A Call to Arms for Antimicrobial Resistance

Today, antimicrobial resistance (AMR) infections are killing more people than HIV or malaria. In 2022, a Lancet paper showed that around 1.27 million deaths were attributable to AMR; another 5 million deaths were associated with AMR globally in 2019 (1). By 2050, the annual number of deaths from AMR could be 10 million (2).

Frankly, we’re in a bit of a mess. Resistance is increasing and we don’t have enough new antibacterial drugs in the pipeline. A 2021 report from the WHO shows that there are only 77 drugs in the clinical antibacterial pipeline – and only 27 of those are for WHO priority pathogens (3). Compare this with the hundreds of drugs being developed for breast cancer and it’s clear there is an imbalance.

The first penicillin resistant organisms were identified even before penicillin was first used. Bacteria reproduce at a rapid rate that massively outstrips our ability to develop new drugs to counter the evolution. Poor prescribing practices have not helped the situation. For a long time, antibiotics were handed out by doctors like candy, and, if a patient fails to complete the course or effectively clear a particular outbreak, there is the possibility for resistance to develop. Resistant organisms can pass from people to animals, from animals to people, and into the environment.

Where are all the drugs?
 

Big pharma’s cessation of antibiotics R&D has been driven by a few different factors. In the early 1980s, the HIV crisis began, and a large amount of microbiological and drug development know-how pivoted from microbial infections to HIV. There have been massive successes in the treatment of HIV, of course, but too few resources pivoted back to microbial infections. With the original antibiotic drugs off patent, there was less money to be made, so manufacturing facilities were closed, repurposed, or sold off.

Fundamentally, we need new drugs to be launched to tackle microbial infections, but we don’t want to use them – unless we absolutely have to. Biopharma’s business model is to develop a new drug, prove that it meets an unmet need or is better than something that is already on the market, and then go out and sell as many doses as possible at the highest price possible. Given the increasing prevalence of AMR, however, there is no way that we want a valuable new drug that overcomes a particular resistance mechanism being widely used; all that will do is more quickly drive resistance to the new drug. We need money to be spent on development, and then we need to keep that drug on the shelf and only use it as a last resort. This approach completely disrupts the pharma industry’s traditional economic model – and because biopharma companies and their investors are hugely rational people, they take the sensible decision to put all their money into cancer or other chronic diseases.

Let’s talk about pricing reform
 

In the UK, there have been many discussions (which I have been involved in) about reimbursement reform to fund innovation in antimicrobial drug development. The idea is to decouple the reward received by biopharma companies from the volume of drugs used by implementing a subscription model that pays a set price per year over an agreed period, regardless of how much of the drug is actually used. Following the recent success of a pilot study involving two new antibiotics (Pfizer’s ceftazidime-avibactam and Shionogi’s cefiderocol), which paid £10 million per year over 10 years, the National Health Service (NHS) announced plans in July 2023 to expand this model to more pharmaceutical companies and roll it out across the whole of the UK. Under the new proposal, drug makers would receive up to £20 million a year for selling their novel antibiotics in the UK no matter how many were prescribed.  

What about internationally? In the US, there was an AMR policy being prepared that had bipartisan support. However, it became mired in US partisan politics over other matters. Some elements have now been built into the Biden administration’s healthcare bills, but it’s still very frustrating that progress has been so slow. The COVID-19 pandemic hasn’t helped the matter because it sucked all the resources and attention from other issues, including AMR.

The EU has a different set of problems; it is grappling with the balance of what needs to be done at the EU competency level, and what needs to be done at the member state level. Each member state has its own healthcare, reimbursement, and insurance systems. There are a lot of structural questions and though the European Commission has published encouraging proposals, I can’t see a permanent EU system being agreed quickly. Issues are still being debated, but we’ve already had multiple G7, G20, and UN meetings.  Perhaps the forthcoming UN General Assembly High Level Meeting on AMR in 2024 will provide the focus needed to get difficult decisions made and these important measures across the line.

One interesting international initiative that is seeing success, however, is CARB-X (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator), which is located at Boston University, and funded through a consortium of international governments and foundations, including the UK’s Wellcome Trust. CARB-X helps support antibacterial projects through early development. Over the past year, it has helped eight projects progress to phase I and Ib trials. The idea is to help companies progress until they attract private support – but this private funding is not materializing and it all comes back to uncertainty about reimbursement. An investor once told me, “We understand the need, but we can’t put a value on anything. We don’t even know how these drugs will be paid for. How do we know what to invest and how are we going to get a return?”

We need to find ways to support these partnerships and the small and medium-sized enterprises (SMEs) involved. A great deal of the R&D effort for antimicrobial drug development has fallen on SMEs, but they often don’t have the funds to move projects forward. The UK’s Biotechnology and Biological Science Research Council (BBSRC) has invested over £100 million in fundamental science with research institutes and universities, but translational science into industry is happening slowly and at a small scale. Five years ago, there were only around 27 SMEs in the UK working on AMR and most of these only had 12 months-worth of cash. Further support for these SMEs is needed by more actively bringing together government funding, big pharma, philanthropic organizations and investors.

Again, in the UK, there is an effort to address this via the Infection Innovation Consortium (iiCON), which works with industry, academics, clinicians, and the NHS to support the development of anti-infectives right from concept to adoption.

A different kind of AMR strategy
 

Putting politics aside for now, let’s consider what is being done in terms of drug development solutions. We certainly need new antibiotics, but we shouldn’t stop there; there are other drug development approaches that can combat AMR. It’s all about innovation, innovation, innovation! I’d like to share some information about two lead programs at Infex Therapeutics: RESP-X and MET-X. Neither of these drugs are antibiotics, but they are good examples of how creativity can be applied to AMR.

