Plazomicin's BSI Indication Gets 'No' From Advisory Panel, But US FDA Still Might Approve Under LPAD Pathway
Executive Summary
Achaogen should at least be reassured by advisory committee's unanimous 'yes' vote for plazomicin's cUTI indication.
The US FDA's Antimicrobial Drugs Advisory Committee voted 11 to 4 that Achaogen Inc.'s plazomicin sulfate injection did not show substantial evidence of safety and efficacy for the treatment of bloodstream infections (BSIs) in patients with limited or no treatment options, but the agency still might approve the aminoglycoside antibiotic for the indication under the 21st Century Cures Act's limited population (LPAD) pathway.
Several of the "no" voters for the BSI indication expressed that they were reluctant with their final decision, but they were generally most concerned about the Phase III trial size, as there were only 29 patients in the BSI cohort.
"The limitation that I just could not overcome was the small numbers. At most we have a study of 29 patients with blood stream infection," said Michael Green, a professor at the University of Pittsburgh School of Medicine. "At worst, we have a study that's less than that. And so while we desperately need new drugs, I just don't think we have enough data to approve for this indication."
Green also stressed that there were several other factors confounding the efficacy evaluation, including the changes in the protocol and the original statistical plan.
University of Pennsylvania Perlman School of Medicine Professor Vincent Lo Re offered a similar assessment.
"I appreciate the sample size is going to be small for these studies," he said.
"But to me, this study had far too many limitations to assure the efficacy of plazomicin."
A large portion of the "no" voters explained that it was the threshold of "substantial evidence" that helped to sway their vote.
In the briefing documents released in advance of the meeting, FDA laid out several concerns with plazomicin's efficacy analysis for the BSI indication. The Phase III CARE trial was stopped after two years because of enrollment difficulties, and there was no formal hypothesis testing.
Although the trial was initially designed with a superiority design, the small trial population size, a 90% confidence interval and a lack of inferential statistics led to the agency conducting a non-inferiority analysis. But even the non-inferiority analysis had several confounding factors of its own, complicating the assessment of efficacy in BSIs. (Also see "Plazomicin's BSI Indication Could Be First LPAD Drug – If Achaogen Can Convince US FDA Of Efficacy" - Pink Sheet, 30 Apr, 2018.)
Plazomicin is currently under a priority review at FDA with a Prescription Drug User Fee Act (PDUFA) date of June 25. If approved for the BSI indication, the aminoglycoside antibiotic would be the first FDA-approved drug to be backed under the LPAD pathway, Sumathi Nambiar, director of the Division of Anti-Infective Products in the Office of Antimicrobial Products, noted.
Achaogen did not request a review for the cUTI indication under the LPAD pathway.
FDA May Still Approve BSI Indication Under LPAD
Although the advisory committee voted by a wide margin that plazomicin failed to demonstrate substantial evidence of safety and efficacy for the BSI indication, the agency still may approve the indication under LPAD.
Under the Cures Act, the LPAD provision specifically allows FDA the flexibility to approve antimicrobial drugs based on a limited population if the drug treats a life-threatening infection in a limited population of patients with unmet needs. It allows FDA to approve such a drug by accepting greater uncertainty, and also requires that any drug approved under the pathway come with a prominent display of the phrase "Limited Population" in the label. (Also see "Antibiotic Development: Limited Population Pathway In US Removes Barrier" - Pink Sheet, 29 Mar, 2017.)
One factor that may nudge the FDA toward an LPAD approval is a need for new antibiotics, a theme that was prominent throughout the meeting. It was highlighted by discussions about infections caused by multidrug-resistant (MDR) Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE). Both panelists and open public hearing speakers spoke of adding as many tools to the toolbox as possible.
Additionally, while the "yes" voters conceded there were several limitations with the CARE trial, they went on to make strong cases for an LPAD approval.
Demetre Daskalakis, acting deputy commissioner of the New York City Department of Health's Division of Disease Control, pointed to several factors justifying his "yes" vote, including that the drug would be limited to patients with limited or no alternative treatment options, along with its strong safety profile. He also pointed to the totality of the data, which included an animal model, in-vitro data, an understanding of the class of drug and a mortality endpoint, which showed a numerical trend favoring plazomicin over colistin.
"In my opinion, the totality of the evidence does demonstrate substantial proof that this agent does work, and that it does have a very good safety profile."
Harvard Medical School Professor and committee Chairman Lindsey Baden concurred. He called the trial "imperfect," but also pointed to the totality of the data as showing a signal for efficacy.
"To me, the totality of those data are compelling that there is meaningful activity of this agent for an unmet need," Baden said.
In a May 2 statement following the advisory committee vote, Achaogen CEO Blake Wise propped up the possibility of an LPAD approval in spite of the negative committee vote for the BSI indication.
“Regarding bloodstream infections, the Limited-Population Antibacterial Drug pathway, or LPAD, is a novel approach that enables the FDA to consider the benefits and risks for the sickest patients who have few or no available treatment options, and to approve antibiotics like plazomicin that we believe, have the potential to address these limited patient populations," Wise said.
In sum, a strong safety profile, a need for more antibiotics, evidence of a mortality benefit and a limited indication may push FDA to overrule its negative advisory panel vote.
Lo Re, however, cautioned against setting the LPAD approval bar too low.
"For me, we need further evaluation of efficacy," he said. "I don't think that this should be the bar that we set for the limited population for antibacterial drugs in the pathway. I think the challenge for the agency going forward is to more effectively articulate what the bar should be."
cUTI Indication Gets The Nod
The panel did vote that plazomicin demonstrated safety and efficacy for the treatment of complicated urinary tract infections (cUTI) in patients with limited or no treatment options by a 15 to 0 margin.
The panel unanimously backed the evidence threshold for the cUTI indication in patients with limited or no alternative treatment options. Safety and efficacy were demonstrated in a Phase III non-inferiority trial comparing plazomicin with meropenem.
But committee members nevertheless wanted to see more data related to the safety profile. There was a signal for nephrotoxicity – as is common of aminoglycoside – and also possibly ototoxicity, which panelists felt needed to be better characterized in more patients. Overall, however, members felt the safety profile was strong.
Panelists also wanted to see more data related to dosing and microbiologic activity. Lo Re and Joanna Schaenman, a professor at the David Geffen School of Medicine at UCLA specifically called for postmarketing studies for more data in their comments.
There were additionally several calls for clear guidance on therapeutic drug monitoring (TDM) in the labeling.
“We are encouraged by the Committee's unanimous vote in favor of plazomicin for complicated urinary tract infections (cUTI)," Wise said in a statement. "The discussion underscored the real-world challenges that healthcare providers face every day given limited or inadequate treatment options for certain pathogens."