In the face of a growing threat of antimicrobial resistance (AMR), one company is making remarkable strides in developing innovative solutions to an impending global crisis.
AMR causes 1.2 million deaths annually.
By 2050, this figure is projected to reach 10 million, surpassing cancer in annual deaths and costing the global economy $66 trillion.
The need for effective solutions is more critical than ever, but a “broken” business model is stalling innovation.
In the current system, new antibiotics are often shelved by clinicians, used only as a last resort when more established therapies fail.
The result is a sector with little financial return for emerging antibiotic companies and their investors.
Earlier this year, Kirsty Smitten, co-founder and CEO of MetalloBio, took home the Young Health Tech Leader of the Year at the 2023 Health Tech World Awards.
The biotech startup, founded by Smitten and co-founder Jim Thomas, is looking to revolutionise antibiotic drug development.
Health Tech World sat down with Smitten to delve into the enormous threat of AMR, the “broken” financial model that is holding back innovation and MetalloBio’s game-changing technology, which could hold the key to fighting back against antibiotic resistance.
“Of the last four biotech startups that have brought an antibiotic to the clinic, three of them have folded within months of getting approval,” Smitten said.
“They’re having to wind down even though they’ve just had a drug approved and that’s because that market return just isn’t there.
“Because of that broken business model, no one’s going into the space. A lot of large pharma [companies] have withdrawn from the space.
“The problem is that we don’t have any drugs coming through that can help.”
New models are being introduced to change the system, but as a new antibiotic drug takes upwards of a decade to reach the market, time is ticking.
From PhD project to patented tech
MetalloBio’s journey began during Smitten’s PhD, where she pursued a passion for chemistry and microbiology at Sheffield University, working alongside Thomas.
The research they conducted delved into compounds that were first explored in 1952 but had been overshadowed by the emergence of penicillin and other antibiotics.
With the rise of antibiotic resistance, renewed interest has emerged in these compounds as a new class of antibiotics.
Initially, Thomas was using these compounds for applications in oncology, but a funding opportunity enabled them to shift their attention to antibiotics.
Through her PhD research, Smitten discovered the immense potential of the compounds in combating infections caused by gram-negative bacteria, including strains such as E. coli and Pseudomonas.
Gram-negative bacteria are defined by having two cell membranes and a cell wall, as opposed to gram-positive bacteria which have just one membrane.
This makes the former harder to treat with current antibiotics on the market.
The results from Smitten’s research were astounding. The compounds proved to be thousands of times more potent than existing antibiotics.
Given the urgent need for new antimicrobial agents, they filed a patent for the compounds’ composition in April 2019.
Later, Smitten and Thomas participated in Innovate UK’s Innovation to Commercialisation of University Research (ICURe) Programme, a pre-accelerator initiative that confirmed the market demand for their technology.
“The ICURe programme went really well,” Smitten said. “There was obviously a need for our tech; we had quite a lot of interest from big pharma companies even though we were quite early stage.
“Then we ended up spinning the company out in March of 2021, about two and a half years ago now.”
A new class of antibiotics
A new antibiotic class has not reached the clinic in over 35 years.
Even in the face of a potentially devastating crisis, 90 per cent of antibiotics in the development pipeline are still based on traditional antibiotic classes.
While the remaining 10 per cent are categorised as new classes, these are mostly still based on traditional modes of action, the mechanisms that kill bacteria or slow bacterial growth.
“They have the same modes of action as the current drugs and a lot of resistance mechanisms are to the mode of action,” Smitten explained.
“Resistance is going to emerge to those drugs as well.”
MetalloBio has departed from the traditional approach by developing metal-based therapeutic compounds that are completely different to current drugs, both in composition and mode of action.
What sets MetalloBio’s technology apart is its use of inorganic chemistry, in contrast with traditional antibiotics that are based on organic compounds.
By employing a completely different chemical approach, MetalloBio aims to disrupt the resistance mechanisms that bacteria develop against existing drugs.
“What we’ve done is use a completely different chemistry to what is currently used,” Smitten explained. “Every antibiotic is an organic compound and we’ve used inorganic chemistry.
“We’ve done that to try and stop the resistance mechanisms – which occur to those drugs – from occurring to ours.”
“We hit the bacteria from four different points within the cell, which means if a resistance mechanism emerges to one of the targets, we’ve still got three other targets there. That’s a way that we can evade resistance.”
