Antibiotic Apocalypse: Part I

The World Health Organization (WHO) recently described antibiotic resistance as a threat to the achievements of modern medicine. “A post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century,” the WHO explained, as it released its Antimicrobial Resistance Global report on Surveillance in April of this year (1).

The industry has been aware of the growing issue of drug resistant bacteria for some time. In Europe, for example, ‘The Microbial Threat’ conference, held in Copenhagen in 1998, encouraged a number of EU companies to establish national surveillance of microorganisms resistant to antibiotics. This was also the first time that antibiotic resistance became an official EU issue, although before then the European Commission had tried to address the problem through various isolated measures (2).

The good news is that governments and drug makers alike are taking the problem very seriously. This year, as of September 2014, the FDA had approved three new antibiotics and we’ve also seen companies such as Roche returning to antibiotic R&D. Many governments are also paying close attention to the problem, which is leading to new incentives and initiatives to help pharma companies get to work – and the recent comments from the WHO are likely to inspire further efforts in the search for the next generation of antibiotic medicines.

Here, I review progress so far and explore the next generation of initiatives from both governments and non-governmental organizations designed to  kick-start antibiotic development.

Resistance is not so futile

When antibiotics first came into widespread use around 70 years ago, they were viewed as wonder drugs against infection. However, Alexander Fleming, who accidentally discovered penicillin in 1928, warned of bacteria’s ability to become resistant to antibiotics in his Nobel Prize speech in 1945.

Bacterial pathogens have to adapt to survive and evade their host’s immune response. Drug resistance occurs naturally through genetic mutations or by acquiring resistance from another bacterium through conjugation, where genetic material is transferred from one bacterium to another. Inappropriate use of antibiotics has accelerated the natural selection of bacteria, which have adapted accordingly and resulted in many multi-drug resistant (MDR) pathogens – or ‘superbugs’.

Up until the 1970s, there was a huge amount of discovery and development activity, resulting in dozens of different antibacterial classes. Since then, the antibiotic landscape has been largely stagnant while bacteria have continued to evolve. According to the WHO, very high rates of resistance have been observed in bacteria causing common infections in all regions. Around 3.6 percent of new global TB cases and 20.2 percent of previously treated TB cases are estimated to be MDR. We’ve also seen the emergence of extensively drug resistant (XDR)-TB, which is resistant to most traditionally effective treatments (1). A few new classes of antibiotics have been launched since 2000, but most have only one drug within them.

Finding new antibiotics is not easy; the low-hanging fruit have already been picked and bacteria are well equipped for survival. Often, killing the bacteria is not the problem for researchers – it’s accomplishing that without killing the human host too.

Incentives and initiatives

Despite dramatic use of the word ‘apocalypse’ in our title, it’s not quite the end of the world yet. We’re certainly in a lamentable position, but many believe the tide is starting to turn as governments and other organizations wake up to the problem and begin to take action to make discovery and commercialization easier for the pharma industry.

In the US, the FDA introduced its Generating Antibiotic Incentives Now (GAIN) program in 2012 to encourage more companies to pursue antibiotic development. GAIN grants qualifying new antibiotics (those that target specific pathogens as listed by the FDA) fast track and priority review status, as well as an extra 5 years of exclusivity. A number of new antibiotics have already benefitted from this program; three of which launched this year for acute bacterial skin and skin structure infections. As part of the program, FDA has also established an Antibacterial Drug Development Task Force, which includes in its goals the ongoing evaluation of existing FDA guidance for antibiotics and the exploration of new scientific approaches to facilitate drug development in the area.

US legislators have recently been working on the DISARM (Developing an Innovative Strategy for Antimicrobial Resistance) Act. Where GAIN focuses on creating a fast-track FDA review process, DISARM aims to address four core actions that were identified in a November 2013 report from the US Centers for Disease Control: (i) preventing infections and the spread of resistant bacteria, (ii) better tracking of resistance and antibiotic use, (iii) improved use of antibiotics, and (iv) the development of new antibiotics to treat resistant infections. DISARM will also try to overcome some of the financial disincentives for companies by making reimbursement rules more favorable. For example, the US federal healthcare program Medicare currently only reimburses inexpensive, commonly used antibiotics rather than the latest innovations.

As noted earlier, European regulators have been discussing drug resistance seriously since 1998. Indeed, the European Commission took an early lead by developing the European Community Strategy Against Antimicrobial Resistance.

In 2009, an EU–US summit took place, resulting in the formation of the Transatlantic Task Force on Antimicrobial Resistance. The task force aims to increase levels of communication, coordination and cooperation for human and veterinary antimicrobials. Activities include regular meetings and teleconferences between the EMA and the FDA to discuss recommendations on clinical trial designs for new antibacterial drugs, feasible approaches to facilitate trials, and regulatory options available to medicine developers.

