Antibiotic Apocalypse: Part II

It’s not easy to buy antibiotics over-the-counter in most countries, but lax prescription practices and poor compliance have led to an increase in drug-resistant microbes. A UK study published at the end of September claimed that in 2012 prescribed antibiotics could have been failing 15 percent of the time – up 12 percent from 1991 (1).

Last month in Antibiotic Apocalypse: Part I, we covered the problem of drug resistance and the initiatives being launched to help kick start development. Here, we  look at the ‘fall and rise’ of antibiotics.

Abandoning antibiotics

Many pharmaceutical companies have been neglecting antibiotic R&D for years. As well as being scientifically challenging, new antibiotics carry a significant business disadvantage. Despite being expensive to develop, they are only used in small amounts and for a short duration, so the return on investment is often not attractive – a fact that is compounded by payers who are reluctant to shell out for newer, expensive alternatives when cheaper antibiotics are available – however ineffective they may be.

Pfizer’s 2011 decision to close its antibiotic research facility in Connecticut came as a big blow to the antibiotic space. Originally, the company said that it would move its antibiotics research to China, but that hasn’t yet happened – despite Pfizer indicating the move would take around two years (2). In July, Sanofi withdrew from a partnership with KalaBios to develop the monoclonal antibody KB001-A. Sanofi was developing the drug against Pseudomonas aeruginosa (Pa) pneumonia in intensive care patients; KaloBios was focused on treatment for Pa lung infections in cystic fibrosis patients. In August, Novartis rehomed its experimental TB drugs by licensing them to the Global Alliance for TB Drug Development, a non-profit organization. The deal included the indolcarboxamides class of drugs, which are active against drug sensitive and multi-drug resistant strains of TB.

Fortunately, there are rays of hope. Several small companies have seen opportunity amongst the challenges. And there are some big pharma players too; Roche recently announced its intention to return to antibiotics R&D after quitting in 1999 (see sidebar “Roche Returns” on page 44). And Merck, AstraZeneca and GlaxoSmithKline (GSK) are all still active in the field. With several new antibiotics receiving regulatory approval and the pipeline finally picking up, we could be at the beginning of an antibiotic research resurgence.

The year of the antibiotic

The FDA approved three new antibiotics in 2014 through its Generating Antibiotic Incentives Now (GAIN) program, which was introduced in 2012 to provide stimulatory benefits, such as extended exclusivity and fast-track and priority review status. The new drugs – Dalvance (dalbavancin), manufactured by Durata Therapeutics; Orbactiv (oritavancin), manufactured by The Medicines Company; and Sivextro (tedizolid phosphate), manufactured by Cubist Pharmaceuticals – all target skin infections.

Cubist Pharmaceuticals is clearly looking to make a big impact. It has another antibiotic currently under FDA and EMA review called ceftolozane/tazobactam for the treatment of complicated urinary tract and complicated intra-abdominal infections – and other potential antibiotics are undergoing clinical trials at the company. In mid-September, Cubist announced the opening of new international headquarters in Zurich (its corporate headquarters are in Massachusetts in the US), and its intention to focus on the launch of potential new antibiotics in Europe in 2015. In 2014, the company planned to spend $400 million on antibiotic R&D. “Bringing antibiotics to market under current conditions is hard, but we’ve proven our strategy works. Our therapies aren’t appropriate for every bacterial infection; we tackle the serious bugs and that is why resistance to our therapies is very low,” said a spokesperson.

In terms of big pharma, Merck has also taken advantage of the GAIN framework with its investigational antibiotic relebactam, which received designated status at the start of September 2014 for treating complicated urinary tract infections, complicated intra-abdominal infections and hospital-acquired/ ventilator-associated bacterial pneumonia. The drug is currently in Phase II trials in combination with another Merck antibiotic, imipenem/cilastatinm. Phase III trials are planned for 2015.

