Slowly but surely the Generating Antibiotic Incentives Now (GAIN) Act introduced a couple of years ago is starting to exert a positive influence in the quest for the globally recognized urgent need for new antimicrobial therapies. Companies are taking advantage of all the legislation offers, including the FDA's Qualified Infectious Disease Products (QIDP) designation, which allows companies to achieve fast track status, priority review and extended exclusivity for subsequently approved drugs. At last count, the agency said it had granted 52 QIDP designations to 35 different molecules. And there will be certainly more to add to that list in the near future.

NEW ANTIBIOTICS

Encouragingly, in the past few months, we have also seen the approval of three new antibiotics, and there are a number of other potential therapies in late stage development. (See Table for a selected list of these compounds in development, below.)

In August, the FDA approved Parsippany, N.J-based The Medicines Co.'s antibiotic Orbactiv (oritavancin) making the acute care specialist the third player to get the green light to market an antibiotic product this year. The therapy is approved to treat acute bacterial skin and skin structure infections (ABSSSIs) caused by gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). (See BioWorld Today, Aug. 7, 2014.)

In June, Cubist Pharmaceuticals Inc. gained FDA approval for Sivextro (tedizolid phosphate) its once-daily oxazolidinone antibiotic for treating certain gram-positive bacterial infections, including MRSA. And a month earlier, Durata Therapeutics Inc. received the FDA approval for its antibiotic dalbavancin for use in acute bacterial skin and skin structure infections caused by gram-positive microorganisms, including MRSA. (See BioWorld Today, June 24, 2014, and May 27, 2014.)

Although Medicines Co. developed Orbactiv for the treatment of ABSSSI, it said it is also exploring the antibiotic's application in other indications, including for the treatment of Clostridium difficile, prosthetic joint infections, anthrax and other gram-positive bacterial infections.

The company also has three remaining products in line for potential approval during the next 12 to 18 months. With its purchase of Rempex Pharmaceuticals Inc., it added Carbavance, a beta-lactase inhibitor designated RPX7009. The compound is designed to inhibit Klebsiella pneumonia carbapenemases, the enzyme that acts as the primary resistance mechanism to carbapenems.

ACQUISTIONS PAYING OFF

Also benefitting from an acquisition was Cubist whose Sivextro realized the first big payoff from its $704 million acquisition of Trius Therapeutics Inc. Cubist's pipeline is also full of several products in late-stage testing, including the investigational gram-negative antibiotic ceftolozane/tazobactam, also known as CXA-201, as a potential treatment for complicated urinary tract infections and complicated intra-abdominal infections. The FDA has accepted for review its new drug application for ceftolozane/tazobactam and the agency has assigned the drug a Dec. 21 PDUFA date.

Cubist had a strong presence at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) earlier this month, Steven Gilman, chief scientific officer of Cubist, told BioWorld Insight. The firm's presntations provided a good perspective on the company's commitment to identifying treatments for drug-resistant gram-positive and gram-negative bacteria that cause serious infections.

"The meeting reaffirmed that there are still significant public health concerns about multidrug-resistant pathogens," Gilman noted. "It also pointed to the fact that there still remains only a small number of companies that are deeply involved in the space."

Recognizing the need for new therapies the company hopes to deliver at least four new antibiotics in support of the Infectious Diseases Society of America goal of 10 new antibiotics by 2020. It projects that it will invest approximately $400 million this year alone on antibacterial R&D.

Another company in the thick of antibiotics R&D is South San Francisco-based Theravance Biopharma Inc., with one approved product under its belt, Vibativ (telavancin), a once-daily, injectable lipoglycopeptide antibiotic for treating hospital-acquired and ventilator-associated bacterial pneumonia caused by Staphylococcus aureus.

The company has been committed to the antibiotics field for many years, Frank Pasqualone, senior vice president, development and operations at the company told BioWorld Insight.

Given the experience that the company has gained, its main focus going forward is to broaden the clinical scope of Vibativ against difficult-to-treat infections. "We have an aggressive clinical development program to expand Vibativ's product profile and are going to invest in a phase III registration trial for bacteremia," Pasqualone said.

The trial will be a multicenter, randomized, open-label study and is expected to enroll its first patient by the end of the year. It is designed to evaluate the noninferiority of the product in treating S. aureus bacteremia as compared to standard therapy.

Vibativ has a dual mechanism of action, which differentiates the product from the two single-mechanism antibiotics currently approved for the condition and also suggests that it may be less prone to resistance than other antibiotics. The first mechanism is similar to that of vancomycin by binding to and preventing polymerization of bacterial cell wall constituents, weakening the cell and causing cell death. It also interacts with the cell membrane, causing depolarization, again leading to cell death.

The company has also made a commitment to find out as much as it can about treatment and outcomes of telavancin. With that in mind, it is undertaking a proactive program designed to expand the product's profile and increase physicians' awareness about utilization in the right patient populations. That will be achieved through the Telavancin Observational Use Registry (TOUR) designed as a multicenter, observational, prospective study that will enroll approximately 1,000 patients from about 50 sites in the U.S.

MINING DATA

"We will mine the data from the study and provide useful information on the most effective use of telavancin back to the physicians," said Pasqualone.

After the overuse of antibiotics in years past, Pasqualone said he believes that we have started to become much more judicious with the use of antibiotics and the company's TOUR study will also contribute in helping health care providers continue that important trend.

Antibacterial stewardship was a central theme at the ICAAC meeting, said Gilman, and it is a major focus at Cubist. "Stewardship should be devised to optimize therapy not implemented just to merely save costs."

Another important aspect is the need to keep a step ahead of the organisms that cause infections and that will require continuous monitoring of resistance trends.

Following the release of the President's Council of Advisors on Science and Technology (PCAST) Antibiotic Resistance Report, Cubist said it commended the initiatives "for elevating the conversation and offering their recommendations to address the global health threat." (See BioWorld Insight, Sept. 22, 2014.)

"As the PCAST report states, there is no silver bullet to refill the pipeline and that is why we need to consider additional reforms."

It was a sentiment expressed by Pasqualone: "As a company, we are supportive of the White House's position regarding minimizing the spread of 'superbugs' including MRSA and furthering research in these areas of difficult-to-treat pathogens/infections."