This month, the UK government's review of antimicrobial resistance sent alarm bells ringing in Whitehall and issued a call for new medicines to kill antibiotic-resistant superbugs. With big pharma out of the game, small pharma is stepping up to the plate

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When economist and government minister Jim O'Neill published the final version of his long-awaited report at the end of May, its message was clear – antimicrobial resistance (AMR) is perhaps the single biggest threat in modern medicine. The report concludes that antibiotic-resistant superbugs could kill 10 million people a year by 2050 – or one person every three seconds, more than all cancers combined today – and wreak economic havoc, costing the world's health systems $100 trillion.

"As with all forecasts of this sort, it is of course possible that our estimates may turn out to be too large, but we believe it is even more likely that they could be too small," O'Neill writes in the foreword. "We did not even consider the secondary effects of antibiotics losing their effectiveness, such as the risks in carrying out caesarean sections, hip replacements or gut surgery. In the short 19 months since we started, new forms of resistance have emerged that we did not contemplate occurring so soon."

O'Neill stresses the need for new antibiotics. "A truly new class of antibiotic has not been seen for decades because the lack of incentives for investment has led to reduced R&D," concludes the report. "Many of the 'low hanging fruit' in terms of development have already been picked." Big pharma has largely been out of the game in the last few decades, it notes, citing that while there were close to 800 possible oncology medicines in the pipeline in 2014 in the US alone, the total global antibiotic pipeline has fewer than 50 molecules.

Campaigning charity Antibiotic Research UK (ANTRUK) agrees with O'Neill that there has been a lack of commercial incentives for companies to take R&D risks. "Drugs like those used to treat cancer are often given for life and so provide a sufficient income stream to pharmaceutical companies to warrant research investment," it says. "Antibiotics are given for just a short course of treatment and so sales are very limited. If a new antibiotic is reserved only for use in treating resistant infections, then most of the time it will sit on the pharmacy shelf not being used. Again this disincentivises any commercial company to develop new antibiotics."

With a renewed focus on AMR, big pharma has started to take interest, with Allergan and AstraZeneca joining forces earlier this year to develop a combination of existing antibiotics aztreonam and avibactam, while MSD bought antibiotic developer Cubist for $9.5 billion in 2015. However, these remain the exception, not the rule.

Small company, big problem
Many smaller firms, however, have their eye firmly on the AMR ball. "The role of smaller pharma companies in antibiotics has really changed over the last 20 years, because most of the big companies left the field and the smaller ones have been trying to fill the gap," says Ursula Theuretzbacher, founder of the Center for Anti-Infective Agents in Vienna. "Most new drugs in development have been discovered in small companies that are often spin-offs from universities or have in-licensed research projects from them."

Bill Love, CEO of Brighton-based Destiny Pharma, agrees, saying that if big pharma decided to re-enter the field, it would have to start from scratch. "SMEs are more than halfway along that road; by partnering, big pharma can bring new antibiotics to the market in three or four years rather than 15."

With AMR growing, companies are trying innovative approaches to antibiotic development including a focus on underutilised mechanisms of action, says Theuretzbacher, who led a 'Pipeline Corner' session at the European Congress of Clinical Microbiology and Infectious Diseases in April to give small companies the chance to show off their pipelines to a wider audience.

One of the most common new approaches highlighted at the event was targeted therapy. "20 years ago only broad-spectrum antibiotics were thought to be valuable because you didn't have to think about diagnostics and could give every patient the same drug," she says, "Of course, that was the basis for our resistance problem now, so today we consider a pathogen-specific, or really small-spectrum, focus. You're treating what is necessary."

However, there are barriers to overcome. "We don't have a clinical development path for single-pathogen drugs. From a public health perspective, we need new classes, however, that's difficult to achieve so most companies take known classes and modify them."

A key issue is the ability to identify the pathogen involved in the clinical setting. "Physicians can't always diagnose them and, if you don't know what pathogen it is, you would never give a small-spectrum antibiotic to a severely ill patient. We would have to change a lot about how we treat patients," says Theuretzbacher.

ANTRUK is researching 'antibiotic resistance breakers'. "We will be screening the pharmacopeia to see whether drugs used for another purpose can overcome resistance to four main bacterial species," says the charity's chief executive Colin Garner. "There is evidence that this could work and a number of common drugs, such as Imodium (loperamide), have been shown to be potential antibiotic resistance breakers." As well as the obvious cost benefits of repurposing existing drugs, development will be quicker, he says. "The attraction of a repurposed drug is that you know a lot about it, in terms of pharmacokinetics, toxicology and safety, so you should be able to get into the clinic quicker than a new chemical entity."

An underused mechanism of action has given Destiny Pharma its antibacterial drug XF-73. "Our approach is to target the bacterial membrane, a very underutilised target," says Love. "Because it attacks the membrane, the drug acts in minutes, not hours like most antibiotics. It binds to the membrane and makes it leaky so that vital components leak out, killing the bacteria very rapidly.

