A second attempt by Nabriva Therapeutics plc to win U.S. approval for the antibiotic Contepo (fosfomycin) has been undone by COVID-19. Manufacturing issues stymied the original NDA. This time, restrictions of FDA staff travel to Europe sunk the venture, leading to a new complete response letter (CRL) for the candidate as a potential treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis.

The company warned of the potential for the CRL in May. On June 19, when it announced the CRL, it said the FDA did not request any new clinical data, nor did it raise any other concerns about the safety or efficacy of Contepo in the CRL.

Nabriva CEO Ted Schroeder, frustrated by the impasse, told BioWorld on Monday that his team will work with Contepo’s manufacturers, which are required to initiate some of the requests to the FDA needed to move the program ahead. His team may also request a type A meeting in which it could again ask the agency to use a mutual recognition agreement with the EMA, which should allow it to rely on the EMA’s GMP inspections. “At the moment, we’re trying to figure out how we get to a strategy that helps the agency think creatively about how they may move forward,” he said.

Shares of the Dublin-based company (NASDAQ:NBRV) fell 4.4% to 79 cents on June 22, down 40.2% year to date.

The FDA told BioWorld on June 19 that it's continuing to assess the feasibility of a return to routine foreign inspections as conditions improve. As it monitors for change, it's relying on both the Department of State as well as its own domestic and foreign regulatory counterparts to inform that stance. For now, the State Department continues to advise against international travel. Meanwhile, the regulator is implementing alternative approaches to on-site surveillance inspections and has continued to perform mission critical inspections on a case-by-case basis, an agency representative said.

The alternative inspections can include among other things, evaluating paper and electronic records in lieu of conducting an on-site inspection on an interim basis, the agency said in March. In that respect, inspections conducted from afar parallel a major component of the usual in-person work, in which inspectors review paper and electronic documents for signs of proper management and validity while visiting clinical sites, Chad Landmon, chair of the intellectual property and FDA practice groups at Axinn, Veltrop & Harkrider LLP, told BioWorld. But that approach doesn't really replace the type of pre-approval inspections contractors are likely to face ahead of a potential drug approval, he said.

The initial CRL, issued on April 30, 2019, requested that Nabriva address issues related to facility inspections and manufacturing deficiencies at one of its contract manufacturers prior to FDA approval of the application.

The initial outcome, as well as the more recent development, was likely dispiriting to former shareholders of fosfomycin originator, Zavante Therapeutics Inc., who saw the company acquired for about 8.2 million Nabriva common shares in July 2018. They stand to see a $25 million regulatory milestone payout tied to first approval of the drug and up to $72.5 million in potential sales milestone payments.

Take two

Nabriva's resubmission of the Contepo NDA, acknowledged by the FDA around Jan. 8, was supported by data from a pivotal phase II/III trial, Zeus, which met its primary endpoint of statistical noninferiority to piperacillin/tazobactam (Zosyn, Pfizer Inc.) in patients with cUTI, including acute pyelonephritis.

The multicenter, randomized, double-blind Zeus trial evaluated the safety and efficacy of Contepo, then called Zolyd, in 465 hospitalized adults with cUTI or AP, the most common subset of cUTIs. Patients were randomized to 6 g of Contepo as a one-hour I.V. infusion three times daily or 4.5 g I.V. piperacillin/tazobactam as a one-hour infusion three times daily for seven days. Oral step-down therapy was prohibited. Patients with concurrent bacteremia received up to 14 days of therapy.

The primary endpoint, defined as clinical cure plus microbiologic eradication, was assessed in the microbiologic-modified intent-to-treat (MITT) population at the test-of-cure visit on day 19. Contepo achieved an overall success rate of 64.7% (119/184 patients) compared to 54.5% (97/178 patients) for piperacillin/tazobactam, a treatment difference of 10.2% (95% confidence interval [CI]: -0.4, 20.8).

The results of that study put Contepo in a similar league as Vabomere, a combination of vaborbactam and the carbapenem meropenem marketed by Melinta Therapeutics Inc., which was granted FDA approval for the treatment of cUTI, including pyelonephritis, in August 2017.

Contepo has been granted both qualified infectious disease product and fast track designations by the FDA for the treatment of serious infections, including cUTI.

An estimated 3 million cases of cUTIs caused by gram-negative bacteria are treated in U.S. hospitals each year, according to Nabriva. Enterobacteriaceae are the most common culprits and, currently, widespread antibiotic resistance limits the effective treatment options for treating the condition, the company said. According to Cortellis, treatment of UTIs in general has been dominated by quinolones, particularly levofloxacin, over the last 20 years. But fosfomycin has been used in various forms for decades in the EU to treat a range of infections, including gram-negative and gram-positive pathogens and multiple drug-resistant bugs.

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