On September 18, Nabriva Therapeutics announced positive topline results for its investigational antibiotic, lefamulin (formerly BC-3781), which is currently in Phase III of clinical development for patients with community-acquired bacterial pneumonia (CABP), including cases caused by methicillin-resistant Staphylococcus aureus (MRSA).

Specifically, Nabriva’s lead asset met both the FDA and EMA primary efficacy endpoints of noninferiority to moxifloxacin with or without linezolid in its LEAP-1 trial, the first of two pivotal Phase III studies assessing the efficacy and safety of intravenous (IV) and/or oral lefamulin for the treatment of CABP. With these encouraging data in hand, GlobalData expects Nabriva to be well positioned to receive regulatory approval in the US and EU for lefamulin in early 2019.

A systemic pleuromutilin, lefamulin acts by binding to the peptidyl transferase center (PTC) of the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis by preventing correct positioning of the tRNA. The novel antibiotic has exhibited potent in vitro activity against a diverse array of drug-resistant Gram-positive and Gram-negative pathogens, particularly those most frequently associated with skin and respiratory tract infections. Initial demonstration of the safety and efficacy of lefamulin compared with vancomycin in a proof-of-concept Phase II study landed it the FDA’s coveted Qualified Infectious Disease Product (QIDP) designation for acute bacterial skin and skin structure infections (ABSSSI) and CABP in October 2014. Nabriva is currently evaluating its lead pipeline candidate in over 1,200 patients with CABP across two pivotal Phase III trials (LEAP-1 and LEAP-2).

A multicenter randomised controlled trial (RCT), LEAP-1 assessed the efficacy and safety of IV/oral lefamulin compared with IV/oral moxifloxacin with or without linezolid, based on the suspected presence of MRSA, in 551 adults with moderate-to-severe CABP. Topline data from the study showed that lefamulin was noninferior to moxifloxacin +/- linezolid in terms of both early clinical response (ECR) assessed 72–120 hours following initiation of therapy in the intent-to-treat (ITT) population (FDA endpoint; 87.8% vs. 90.2%, respectively [95% confidence interval (CI) -8.5, 2.8]) and an investigator assessment of clinical response at a test of cure visit 5–10 days post-therapy in the modified ITT and clinically evaluable (CE) populations (EMA endpoint; 86.9% vs. 89.4% in the CE population, respectively [95% CI -8.4, 3.4]). Importantly, treatment-emergent adverse events (AEs) occurred with similar frequency across both trial arms (38.1% for lefamulin compared with 37.7% for comparator). Evaluation of oral lefamulin for the treatment of patients with moderate CABP (LEAP-2) is ongoing and should be completed in 2018.

Due to the urgent need for novel antibiotics with potent activity against drug-resistant pathogens—particularly products that possess unique mechanisms of action (MOAs)—GlobalData expects lefamulin to be immediately welcomed by clinicians upon its approval and market entry. According to key opinion leaders (KOLs) interviewed by GlobalData, lefamulin’s status as a first-in-class systemic pleuromutilin should position it for solid uptake in patients with moderate-to-severe CABP, especially in cases where that current standard of care (vancomycin or moxifloxacin +/- linezolid) is ineffective or contraindicated.

If lefamulin is eventually approved, its ability to be administered both orally and intravenously combined with its first-in-class status and broad-spectrum activity against difficult-to-treat pathogens represent key advantages over many of the antibiotics most frequently prescribed to treat CABP. Nevertheless, lefamulin stands to enter a highly competitive, heavily genericised marketplace, with future competition expected from pipeline candidates such as Melinta’s Baxdela (delafloxacin), Paratek’s omadacycline (formerly PTK-0796), and Melinta/Cempra’s Solithera (solithromycin). Antibiotic stewardship programs, driven by the growing fear of antibiotic resistance, will also preclude lefamulin from front-line use, thereby limiting its commercial potential independent of product-specific competition.

Given the aforementioned challenges, lefamulin’s commercial success is far from guaranteed despite favorable results in the clinic to date. In order to successfully recoup its substantial investment in lefamulin upon its anticipated approval in early 2019, Nabriva must bolster the drug’s promising clinical profile with a shrewd pricing strategy and targeted physician education campaigns in order to encourage its prescription in an increasingly competitive antibiotics marketplace.