Importantly, one of these targets can prevent horizontal gene transfer. This is significant as it prevents resistance from transferring between bacteria.
As a result, MetalloBio’s drugs demonstrate little to no emergence of resistance, which has been confirmed through rigorous testing.
“We’ve basically got a drug that exhibits little to no emergence of resistance,” Smitten added.
“We’ve done four months of passaging, and we see no decrease in that activity. There’s no resistance emerging to the compounds.”
MetalloBio’s experimental antibiotic has been tested on around 150 different strains of bacteria, showing efficacy against all of them. Included in this list is every one of the WHO’s ‘priority pathogens’.
In other words, the bacteria, which are causing the highest number of deaths globally.
Another significant advantage of the compound is its ability to serve as a light microscopy agent due to the presence of metal ions in the compound.
This enables researchers to track the antibiotic’s movement within cells and monitor the clearance of infections in live mammalian models.
This tracking capability is not possible with organic antibiotics.
Preventing the spread of bacteria in hospitals
In addition to developing new drugs, MetalloBio is using its metal-based compound to develop antibacterial coatings, which act as a preventative measure for the spread of infection in clinical settings.
The coating can be applied to various medical devices, including catheters, endotracheal tubes and stents, along with non-medical items like door handles.
Metal-based coatings already exist in the healthcare sector, containing a combination of silver, copper, zinc and the antibiotic gentamicin.
These current coatings, however, are expensive and, according to Smitten, relatively ineffective.
“Clinicians basically just don’t use them,” Smitten said.
“They’ll just put a catheter in; if you get an infection, they’ll pull it out, give you antibiotics and then put a new catheter in, which for the patient isn’t exactly ideal.”
Due to the high cost of silver and copper, current coatings cost in the realm of £15 per catheter.
MetalloBio’s new alternative, on the other hand, has the potential to be made available for as little as £1 if sufficiently scaled up.
Smitten hopes to see the company’s coatings being used in a clinical setting in two to three years depending on the outcomes of upcoming animal and IND filing studies.
The timescale for bringing a new antibiotic drug to the market is significantly longer.
If toxicology studies and clinical trials go according to plan, the drug could be in the hands of clinicians by 2029.
Navigating an underfunded industry
MetalloBio has faced its fair share of obstacles in its journey, particularly in securing investment.
Investors tend to shy away from antibiotics, Smitten said, perceiving the field as a high-risk venture.
Despite having compelling data, the startup has struggled to attract private investment.
However, their success in securing grant funding, amounting to approximately 1.5 million, has propelled them forward.
The ability to raise investment remains an ongoing challenge that MetalloBio aims to overcome.
“The biggest challenge is funding,” Smitten said.
“Unfortunately, you can’t do a big race for a couple of years. It has to be bits and bobs to get us through.
“I think we’re in a position where we will get there. We’re good at getting grant funding.
“I think we’re about to close a round now, which will take us to phase I [clinical trials], so we are hopefully in a good position.”
The tech is almost there, but is the industry?
Addressing these challenges and transforming the landscape of antibiotic development requires systemic changes.
The UK has taken the lead in pioneering new models to incentivise antibiotic drug development.
A proposed NHS subscription model seeks to provide annual subscription payments based on the value of the drug rather than the amount it is used.
Right now, the NHS budget for its “Netflix-style” subscription model is restricted to £10 million, which according to Smitten, will not be enough.
“But, if every G7 country matches it in terms of their GDP […] then it will improve,” she said.
Australia has introduced a similar system, while the US is not far behind as organisations continue to put pressure on lawmakers to advance the PASTEUR Act.
Originally introduced five years ago, the act, which proposes another subscription-style model, has failed to pass through Congress.
Big pharma is also beginning to re-enter the space as the likes of Boeing Ingelheim and Johnson & Johnson introduce new funding projects for early-stage antibiotic companies.
If the momentum continues, Smitten is optimistic about the future of the field. But if investment continues to stagnate, the world may have to brace itself for another major health crisis in the coming decades.
“I think if every country follows what we’re doing with the subscription model, then I think we’re moving in the right direction,” Smitten said.
“I think big pharma coming back in is going to improve things.
“At the moment, no startup wants to go into [antibiotics] because there’s no exit, there’s no pharma company that’s going to buy you out or anything like that.
“As Big Pharma come back in and there’s more funding available, things will improve. It’s just going to take time.
“Everyone needs to realise that it’s going to be the next pandemic unless we do something about it.”