FDA Panel Recommends Plazomicin for cUTI but Not BSI

The US Food and Drug Administration's (FDA's) Antimicrobial Drugs Advisory Committee yesterday recommended plazomicin (Achaogen Inc) for complicated urinary tract infections (cUTIs) but not for bloodstream infections (BSIs) in adults with limited or no treatment options.

The panel overwhelmingly recommended (15 "yes" and 1 "no vote") plazomicin for adults with "cUTIs, including pyelonephritis, caused by the following susceptible microorganism(s): Escherichia coli (including cases with concurrent bacteremia), Klebsiella pneumoniae, Proteus spp (including Proteus mirabilis and Proteus vulgaris), and Enterobacter cloacae." There are only limited safety and efficacy data on plazomicin; therefore, it should be reserved for patients with limited or no alternative treatment options for both indications, according to the panel.

"[E]vidence was provided supporting safety and effectiveness for this particular indication. Although there was only a single noninferiority trial…I thought the in vitro study using clinical isolates and animal studies as well as the limited bloodstream infection data all supported the idea that the drug was effective, especially in the framework of the LPAD [limited population pathway for antibacterials and antifungal drugs] labeling plan, and the clear unmet need of having additional treatments for MDR [multidrug-resistant] gram-negative infections," said voting committee member Joanna M. Schaenman, MD, PhD, assistant professor of medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California.

The panel voted against (4 "yes," 11 "no," and 1 "no vote") recommending plazomicin for BSI in patients with limited or no treatment options.

Although the only phase 3 trial for patients with BSI was an "imperfect" study, the totality of the data warranted his "yes" vote, said committee chairperson, Lindsey R. Baden, MD, director of clinical research, Division of Infectious Diseases, Brigham and Women's Hospital, and associate professor, Harvard Medical School, both in Boston, Massachusetts. "This is not a trivial undertaking, and this is not a trivial problem that we are faced with," he said.

"The totality of the data, including the in vitro data, the animal model, the understanding of the mechanism, the understanding of prior agents in the class and activity, the 009 bacteremic data, plus [Study] 007 having a mortality endpoint…to me the totality of those data are compelling that there is meaningful activity of this agent for an unmet need," Baden explained.

Limited Population Approval Pathway

Plazomicin is an intravenous next-generation aminoglycoside that inhibits bacterial protein synthesis.

The drug was reviewed under the FDA's LPAD pathway, which allows the FDA to approve drugs that are intended to treat serious or life-threatening infections in a limited population of patients who have unmet needs. Complicated UTIs and BSIs are increasingly being caused by drug-resistant and multidrug-resistant organisms for which limited or no treatment options exist.

Labeling for LPAD products prominently displays the term "Limited Population" with the statement, "This drug is indicated for use in a limited and specific population of patients."

The votes followed the committee's consideration of data from two phase 3 trials: Evaluating Plazomicin in cUTI (EPIC; Study 009) and Combating Antibiotic Resistant Enterobacteriaceae (CARE; Study 007).

EPIC Trial Demonstrates Noninferiority to Meropenem for cUTI

In EPIC, the microbiological modified intent-to-treat (mMITT) population included 388 adults with cUTI, including acute pyelonephritis, who needed hospital care and intravenous antibacterial medications. Patients were randomly assigned to receive plazomicin (n = 191) or meropenem (n = 197).

Co-primary endpoints were composite microbiological eradication and clinical cure rate in the mMITT population; these were assessed at the day 5 and test-of-cure visits. Secondary endpoints included primary endpoints measured at different points during the study.

Plazomicin demonstrated noninferiority for the FDA-specified primary efficacy endpoints.

The study was primarily conducted in Eastern European countries, and almost all participants were white; therefore, the results may not be generalizable to other populations.

