Xenleta (lefamulin oral) / Nabriva Therap, Sumitomo Pharma - LARVOL DELTA

The Convenient Use of Fluorescamine for Spectrofluorimetric Quantitation of Novel Antibiotic Drug Lefamulin (Xenleta) in Pure Form, Pharmaceutical Formulation and Spiked Biological Fluid; Application to Content Uniformity Testing and Evaluation of Method Greenness. (PubMed, Luminescence) - "Additionally, the approach was used to examine the content uniformity in accordance with US Pharmacopeia requirements. Furthermore, the results of the ecology scale scores indicated that the analytical process involved was green."

Journal

Lefamulin for Mycoplasma genitalium treatment failure in Australia and the USA: a case series and pilot open-label parallel arm randomised trial. (PubMed, Sex Transm Infect) - "While cure rates were low, lefamulin was effective in some individuals with MG treatment failure. Additional antibacterial agents for multidrug-resistant infections are needed."

Journal • Gastrointestinal Disorder • Infectious Disease • Inflammation • Urology

Lefamulin dosing optimization using population pharmacokinetic and pharmacokinetic/pharmacodynamic assessment in Chinese patients with community-acquired bacterial pneumonia. (PubMed, Front Pharmacol) - "This study proved that intravenous and oral administrations of lefamulin can reach preclinical PK/PD targets of S. pneumoniae and S. aureus. These findings support the optimal use of lefamulin for the safe and effective treatment of Chinese CABP patients."

Journal • PK/PD data • Infectious Disease • Pneumococcal Infections • Pneumonia • Respiratory Diseases

In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice. (PubMed, Int J Mol Sci) - "Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS."

Journal • Preclinical • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Influenza • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • CD4 • CD8 • CSF2 • IFNG • IL17A • IL6 • TNFA

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate. (PubMed, J Med Chem) - "Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin...The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections."

Journal • Infectious Disease • CYP3A4

Physiologically-based pharmacokinetic modeling of the drug-drug interaction between ivacaftor and lefamulin in cystic fibrosis patients. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The predicted change in ivacaftor PK when co-administered with oral lefamulin was less than observed between ivacaftor and fluconazole. These results suggest a low liability for a DDI between lefamulin and ivacaftor in patients with CF."

Journal • PK/PD data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CYP3A4

Safety and Pharmacokinetics Following Oral or Intravenous Lefamulin in Adults With Cystic Fibrosis. (PubMed, Clin Ther) - P1 | "These results show similar lefamulin pharmacokinetic and safety profiles between patients with CF and healthy volunteers receiving the same oral and IV doses, suggesting no need for lefamulin dose adjustment in patients with CF and indicating the potential of lefamulin as therapy for lung infections in patients with CF."

Journal • PK/PD data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

7-Year (2015-21) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms. (PubMed, J Antimicrob Chemother) - "Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance."

Journal • Preclinical • Infectious Disease • Influenza • Pneumococcal Infections • Pneumonia • Respiratory Diseases

Lefamulin for M. Genitalium Treatment Failures (clinicaltrials.gov) - P1/2 | N=12 | Terminated | Sponsor: University of Washington | N=40 ➔ 12 | Trial completion date: Apr 2023 ➔ Nov 2023 | Suspended ➔ Terminated | Trial primary completion date: Apr 2023 ➔ Nov 2023; At Sponsor Request

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease

Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Lefamulin in Healthy Chinese Subjects. (PubMed, Antibiotics (Basel)) - "This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus."