Other practical efforts have followed in recent years. In March 2012, Europe’s Innovative Medicines Initiative (IMI), a public–private partnership, launched the New Drugs for Bad Bugs program, which offers funding to help support promising projects in the field. Three projects are currently underway: COMBACTE (Combatting Bacterial Resistance in Europe), TRANSLOCATION, and ENABLE (European Gram-negative Antibacterial Engine). COMBACTE is a public–private partnership that will mainly be devoted to performing clinical trials of new antibiotics through a network of experienced investigators, as well as designing and supporting tests to support diagnosis. TRANSLOCATION will focus on increasing understanding of how to get antibiotics into multi-resistant Gram-negative bacteria by studying the molecular basis of cell wall permeability. ENABLE will focus on developing antimicrobial candidates against Gram-negative bacteria for testing.

At the end of 2013, the EMA also organized an event with the European Commission to look at the regulatory options for approving antibiotics and how to make the most of the current armamentarium. Around the same time, the agency released an addendum to its guideline on the evaluation of medicinal products indicated for the treatment of bacterial infections, which outlines new approaches to development, in addition to giving guidance on data-gathering strategies to facilitate the marketing authorization process (3).

Worth noting is an interesting development in the UK – a new £10 million (around $16 million) award called the Longitude Prize. The prize was set up by the UK government as a grand innovation challenge to solve what the UK Prime Minister described as the biggest problem of our time. Antimicrobial resistance was selected as the subject of the challenge in a public vote. The full details have not yet been announced but entries will be open shortly. The aim is not to develop a new antibiotic, but rather to create a point-of-care diagnostic that helps clinicians to distinguish between viral and bacterial infections quickly, and make better decisions about which antibiotic (if any) to prescribe. It will likely be impossible to completely eliminate antibiotic resistance because of the speed at which microbes evolve, but reducing misdiagnosis and overprescription would at least make some impact.

Now, the pharmaceutical industry must make the most of the initiatives that have been put in place. As of June 2014, there were at least 43 antibiotics in development, seven of which were in Phase III clinical trials (4). In Antibiotic Apocalypse: Part II next month, we take a closer look at the next generation of antibiotics, with input from GSK and Roche.

The Battle Against Bacteria

Helen Boucher, a member of the Infectious Diseases Society of America (IDSA), gives her latest battle report from the war on drug resistance.

How bad is the situation?

We’re right on the edge of going back to an era when we didn’t have antibiotics. If that happens, we won’t be able to do the things that our patients take for granted: taking care of premature infants, performing transplant surgery, open-heart surgery, and administering chemotherapy… the list goes on and on.

What about positive developments?

We’ve seen two positive things. The first is that three new drugs have been approved this year. The fact that companies felt there was a regulatory path forward allowed them to develop these drugs. The concern is that we still haven’t seen the drugs our patients most desperately need, such as those for Gram-negative infections, so we’re hoping that some of the newer initiatives that have come along will help in that regard. The other positive development relates to some of the legislative efforts.

Does more need to be done?

Despite the GAIN act, we’re still hearing from drug development companies that scientific, economic and regulatory barriers are still a huge problem. At IDSA, we have been advocating for further incentives and measures to stimulate development of antibiotics. In terms of legislation, the ADAPT (Antibiotic Development to Address Patient Treatment) act would help remove some of the regulatory barriers. In addition, IDSA supports economic incentives for drug development. We’ve done a lot of work on tax credits and we’re also advocating for reimbursement reform so that antibiotics can be valued. This is an area that’s really gained momentum. The DISARM act, which will allow for a different kind of payment for antibiotics, provides another legislative incentive.
We’re also very focused on investing in diagnostic tests to make sure that we use the antibiotics we do have as appropriately as possible. If we can better ascertain what infection a patient has, we can ensure the use of the best treatment.

How can we facilitate the development of antibiotics?

Public–private partnerships provide an important role in stimulating antibiotic discovery and development. The Innovative Medicines Initiative (IMI) and the New Drugs for Bad Bugs initiative is a public–private partnership that appears to be incredibly effective; some of the things we’ve seen out of the IMI are revolutionary in terms of collaboration and in allowing the key stakeholders to work together to address the problem. It’s not just about developing new antibiotics either. We need to understand more about what’s happening with resistance in a real-time way: where the problem is and what’s ahead of us

Tell us about the IDSA’s 10 by 20’  initiative…

IDSA’s 10 x 20’ initiative seeks a global commitment to produce ten new systemically available antibiotics by 2020. We have four new drugs now, which is better than a couple of years ago, but there is a long way to go! Part of what’s important about the goal is the 10-year horizon. Our message in all our advocacy over the past years has been that as well as meeting the needs of today we also need a robust and renewable pipeline of antibiotics for the future.