Nabriva Therapeutics plc (NASDAQ: NBRV), a biopharmaceutical company engaged in the commercialization and development of innovative anti-infective agents to treat serious infections, announced today that The Journal of Emergency Medicine has published results from a post-hoc analysis of clinical data from the pivotal Lefamulin Evaluation Against Pneumonia (LEAP) 2 Phase 3 clinical trial. Avoiding hospitalization, with an outpatient 5-day regimen of oral XENLETA, as an alternative to the fluoroquinolone, moxifloxacin, was demonstrated in patients with moderate to severe community-acquired bacterial pneumonia (CABP), including those aged 65 years or older with comorbidities. The U.S. Food and Drug Administration (FDA) approved XENLETA for the treatment of adults with CABP in August 2019. XENLETA is the first IV and oral antibiotic with a novel mechanism of action approved by the FDA in nearly two decades.
“In the treatment of CABP, initiating appropriate empiric oral antimicrobial therapy in the outpatient setting can result in significant economic benefits and successful infection control,” said Dr. Frank LoVecchio, DO, MPH, FACEP, Professor, University of Arizona and Creighton College of Medicine, Phoenix, AZ and lead author of the study. “This analysis suggests that patients who might be considered for hospital admission, either due to advanced age, comorbidities or difficult-to-treat pathogens, can be managed effectively as outpatients using a 5-day monotherapy course of oral XENLETA, as an alternative to fluoroquinolones.”
The LEAP 2 trial compared efficacy and safety of oral lefamulin 600 mg every 12 hours (5 days) versus oral moxifloxacin 400 mg every 24 hours (7 days) in adults (inpatients and outpatients) with Pneumonia Outcomes Research Team (PORT) risk classes II‒IV utilizing two outcome assessments of Early Clinical Response (ECR), an on-therapy endpoint, and Test of Cure (TOC), a post-therapy endpoint. In the post-hoc analysis, investigators examined data of 310 patients who started treatment as outpatients; 151 patients were treated with lefamulin and 159 were treated with moxifloxacin. Demographics and baseline clinical characteristics were generally similar between treatment groups and were broadly reflective of the patient population with CABP. In this cohort, 30% of outpatients were aged 65 years and older, and approximately 15% were aged 75 years and older. Among outpatients, the majority (lefamulin, 77%; moxifloxacin, 76%) entered the study with at least one comorbid condition or risk factor, such as age (65 or older), smoking history, history of hypertension, baseline liver enzyme elevation, moderate to severe renal impairment, history of asthma/COPD, diabetes mellitus, or history of arrhythmia), and 25% of patients in the lefamulin group and 29% in the moxifloxacin group had at least three comorbid conditions or risk factors.
Study findings showed that success rates at ECR/TOC for outpatients treated with oral lefamulin were high and similar to outpatients treated with moxifloxacin (lefamulin, 91% vs. moxifloxacin, 89%/90%), including those with PORT risk class III/IV (lefamulin, 89%/91% vs. moxifloxacin, 88%/91%) and CURB-65 scores of 2‒3 (lefamulin, 87%/90% vs. moxifloxacin, 82%/88%). In addition, the TOC success rate was maintained through late follow-up (Day 30±3 days) in both the lefamulin (91%) and moxifloxacin (90%) groups in outpatients.
Full results of the post-hoc analysis of LEAP 2 data is included in the paper titled: Oral 5-Day Lefamulin for Outpatient Management of Community-Acquired Bacterial Pneumonia: Post Hoc Analysis of the Lefamulin Evaluation Against Pneumonia (LEAP) 2 Trial, published in The Journal of Emergency Medicine, March 14th, 2021.
LEAP 2 Study
The Phase 3, double-blind, double-dummy, parallel-group, noninferiority randomized trial was conducted in 99 sites in 19 countries. The clinical trial randomized 738 patients 18 years of age or older who had had PORT risk class II, III, or IV, radiographically documented pneumonia, acute illness, greater than three CABP symptoms, and greater than two vital sign abnormalities. Randomization was stratified by PORT risk class (II vs III/IV), geographic region (US vs ex-US), and prior receipt of a single dose of short-acting antibiotic therapy for CABP (yes vs no). Per protocol, ≤25 percent of the study population could have received a single dose of a short-acting antibiotic, and ≥50 percent were to have PORT risk class of III or IV. The first patient visit was on August 30, 2016, and patients were followed for 30 days, with the final date of follow-up on January 2, 2018.1
Pneumonia is an infection of the lung that can be serious and fatal, especially among older adult patients with comorbidities. There are approximately five million cases of pneumonia in the U.S. each year, and pneumonia is the fifth leading cause of hospitalization and one of the leading causes of infection-related death. Streptococcus pneumoniae is the most common cause of bacterial pneumonia in the U.S. According to data from the SENTRY Antimicrobial Surveillance Program, in the U.S., approximately 30 to 60 percent of S. pneumoniae, depending on region, are macrolide-resistant. In a recent publication, these findings were corroborated; macrolide-resistant S. pneumonia had been shown to be significantly more common in outpatients vs. inpatients, with rates as high as 45.3 percent vs. 37.8 percent, respectively, in isolates from 329 US hospitals from 2018-2019.2 In addition to macrolides, fluoroquinolones are another common treatment option for CABP. This broad-spectrum class is an effective option; however, fluoroquinolones carry boxed warnings for several significant safety concerns.