Journal • PK/PD data • Infectious Disease • Pneumococcal Infections • Pneumonia

EFFICACY AND SAFETY OF LEFAMULIN IN CHINESE ADULTS WITH COMMUNITY-AQUIRED BACTERIAL PNEUMONIA (CABP): RESULTS OF LEFAMULIN EVALUATION AGAINST PNEUMONIA (LEAP-CHINA) STUDY (CHEST 2023) - " Adults with CABP were randomized 2:1 to receive lefamulin 150 mg IV Q12 hours or moxifloxacin 400 mg IV Q24 hours. This bridging trial met the consistency criteria with LEAP 1, supporting the noninferiority conclusion of lefamulin to moxifloxacin. The frequency of TEAEs was comparable between the two groups. CLINICAL IMPLICATIONS: Lefamulin is a promising new option as empirical monotherapy for Chinese adults with CABP."

Clinical • Infectious Disease • Pneumonia • Respiratory Diseases

Assessing Boron-Pleuromutilin AN11251 for the Development of Antibacterial Agents. (PubMed, Molecules) - "The recent approval of lefamulin for both intravenous and oral doses in humans to treat community-acquired bacterial pneumonia has prompted investigations in modifying the structure to broaden the antibacterial spectrum, enhance the activity, and improve the pharmacokinetic properties. AN11251 has potent activities against the Gram-positive bacterial pathogens tested, including various drug-resistant strains, and against the slow-growing mycobacterial species. Finally, we employed PK/PD modeling to predict the human dose for treatment of disease caused by Wolbachia, Gram-positive bacteria, or Mycobacterium tuberculosis, which might facilitate the further development of AN11251."

Journal • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Lefamulin for M. Genitalium Treatment Failures (clinicaltrials.gov) - P1/2 | N=40 | Suspended | Sponsor: University of Washington | Recruiting ➔ Suspended

Trial suspension • Infectious Disease

Study to Assess the Safety and PK of Oral and IV Xenleta in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: Nabriva Therapeutics AG | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Jan 2023 | Trial primary completion date: Mar 2023 ➔ Sep 2022

Trial completion • Trial completion date • Trial primary completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections. (PubMed, Front Pharmacol) - "Dose-range and dose-fractionation experiments with N. gonorrhoeae reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2 mg/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs)."

Journal • PK/PD data • Infectious Disease • Pneumonia • Respiratory Diseases

Nabriva Therapeutics Announces Positive Topline Results from Phase 1 Trial of XENLETA (lefamulin) in Adult Patients with Cystic Fibrosis (GlobeNewswire) - P1 | N=13 | NCT05225805 | Sponsor: Nabriva Therapeutics AG | "Nabriva Therapeutics plc...announced positive topline results from their Phase 1 clinical trial that assessed the safety and pharmacokinetics (PK) of oral and intravenous (IV) XENLETA® (lefamulin) in adult patients with cystic fibrosis (CF)....'In addition, XENLETA was well-tolerated and the adverse event profile in CF patients was consistent with that described across our clinical program'...look forward to sharing the complete results with the medical community in the first half of 2023.'"

P1 data • PK/PD data • Cystic Fibrosis

Nabriva Therapeutics Pivoting Strategic Focus Reports Third Quarter Financial Results and Provides Corporate Update (GlobeNewswire) - "Three Months Ended September 30, 2022 and 2021: Research and development expenses for the three months ended September 30, 2022 were $4.0 million compared to $3.2 million for the three months ended September 30, 2021. The $0.8 million increase was primarily due to a $0.5 million increase in consulting fees and a $0.4 million increase in research materials and purchased services driven by our Phase 1 trial to assess the safety and pharmacokinetics of oral and intravenous XENLETA for the treatment of resistant bacterial infections in adult patients with cystic fibrosis."

Commercial • Cystic Fibrosis

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF THE COMBINATION OF IVACAFTOR AND LEFAMULIN IN PATIENTS WITH CYSTIC FIBROSIS (CHEST 2022) - "The CYP3A4 component assigned in the model was verified against itraconazole, fluconazole and ketoconazole DDI data. A previously developed and validated PBPK model for lefamulin was applied and the CYP3A4 inhibition constant (Ki) was verified against midazolam DDI data collected in clinical studies... The predicted change in ivacaftor PK when co-administered with oral lefamulin was less than that observed with co-administration of ivacaftor and fluconazole (a known moderate CYP3A inhibitor). CLINICAL IMPLICATIONS: These results suggest a low liability for a CYP3A-mediated DDI between lefamulin and ivacaftor in CF patients."