Merck claims its scientists were among the first to investigate penicillin and that the company was also one of the pioneers in the mass production of the antibiotic. Currently, it has two new drugs in development – MK-3415A and MK-8228 – that target C. difficile recurrence and human cytomegalovirus (CMV)-related infection, respectively. MK-3415A is a combination of two monoclonal antibodies, actoxumab and bezlotoxumab, that target two C. difficile pathogenic toxins (A and B). The idea is to use MK-3415A to neutralize the toxins, while using antibiotics to kill the bacteria. Letermovir (MK-8228) is currently undergoing Phase III clinical testing for preventing CMV infection in high-risk bone marrow transplant patients. It is administered once daily, either as an oral tablet or intravenously.

AstraZeneca’s investigational AZD0914 drug for treating uncomplicated gonorrhoea was also awarded fast-track status through GAIN and is currently entering Phase II. AstraZeneca has the largest pipeline of all the big pharma companies. As of June 30 this year, the company had nine compounds targeting a range of infections (including TB, MRSA, and serious S. aureus infection) in Phase I and II trials, and three in Phase III or registration: CAZ AVI RECLAIM for serious infections, CAZ AVI REPROVE for hospital-acquired pneumonia (both are being developed with Forrest Laboratories) and Zinforo, which launched in the EU in 2012 for serious skin infections or community-acquired pneumonia, and has now also been filed in China.

GSK has taken a slightly different approach to boost its antibiotic pipeline by making use of public–private partnerships. In particular, the company is heavily involved in programs run by Europe’s Innovative Medicines Initiative (IMI). The company told The Medicine Maker that, “Tackling antibiotic resistance is a challenge we want to be part of solving but no one company can do this alone. Antibiotics research is one of the areas where we believe taking a more open-minded approach to sharing information and engaging in public–private partnerships will help to address some of the key barriers to the development of effective new medicines.”

GSK has several antibiotics in very early development and a topoisomerase inhibitor (2140944 ) in Phase II that has received significant funding from the US Biomedical Advanced Research and Development Authority. GSK described the partnership as “unique” since it allows the company to work on various projects rather than a single molecule. If a molecule fails, focus can quickly switch to something more promising without the need for new contracts. 2140944 is expected to move into Phase III in 2015/16.

As noted, Roche has returned to the antibiotics space and several other companies are also having antibiotic R&D success. For example, Wockhardt received GAIN status for two MRSA drugs, WCK 771 and WCK 2349, and Cempra Pharmaceuticals, which specifically focuses on antibacterials, recently received a $10-million milestone payment from Toyama Pharmaceutical for its work on solithromycin, a ketolide antibiotic under development. The payment was made after Toyama received regulatory clearance to begin a Phase II trial of solithromycin in Japan. At the end of September, Cempra itself announced that it had finished enrolment for the global Solitaire-Oral Phase III clinical trial of oral solithromycin for severe community-acquired bacterial pneumonia. The data are expected to be announced in the first quarter of 2015. A second antibiotic, Taksta (CEM-102), is also in clinical trials for prosthetic joint infections.

Of course, many investigational drugs don’t make it to market, but we can at least expect more drugs to enter the pipeline as GAIN and other recent incentives gather momentum.

Antibiotics and academia

Academic researchers have also been investigating the mechanisms behind drug resistance and identifying new classes of antibiotics.

One development that made headlines in late September came from the Massachusetts Institute of Technology where researchers used genetic engineering to tackle drug-resistant bacteria. Teams led by Timothy Lu, an associate professor of biological engineering, electrical engineering and computer science, found two different methods of potentially fighting drug resistance (3). The first is to use new CRISPR gene-editing technology to target those genes responsible for antibiotic resistance. The second approach involves a new system called CombiGEM, which can be used to search for genetic combinations that make bacteria vulnerable to antibiotics. It’s designed as a high-throughput technology, but while it reveals what combinations render bacteria vulnerable, it leaves a great deal of downstream work to translate any findings into drugs that mimic the effects.

