Date: 2015-10-13
Type of information: Presentation of results at a congress
phase:
Announcement: presentation of results at the 2015 Infectious Diseases Week conference (ID Week 2015) in San Diego
Company: Nabriva Therapeutics (Austria)
Product: lefamulin (BC 3781)
Action
mechanism: antibioctic/pleuromulin derivative. Lefamulin (BC 3781) belongs to the first generation of pleuromutilins to combine excellent systemic bioavailability with substantial activity against Gram-positive pathogens, and fastidious Gram-negative pathogens plus atypical pathogens. Pleuromutilins interfere with bacterial protein synthesis via a specific interaction with the 23S rRNA of the 50S bacterial ribosome subunit. These antibacterials have a distinct anti-bacterial profile. Their unique mechanism of action implies a very low probability of cross resistance with other antibacterials. In an industry first, Nabriva\'s world class medicinal chemistry expertise achieved the development of intravenous and orally available pleuromutilins clearing the way for i.v. and oral therapy with this antibiotic class. This achievement constitutes a significant milestone in providing appropriate medication for the treatment of life-threatening bacterial infections offering a distinctly different class of antibiotics for the treatment of bacterial diseases. Lefamulin is highly active against multi-drug resistant (MDR) pathogens including Methicillin resistant Staphylococcus aureus (MRSA), MDR Streptococcus pneumoniae, Vancomycin resistant Enterococcus faecium.
Disease: community-acquired bacterial pneumonia (CABP)
Therapeutic area: Infectious diseases
Country:
Trial details:
Latest
news: * On October 13, 2015, 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 that one poster was presented on lefamulin at the 2015 Infectious Diseases Week conference (ID Week 2015) in San Diego. The poster abstract is as follows: Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment (TA) Analyses Supporting Lefamulin Dose Selection for the Treatment of Patients with Community-Acquired Bacterial Pneumonia (CABP). Sujata M. Bhavnani, PharmD, MS, Paul G. Ambrose, PharmD, FIDSA, Wolfgang W. Wicha, M.S., Zrinka Ivezic-Schoenfeld, Ph.D., William T. Prince, Ph.D., MB, BChir, FFPM and Christopher M. Rubino, Pharm.D. Background: Lefamulin is a semi-synthetic intravenous (IV) and oral pleuromutilin antibiotic entering Phase 3 late-stage clinical development for CABP. Lefamulin is active against pathogens commonly associated with CABP, including multi-drug resistant (MDR) S. pneumoniae (SP), M. pneumoniae, and S. aureus (SA). Using in vitro, non-clinical PK-PD, and clinical pharmacokinetic (PK) data, PK-PD TA analyses were performed to provide support for the selection of a lefamulin dosing regimen for the treatment of patients with CABP. Methods: Data utilized included a population PK (PPK) model describing the disposition of lefamulin developed using Phase 1 and 2 data, non-clinical PK-PD targets based on neutropenic murine-lung infection models and MIC data from isolates collected from North America (NA) and the European Union (EU) for lefamulin against SP and SA (SENTRY Program). The PPK model used was a 3-compartment model with first-order elimination with saturable protein binding. Lefamulin concentrations in epithelial lining fluid (ELF) were modeled using first-order rate constants into and out of the ELF compartment. Using the PK parameter estimates, ELF and free-drug plasma concentration-time profiles were generated for 2000 simulated patients following lefamulin 150 mg IV q12h; Day 1 AUC0-24 values were calculated. Non-clinical ELF and free-plasma AUC:MIC ratio targets (median and second highest) associated with a 1-log10 CFU reduction from baseline for SP and SA were evaluated. Percent probabilities of PK-PD TA by MIC value and over MIC distributions for SP and SA were determined. Results: Percent probabilities of PK-PD TA by MIC are shown for SP and SA for ELF targets in the Figure. Percent probabilities of attaining median ELF AUC:MIC ratio targets were 97.0% at the MIC99 of 0.5 mg/L for SP and 99.4% at the MIC99 of 0.25 mg/L for SA. For the second highest targets, >=97.0% PK-PD TA was achieved at MIC90 values for each pathogen. Overall percent probabilities of attaining AUC:MIC ratio targets for SP and SA based on NA and EU MIC data were >=96.6%. Results based on plasma targets were similar for SP and SA. Conclusion: Results of these PK-PD TA analyses for SP and SA provide support for the selection of lefamulin 150 mg IV q12h for the treatment of patients with CABP. Nabriva is developing lefamulin, to be the first systemically available pleuromutilin for human use and expects to begin enrolling patients in the first of two Phase 3 clinical studies of lefamulin for the treatment of community acquired bacterial pneumonia (CABP) in the fourth quarter of 2015.
