese pharma company Shionogi. The project, COT-143, is a novel therapy designed to help the body tackle Pseudomonas aeruginosa (Pa) infections, a hard-to- treat and often drug-resistant pathogen recognised by the WHO as a critical priority threat to human health.
The pathogen is found in soil, water, skin and most man-made environments throughout the world. Because it thrives on moist surfaces, the bacterium is capable of contaminating medical equipment, including catheters, causing infections in hospitals and the community.
It is associated with serious illnesses such as cystic fibrosis and causes severe infections including pneumonia and urinary tract infections. The consequences of such severe infections include drug-resistant pneumonia and sepsis, and often prove fatal.
COT-143 is a novel humanised monoclonal antibody. It does not kill bacteria directly but targets a virulence element that effectively disables the immune system from acting against the infection. COT-143 exerts its anti-virulence activity through inhibition of the PcrV component of the type 3 secretion system (T3SS), a key virulence mechanism of Pa.
COT-143 has already produced encouraging results in preclinical studies and has shown to be safe in regulatory toxicology tests in preparation for first-in-human clinical trials. AMRC will initiate cGMP manufacturing of the drug in 2020, and aims to start phase 1 clinical trials at the beginning of 2021.
The AMRC also ended 2019 by achieving a key milestone, the nomination of a preclinical development candidate in our MET-X programme, tackling drug resistance conferred by NDM-1 and other metallo-β-lactamase (MBL) enzymes. The MET-X programme was in-licensed from Swedish company Medivir and is focused on a novel small molecule that, when used in combination with β-lactam antibiotics, restores their function.
Bacteria containing NDM-1 and other MBL enzymes represent a serious threat to public health. NDM-1, for example, was first identified in 2008 and has already caused significant fatalities due to resistant infections of the blood, urinary tract, lungs and wounds.
There were over a thousand cases of infection in the UK in 2018, rising from zero over the last ten years. In some areas of India and China, the problem is already endemic and there’s a big pool of MBL-producing bacteria waiting to come our way, initially spread by international travellers.
MBL enzymes break down β-lactam antibiotics, including the so-called drugs of last resort, the carbapenems. The bugs have evolved so that they produce an enzyme that uses the metal zinc to destroy the β-lactam chemical structure and render antibiotics inactive.
Most worryingly, this resistance mechanism is easily transferable from one species of bacteria to another, and has the potential to greatly diminish the number of treatment options for organisms such as Escherichia coli, Acinetobacter baumannii and Klebsiella pneumoniae.
Our MET-X programme is one of the first and, we hope, most effective broad-spectrum therapies against a wide range of enzymes and organisms, and our new drug has been shown in lab studies to restore the activity of these important β-lactams.
The AMRC’s scientists have now got 12 months of work to do to confirm that the new drug is safe for use in humans, and to manufacture trial quantities of the drug to support first clinical trials planned for late 2020.