The growth of antibiotic-resistant "superbugs" is leading to the fear that it is only a matter of time before the world is faced with an infectious disease of pandemic proportions. Despite this situation, research and development for new antibiotics has languished. Indeed, it has been an uncomfortable subject to raise in industry circles but the plain fact is that the emergence of antibiotic resistant strains of bacteria are outpacing our ability to bring novel medicines to market.

The medicine cabinet for new antibiotics is almost empty. It's a legacy of big pharma's decision to exit what was seen as an unprofitable area of research in which to invest. There are only four companies still actively conducting research, down from 18 companies active in the field in the early 1990s.

In the past few months however, the "penny may have dropped" that more research is needed with both Europe and the U.S. setting in motion programs designed to accelerate the development new antibiotics.

In Europe the "NewDrugs4BadBugs" research program represents a pioneering approach to antibiotic research that will bring pharmaceutical and biotechnology companies together to work alongside public partners to tackle the rising threat from antimicrobial resistance and address some of the key barriers to the development of effective antibiotics. The program is part of the European Commission's Action Plan against the rising threats from antimicrobial resistance, launched in November last year. (See BioWorld Today, May 30, 2012.)

In the U.S., the Generating Antibiotic Incentives Now (GAIN) program, included in the FDA Safety and Innovation Act (FDASIA), also is designed to provide pharmaceutical and biotechnology companies with incentives to develop innovative antibiotics. The GAIN provisions are intended to improve upon the depressing statistics that between 2008 and 2010, only two new antibiotics were approved compared with the 16 introduced to the market during the period 1983 to 1987. (See BioWorld Insight, June 11, 2012.)

The GAIN Act will provide incentives for development of qualified infectious disease products, including antibiotic drugs for resistant pathogens, and companies may benefit by receiving fast track status, priority review, or exclusivity for its products. Under the GAIN Act, the FDA will be required to provide sponsors of qualified infectious disease products with written recommendations for nonclinical and clinical studies necessary for approval, and to review and revise, as appropriate, guidelines for conduct of trials for antibiotic drugs.

It remains to be seen how these initiatives will play out but some of the companies that could benefit were in San Francisco last week presenting results at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Novel Targets

Trius Therapeutics Inc., for example, reported on preclinical studies related to a new class of broad-spectrum, gram-negative antibacterial agents that are directed against novel targets Gyrase B (GyrB) and ParE. (See BioWorld Today, Sept. 13, 2012.)

Currently there are no antibiotics in clinical use that inhibit both GyrB and ParE – two microbial enzymes essential for the replication of bacteria. The data showed significant potency in treating challenging gram-negative bacteria associated with hospital-acquired infections, such as Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumonias, and biodefense pathogens such as Yersinia pestis (plague), Francisella tularensis, Burkholderia mallei and Burkholderia pseudomallei.

According to Piper Jaffray analyst Edward Tenthoff, Trius' new gyrase inhibitor program represents "a huge potential for the company." This is in addition to its antibiotic tedizolid phosphate for acute bacterial skin and skin structure infections, which completed one successful Phase III trial and is in another Phase III trial. (See BioWorld Today, Dec. 20, 2011.)

"The GAIN Act provides companies like Trius with new regulatory options that can facilitate our efforts to develop effective new treatments for infections caused by drug resistant bacteria," said Jeffrey Stein, president and CEO of Trius, in a statement.

If the current Phase III results are positive, Tenthoff notes that Trius could file a new drug application in the second half of 2013 and tedizolid could reach the market under accelerated review under the GAIN Act by mid-2014.

Rib-X Pharmaceuticals Inc., of New Haven, Conn., is another company that has had positive things to say about the advantages of the GAIN Act. At ICAAC the company reported data demonstrating the broad-spectrum activity of its RX-04 compounds, including when administered at single low doses. A study conducted in a Streptococcus pneumoniae lung infection model established the potential for that class of compounds to address respiratory pathogens. Studies also showed the activity of those antibiotics across a diverse array of bacterial pathogens, including five major biodefense pathogens. (See BioWorld Today, Sept. 13, 2012.)

According to Erin Duffy, chief scientific officer at Rib-X, the RX-04 program has significant potential to produce drug candidates that directly address urgent public health threats caused by the most difficult to treat pathogens.