The FDA approved Avycaz (ceftazidime/avibactam) to treat adults with complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs), offering a promising option to fight drug-resistant superbugs. Avycaz, which combines a cephalosporin that demonstrated in vitro activity against certain gram-negative and gram-positive bacteria and a non-beta-lactam beta-lactamase inhibitor, will be marketed in North America by developer Actavis plc, of Dublin, and elsewhere by partner Astrazeneca plc, of London.

The drug received a priority review based on phase II data and supporting in vitro data and was approved as a qualified infectious disease product, or QDIP, through the Generating Antibiotics Incentives Now Act, making it eligible for the FDA's fast track program and a five-year extension of exclusivity under the Hatch-Waxman Act. While in development, ceftazidime-avibactam was among a handful of candidates identified by the Infectious Diseases Society of America as addressing multidrug-resistant (MDR) gram-negative bacilli (GNB) bacteria, which are the most difficult drug-resistant pathogens to treat and have the fewest treatment options. (See BioWorld Today, April 22, 2013.)

The priority review and QDIP designations limit the drug's use to patients with limited or no other therapeutic options.

Approval was supported, in part, by the FDA's previous findings of efficacy and safety for ceftazidime to treat cIAI and cUTI. The contribution of avibactam to Avycaz was primarily established through in vitro data and animal models of infection. Avibactam inactivates and protects ceftazidime from degradation by key beta-lactamases, including extended spectrum beta-lactamases, or ESBL, Klebsiella pneumoniae carbapenemase, or KPC, and AmpC-producing pathogens.

Avycaz was studied in two randomized, blinded, active-controlled phase II trials – one each in cIAI and cUTI, including pyelonephritis. The phase II studies were not designed for inferential testing against active comparators. However, the company also conducted several phase III studies and is evaluating Avycaz in additional phase III trials in cIAI and cUTI. Those studies are targeted for completion in late 2015, according to Cortellis Clinical Trials Intelligence.

The company plans to submit the phase III results to the FDA as a supplemental new drug application, according to C. David Nicholson, executive vice president for global brands research and development at Actavis.

The drug, which is expected to be available by midyear, was approved to treat cIAI in combination with metronidazole.

Treatment in cUTI includes the targeting of pyelonephritis caused by designated bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa (P. aeruginosa). Sales of the drug are projected to exceed $490 million annually in 2020, according to Cortellis Competitive Intelligence.

'BUGS WILL CONTINUE TO EVOLVE'

Avycaz has a history almost as complicated as the diseases it targets. Actavis gained the drug in its $28 billion acquisition of Forest Laboratories Inc., which, in turn, acquired North American rights to the drug in 2009 in conjunction with Astrazeneca's purchase of antibiotic developer Novexel SA, of Paris. Forest had previously owned a piece of the broad-spectrum beta-lactamase inhibitor, then known as ceftazidime/NXL104, and paid Novexel – as an Astrazeneca property – $210 million as part of an overall deal valued at up to $505 million. (See BioWorld Today, Dec. 24, 2009, and July 3, 2014.)

Forest and Astrazeneca then split development costs of ceftazidime/NXL 104 and a second candidate, ceftaroline/NXL 104 (now ceftaroline/avibactam), which remains in development.

Actavis further expanded its infectious disease product portfolio last year with the purchase of Durata Therapeutics Inc. for $675 million, plus contingent value rights of up to $5 per share linked to regulatory and commercial milestones for lead product Dalvance (dalbavancin), which had gained FDA approval earlier in the year. (See BioWorld Today, May 27, 2014, and Oct. 10, 2014.)

Thus, "Avycaz is an important addition to the range of products we've been making available" in the antibacterial market, Nicholson maintained.

But Actavis isn't the only game in town targeting gram-negative pathogens. In December, the FDA also approved Zerbaxa (ceftolozane/tazobactam) to treat cIAI and cUTI. Days earlier, Merck and Co. Inc., of Whitehouse Station, N.J., acquired that drug's developer, Cubist Pharmaceuticals Inc., for $102 per share in cash, for a total transaction value of approximately $9.5 billion. (See BioWorld Today, Dec. 9, 2014.)

