Nabriva Therapeutics Announces Positive Topline Results from Global, Phase 3 Clinical Trial Evaluating IV and Oral Lefamulin for the Treatment of Community-Acquired Bacterial Pneumonia
- Lefamulin met all primary
- Conference call and webcast today at
In the LEAP 1 trial, Nabriva Therapeutics’ first of two pivotal Phase 3 clinical trials of lefamulin in patients with CABP, lefamulin met the
“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.
Lefamulin also met the primary endpoints for the
“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.
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.
About LEAP 1 Trial Design
LEAP 1 was a multi-center, randomized, controlled, double-blind, global study comparing lefamulin to moxifloxacin, a fluoroquinolone antibiotic, with or without linezolid. The trial was designed to evaluate the efficacy and safety of lefamulin (IV/oral) compared to moxifloxacin (IV/oral), with or without linezolid, in 551 adults with moderate to severe CABP. Linezolid (or matching placebo for the lefamulin arm) could be added to treatment if an investigator suspected that a patient was infected with methicillin-resistant S. aureus (MRSA) prior to randomization, as moxifloxacin is not approved to treat MRSA. Lefamulin was dosed at 150 mg IV every 12 hours. The comparator drugs were dosed according to their approved labeling, with moxifloxacin dosed at 400 mg IV daily and linezolid at 600 mg IV every 12 hours. Based on pre-defined criteria, investigators had the option to switch patients to oral therapy after three days (at least six doses) of IV study medication. Study drugs were administered orally as one lefamulin 600 mg tablet every 12 hours, moxifloxacin at 400 mg daily and linezolid at 600 mg every 12 hours. All patients enrolled in this trial had a PORT class severity of at least 3 on a scale of 1 to 5 (other than one patient in the moxifloxacin with or without linezolid treatment group), which corresponds to moderate to severe clinical disease. Randomization was 1:1 and was stratified by PORT risk class, geography and exposure to prior antibiotics. Patients who received more than a single dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization were excluded from participating.
For LEAP 1, the primary efficacy endpoint for the
Additional Phase 3 Clinical Trial Ongoing
Nabriva Therapeutics’ second pivotal Phase 3 clinical trial, LEAP 2, is a multi-center, randomized, controlled, double-blind, global study comparing oral lefamulin to moxifloxacin. LEAP 2 is designed to evaluate the efficacy and safety of oral lefamulin compared to oral moxifloxacin in patients with moderate CABP. All patients enrolled in LEAP 2 have a PORT class severity of 2 to 4 on a scale of 1 to 5, which corresponds to moderate disease. Nabriva is targeting the enrollment of approximately 738 patients in LEAP 2. The company expects to complete enrollment in the fourth quarter of 2017, and to have topline data available in the spring of 2018.
Conference Call and Webcast
The company will host a conference call and webcast at
Based on Nabriva Therapeutics’ combined analysis of the U.S. Centers for Disease Control and Prevention’s 2007 National Ambulatory Medical Care Survey, the National Hospital Ambulatory Medical Care Survey and 2013 data from the Healthcare Cost and Utilization Project,
Any statements in this press release about future expectations, plans and prospects for Nabriva, including but not limited to statements about the development of Nabriva’s product candidates, such as plans for the design, conduct and timelines of Nabriva’s ongoing Phase 3 clinical trial of lefamulin for CABP, the clinical utility of lefamulin for CABP and Nabriva’s plans for filing of regulatory approvals and efforts to bring lefamulin to market, the development of lefamulin for additional indications, the development of additional formulations of lefamulin, plans to pursue research and development of other product candidates, the sufficiency of Nabriva’s existing cash resources and other statements containing the words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “likely,” “will,” “would,” “could,” “should,” “continue,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the uncertainties inherent in the initiation and conduct of clinical trials, availability and timing of data from clinical trials, whether results of early clinical trials or trials in different disease indications will be indicative of the results of ongoing or future trials, whether results of Nabriva’s first Phase 3 clinical trial of lefamulin will be indicative of the results for its second Phase 3 clinical trial of lefamulin, uncertainties associated with regulatory review of clinical trials and applications for marketing approvals, the availability or commercial potential of product candidates including lefamulin for use as a first-line empiric monotherapy for the treatment of moderate to severe CABP, the sufficiency of cash resources and need for additional financing and such other important factors as are set forth under the caption “Risk Factors” in Nabriva’s annual and quarterly reports on file with the
(with or without linezolid)
|Microbiological ITT (microITT)||N = 160 (58.0%)||N = 159 (57.8%)|
|Baseline Pathogen||N||ECR (%)||N||ECR (%)|
|S. pneumoniae (SP)||82/93||88.2||%||91/97||93.8||%|
|Penicillin-Susceptible SP (PSSP)||17/21||81.0||%||16/18||88.9||%|
|Penicillin-Intermediate SP (PISP)||5/5||100||%||2/2||100||%|
|Penicillin-Resistant SP (PRSP)||2/2||100||%||2/3||66.7||%|
|Multidrug-Resistant SP (MDRSP)||6/6||100||%||5/6||83.3||%|
|Macrolide-Resistant SP (MRSP)||6/6||100||%||5/6||83.3||%|