XENLETA® (lefamulin) is a first-in-class semi-synthetic pleuromutilin antibiotic for administration in humans discovered and developed by the Nabriva Therapeutics team. It is designed to inhibit the synthesis of bacterial protein, which is required for bacteria to grow. XENLETA’s binding occurs with high affinity, high specificity and at molecular sites that are different than other antibiotic classes. Efficacy of XENLETA was demonstrated in two multicenter, multinational, double-blind, double-dummy, non-inferiority trials assessing a total of 1,289 patients with CABP. In these trials, XENLETA was compared with moxifloxacin and in one trial, moxifloxacin with and without linezolid. Patients who received XENLETA had similar rates of efficacy as those taking moxifloxacin alone or moxifloxacin plus linezolid. The most common adverse reactions associated with XENLETA include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. For more information, please visit www.xenleta.com.
About Nabriva Therapeutics plc
Nabriva Therapeutics is a biopharmaceutical company engaged in the commercialization and development of innovative anti-infective agents to treat serious infections. Nabriva Therapeutics received U.S. Food and Drug Administration approval for XENLETA (lefamulin), the first pleuromutilin antibiotic for community-acquired bacterial pneumonia (CABP). Nabriva Therapeutics is also developing CONTEPO™ (fosfomycin) for injection, a potential first-in-class epoxide antibiotic for complicated urinary tract infections (cUTIs), including acute pyelonephritis. Nabriva entered into an exclusive agreement with subsidiaries of Merck & Co. Inc., Kenilworth, N.J., USA to market, sell and distribute SIVEXTRO® (tedizolid phosphate) in the United States and certain of its territories. For more information, please visit https://www.nabriva.com.
INDICATION AND IMPORTANT SAFETY INFORMATION
XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
IMPORTANT SAFETY INFORMATION
XENLETA is contraindicated in patients with known hypersensitivity to XENLETA or pleuromutilins.
XENLETA tablets are contraindicated for use with CYP3A4 substrates that prolong the QT interval.
WARNINGS AND PRECAUTIONS
XENLETA has the potential to prolong the QT interval. Avoid XENLETA in patients with known QT prolongation, ventricular arrhythmias, and patients receiving drugs that may prolong the QT interval.
Based on animal studies, XENLETA may cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.
Clostridium-difficile associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including XENLETA, with severity ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.
The most common adverse reactions (≥2%) for (a) XENLETA Injection are administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, and headache and (b) XENLETA Tablets are diarrhea, nausea, vomiting, and hepatic enzyme elevation.
USE IN SPECIFIC POPULATIONS
In patients with severe hepatic impairment, reduce the dosage of XENLETA Injection to 150 mg infused over 60 minutes every 24 hours. XENLETA Tablets are not recommended in patients with moderate or severe hepatic impairment due to insufficient information to provide dosing recommendations.
Avoid XENLETA Injection and Tablets with concomitant strong or moderate CYP3A or P-gp inducers. Monitor for reduced efficacy of XENLETA.
Avoid XENLETA Tablets with strong CYP3A or P-gp inhibitors.
Monitor for adverse reactions of sensitive CYP3A substrates administered with XENLETA Tablets.
XENLETA has not been studied in pregnant women. Verify pregnancy status in females prior to initiating XENLETA and advise females to use contraception during treatment and for 2 days after the final dose. Lactating women should pump and discard milk for the duration of treatment with XENLETA and for 2 days after the final dose.
To report SUSPECTED ADVERSE REACTIONS, or administration during pregnancy, contact Nabriva Therapeutics US, Inc. at 1-855-5NABRIVA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see Full Prescribing Information for XENLETA.
Any statements in this press release about future expectations, plans and prospects for Nabriva Therapeutics, including but not limited to statements about its ability to successfully launch and commercialize XENLETA for the treatment of CABP, including the availability of and ease of access to XENLETA through major U.S. specialty distributors, marketing exclusivity and patent protection for XENLETA, the development of CONTEPO for cUTI, the clinical utility of XENLETA for CABP and of CONTEPO for cUTI, plans for and timing of the review of regulatory filings for CONTEPO, efforts to bring CONTEPO to market, the market opportunity for and the potential market acceptance of XENLETA for CABP and CONTEPO for cUTI, the development of XENLETA and CONTEPO for additional indications, the development of additional formulations of XENLETA and CONTEPO, plans for making lefamulin available in China, plans to pursue research and development of other product candidates, expectations regarding the ability of customers to satisfy demand for XENLETA with their existing inventory, the sufficiency of Nabriva Therapeutics’ existing cash resources and its expectations regarding anticipated revenues from product sales and how far into the future its existing cash resources will fund its ongoing operations 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: Nabriva Therapeutics’ ability to successfully implement its commercialization plans for XENLETA and whether market demand for XENLETA is consistent with its expectations, Nabriva Therapeutics’ ability to build and maintain a sales force for XENLETA, the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, 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 studies in different disease indications will be indicative of the results of ongoing or future trials, uncertainties associated with regulatory review of clinical trials and applications for marketing approvals, the availability or commercial potential of CONTEPO for the treatment of cUTI, the ability to retain and hire key personnel, the availability of adequate additional financing on acceptable terms or at all and such other important factors as are set forth in Nabriva Therapeutics’ annual and quarterly reports and other filings on file with the U.S. Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Nabriva Therapeutics’ views as of the date of this press release. Nabriva Therapeutics anticipates that subsequent events and developments will cause its views to change. However, while Nabriva Therapeutics may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Nabriva Therapeutics’ views as of any date subsequent to the date of this press release.
1 Alexander E, Goldberg L, Das A. et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial. JAMA. 322(17):1661-1671.
2 Gupta, V., Yu, K. C., Schranz, J., Jokinen-Gordon, H., & Gelone, S. P. (2021). A multicenter evaluation of the US prevalence and regional variation in macrolide-resistant S. pneumoniae in ambulatory and hospitalized adult patients in the US [published online February 4, 2021]. Open Forum Infectious Diseases, 8, ofab063. doi:https://doi.org/10.1093/ofid/ofab063