The FDA approved two other antibacterials last year – Sivextro (tedizolid, Cubist) in June and Orbactiv (oritavancin, The Medicines Co.) in August – but those drugs target gram-positive bacteria infections, including methicillin-resistant Staphylococcus aureus, or MRSA. (See BioWorld Today, June 24, 2014, and Aug. 7, 2014.)

However, another gram-negative candidate could be on the way with a combination beta-lactamase inhibitor/carbapenem candidate, dubbed Carbavance, developed by Rempex Pharmaceuticals Inc. The company was acquired at the end of 2013 by The Medicines Co., of Parsippany, N.J., which last year moved Carbavance into a pivotal program in carbapenem-resistant Enterobacteriaceae, or CRE – one of the deadliest gram-negative bugs. (See BioWorld Today, Dec. 5, 2013, and Nov. 6, 2014.)

Just last month, Roche AG, of Basel, Switzerland, expanded its footprint in the antibacterial space in a big way, paying $750 million for a phase I beta-lactamase inhibitor, OP0595, that targets beta-lactamase enzymes in combination with new or existing beta-lactam antibiotics to enhance their effectiveness in difficult-to-treat bacterial infections. That deal was inked with Meiji Seika Pharma Co. Ltd., of Tokyo, and Canada's Fedora Pharmaceuticals Inc., which collaborated on the drug's early development. (See BioWorld Today, Jan. 14, 2015.)

Earlier, Roche crafted a series of deals for antimicrobial assets, including in-licensing of POL7080 (now RG7929) to treat MDR bacterial strains of P. aeruginosa from Polyphor Ltd., of Allschwil, Switzerland, and inking a global collaboration and license agreement with Discuva Ltd., of Cambridge, UK, to discover and develop antibiotics for life-threatening infections caused by MDR gram-negative bacteria. Roche and Atlas Venture-backed Spero Therapeutics LLC, of Cambridge, Mass., also are partnered in an effort to develop anti-infectives for drug-resistant bacterial infections, targeting a pathway that involves both virulence and persistence of gram-negative bacteria such as P. aeruginosa. (See BioWorld Today, Nov. 5, 2013, and April 10, 2014.)

But Roche is an exception in the space, where most antibacterial candidates are the purview of smaller pharmas and biotechs, said Jose Vazquez, professor of medicine, chief of infectious diseases and chairman of the antimicrobial subcommittee at the Medical College of Georgia/Georgia Regents University. Vazquez was a principal investigator in the original study of ceftazidime-avibactam at Novexel.

The need for new drugs is great, he emphasized.

"CRE is found in 48 of the 50 states now," Vazquez said, adding that MDR gram-negative strains that once existed only as hospital-acquired infections – especially those related to Escherichia coli (E. coli) – have spread to community settings and are increasing in frequency.

"We're seeing more bacteria that are resistant, and we're seeing more multidrug resistance in hospitals," he told BioWorld Today. "Given a little time, it will leak into the community. As a result, we've had to modify how we give treatment."

In the clinical setting, patients for whom Avycaz may be indicated, especially for cUTI, include many with lower limb paralysis or amputation who are more susceptible to infections that migrate to the kidney and may co-exist with bloodstream infections, according to Vazquez. The widespread presence of E. coli infections has exacerbated that phenomenon, he said.

The use of a non-beta-lactam beta-lactamase inhibitor makes Avycaz more potent and offers broader-spectrum activity, and the combination may slow – though it won't prevent – eventual resistance.

"Organisms are very adaptive and resilient," Vazquez conceded. "The only time an antibiotic doesn't develop resistance is when it's not used."

Nicholson agreed, acknowledging that "You can't really beat nature. Bugs will continue to evolve, and genomes will continue to mutate. The trick is to stay ahead of nature as long as possible while continuing to discover and develop novel antibiotics."