Finally, the market wakes up to resistance

MRSA bacteria. Image courtesy University of Texas Health Science Centre.

The field was out of fashion – deserted in favour of developing treatments for chronic diseases that are dispensed over a long term – but now the confluence of medical need, new targets and new discovery technologies is turning the tide.

The number of new antibiotics approved for use by the US Food and Drug Administration has fallen by 56 per cent in the last 20 years. Only two new classes of antibiotics, which work via a novel mechanism of action, have been approved since 2000, linezolid and daptomycin.

But as resistant strains of bacterial infections like methicillin-resistant Streptococcus aureus (MRSA) and streptococcal pneumonia threaten to take hold in hospitals, and to spread to the wider community, there is a growing need for new, effective treatments.

The increasing problem of antibiotic resistance was acknowledged in an EU research programme launched in March with €11.5 million funding over five years to focus on genomics-based approaches to antibiotic-resistant infections.

On top of the threat posed by hospital-acquired infections, the aftermath of 11 September 2001 sparked concerns about bioterrorism and the possibility of engineering pathogens to make them resistant to currently available antimicrobial drugs.

Pharma gets back into antibiotics

Novartis is paying £305.1 million cash for NeuTec, a company spun out of Manchester University in 1997 to develop treatments for hospital–acquired infections, such as the infamous MRSA, based on antibodies from patients who survived infections caught following surgery.

On a smaller scale, in May, Merck agreed a strategic partnership with Intercell AG of Vienna, to develop antibody-drugs against MRSA. The Austrian company, which in common with NeuTec works on antibodies from patients who recover from infections, has a similar deal with Kirin Brewery of Tokyo, Japan in Steptococcus pneumoniae.

But it was Pfizer that set the market alight in September last year, when it paid $1.9 billion for US biopharmaceutical company Vicuron Pharmaceuticals, a specialist in the development of antibiotics for hospital and community acquired infections.

The semi-detached approach

Before this, pharma had recognised the market need for new antibiotics, but simultaneously signalled that they were not a priority, by spinning out antibiotic portfolios. In October 2000 F. Hoffman La Roche span out Basilea Pharmaceutica to commercialise its antibiotic and antifungal intellectual property. The value of the technology was demonstrated in February 2005 when Basilea signed a $302 million deal with Cilag (part of Johnson & Johnson) for its lead product ceftobiprole.

Similarly, in December 2004, Sanofi-Aventis span out Novexel to develop antibiotics. At the time, the company raised €40 million in a round led by Atlas Venture. More recently, Sandoz (which is owned by Novartis) span out Nabriva, a small molecule antibiotic research company, in February this year. The company raised €42 million in a funding round led by Nomura Phase4 Ventures of London.

Rodger Novak, CEO of Nabriva, said the company would develop broad-spectrum antibiotics. “We hope to bring a treatment for respiratory tract infections to Phase I in the next 12 months.” David Chiswell, founder and former CEO of Cambridge Antibody Technology Group, has been appointed chairman.

The changing trend

“Bugs are developing and changing all the time and we need to keep ahead,” says Matt Borg, Chief Operations Officer at RecombinoGen, of Guildford, UK.

To date RecombinoGen has raised over £500,000 to develop novel antibiotics effective against a number of multi-drug resistant bacteria, including MRSA. The company recently secured funding from the University of Surrey Seed Fund and a grant from the South East England Development Agency, and has attracted Robert Mansfield, former CEO of Vernalis, as executive chairman.

Recombinogen’s High Frequency Recombination technology allows the rapid and targeted modification of bacteria based on an understanding of the role of individual bacterial genes. The company is applying the technique to modify existing antibiotics that are based on bacterial metabolites, in a bid to renew their effectiveness against resistant bugs.

“We haven’t yet progressed to clinical trials but, so far, the results from our new drugs have been very positive against streptococcal pneumonia and MRSA,” says Borg. The next step is to outlicense. “There is a growing realisation in the pharmaceutical world that antibiotic resistance is a serious threat so there is quite a lot of pressure to get as many drugs to the market as possible.”

“It is generally perceived that, with new classes of antibiotic, the likelihood of resistance is lower. This means that the more new classes we have, the better,” Borg explains.

Genomics intervenes

Genomics is increasingly showing its influence in the field, as demonstrated by Arrow Therapeutics plc of London, which has a platform technology the simultaneous detection of all genes necessary for bacteria to survive, and can rank each in terms of its relative importance.  Similarly, F2G Ltd of Manchester has a technology platform for pinpointing virulence genes in fungi.    

Prolysis Ltd is taking a different tack. Its lead programme is GYR-767, an inhibitor of DNA gyrase enzymes involved in DNA supercoiling, which targets two enzymes that are essential for bacterial survival. The second programme, CDI-936, targets staphylococcal infections, including MRSA. It works by inhibiting FtsZ, a protein essential to cell division, preventing bacteria forming a septum.

“I think there has been quite a sea change in the last year as people are starting to recognise that antibiotic resistance is a growing threat, and that it is economically important,” says Lloyd Czaplewski, research director. “Antibiotics were not seen as trendy by VCs in the early 90s but there has been a big boost in funding in the last year.”

Prolysis is based on research carried out at Oxford University by Jeff Errington, an expert in the bacterial cell cycle. The company raised $9.9 million last year from existing investors, and is now looking for partnering deals.

“In our work we look at the whole bacterial cell and search for novel activities inside the cells that we can therapeutically target,” said Czaplewski. “A great deal of current research on antibiotics is hampered by the fact that positive results from lab assays are not always reliable indicators of what will happen in the bacterial cell as a whole.”

Not all new

The potential of bacteriophages, tiny viruses that specifically infect bacterial cells, was originally overshadowed by the development of penicillin, but antibiotic resistance has stimulated renewed interest. Phico Therapeutics has revived their fortunes with SASPject. This uses a bacteriophage to deliver a broad spectrum antibacterial protein, which prevents bacteria from replicating.

Last year, the company raised almost £700,000 from business angels including Cambridge Capital Group, Oxford Investment Opportunity Network (OION) and institutional investor Providence Investment Company.

No single antibiotic is perfect but the market urgently needs new, effective alternatives to the current treatments that bugs that are continually managing to evade through mutation. All of these new technologies appear provide potential solutions and their creators are gradually re-establishing the flow of investment into this area after a lull that has left us with a serious shortage of choices.