DUBLIN – Nabriva Therapeutics AG is getting up to $120 million in a staged series B round to progress its pipeline of pleuromutilin antibiotics. A first tranche of $50 million will kickstart phase III development of its lead compound, lefamulin (BC 3781), in community-acquired pneumonia (CAP). A series of triggers will then result in further flows of funding, which would take the program up to and beyond regulatory filings on each side of the Atlantic.

"The $50 million is a real endorsement to getting us moving and on the critical path," Colin Broom, CEO of Vienna-based Nabriva, told BioWorld Today. "Based on this financing, we're very focused on executing on the development plan and on commercializing ourselves in the U.S." A first study will kick off later this year, and a second will follow early in 2016. Top-line data are expected by early and late 2017, respectively. "Our target is to submit in 2018," Broom said.

A lot of the regulatory risk associated with antibiotic development has been removed, following the creation of more transparent clinical development guidelines and the definition of clinical endpoints. Even though the EMA remains fixed on classical clinical cure rates, while the FDA is moving toward measuring early clinical responses, each can be catered to within a single protocol – and that is what Nabriva intends to do with its upcoming phase III trials.

The studies will employ moxifloxacin, a fluoroquinolone, as the main comparator, while those in the control arm who have suspected Staphylococcus aureus infections will also receive Zyvox (linezolid), an oxazolidinone marketed by Pfizer Inc., of New York.

"The regulatory pathway is now very clear for the CAP indication," Broom said. Even though the company's proof-of-concept trial was in acute bacterial skin and skin structure infections, the shift to CAP does not add any great clinical risk, he said. "The data from animal and some human studies suggest pneumonia is a better target," Broom said. "If an antibiotic works in one indication, it's likely to work in another." And the company has a safety database based on more than 400 patients and healthy volunteers, which provides it with significant reassurance on that front. "Antibiotics tend to fail due to toxicity," he said.

Lefamulin was previously the subject of a deal with Forest Laboratories (now part of Dublin-based Actavis plc), under which Nabriva received $25 million up front plus 12 months of R&D funding, while Forest received an option to buy the company. However, that agreement lapsed in July 2013. "Forest were really interested, but their strategy changed completely," Broom said, referring to a Carl-Icahn-driven shift to a more short-term strategy. The outcome was "all the better from our perspective," he said.

The company has substantial – yet, Broom said, conservative – sales expectations for the product. "In CAP alone, we certainly see this as being over a $500 million product, excluding other indications, which we would like to explore in the near future," he said. The product also has potential in hospital-acquired infections, osteomyelitis (a bone infection), prosthetic joint infections, sexually transmitted disease and pediatric infections. Skin infection is now a crowded area, so the company may not enter it.

Pleuromutilins were discovered as far back as the 1950s. Pleuromutilins inhibit bacterial protein synthesis by binding specific sites on the 50S subunit of the ribosome. Nabriva has developed molecules that specifically disrupt the activity of the peptidyl transferase center of the bacterial ribosome. "That's the bull's eye, if you like, of the ribosome. It's a very well conserved area," Broom said. "That augurs well for the slow development of resistance."

A couple of pleuromutilin antibiotics were approved for veterinary use over the years. Their potential in humans has only been explored more recently. London-based Glaxosmithkline plc gained approval for a topical antibiotic, Altabax (Altargo; retapamulin), for treating impetigo in 2007, but it has never been a major earner for the company. Sales peaked at €45 million (US$67 million) in 2008, after which the company stopped breaking out the individual number.

Vivo Capital and Orbimed co-led the latest Nabriva round. The syndicate also included EcoR1 Capital and Tavistock Life Sciences' Boxer Capital arm, as well as existing investors HBM, Phase4 Partners, Wellcome Trust, GLSV and Novartis Venture Fund.