Nabriva Therapeutics, a clinical-stage biopharmaceutical company engaged in the research and development of novel anti-infective agents to treat serious infections, with a focus on the pleuromutilin class of antibiotics, announced positive topline results from the lefamulin evaluation against pneumonia (LEAP 1) trial, which evaluated the safety and efficacy of intravenous (IV) to oral lefamulin in patients with community-acquired bacterial pneumonia (CABP). CABP is the leading cause of infectious death in the United States.
In the LEAP 1 trial, Nabriva Therapeutics’ first of two pivotal Phase 3 clinical trials of lefamulin in patients with CABP, lefamulin met the U.S. Food and Drug Administration (FDA) primary endpoint of non-inferiority (NI, 12.5% margin) compared to moxifloxacin with or without adjunctive linezolid for early clinical response (ECR) assessed 72 to 120 hours following initiation of therapy in the intent to treat (ITT) patient population. In the trial, ECR rates were 87.3% for lefamulin and 90.2% for moxifloxacin with or without linezolid (treatment difference -2.9 [95% confidence interval (CI) -8.5, 2.8]).
“These Phase 3 data provide strong evidence of the potential of lefamulin to treat adults with CABP and provide an alternative to a current gold standard treatment regimen,” said Dr. Colin Broom, chief executive officer of Nabriva Therapeutics. “Due to lefamulin’s flexible dosing and targeted spectrum of activity against the pathogens most commonly associated with CABP, including multidrug-resistant strains, we believe that lefamulin is well suited to be a first-line empiric monotherapy. I am extremely proud and appreciative of the Nabriva Therapeutics team that has advanced lefamulin, which has the potential to be the first in a new class of antibiotics for CABP in more than 15 years, from initial discovery in our labs to this important milestone. We continue to execute on our second pivotal trial evaluating oral lefamulin for the treatment of CABP, with enrollment expected to complete in the fourth quarter of 2017 and topline results anticipated in the spring of 2018.”
Lefamulin also met the primary endpoints for the European Medicines Agency (EMA) of non-inferiority (NI, 10% margin) compared to moxifloxacin with or without adjunctive linezolid in the modified intent to treat (mITT) and clinically evaluable at test of cure (CE-TOC) populations based on an investigator assessment of clinical response (IACR) at a test of cure visit (5 to 10 days following the completion of study therapy). IACR rates for the mITT population were 81.7% for lefamulin and 84.2% for moxifloxacin with or without linezolid (treatment difference -2.6 [95% CI -8.9, 3.9]) and for the CE-TOC population were 86.9% for lefamulin and 89.4% for moxifloxacin with or without linezolid (treatment difference -2.5 [95% CI -8.4, 3.4]). IACR is also a key secondary endpoint for the FDA.
“Community-acquired bacterial pneumonia is a common and potentially life-threatening illness for which presently available recommended antimicrobials have potential limitations often associated with resistance or safety,” said Dr. Thomas M. File Jr., M.D., MS, chair of the Infectious Disease Section, Northeast Ohio Medical University, and chair of the Infectious Disease Division, Summa Health. “With bacterial resistance continuing to increase, patients and physicians are in need of new safe and effective treatment options that adhere to the principles of antibiotic stewardship. These positive topline results evaluating the efficacy and safety of lefamulin in patients with community-acquired bacterial pneumonia are promising.”
In addition, in LEAP 1, ECR by pathogen was similar to the overall response rates and was comparable between treatment arms. Detailed results on a pathogen-by-pathogen basis in the microbiological intent to treat (microITT) population are included in Appendix A to this release.
LEAP 1 enrolled 551 patients: 276 in the lefamulin arm and 275 in the moxifloxacin with or without linezolid arm. Patients who were aged 65 or older represented 47.8% of the patients in the lefamulin arm compared to 39.3% of the patients in the moxifloxacin with or without linezolid arm. The lefamulin arm enrolled 196 (71.0%), 76 (27.5%) and 4 (1.4%) patients with a Pneumonia Outcomes Research Team (PORT) class of 3, 4 and 5, respectively. The moxifloxacin with or without linezolid arm enrolled 1 (0.4%), 201 (73.1%), 70 (25.5%) and 3 (1.1%) patients with a PORT class of 2, 3, 4 and 5, respectively.
In the LEAP 1 trial, a similar rate of treatment-emergent adverse events (TEAEs) was observed in the lefamulin arm (38.1%) and the moxifloxacin with or without linezolid arm (37.7%). In addition, the rates of TEAEs leading to study drug discontinuation were 2.9% for lefamulin versus 4.4% for moxifloxacin with or without linezolid, and the rates of withdrawal from the trial were 1.8% for lefamulin versus 4.0% for moxifloxacin with or without linezolid. Death occurred with similar frequency in both arms, with 6 patients dying in the lefamulin arm (2.2%) and 5 patients dying in the moxifloxacin with or without linezolid arm (1.8%).
Adverse events reported in greater than 2.0% of patients receiving study drug (lefamulin versus moxifloxacin with or without linezolid, respectively) were hypokalemia (2.9% versus 2.2%), nausea (2.9% versus 2.2%), insomnia (2.9% versus 1.8%), infusion site pain (2.9% versus 0%), infusion site phlebitis (2.2% versus 1.1%), alanine aminotransaminase (ALT) increase (1.8% versus 2.2%) and hypertension (0.7% versus 2.2%).
Of note, while no documented cases of Clostridium difficile infection were reported in either treatment group, diarrhea was observed in 0.7% and 7.7% of subjects receiving lefamulin and moxifloxacin with or without linezolid, respectively, with a lower overall rate of gastrointestinal TEAEs in the lefamulin arm compared to the moxifloxacin with or without linezolid arm (6.6% versus 13.0%). In addition, no meaningful differences between the lefamulin and moxifloxacin with or without linezolid arms were observed in cardiac (2.9% versus 4.0%) or hepatobiliary (0.7% versus 1.5%) TEAEs.
Elevations in liver transaminases (>3 times the upper limit of normal (ULN)) were comparable in both treatment groups: ALT (7.1% versus 6.4%) and aspartate aminotransferase (AST) (4.1% versus 2.6%) in the lefamulin and moxifloxacin with or without linezolid treatment groups, respectively. Elevations in liver transaminases (>5 times the upper limit of normal (ULN)) occurred in both treatment groups: ALT (2.2% versus 1.9%) and aspartate aminotransferase (AST) (0.7% versus 0.7%) in the lefamulin and moxifloxacin with or without linezolid treatment groups, respectively. No patient in either treatment group met Hy’s Law criteria, which is an indicator for severe liver damage.
Changes in QT interval, a measure of the heart’s electrical cycle, that were of potential clinical concern were uncommon. At steady state, maximum increases in QT interval between 30 to 60 msec occurred in 12 (4.6%) and 14 (5.4%) of patients receiving lefamulin and moxifloxacin with or without linezolid, respectively. In addition, compared to no patients in the lefamulin arm, one patient in the moxifloxacin arm had an increase in QT interval greater than 60 msec, and one patient in each treatment arm had an increase in absolute QT interval to greater than 500 msec.
Further analysis of the LEAP 1 trial results including analysis of additional patient population groups in the trial and secondary and exploratory endpoints related to these populations groups is ongoing and additional results will be presented at upcoming scientific congresses.