Lefamulin Evaluation Against Pneumonia 2 (LEAP 2) Study Results Published in the Journal of the American Medical Association
In the study, the second of two global, pivotal Phase 3 clinical trials of lefamulin, clinicians evaluated the safety and efficacy of five days of oral lefamulin compared to seven days of oral moxifloxacin, a respiratory fluoroquinolone, in adult patients with moderate CABP (PORT risk class II, III, or IV). In this study, a short course (5-days) of lefamulin was shown to be noninferior to a 7-day regimen of moxifloxacin for the treatment of CABP. Lefamulin achieved high clinical response rates for both typical (Streptococcus pneumoniae - including multi-drug resistant strains, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus), as well as atypical pathogens (Mycoplasma pneumoniae, including macrolide-resistant strains, Chlamydophila pneumoniae, and Legionella pneumophila). Both lefamulin and moxifloxacin were generally well tolerated with low and similar incidence of discontinuations due to adverse events.
“The increasing prevalence of antimicrobial resistance in the most common causative pathogens of CABP, along with growing evidence of safety concerns with fluoroquinolones makes a compelling case for the development of new antibacterial classes with novel mechanisms of action (MOA) to treat patients with CABP,” said
The publication, entitled “Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults with Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial,” is available online.
In a related editorial published in the same edition, entitled “Lefamulin – A New antibiotic for Community-Acquired Pneumonia,” author
LEAP 2 Study
The Phase 3, double-blind, double-dummy, parallel-group, noninferiority randomized trial was conducted in 99 sites in 19 countries. The clinical trial randomized 738 patients 18 years of age or older who had had Pneumonia Outcomes Research Team (PORT) risk class II, III, or IV, radiographically documented pneumonia, acute illness, greater than three CABP symptoms, and greater than two vital sign abnormalities. Randomization was stratified by PORT risk class (II vs III/IV), geographic region (US vs ex-US), and prior receipt of a single dose of short-acting antibiotic therapy for CABP (yes vs no). Per protocol, ≤25 percent of the study population could have received a single dose of a short-acting antibiotic, and ≥50 percent were to have PORT risk class of III or IV. The first patient visit was on
Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368).
The primary endpoint for the study was early clinical response (ECR) at 96±24 hours after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in greater than two or more of the four CABP symptoms, having no worsening of any CABP symptoms, and not receiving any non-study antibacterial drug for current CABP episode.
Study results showed that ECR rates were 90.8 percent with lefamulin and 90.8 percent with moxifloxacin, meeting the noninferiority margin of 10 percent. IACR rates were 87.5 percent with lefamulin and 89.1 percent with moxifloxacin in the modified ITT population and 89.7 percent and 93.6 percent, respectively, in the clinically evaluable population at test of cure. Lefamulin was well tolerated during the trial. The most frequently reported treatment-emergent adverse events for lefamulin were diarrhea, nausea and vomiting, predominantly mild to moderate, manageable and which rarely led to discontinuation.
“The results from this randomized clinical trial will inform more clinicians of lefamulin’s potential as an effective alternative to commonly used antibiotics, such as fluoroquinolones or macrolides, to fight community acquired pneumonia, which affects five million Americans each year,” said
XENLETA (lefamulin) is a first-in-class semi-synthetic pleuromutilin antibiotic for systemic administration in humans discovered and developed by the
INDICATION AND IMPORTANT SAFETY INFORMATION
XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
IMPORTANT SAFETY INFORMATION
XENLETA is contraindicated in patients with known hypersensitivity to XENLETA or pleuromutilins.
XENLETA tablets are contraindicated for use with CYP3A4 substrates that prolong the QT interval.
WARNINGS AND PRECAUTIONS
XENLETA has the potential to prolong the QT interval. Avoid XENLETA in patients with known QT prolongation, ventricular arrhythmias, and patients receiving drugs that may prolong the QT interval.
Based on animal studies, XENLETA may cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including XENLETA, with severity ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.
The most common adverse reactions (≥2%) for (a) XENLETA Injection are administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, and headache and (b) XENLETA Tablets are diarrhea, nausea, vomiting, and hepatic enzyme elevation.
USE IN SPECIFIC POPULATIONS
In patients with severe hepatic impairment, reduce the dosage of XENLETA Injection to 150 mg infused over 60 minutes every 24 hours. XENLETA Tablets are not recommended in patients with moderate or severe hepatic impairment due to insufficient information to provide dosing recommendations.
Avoid XENLETA Injection and Tablets with concomitant strong or moderate CYP3A or P-gp inducers. Monitor for reduced efficacy of XENLETA.
Avoid XENLETA Tablets with strong CYP3A or P-gp inhibitors.
Monitor for adverse reactions of sensitive CYP3A substrates administered with XENLETA Tablets.
XENLETA has not been studied in pregnant women. Verify pregnancy status in females prior to initiating XENLETA and advise females to use contraception during treatment and for 2 days after the final dose. Lactating women should pump and discard milk for the duration of treatment with XENLETA and for 2 days after the final dose.
To report SUSPECTED ADVERSE REACTIONS, or administration during pregnancy, contact
Please see Full Prescribing Information for XENLETA.
Any statements in this press release about future expectations, plans and prospects for
Source: Nabriva Therapeutics US, Inc