"Given the continued emergence of resistance to both old and new antimicrobial agents, limited existing treatment options, and a continued need for additional antibiotic options for persons with complicated UTIs, this new antibiotic will fill that important unmet need…additional postmarketing studies on safety would be valuable," said voting committee member Vincent Lo Re, MD, MSCE, assistant professor of medicine and epidemiology, Division of Infectious Diseases, Department of Medicine, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

CARE: Troubled Study in Patients With HABP/VABP or BSI

CARE was a phase 3, multicenter, randomized, open-label trial that studied the efficacy and safety of plazomicin compared with colistin in patients with hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP) or BSI caused by carbapenem-resistant Enterobacteriaceae (CRE).

Several panel members expressed regret about having to vote against plazomicin for this indication on the basis of the phase 3 trial.

CARE had difficulty enrolling participants, which led to several protocol changes during the study. The FDA agreed the applicant could combine HABP/VABP and BSI because both are severe, highly fatal infections. The study was also amended to add a second, uncontrolled, open-label cohort to allow patients who were ineligible for cohort 1 to receive plazomicin.

Cohort 1 included 39 patients randomly assigned to receive colistin (n = 21) or plazomicin (n = 18). All but two patients were in the mMITT population. Most patients in this cohort had BSI (colistin group, 15 of 20; 75%; plazomicin group, 14 of 17; 82%). Patients in both treatment groups could receive adjunctive antibacterial treatment.

Before randomization, patients in cohort 1 were assigned to receive a 7- to 14-day course of meropenem or tigecycline intravenously as adjunctive therapy.

Cohort 2 evaluated plazomicin regimens in patients with BSI or HABP/VABP caused by CRE and evaluated plazomicin monotherapy in patients with cUTI caused by CRE. Cohort 2 included 30 plazomicin-treated patients. Of them, 27 of 30 (90%) were in the mMITT population and were infected with a baseline CRE pathogen, K pneumoniae: 14 patients had BSI, 9 patients had HABP/VABP, and 4 patients had cUTI. All 27 participants were enrolled in the study in Greece, and most were male.

The study's primary efficacy endpoint was initially day 28 all-cause mortality and was later expanded to include both day 28 all-cause mortality or significant disease-related complication (SDRC).

Numeric trends favored the study drug for both primary endpoints. The original primary endpoint, day 28 all-cause mortality, occurred in 8 of 20 (40.0%) compared with 2 of 17 (11.8%) of those in the colistin and plazomicin groups, respectively. Day 28 all-cause mortality or SDRC rate was 10 of 20 (50.0%) among those who received colistin compared with 4 of 17 (23.5%) among those who received plazomicin.

The study results left unanswered questions. In patients with BSI, the source was unclear and most patients had intravascular catheters at the time of diagnosis.

"As noted earlier, 10 of 14 and 11 of 15 plazomicin and colistin BSI patients, respectively, had negative or no cultures on day 1. Given that patients could have had a single positive blood culture (for inclusion) and empiric treatment any time in the 96 hours prior to starting study regimen, it is possible patients had already been significantly treated/improved prior to starting study therapy," the FDA explains in their briefing document. "Moreover, at least two patients in the plazomicin arm only received one day of plazomicin therapy before being switched to a polymyxin-based regimen, raising questions about the contribution of plazomicin to these patients' clinical outcomes."

Safety

Adverse effects were consistent with those of other aminoglycoside medications. The researchers noted a "signal" for nephrotoxicity, which was primarily moderate in severity and resolved. Ototoxicity, another adverse effect associated with aminoglycosides, was not seen; however, there is no clear evidence that ototoxicity does not develop in patients who receive plazomicin.

"This study clearly had a number of limitations that impacted the interpretation of results to support the approval for a bloodstream infection indication — the changes in the protocol [and] the modifications to the original statistical plan clearly created challenges, but the limitation that I just could not overcome were the small numbers…while we desperately need new drugs, I just don't think we have enough data to approve for this indication," Michael D. Green, MD, MPH, professor of pediatrics, surgery and clinical & translational science, University of Pittsburgh School of Medicine, Division of Infectious Diseases, and director, Antimicrobial Stewardship & Infection Prevention, Children's Hospital of Pittsburgh, Pennsylvania, said of his "no" vote.

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