BioWorld Today Contributing Writer

Enanta Pharmaceuticals Inc. is banking on bicyclolides with a new $42.7 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to support five years of development of the drugs as medical countermeasures against biodefense category A and B bacteria.

Bicyclolides, a new class of bicyclic antibiotics, have shown strong activity against resistant pathogens, including superbugs like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). Enanta will use the funds to advance new bicyclolide candidates into clinical development.

Bicyclolides were invented by Enanta. The molecules have a dual ring structure, which is different from other antibiotic agents.

"The bugs have not really encountered structures like this in the past," Enanta CEO Jay R. Luly told BioWorld Today.

Enanta designed them to bind to the bacterial ribosome, and investigators have found the drugs to be effective against a broad range of pathogens, including MRSA, VRE and resistant streptococci, as well as biodefense pathogens like anthrax, plague and tularemia.

The Watertown, Mass.-based company originally focused on respiratory tract infections, but, like the pathogens its products attack, Enanta has adapted and changed to take advantage of opportunities presented by the results of its experiments with the drugs.

Luly said respiratory tract infections are a "pretty tough area" for a small company to be competitive in. "You need a large sales force, and so on," he said. The bicyclolide molecules showed activity against MRSA and VRE, so Enanta began pursuing those in addition to the original set of respiratory infections. Adding serious hospital-acquired infections gave it more room to compete as a small biotech company.

It turned out that the compounds worked well not only against hospital-acquired MRSA, but community-acquired MRSA strains as well. That was good news for Enanta, because community-acquired MRSA is becoming much more common and is an area of increasing need.

And when the compounds showed activity against biodefense pathogens, an opportunity to seek funding through government biodefense contracts arose.

The company outsourced some studies of bicyclolides against a set of biodefense pathogens, and when the NIAID put out its broad area announcement (BAA) for the contract, it was ready to make a proposal.

Much of the work supported by the NIAID contract, through Phase I studies, will be directly applicable to development of the drugs in its nonbiodefense indications. "It doesn't matter what your indication is," Luly said. "Those steps are the same. It could be for any indication."

Based on Enanta's early studies, there are indications that the bicyclolide class of antibiotics will be difficult-to-impossible for bacteria to overcome with drug resistance.

Enanta's resistance tests showed that it is difficult to induce resistance to bicyclolides in pathogens. The drugs have a primary and secondary binding site within the bacterial ribosome.

The natural strategy for bacteria to develop resistance to the drug is to remove that binding site. That mutation would be a rare event all by itself. Because there is an auxiliary binding site, as well, the odds against a bacteria undergoing the multiple mutations necessary to resist the bicyclolide become extremely high, creating a very high barrier for resistance.

Luly described Enanta as a "well-capitalized private company." However, it is also a company on the lookout for lucrative funding opportunities. "Even well-capitalized private companies are always looking for ways to stretch the dollar further, especially in these tough times where capital is expensive."

In addition to this year's enviable $42.7 million NIAID contract, Enanta took home several Therapeutic Discovery Tax Credit awards in 2010. Those awards were part of the Patient Protection and Affordable Care Act signed by President Obama in March 2010, setting aside $1 billion in tax credits or grants for small- to medium-sized companies in the biotech and pharmaceutical industries.

"We have radar out looking for alternate funding vehicles all the time," Luly said.

In addition to its antibiotic programs, Enanta also has an interest in hepatitis C virus (HCV). In April, Enanta and its partner Abbott reported 12-week results from a Phase II trial of ABT-450/r (ABT-450 and ritonavir), an oral protease inhibitor for HCV, which showed that 92 percent of patients taking ABT-450/r once daily combined with the standard-of-care ribavirin and pegylated interferon-alpha achieved complete early virologic response at 12 weeks.

HCV protease is the target of telaprevir, successfully marketed by Vertex Pharmaceuticals Inc.

Luly said that the HCV program is "going exceptionally well," and he views the market for antibacterials as ascendant.

"Antibacterials have come up and down . . . the time for antibiotics is coming back up again," Luly noted. "One thing that's always true is that bugs never go to sleep. They keep mutating and mutating and mutating and creating more resistance. The FDA and drug companies are going to have a serious public health situation on their hands if people don't take steps to replenish pipeline."