New analyses of pivotal trial data for the first-in-class antibiotic lefamulin (Xenleta) reinforce its efficacy and safety relative to fluoroquinolones, making it suitable for “outpatients and nonsevere inpatients,” a researcher said.
Speaking at CHEST 2021, the American College of Chest Physicians’ annual meeting being held online this year, Thomas File Jr., MD, MSc, of Summa Health in Akron, Ohio, presented subgroup analyses indicating that the drug was as effective as moxifloxacin, a staple in bacterial pneumonia therapy, in both multilobar and unilobar cases.
That was true both overall and in the roughly two-thirds of patients whose pneumonia was caused by Streptococcus pneumoniae, according to data pooled from the two trials that underpinned lefamulin’s approval in 2019.
File, a former president of the Infectious Diseases Society of America, noted that lefamulin was the first drug in the pleuromutilin inhibitor class to be cleared for systemic use in humans. (Another agent in the class, retapamulin (Altabax), is available for topical use, and others have been used in animals for many years.) Its mechanism is somewhat similar to that for macrolide antibiotics, in that its ultimate target is the bacterial ribosome, but it differs enough that it remains effective in organisms resistant to macrolides.
In sum, said File, the pooled data show lefamulin to be a valid alternative to fluoroquinolones in pneumonia patients at risk for progressing to severe illness.
Called LEAP, for Lefamulin Evaluation Against Pneumonia, the trials tested the agent head-to-head against moxifloxacin for noninferiority in a total of about 1,300 patients with pneumonia. LEAP-1 enrolled 551 patients with pneumonia in PORT risk classes III-V, randomized to IV lefamulin or moxifloxacin with an option for both drugs to switch to oral dosing; LEAP-2, with 738 participants, was similar except patients had generally milder disease (PORT classes II-IV) and both drugs were given orally throughout.
Lefamulin was given for 5-7 days in LEAP-1 and 5 days in LEAP-2, while moxifloxacin treatment lasted 7 days in both trials. The LEAP investigators examined clinical cure rates at two points: 3-5 days after starting treatment (“early response”) and 5-10 days after the last dose as determined by site physicians (“test of cure” or TOC).
File’s presentation covered 676 patients in the two trials who had radiologically confirmed multilobar (n=208) or unilobar infiltrates (n=468). About half of this group had PORT class III pneumonia; just under half of those with multilobar infiltrates were 65 or older, whereas about one-third of the group with unilobar involvement were in that age range.
Response were as follows:
- Early unilobar: 91.6% lefamulin, 93.8% moxifloxacin
- Early multilobar: 84.7% lefamulin, 90.0% moxifloxacin
- TOC unilobar: 86.2% lefamulin, 88.9% moxifloxacin
- TOC multilobar: 77.1% lefamulin, 80.0% moxifloxacin
Rates in the 439 patients with S. pneumoniae were nearly identical to those in the overall group, File reported.
Treatment-emergent adverse events were similar except for somewhat more frequent reports of gastrointestinal issues such as nausea and diarrhea. The latter, for example, was recorded in about 7% of those assigned to lefamulin versus 3%-4% with moxifloxacin. File said the difference was largely driven by oral dosing in LEAP-2.
Following the online presentation, an audience member questioned File about QTc prolongation, a known side effect of lefamulin (noted on the drug’s label) as well as other antibiotic classes. File responded that there was no major difference, but that three patients receiving moxifloxacin stopped treatment because of this effect, versus only one in the lefamulin groups.
The LEAP studies were funded by lefamulin’s manufacturer, Nabriva Pharmaceuticals, and two study authors were employees of the company.