"We have conducted a repeat-exposure test for 55 days in a row. We studied the five most common MRSAs with several common antibiotics along with XF-73. All the antibiotics failed, even after just a couple of exposures. However with XF-73 there was zero resistance; our drug killed them at exactly the same concentration on day zero as at day 55."

The research team believes the drug is killing bacteria so quickly they don't get the chance to mutate. "We'd never say that bacteria will not become resistant to our drug but it does predict a long clinical lifetime, much longer than traditional antibiotics," says Love.

Another SME using an underutilised mechanism of action is Motif Bio, whose candidate drug was originally developed by Roche. "What is different about iclaprim is that it goes inside the bacteria and inhibits the enzyme dihydrofolate reductase (DHFR)," says CEO Graham Lumsden. "This prevents DNA production by the bacteria, killing them. A lot of antibiotics don't kill the bacteria, they just prevent division, which could leave behind all the genetic material that can mutate and develop resistance."

Iclaprim is the only antibiotic with this mechanism, with one exception, he says. "The exception is trimethoprim, however, it is often used in combination with sulphonamides which many patients can't tolerate."

Not only is the drug designed to be more potent than trimethoprim – allowing it to be used as monotherapy – it should also tackle the trimethoprim resistance mutation. In tests, bacteria did not develop resistance to the drug after 22 exposures, despite developing resistance to trimethoprim and rifampin after only a couple of exposures, says Lumsden.

"If you imagine trimethoprim attaching to a bacteria on two sites, if the bacteria mutates and those sites are no longer on the outside there's nothing for trimethoprim to attach to," he says.  "Iclaprim uses five, six, seven, eight attachment sites to minimise that risk."

An uphill battle
While smaller companies may be the best hope for new antibiotics, they face the same economic and development challenges that have put big pharma off, as well as many unique to SMEs.

Theuretzbacher works with the DRIVE-AB project, funded by the EU Innovative Medicines Initiative, which has identified several key problems. "We asked European SMEs about problems and bottlenecks," she says. "It led to the creation of an antibacterial SME association, the Biotechs from Europe Innovating in Antimicrobial Resistance (BEAM) Alliance, because companies wanted to be more visible. Even funders like the EU didn't know who to address because there were so many little companies.

"As it doesn't get as much funding as other fields, basic research at universities needs to be supported more. Money is a factor, of course, but it's not just about that. Because big pharma left the field 20 years ago, a lot of really experienced people moved to other fields or have retired so we have a big gap in expertise. Even with great, younger people, a lot of our 'discoveries' are actually rediscoveries as we don't have this continuous experience."

Clinical development is also a bottleneck, says Theuretzbacher, as we are only interested in antibiotics that are active against the most resistant bacteria. "Patients that have these kinds of infections are usually very sick," she adds, "so doing clinical trials is verydifficult."

US vs EU
For both Love and Lumsden, Europe has not taken strong enough steps to help address these problems in spite of the threat of AMR.Lumsden welcomes the focus of the O'Neill review but points out that action is needed. "We went in to visit the review committees and they liked what we are doing but they told us they don't have any budget. We've heard things about contract pricing with the NHS for antibiotics, which would be helpful, and we've heard about upfront payments to companies when we get an antibiotic approved, but there's nothing tangible yet."

Progress is quicker in the US, he says, citing incentives for developing antibiotics included in the Generating Antibiotics Incentives Now (GAIN) Act of 2012. One of these is Qualified Infectious Disease Product (QIDP) designation, which allows antibiotics to gain faster FDA approval and extended market exclusivity. Both Motif and Destiny have managed to secure QIDP designation.

"The FDA is a very different animal today than it was a decade ago," says Lumsden. "Back then there wasn't the sense of urgency about running out of time. Now, regulatory teams are stepping up and working closely with us, and it would be nice if that happened in Europe. With QIDP, it takes six months to review an application; in Europe it's still 12 months."Destiny has a clinical trial agreement with the National Institute of Allergy & Infectious Disease, the US government's infectious disease research division. "There's a lot more interest in the US," says Love. "There have been active steps, although they're not as big as everyone would like. In Europe, there are lots of words and reviews, but not much actual support."

The need for charities
For ANTRUK's Garner, the charitable sector is vital in tackling AMR, with some clear advantages. "Charities have made massive contributions in therapeutic areas like cancer, Alzheimer's and heart disease, and we can make a big contribution here too," he says. "It's surprising that we're the first charity formed to tackle AMR. Fleming talked about the problem in 1945, so why's it taken so long to reach public consciousness?"Without shareholders, return on investment and filing patents are not the driving force for charities, he says. "We could probably do things that would not interest the industry because they could not see how to make money out if it."

Theuretzbacher stresses the need for a holistic view. "We need policies for sustainable use. It's about new economic models that are based on innovation, sustainable use and equitable access to antibiotics, but that's a combination of factors that are really hard to achieve. It's a big effort, but it is possible."

(Click to read the full version of this article in the online magazine)