In March 2014, a team from the University of Notre Dame used in silico screening to identify a new class of non-β-lactam antibiotics called oxadiazoles, which showed promise in mouse models of infection (4). More than one million compounds were screened in the process and oxadiazole was found to inhibit a penicillin-binding protein (PBP2a), and biosynthesis of the cell wall, which aids MRSA’s drug resistance.

In addition to seeking new antibiotics and enhancing our understanding of bacteria, work on diagnostics offers a different angle of attack. For example, a rapid diagnostic test for multi-resistance to broad-spectrum antibiotics has been developed at the University of Fribourg (5). The large-scale application of such tests could help to control the spread of certain traits to antibiotic resistance – and guide the few remaining treatment options.

All things considered, it has been a good year for antibiotics. But the war on resistance is far from over and we are still seeing antibiotics being prescribed in inappropriate situations; this was highlighted recently when it emerged that Thomas Eric Duncan, the first patient to develop Ebola in the US, was originally sent home with antibiotics from the hospital he visited after falling ill.

Continued (or better yet increased) focus from pharmaceutical companies, academia, and world governments will help to give us a fighting chance for the future, but we’ll also need to see increased vigilance from medical staff with regards to curbing overuse.

Roche Returns

We caught up with Janet Hammond (Global Head of Infectious Diseases at Roche Pharma Research and Early Development) about the company’s return to the antibiotic field.

Roche has a history in antibiotics – why did it move out of the space?

Roche indeed has a long history of antibiotics development; it introduced Bactrim in 1969, and its active ingredient co-trimoxazole has since been administered in about two billion doses. Bactrim and its generic forms have become a standard treatment for infection, particularly in developing countries. In 1982, Roche launched Rocephin, a broad-spectrum once-daily injectable antibiotic used to treat a wide range of bacterial infections. Rocephin quickly became Roche’s top-selling drug and the world’s number one injectable antibiotic.
We exited the antibiotics space in 1999 – at that time, it seemed that the unmet medical need was largely addressed.

What prompted Roche’s recent return?

The incidence of drug-resistant infections is creating an urgent demand for new therapeutic options, so we believe that this is now an area of unmet need and have accordingly decided to re-enter the antibiotics R&D arena.
In our antibiotics efforts we will focus on targeting a single pathogen. For example, RG7929 is an investigational compound targeting the lipopolysaccharide-assembly protein located on the outer membrane of Pseudomonas aeruginosa. A phase II clinical trial evaluating RG7929 as an antibacterial therapy is ongoing.

How can governments and regulators help?

Governments and regulatory authorities have already created special pathways for new antibiotics given the very high unmet need. Moreover, regulatory agencies have provided major incentives for antibiotic developers to research and develop new compounds. For instance, the FDA recently created the Qualified Infectious Disease Product designation for antibiotics in development that are active, both in vitro and in animal models, against multi-drug resistance species. The EMA has recently introduced guidance for the pathogen-specific approach.
Separately, we are convinced that the development and approval of point-of-care, pathogen-specific assays that can be used at the bedside is necessary to avoid or reduce empirical prescribing and thus potentially reduce the development of resistance. Therefore, pathogen-specific diagnostic methods are being encouraged by both regulators and infectious disease experts.

How do new antibiotic development programs differ from pre-1999 efforts?

Our understanding of microbiology has advanced considerably since the 1990s – we now have the bacterial genome sequenced for all pathogens, we understand much more about bacterial metabolism, and other ways in which bacteria are able to colonize and invade to cause infections. This new knowledge allows us to address and find new targets and ways of diagnosing and treating infection.
Bacteria will continue to evolve to elude our attempts to control them and it is increasingly apparent that we will need to continue to develop new ways to address what will be an ongoing problem. To combat the growing threat of resistance, Roche has established three pillars of antibacterial research: overcoming resistance, identifying new targets and tackling virulence or host factors. We have identified the need to not only develop broad-spectrum antibiotics but also pay attention to the requirement for narrow-spectrum agents.