Skipping Past Congress: Limited Use For AZ/Actavis Antibiotic Gets FDA Review
This article was originally published in The Pink Sheet Daily
Executive Summary
Dec. 5 advisory panel for AstraZeneca/Actavis’ gram-negative antibiotic should shed light on how FDA envisions limited-use pathway requirements and labeling might work; FDA officials maintain the agency doesn’t need LPAD legislation to approve limited use antibiotics.
AstraZeneca PLC/Allergan PLC’s Dec. 5 advisory panel review of its gram-negative combination antibiotic ceftazidime/avibactam includes a proposed “limited use indication,” for aerobic-gram negative infections with limited treatment options, demonstrating what FDA has said for years – it doesn’t need Congress to pass the ADAPT Act to approve antibiotics for narrow indications based on limited data sets.
The meeting should offer an important first glance at how FDA is putting the limited population antibacterial drug pathway (LPAD) approach into action. Revealing details that could emerge may include the trial designs FDA requested for the limited use indication, how FDA expects labeling would look, what kinds of post-market studies it will expect, and what types of stewardship efforts, if any, it may be able to ask sponsors to engage in to help control the limited use.
The LPAD pathway was a late proposal during the debate on the 2012 FDA Safety and Innovation Act, but missed the legislative train, which included market exclusivity benefits of the Generating Antibiotic Incentives Now provisions (Also see "With GAIN In Place, Antibiotic Improvements Depend On FDA Implementation" - Pink Sheet, 13 Aug, 2012.).
The concept has been reintroduced in the pending ADAPT legislation, and could find a home in the legislative package that Energy & Commerce Committee Chairman Fred Upton, R-Mich., is developing as part of the 21st Century Cures Infinitive (Also see "Biomedical Reform Legislation Draft Could Be Released By January" - Pink Sheet, 11 Sep, 2014.).
The idea behind LPAD is to allow for faster antibiotic approvals and incentivize developers of products for antibiotic-resistant disease, by allowing for narrow indications based on more limited data gathered for small patient populations with unmet medical need.
FDA leadership, including the Center for Drug Evaluation and Research’s Bob Temple, deputy director for clinical science, CDER Director Janet Woodcock and Ed Cox, director of the Office of Antimicrobial Products, have all said that the agency already has this authority through existing regulations (Also see "Targeted Antibiotics Could Get Limited Data Approval Option From FDA" - Pink Sheet, 11 Feb, 2013.).
However, FDA has worried about its inability to control off-label use and the stewardship implications if it approves antibiotics under this limited-use paradigm (Also see "FDA Worries About Off-Label Use, Stewardship With Limited-Population Approval Pathway" - Pink Sheet, 11 Feb, 2013.).
A $10,000 Drug?
The Anti-Infective Drugs Advisory Committee will review AstraZeneca/Actavis’ ceftazidime/avibactam for injection for complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI), including acute pyelonephritis and a limited use indication: aerobic gram-negative infections with limited treatment options, a Nov. 7 Federal Register notice says.
Ceftazidime/avibactam was already allowed regulatory flexibility. FDA permitted a 505(b)(2) NDA based on Phase II data and references to existing drugs because the active antibiotic component ceftazidime is already approved, and the novel agent, avibactam serves primarily to expand the antibiotic’s coverage.
Phase III data in cIAI and cUTI are expected to be submitted as a supplement to FDA when the data are finalized. AstraZeneca announced positive top-line data from two Phase III studies investigating the combo in hospitalized adults with cIAI in August.
The combo was administered with metronidazole and compared to meropenem. Pooled data from both studies per agreement with the FDA and European Medicines Agency showed ceftazidime/avibactam was statistically non-inferior to meropenem. The combo met the primary endpoint of clinical cure rate 28 to 35 days after randomization and treated patients infected with ceftazidime-resistant bacteria as effectively as meropenem. Adverse event rates were similar in both study arms.
The combination product works by combining ceftazidime, a cephalosporin, part of a drug class called beta-lactamase, with a novel beta-lactamase inhibitor that helps protect the active antibiotic against the destroyer enzymes that bacteria have developed to fight off beta-lactamase antibiotics (Also see "Market Snapshot: Gram-Negative Antibiotics Progress As Urgency Grows" - Pink Sheet, 3 Mar, 2014.).
Antibiotics to treat resistant gram-negative infections are of a particularly high public health need, in the already struggling antibiotic marketplace. As such, drug makers have indicated they expect new gram negative treatments could command higher prices.
Industry has floated a price point of $10,000 and higher for a course of antibiotic therapy that addresses high unmet medical need and AstraZeneca/Actavis are positioned to be one of the first to test this theory.
Cubist Pharmaceuticals Inc.’s pending NDA for Zerbaxa (ceftolozane/tazobactam), which has a Dec. 21 user fee date, could beat the A-Team to market, however. Cubist’s product is under review for cIAI and cUTI, including infections caused by multi-drug resistant Pseudomonas aerguinosa (Also see "Reinvigorated Antibiotics Pipeline Could Produce Four NMEs In 2014" - Pink Sheet, 30 Jul, 2014.).
A decision on AstraZeneca/Acatvis’ combo is expected in the first quarter of 2015. Both drugs were granted Qualified Infectious Disease Product status, a part of the GAIN provisions which provides for fast-track, priority review and an additional five years of exclusivity to be added to other exclusivities.
Forest Laboratories Inc., now subsumed into Actavis, holds the North American rights to the combination, while AstraZeneca holds the rights to commercialize the product elsewhere.
The drug also is being studied in nosocomial pneumonia and for the treatment of cIAI and cUTI patients with ceftazidime-resistant infections.