Allergan PLC/AstraZeneca PLC received a limited use indication for the gram-negative antibiotic Avycaz (ceftazidime/avibactam), setting up a test-run for how FDA may handle a formal limited-population drug approval pathway.

The combination antibiotic was cleared Feb. 25 based on Phase II data, for use in adults with complicated intra-abdominal infections (cIAI) including kidney infections, and complicated urinary tract infections (cUTI) in combination with metronidazole.

The indication and usage sections of labeling come with a caveat that because only limited clinical safety and efficacy data for Avycaz are currently available, use is to be reserved for patients who have limited or no alternative treatment options.

The Phase II data for the approved indications were from trials not designed with any formal hypotheses for inferential testing against the active comparators, FDA noted in announcing its approval of the drug.

FDA denied a third indication for aerobic gram-negative infections, including hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) and bacteremia, because the company had no clinical trial data in that setting.

Actavis said it did not receive a “complete response” letter for this indication but will submit data from ongoing Phase III studies for this indication as a supplemental NDA. The studies should be completed by the end of 2015. Phase III data for the approved indications also will be submitted to FDA as part of the sNDA.

The application was a 505(b)(2) NDA relying on the agency’s previous findings of safety and effectiveness of ceftazidime, which has been approved as a single agent since the 1980s. The novel agent, avibactam, was added to the drug to help expand its coverage and fight off bacteria that have developed resistance to ceftazidime.

The rejection of the HABP/VABP indication may give sponsors a clue as to where FDA draws the line on flexibility for those developing antibiotics that address unmet need. It also offers a sense of what FDA may do if Congress enacts a formal limited population antibiotic development pathway (LPAD). FDA’s advisors drew a similar line at the drug’s advisory panel Dec. 5, saying human data were not optional for approval ([A#14141205006]).

While Actavis had Phase II studies for cUTI and cIAI and some preliminary Phase III data for FDA to review, for HABP/VABP it relied only on clinical experience with ceftazidime alone, efficacy of the combo in animal models of bacteremia and pneumonia, and an epithelial lining fluid (ELF) study demonstrating that ceftazidime and avibactam are able to penetrate in ELF to a similar extent and with similar kinetics.

The limited population approach to antibiotic development has been pushed for on Capitol Hill since the last prescription drug user fee reauthorization in 2012. Draft legislation put forth by the House Energy and Commerce Committee Jan. 27, the 21^st Century Cures Act, includes an LPAD pathway that would allow for the approval of antimicrobials or antifungals designed to treat a serious or life-threatening disease or infection in a limited group of patients ([A#14150127007]).

The draft bill says FDA and sponsors would agree on a development program that could allow for the use of alternative endpoints, Phase II data and real-world data; FDA’s advisors have endorsed a similar concept. However, FDA officials have long held they have existing regulatory authority for such approvals Also see "Targeted Antibiotics Could Get Limited Data Approval Option From FDA" - Pink Sheet, 11 February, 2013..

Yet, FDA told “The Pink Sheet” DAILY that although it has the authority to approve antibacterial drug products for limited populations, “it does not have a well-defined pathway to speed the approval of those products.”

The agency said it has approved other antimicrobials for use in limited populations or for use in patients with disease refractory to other treatments, citing the December 2012 approval of Johnson & Johnson’s Sirturo (bedaquiline) for treating multi-drug resistant tuberculosis in patients without other therapeutic options and the HABP/VABP indication of Innoviva Inc.’s Vibativ (telavancin), which states that the drug should be reserved for use when alternative treatments are not suitable Also see "Theravance Re-Introduces Vibativ In The U.S. Independently (For Now)" - Pink Sheet, 14 August, 2013..

Avycaz Label Notes Increased Mortality In Phase III

While FDA said Avycaz’s approval was based on Phase II data, the label indicates the agency is incorporating Phase III data as it is made available.

The clinical trials section notes increased mortality of Avycaz patients in a Phase III study, which was correlated to renal function.

More patients on Avycaz plus metronidazole died in a Phase III cIAI study (13/529 or 2.5%) compared to those on meropenem (8/529 or 1.5%). The death imbalance was driven by patients with renal impairment: eight of 31 renally impaired patients on Avycaz and metronidazole died (25.8%) compared to three of 35 (8.6%) renally impaired patients in the control arm. When patients with normal renal function or mild renal impairment were examined, the death rate in both arms was equal.

Concerns about lower clinical cure rates in patients with moderate renal impairment were raised at the advisory committee; both FDA and the sponsor proposed dosage adjustments and the advisory panel recommended either a warning or boxed warning.

The approved labeling includes a warning of decreased efficacy in patients with renal impairment and the need to monitor creatinine levels at least daily. The label also offers dosage adjustments based on creatinine levels.

Cubist Pharmaceuticals Inc.’s(now Merck & Co. Inc.) gram-negative antibiotic for cUTI and cIAI, Zerbaxa (ceftolozane/tazobactam), approved in December 2014, also came with a warning about decreased efficacy in renal patients ([A#00150105009]).

FDA also set a mandatory post-marketing requirement for a clinical trial to assess the signal of increased mortality and decreased efficacy in patients with moderate renal impairment, though it also allows for submission of data from the Phase III cIAI trial to fulfill the requirement. The approval letter notes Actavis submitted a timetable for resolving this issue on Feb. 11 and a final report is due by December 2015.

The agency also attached a post-marketing requirement for a prospective study, over a five-year period, to assess the emergence of resistance to Avycaz in the target population of bacterial infections identified in labeling. That includes Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in cIAI and E. coli, K. pneumoniae, Citrobacter koseri, Enterobacter aerogenes, E. cloacae, Citrobacter freundii, Proteus spp., and P. aeruginosa in cUTI.

Avycaz is the fifth qualified infectious disease-designated product (QIDP) approved by FDA, giving it five additional years of marketing exclusivity.

Actavis will market the drug in the U.S. and said it will be available in the second quarter of 2015. AstraZeneca has rights to the drug outside the U.S. but is waiting for the Phase III data to submit for regulatory approvals.

Actavis’ Avycaz Approval Shows How FDA Handles Limited-Data, Limited-Use Antibiotic

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