Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities

Abstract

Background: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management.

Methods: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin.

Results: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified.

Conclusions: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities.

Trial registration: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Keywords: Antibiotic; Clinical response; Lefamulin; Pleuromutilin; Pneumonia.

Fig. 1

a ECR response in the pooled ITT population, b patients meeting ECR criteria by visit in the pooled ITT population, and IACR success by visit in the pooled c mITT and d CE populations. CE clinically evaluable, ECR early clinical response, EOT end of treatment, IACR investigator assessment of clinical response, ITT intent to treat, LFU late follow-up, mITT modified ITT, TOC test of cure

Fig. 2

Patients with resolution of all baseline clinical signs and symptoms* of CABP by visit (pooled ITT population). *Dyspnea, cough, purulent sputum production, and chest pain. CABP community-acquired bacterial pneumonia, EOT end of treatment, ITT intent to treat, LFU late follow-up, TOC test of cure

Fig. 3

Subgroup analysis of a ECR in the pooled ITT population and IACR at TOC in the pooled b mITT and c CE populations. See Table 1 footnotes for subgroup definitions. ATS American Thoracic Society, CE clinically evaluable, COPD chronic obstructive pulmonary disease, ECR early clinical response, IACR investigator assessment of clinical response, ITT intent to treat, mITT modified ITT, PORT Pneumonia Outcomes Research Team, SIRS systemic inflammatory response syndrome