The committee voted 14 to 2 that substantial evidence of efficacy and safety for cefiderocol was provided for the treatment of cUTI including pyelonephritis in patients with limited or no alternative treatment options.
Today the US Food and Drug Administration convened a meeting of the Antimicrobial Advisory Committee to discuss the new drug application of cefiderocol. The application, submitted by Shionogi Inc., proposes the agent for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis due to gram-negative bacteria in patients with limited or no other alternative treatments.
Cefiderocol is a siderophore cephalosporin. Its mechanism of entry and stability is active against all classes of β-lactamases, which enables it to overcome the primary mechanisms of gram-negative bacterial resistance to βlactam antibiotics.
Cefiderocol was evaluated in 3 studies: a randomized, active controlled noninferiority trial for cUTI which compared cefiderocol to imipenem-cilastatin; a descriptive study (CREDIBLE-CR) which compared cefiderocol to best available therapy in patients with infections due to carbapenem-resistant organisms; and top-line results from a recently completed active-controlled noninferiority trial in hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) (APEKS-NP) comparing cefiderocol to meropenem.
During the committee meeting, concern over the increased mortality observed in the CREDIBLE-CR study was expressed.
The CREDIBLE-CR study was a descriptive study with no pre-specified hypothesis testing. In this trial, patients with HABP/VABP, cUTI, and bloodstream infections/sepsis due to carbapenem-resistant organisms were randomized to receive cefiderocol or best available therapy, of which 66% were colistin-based regimens. The study all-cause mortality rate was higher in the cefiderocol group compared to the best available therapy group at Day 14 (18.8% versus 12.2%) and Day 28 (24.8% versus 18.4%) respectively. "The greatest mortality difference disfavoring Cefiderocol was noted in the HABP/VABP subgroup, followed by the BSI/sepsis subgroup," the FDA documents read.
A particular reason for the imbalance in mortality was not identified. However, While no specific reason for the imbalance in mortality could be identified, it appears that some of the deaths were related to the progression of infection/lack of clinical response and were more common in patients with infections due to organisms such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa. The documents indicate whether the difference in mortality is a chance finding or represents a deficit in the activity of cefiderocol in critically ill patients is unclear.
"In summary, while the safety and efficacy of cefiderocol have been demonstrated for the treatment of cUTI, higher mortality in cefiderocol-treated patients was observed in a trial in critically ill patients with a variety of infections due to carbapenem-resistant organisms," The FDA wrote in the preparation documents for the meeting.
"As a clinician evaluating the role of cefiderocol, these are particularly challenging data to piece together," Ryan K. Shields, PharmD, MS, Contagion®'s Multidrug-Resistant Infections Section Editor said. "On one hand, the drug appears safe and effective for the treatment of cUTIs. On the other hand, a carbapenem-resistant pathogen-directed study, that better represents real-world indications for the agent, shows higher rates of death among patients randomized to receive cefiderocol versus best available therapy without a clear explanation."
The committee voted 14 to 2 that substantial evidence of efficacy and safety for cefiderocol was provided for the treatment of complicated urinary tract infections including pyelonephritis in patients with limited or no alternative treatment options.
The 2 committee members that voted no expressed concerns regarding the mortality rates in the CREDIBLE-CR study and called for further research. Many of the individuals that voted yes indicated that cefiderocol is potentially useful when no other options are available for resistant organisms in a cUTI, but that the label needs to strongly note the uncertainty associated with the CREDIBLE-CR data.
Shields echoes these sentiments. "If the drug is approved, clinicians must balance the need for novel antimicrobial agents with the serious warnings of higher mortality rates among critically-ill patients infected by carbapenem-resistant pathogens who were treated with cefiderocol," he told Contagion®.
At the conclusion of the meeting, an agency spokesperson stated that the agency has not made a decision on the overall application nor the review issues identified and highlighted in the committee meeting. It is important to note that the FDA is not bound by the committee’s recommendation, however, the feedback may be considered by the agency in making its final decision regarding approval.
Additionally, the FDA has not fully evaluated data from the APEKS-NP trial. Shields further notes that this data will be crucial in the further development of cefiderocol. "At the time of the [advisory committee] meeting only the top-line results were available. These data will be incredibly important to dissect as the drug moves forward in development given the relatively limited and conflicting evidence that is currently available."
The FDA granted cefiderocol both fast track and Qualified Infectious Disease Product (QIDP) designations in 2015 for cUTI, hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bloodstream infections (bacteremia). The Prescription Drug-User Fee Act (PDUFA) assigned action date for cefiderocol is November 14, 2019.