FDA Issues Complete Response Letter to Nabriva for Intravenous Fosfomycin
The CRL requests that Nabriva address issues related to facility inspections and manufacturing deficiencies at one of Nabriva’s contract manufacturers prior to the FDA approving the New Drug Application.
The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Nabriva Therapeutics for intravenous fosfomycin (Contepo) for the treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis.
According to a press release, the CRL requests that Nabriva address issues related to facility inspections and manufacturing deficiencies at one of Nabriva’s contract manufacturers prior to the FDA approving the New Drug Application. Nabriva plans to request a “Type A” meeting to discuss the FDA’s findings. The FDA did not request any new clinical data and did not raise any concerns with regard to the safety of Contepo.
“We will be working with the FDA in the coming weeks to gain a full understanding of the FDA’s comments, with the goal of bringing this important treatment to patients as quickly as possible,” Ted Schroeder, CEO of Nabriva Therapeutics, said in a statement.
Fosfomycin, which has been available as an intravenous formulation for decades in Europe, is an epoxide antibiotic with activity against drug-resistant organisms such as carbapenem-resistant Enterobacteriaceae, extended-spectrum β-lactamases, and Pseudomonas aeruginosa. Similar to β-lactams, fosfomycin inhibits cell wall synthesis, but is unique in that it inactivates the enzyme responsible for the first step of peptidoglycan synthesis acting earlier than the mechanism of other cell wall active agents. Because of the recent concern in the United States around the rise of resistant pathogens, IV fosfomycin had gained renewed interest because of its activity and demonstrated synergy with other classes of antibiotics.
Nabriva submitted a NDA to the FDA for Contepo in October 2018, and it was accepted in January 2019.
In ZEUS, a phase 3 non-inferiority trial, 6 g IV fosfomycin administered every 8 hours was found to be non-inferior to 4.5 g piperacillin-tazobactam every 8 hours for hospitalized patients with cUTIs, including acute pyelonephritis.
The overall success, defined as combination of clinical cure and microbiologic eradication in the microbiologic modified intent to treat population at the test-of-cure visit, in the cUTIs group was 61% in the fosfomycin arm compared with 42% in the piperacillin-tazobactam arm, resulting in a 19.5% difference, compared with only a 1.7% difference between the treatment arms for patients with acute pyelonephritis. IV fosfomycin was also found to be well-tolerated with a low rate of adverse events.
Jennifer Schranz, MD, chief medical officer at Nabriva Therapeutics, sat down with Contagion® at the recent European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2019) to discuss fosfomycin for injection.
“We've developed fosfomycin, or Contepo, for complicated urinary tract infections, including acute pyelonephritis, which is really important because complicated urinary tract infections are a very common cause of hospitalization, morbidity, and mortality,” Schranz said. “Why Contepo is so interesting is that it's a new class of antibiotics being introduced to US physicians to treat their patients, but it's been used for over 40 years in Europe and its use continues to increase because of its efficacy, its well-tolerated safety profile, and its ability to treat multidrug-resistant pathogens.”
This story is developing.