Clinical • Late-breaking abstract • PK/PD data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

LEFAMULIN EFFICACY IN ADULTS WITH COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA (CABP) IS UNAFFECTED BY OBESITY: POOLED ANALYSIS OF THE LEFAMULIN PHASE 3 CLINICAL TRIAL PROGRAM (CHEST 2022) - "Consistent with in silico pharmacokinetic modeling, data from the pooled LEAP analyses suggest that LEF was a highly efficacious monotherapeutic treatment of CABP, regardless of BMI category. CLINICAL IMPLICATIONS: LEF represents an alternative to fluoroquinolones for treating CABP in patients with a range of BMIs as typically encountered in normal clinical practice."

P3 data • Retrospective data • Asthma • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hypertension • Immunology • Infectious Disease • Obesity • Pneumonia • Respiratory Diseases

Nabriva Therapeutics Completes Patient Enrollment in Phase 1 Trial of XENLETA(lefamulin) in Adult Patients with Cystic Fibrosis (GlobeNewswire) - "Nabriva Therapeutics...announced the completion of patient enrollment in its Phase 1 clinical trial to assess the safety and pharmacokinetics of oral and intravenous XENLETA® (lefamulin) in adult patients with cystic fibrosis (CF)...'With enrollment now complete, we expect to report topline data in the first quarter of 2023.'"

Enrollment closed • P1 data • Cystic Fibrosis

Study to Assess the Safety and PK of Oral and IV Xenleta in Adults With Cystic Fibrosis (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: Nabriva Therapeutics AG | Recruiting ➔ Active, not recruiting

Enrollment closed • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Nabriva Therapeutics Announces First Patient Enrolled in Phase 1 Trial of XENLETA (lefamulin) in Adult Patients with Cystic Fibrosis (GlobeNewswire) - "Nabriva Therapeutics plc...announced that the first patient was enrolled in a Phase 1 clinical trial to assess the safety and pharmacokinetics of oral and intravenous XENLETA® (lefamulin) in adult patients with cystic fibrosis (CF)."

Trial status • Cystic Fibrosis

Nabriva Therapeutics Reports Second Quarter 2022 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Research and development expenses for the six months ended June 30, 2022 were $7.6 million compared to $7.0 million for the six months ended June 30, 2021, which represented an 8% increase. The $0.6 million increase was primarily due to a $0.5 million increase in research materials driven by our Phase 1 cystic fibrosis trial of XENLETA and purchased services, and a $0.1 million increase in travel expenses."

Commercial • Cystic Fibrosis

Tissue Distribution of [C]-Lefamulin into the Urogenital Tract in Rats. (PubMed, Antimicrob Agents Chemother) - "[C]-lefamulin in rats showed rapid, homogeneous distribution into urogenital tissues down to a cellular level, with high tissue:blood ratios in tissues relevant to STI treatment. These results, and the potent in vitro activity of lefamulin against multidrug-resistant bacteria known to cause STIs, will help inform further assessment of lefamulin, including potential clinical evaluation for treatment of STIs."

Journal • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Lefamulin: a New Hope in the Field of Community-Acquired Bacterial Pneumonia. (PubMed, Curr Pharmacol Rep) - "The C(14) side chain is responsible for its pharmacodynamic and antimicrobial properties, together with supporting in overcoming bacterial ribosomal resistance and mutations improvement amplifying the number of hydrogen bonds to the target site. This review aims to highlight the pre-existing treatment options and specific purposes to shed some light upon the development of a new drug lefamulin and its specifications and explore this novel drug's superior efficacy to already existing treatment strategies."

Journal • Review • Infectious Disease • Pneumococcal Infections • Pneumonia • Respiratory Diseases