Category: Professional Posters
Purpose: In the United States, pneumonia is the second most common cause of hospitalization and is a leading cause of infectious death. Macrolide and beta-lactam resistance, combined with safety concerns associated with fluoroquinolones, have created a need for new treatment options for community-acquired bacterial pneumonia (CABP). Lefamulin, a first-in-class systemic pleuromutilin antibiotic in development for IV and oral treatment of CABP in adults, was evaluated in 2 global noninferiority phase 3 trials (LEAP 1 and LEAP 2). We report efficacy and safety from pooled study data stratified by geographic region.
Methods: In LEAP 1, adults with CABP (Pneumonia Outcomes Research Team [PORT] risk class III‒V) received lefamulin 150 mg IV q12h for 5‒7 days or moxifloxacin 400 mg IV q24h for 7 days, with optional IV-to-oral switch (600 mg lefamulin q12h or 400 mg moxifloxacin q24h). In LEAP 2, adults with CABP (PORT II‒IV) received lefamulin 600 mg oral q12h for 5 days or moxifloxacin 400 mg oral q24h for 7 days. Both studies assessed the early clinical response (ECR) at 96±24 hours after first study drug dose in the intent-to-treat (ITT; all randomized patients) population (US Food and Drug Administration [FDA] primary endpoint) and the investigator assessment of clinical response (IACR) at test-of-cure (TOC) 5‒10 days after last study drug dose in the modified ITT (mITT; received ≥1 dose of study drug) and the clinically evaluable (CE; required to meet predefined evaluability criteria) populations (European Medicines Agency [EMA] coprimary endpoints). Pooled analyses used a 10% noninferiority margin. The study protocol and amendments were approved by an independent ethics committee or institutional review board at each study site, and every patient (or legally authorized representative) provided written informed consent.
Results: In the ITT population, 1289 patients were randomized to lefamulin/moxifloxacin (non-European Union Europe [non-EUE], n=313/313; EU, n=175/155; Rest of World [RoW], n=103/118; Latin America [LA], n=42/44; United States [USA], n=13/13). For ECR, lefamulin was noninferior to moxifloxacin (pooled rates: lefamulin 89.3% [577/646] vs moxifloxacin 90.5% [582/643]; difference –1.1%; 95% confidence interval [CI] −4.4%, 2.2%). ECR rates in both groups by geographic region were: non-EUE (lefamulin 88.5% vs moxifloxacin 92.0%), EU (90.3% vs 92.3%), RoW (90.3% vs 85.6%), LA (97.6% vs 90.9%), USA (61.5% vs 76.9%). For IACR success at TOC, lefamulin was noninferior to moxifloxacin in the mITT population (lefamulin 85.0% [545/641] vs moxifloxacin 87.1% [558/641]; difference −2.2%; 95% CI −5.9%, 1.6%), with high response rates in both treatment groups regardless of geographic region: non-EUE (lefamulin 84.6% vs moxifloxacin 90.1%), EU (84.3% vs 84.4%), RoW (84.5% vs 86.3%), LA (92.9% vs 79.5%), USA (84.6% vs 76.9%). IACR results in the CE-TOC population were similar. Treatment-emergent adverse event (TEAE) incidences for lefamulin/moxifloxacin were 34.9%/30.4% overall and by region (non-EUE: 28.0%/21.7%; EU: 37.2%/36.4%; RoW: 44.7%/43.6%; LA: 45.2%/27.3; USA: 61.5%/61.5%). Gastrointestinal disorders were the most frequently reported TEAEs, both overall and by region; diarrhea, nausea, and vomiting trended as most frequent events.
Conclusion: In pooled analyses of the LEAP 1 and LEAP 2 pivotal phase 3 trials that enrolled patients with CABP (PORT risk class II−V), lefamulin was noninferior to moxifloxacin for both the FDA primary endpoint (ECR) and EMA primary endpoint (IACR success at TOC). Efficacy rates with both lefamulin and moxifloxacin were high and similar across all geographic regions, although the number of patients enrolled from the USA was small. Safety/tolerability were similar between treatment groups and across geographic regions. Lefamulin, a first-in-class pleuromutilin, offers a promising alternative to fluoroquinolones as an IV and/or oral monotherapy for empiric treatment of CABP.