Lefamulin appears to be noninferior in safety and efficacy compared with moxifloxicin in the treatment of community-acquired bacterial pneumonia (CABP), especially in cases caused by Legionella pneumophila, according to pooled results from the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and 2 phase 3 trials (LEAP 1: ClinicalTrials.gov Identifier: NCT02559310 and LEAP 2: ClinicalTrials.gov Identifier: NCT02813694). These results were presented during several poster sessions at IDWeek 2019, held from October 2 to October 6 in Washington, DC.1-5
Lefamulin is a novel pleuromutilin antibiotic developed to improve patient outcomes in severe, rapid onset CABP. Researchers conducted LEAP 1 and LEAP 2 to assess early clinical responses (approximately 96 hours after first treatment) and investigator assessment of clinical response success as test of cure (5-10 days after last dose) of treatment with lefamulin.1,2 In LEAP 1, patients with a Pneumonia Outcomes Research Team (PORT) risk of 3 to 5 received intravenous treatment with either 150 mg lefamulin every 12 hours for 5 to 7 days, or moxifloxacin 400 mg once daily for 7 days. In LEAP 2, patients with PORT risk score of 2 to 4, patients received oral treatment with either 600 mg lefamulin for 5 days or 400 mg moxifloxacin for 7 days. Of note, patients with PORT scores ≤3 have predicted mortality rates <3% and are commonly treated as outpatients; patients with scores of 4/5 are frequently hospitalized because of a higher predicted mortality rate (8%-31%).
More than 50% of the study cohort were PORT 3 and roughly 18% were PORT 4/5, which is reflective of the real-world distribution in CABP. Similarly, the researchers noted that patients with a PORT 4/5 score were older and had comorbidities compared with PORT 3 patients. The results demonstrated that early clinical responses were high in both the lefamulin and moxifloxacin groups (90.0% and 91.9%, respectively, for PORT 3; 83.5% and 82.1%, respectively, for PORT 4/5), as were investigator assessment of clinical response success as test of cure (87.2%, and 85.9%, respectively, for PORT 3; 77.5% and 82.8%, respectively, for PORT 4/5).1
In a subsequent modified intention-to-treat population of 65 patients, L pneumophila was identified as the cause of CABP in 9.3% and 9.0% of patients receiving lefamulin and moxifloxacin, respectively.2 Patients in both treatment groups attained similarly high rates of response to therapy on all end points. Further, treatment-associated adverse events were also similar and low in both groups; there was no mortality associated with such events in either group, and although no patients discontinued lefamulin due to adverse events, 2 patients in the moxifloxacin group did.
In a subgroup analysis stratified for age, chronic obstructive pulmonary disease (COPD)/asthma, diabetes, hypertension, arrhythmia, and transaminitis, high efficacy was similar to moxifloxacin in patients who received treatment with lefamulin across all groups.3 Patients in both treatment groups with asthma/COPD, as well as patients with diabetes, demonstrated early clinical responses similar to patients without these illnesses. For example, 89.1% of patients with asthma/COPD who received lefamulin showed an early response compared with 89.4% of their healthy counterparts; in patients treated with moxifloxacin, 91.2% and 90.4%, respectively, demonstrated an early response. In patients with diabetes who received lefamulin, 90.0% showed an early response compared with 89.2% of their healthy counterparts; in the moxifloxacin group the response rates were 86.4% and 91.2%, respectively.
The researchers tracked baseline and post-treatment measurements of the QTcF interval in patients with hypertension, arrhythmia, and those aged >65 years; results demonstrated an elongation of this interval in <7% patients in each category in both treatment groups, and the lefamulin group had a consistently lower incidence of any change across all 3 demographics.3 One study focusing directly on the cardiac safety of lefamulin found that all events were nonserious, and mild or moderate.4 Further, pooled analysis of QTcF interval changes in both LEAP 1 and LEAP 2 showed that post-treatment increases were more common in the LEAP 1 trial cohort, and overall were more common in patients who received moxifloxacin (any increase of >30 ms was found in 22.3% of the moxifloxacin group vs 17.9% of the lefamulin group).4
An analysis of hepatobiliary safety demonstrated overall low rates of increases in transaminases, alkaline phosphatase, and total bilirubin levels.5 Increases in these levels were similar in the lefamulin and moxifloxacin groups, although pooled analysis of LEAP 1 and LEAP 2 data showed a marginally more frequent rate in patients who received lefamulin. Researchers noted that increases in these enzymes were commonly seen within the first week of lefamulin treatment, and then decreased to near normal levels by day 28 follow-up appointments. The injury pattern associated with lefamulin was predominantly hepatocellular or mixed in nature (50% and 40%, respectively), with no demographic predominance. Adverse events occurred in 0.9% of both treatment groups; none were categorized as severe.
Noninferiory and equal or lower incidences of complications associated with treatment identify lefamulin as a possible safe and efficacious alternative for the treatment of CABP.
- Schranz J, Goldberg L, Paukner S, et al. Efficacy in adults with moderate to severe community-acquired bacterial pneumonia (CABP) and pneumonia outcomes research team (PORT) risk class III to V: results of a pooled analysis of lefamulin evaluation against pneumonia (LEAP) 1 and LEAP 2 study outcomes. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. Poster 664
- Schranz J, Das A, Moran G, et al. Efficacy and safety of lefamulin (LEF) versus moxifloxacin (MOX) for Legionella pneumophila (LP) in patients (Pts) with community-acquired bacterial pneumonia (CABP): pooled results from the lefamulin evaluation against pneumonia (LEAP) 1 and LEAP 2 phase 3 clinical trials. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. Poster 663.
- Goldberg L, Das A, Alexander E, et al. Lefamulin (LEF) versus moxifloxacin (MOX) in patients with community-acquired bacterial pneumonia (CABP) at risk for poor efficacy or safety Outcomes: pooled subgroup analysis from the lefamulin evaluation against pneumonia (LEAP) 1 and LEAP 2 phase 3 noninferiority clinical trials. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. Poster 717.
- Darpo B, Das A, Schranz J, Gelone S. Cardiac safety in adults with community-acquired bacterial pneumonia (CABP) treated with lefamulin (LEF) or moxifloxacin (MOX): analysis of lefamulin evaluation against pneumonia (LEAP) 1 and LEAP 2 study results. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. Poster 684.
- Lewis J, Das A, Stein D, Gelone S. Hepatobiliary safety in adults with community-acquired bacterial pneumonia (CABP) treated with lefamulin (LEF) or moxifloxacin (MOX): analysis of lefamulin evaluation against pneumonia (LEAP) 1 and LEAP 2 study results. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. Poster 699.