RESP-X is an anti-virulence, humanized, monoclonal antibody that targets Pseudomonas aeruginosa (Pa) infections, which have been identified by WHO as a critical threat to human health. Pa colonies hide inside a protective biofilm (which prevents antibiotics from reaching them) and are often found inside damaged lungs, such as those of bronchiectasis, COPD, and cystic fibrosis patients. The Pa colonies will be in a dormant state unless there is an opportunity to emerge, such as when a patient’s immune system takes a dip. At this point, Pa switches to a virulent state, and grows a tail and a needle-injection mechanism. From a bioengineering perspective, it’s fascinating. Pa’s hollow needle can inject four different toxins. Pa can kill white blood cells – and patients with depleted immune systems will have very few of these around anyway – and use toxins to invade the lung tissue, causing invasive disease, which can also lead to sepsis. If a bronchiectasis patient gets colonized with Pa, it’s bad news. With a moderate to severe infection, patients have a 40 percent four-year mortality rate. Consider that for a moment: Four out of 10 patients will be dead in the next four years.

RESP-X can be taken in a preventative fashion. An injection every month switches off the virulence mechanism of Pa so, even in a reduced immune state, the patient’s immune system can better fight it off. The results in mice have been fantastic and we’re now working on a phase I study with healthy volunteers. In April 2023, we reported a favorable safety and tolerability profile. If everything continues to work out, we’ll then move to bronchiectasis patients who are long term colonized – and I really hope that we can give patients back a decent quality of life. If we can prevent the bacterial flare ups in these patients, we can avoid the use of antibiotics and slow down the emergence of AMR.

We’ve already spoken with some regulators who have indicated that a drug like this would not need to be treated like an antibiotic because it shouldn’t contribute to resistance. The drug hits both antibiotic-resistant and antibiotic-susceptible strains of Pa by working around Pa’s resistant mechanisms. This means that the drug should be reimbursable in conventional ways.

MET-X takes a different approach. It is a metallo-beta-lactamase inhibitor that targets Gram-negative Enterobacterales. At the start of 2023, it was awarded FDA Qualified Infectious Disease Product (QIDP) designation.

Over time, a number of bacteria have developed a resistance mechanism that uses beta-lactamases – enzymes that essentially chew up the chemistry on beta-lactam antibiotics. In certain bacteria, particularly Gram-negative bacteria, beta-lactamases sit between the outer and inner layers of the bacterial cell. For drugs to kill the bacteria, they have to pass through these layers, which means they will hit the enzyme – and become ineffective.

Beta-lactamases are divided into four different classes; three of which are serine beta-lactamases. There are a variety of drugs and drug combinations available that can work against these. Metallo-beta-lactamases, however, use zinc as a catalyst to degrade beta-lactam antibiotics – and there are few interventions. The pipeline is also very dry, despite bacteria producing these enzymes being endemic in India and China – as well as in UK-based southeast Asian communities. A few years ago, the UK saw an outbreak of klebsiella. A number of patients were treated with colistin, which is considered a last line of defence drug against multidrug-resistant Gram-negative bacteria. By the end of treatment, unfortunately half of the patients had died, and researchers identified colistin resistance in the bugs.

MET-X blocks the ability of bacteria to generate metallo-beta-lactamase. The drug itself isn’t a treatment, but it does switch off production of the enzyme. If it were administered alongside a drug like meropenem – which usually metallo beta-lactamase would prevent from working – it would allow the drug to be effective. Essentially, we hope that MET-X will breathe life back into existing drugs.

We are hoping to start phase I trials soon. So far, we’ve done most of the work with meropenem, but we also have collaborations with pharma companies to look at combinations with other drugs to see if we can restore their efficacy too.

In my view, targeted therapies are needed to prevent widespread resistance. However, some companies are still focused on developing the next broad-spectrum antibiotic, even though payers will want to avoid using them widely to prevent further resistance. The old big pharma mindset of wanting to make the next blockbuster still persists in places.

Putting the issue front and center
 

Here’s a stark warning: If healthcare systems, politicians, investors, and the pharma industry don’t fix the AMR problem, all other investments will be worthless. If your cancer chemotherapy knocks the patient’s immune system, the patient could die from an untreatable infection. Surgeries and wounds could be deadly. There is broad acknowledgement that AMR is a significant issue, but the problems are not being fixed quickly enough. I was involved in putting together a report in 2018 that was used as evidence to inform the UK government’s five-year (2019–2024) action plan for AMR. The same issues highlighted in that report in 2018 are still present today – the recent expansion of the reimbursement reform by the UK’s NHS is an excellent platform to change this situation but more needs to be done.

SMEs have done a lot of the heavy lifting, but they need help. I urge larger pharma companies to look at how to engage with the SME community – and to keep in mind that relatively small amounts of funding can make a big difference.

We also need to raise awareness amongst the general public so that they too can pressure politicians, who currently receive very little (if any) correspondence advocating for more funding for AMR. How can we raise awareness? In a recent consultation, I suggested that AMR should be included on patient death certificates, if it contributed to the cause of death, just as we did with COVID-19. 

Public awareness could also help charities; Antibiotic Research UK receives less than £1 million each year in funding, whereas Cancer Research UK receives around £500 million… 

Right now, not enough people are working on this global health issue. And that really needs to change. For the COVID-19 pandemic, there was an astonishing combined effort into developing and rolling out vaccines, with countries appointing COVID-19 task forces. 

We need the same amount of effort to be dedicated to AMR.