Oral lefamulin a giant LEAP for CABP treatment
The novel pleuromutilin antibiotic lefamulin - now in an oral therapy form - has demonstrated a favourable safety and tolerability profile for community-acquired bacterial pneumonia (CABP) in the LEAP* 2 study, the same result seen for intravenous (IV) lefemulin in the original LEAP 1 study.
Being a new class of antibiotic, lefamulin may offer an empiric treatment option for CABP in an era of increasing antibiotic resistance, according to principal investigator Dr Jennifer Schranz in a company press release. “[The LEAP 2 study] shows that a 5-day short course of lefamulin was noninferior to a 7-day course of moxifloxacin and this is really important for antibiotic stewardship.”
Topline data of the LEAP 2 study has previously shown that oral lefamulin was noninferior to moxifloxacin for both the US FDA primary efficacy endpoint of early clinical response at 96 ± 24 hours after treatment initiation (90.8 percent for both drugs, but treatment with lefamulin was only for 5 days compared with 7 days of moxifloxacin), and the EMA** coprimary endpoint of investigator assessment of clinical response at 5–10 days after the end of treatment (87.5 percent vs 89.1 percent).
In the recent ECCMID 2019 Meeting, the investigators reported on the safety and tolerability data for the second double-blind phase III study of lefamulin in CABP patients, the first one being LEAP 1.
Unlike LEAP 1 which compared intravenous (IV) lefamulin (with an oral switch option) with intravenous moxifloxacin, the current LEAP 2 study randomized patients 1:1 to receive oral lefamulin (600 mg q12h for 5 days) or oral moxifloxacin (400 mg q24h for 7 days). Subjects were 738 patients with CABP of severity PORT risk class II–IV CABP. [ECCMID 2019, abstract O1068]
Overall, treatment-emergent adverse events (TEAEs) occurred in 32.6 percent of patients treated with lefamulin and 25.0 percent of those receiving moxifloxacin. The rates of serious TEAEs (4.6 percent vs 4.9 percent) and TEAEs leading to discontinuation (3.3 percent vs 2.4 percent) were similar between the two groups.
Although gastrointestinal (GI) TEAEs occurred more frequently in the lefamulin group vs the moxifloxacin group (17.9 percent vs 7.6 percent), the events were generally mild and transient. The two most common GI-related TEAEs, diarrhoea (12.2 percent vs 1.1 percent) and nausea (5.2 percent vs 1.9 percent), did not lead to study discontinuation.
Two lefamulin-treated patients and one moxifloxacin-treated patient discontinued treatment due to vomiting. There was one report of Clostridium difficile infection during an extended hospitalization in one patient who had been successfully treated with lefamulin.
“This contrasts with the IV-to-oral switch profile [in LEAP 1] in which higher rates of GI events occurred with moxifloxacin,” the researchers noted.
Incidence of both hepatobiliary TEAEs (1.1 percent vs 0.5 percent) and cardiac TEAEs (2.2 percent vs 2.4 percent) were low in the lefamulin and the moxifloxacin groups. While prolonged QTcF interval was observed in both the lefamulin (four cases) and the moxifloxacin groups (seven cases), “QTcF prolongation was shorter with lefamulin than moxifloxacin with no associated cardiac arrhythmias,” the researchers reported.
“Oral lefamulin monotherapy was generally safe and well tolerated with low discontinuation rates due to TEAEs,” said the researchers. “These results add to the developing favourable safety/tolerability profile of IV and oral lefamulin.”