Phae III LEAP 2 trial success for lefamulin proposed treatment for moderate community-acquired bacterial pneumonia .-Nabriva Therapeutics

Nabriva Therapeutics plc announced positive topline results from its Lefamulin Evaluation Against Pneumonia (LEAP 2) clinical trial, the second of two global, pivotal Phase III clinical trials of lefamulin. LEAP 2 evaluated the safety and efficacy of 5 days of oral lefamulin compared to 7 days of oral moxifloxacin in adult patients with moderate community-acquired bacterial pneumonia (CABP). In September 2017, the company announced positive results from its first Phase III clinical trial, in which intravenous (IV) to oral lefamulin was found to be non-inferior to IV to oral moxifloxacin with or without linezolid.

In LEAP 2, lefamulin met the FDA primary endpoint of non-inferiority (NI, 10.0% margin) compared to moxifloxacin for early clinical response (ECR) assessed 72 to 120 hours following initiation of therapy in the intent to treat (ITT) patient population. ECR was 90.8% for the 5-day treatment course of lefamulin and 90.8% for the 7-day treatment course of moxifloxacin (treatment difference 0.1 [95% confidence interval (CI) -4.4, 4.5]).Lefamulin also met the European Medicines Agency (EMA) primary endpoint for non-inferiority (NI, 10.0% margin) compared to moxifloxacin based on an investigator assessment of clinical response (IACR) 5 to 10 days following the completion of study drug dosing in the modified intent to treat (mITT) and clinically evaluable at test of cure (CE-TOC) patient populations. IACR rates for the mITT population were 87.5% for lefamulin and 89.1% for moxifloxacin (treatment difference -1.6 [95% CI -6.3, 3.1]) and for the CE-TOC population were 89.7% for lefamulin and 93.6% for moxifloxacin (treatment difference -3.9 [95% CI -8.2, 0.5]).

Additional Clinical Trial Information LEAP 2 was a global, randomized, double-blind, double-dummy trial that compared the efficacy and safety of 600 mg of oral lefamulin twice a day for 5 days versus 400 mg of oral moxifloxacin once daily for 7 days in 738 patients (370 in the lefamulin arm and 368 in the moxifloxacin arm). The lefamulin arm enrolled 183 (49.5%), 145 (39.2%) and 40 (10.8%) patients with a Pneumonia Outcomes Research Team (PORT) class of 2, 3 and 4, respectively. The moxifloxacin arm enrolled 189 (51.4%), 133 (36.1%) and 42 (11.4%) patients with a PORT class of 2, 3 and 4, respectively. Almost all patients completed the study (95.8%) through late follow-up, which occurred 30 days after administration of the first dose of study medication. In this trial, lefamulin was generally well tolerated.

The rate of treatment-emergent adverse events (TEAEs) was 32.6% in the lefamulin arm and 25.0% in the moxifloxacin arm. Serious treatment emergent adverse events occurred in 4.6% of lefamulin-treated patients and 4.9% of moxifloxacin-treated patients. One related serious adverse event occurred in a moxifloxacin-treated patient (0.3%). Death within 30 days occurred in three patients in each treatment arm (0.8%).A low percentage of patients discontinued study drug in the lefamulin arm (6.8%) and in the moxifloxacin arm (7.6%).

Comment: Lefamulin will face cheap generic antibiotics with comparable efficacy which are already on the market. But Nabriva thinks lefamulin can carve out a spot as first-line option due to lefamulin’s flexible dosing and targeted spectrum of activity against the pathogens most commonly associated with CABP, including multidrug-resistant strains.