Nabriva Therapeutics plc has gained FDA approval of NDAs for both I.V. and oral formulations of lefamulin, a semisynthetic antibiotic for the treatment of community-acquired bacterial pneumonia (CABP) it will market as Xenleta. It's the first pleuromutilin for systemic use in humans to win FDA approval, leading the first new class of antibiotics for CABP in almost 20 years.

The drug, which received the FDA's qualified infectious disease product designation, received a priority review at the agency and is expected to be available through major U.S. specialty distributors in mid-September. In vitro antimicrobial susceptibility testing will be available at launch, the company said.

Xenleta will have a wholesale acquisition price of $205 per I.V. patient treatment day and $275 per oral patient treatment day. Recommended dosing calls for 150 mg of lefamulin every 12 hours by I.V. over five to seven days or 600 mg orally every 12 hours, with the option to switch from I.V. to oral delivery every 12 hours to complete the treatment course.

The company's EMA filings for lefamulin, validated in June, remain under review.

Shares in the Dublin-based company (NASDAQ:NBRV) fell 3.1% on Monday to $2.21 following an afternoon trading halt ahead of the approval's news. After hours, the stock was trading up 21%.

A new option for treating CABP

Xenleta is the second new therapy to gain FDA approval for CABP within a year, following Paratek Pharmaceuticals Inc.'s I.V. and oral antibiotic, Nuzyra (omadacycline), a tetracycline approved in October 2018. Nuzyra is still awaiting EU approval, but consensus estimates project sales of the antibiotic will hit $12 million in 2019, rising to a peak of $515 million by 2024. (See BioWorld, Oct. 4, 2018.)

Ed Cox, director of the FDA's Office of Antimicrobial Products, said the approval "reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics."

Pneumonia is an infection of the lung that can be serious and fatal, especially among older adults with co-morbidities. The CDC estimates that, each year, about 1 million people are hospitalized with CABP and 50,000 people die from the disease. Nabriva estimates there are about 5 million cases of pneumonia each year and that pneumonia is the fifth leading cause of hospitalization and one of the leading causes of infection-related death.

Anticipating the approval on Aug. 9, H.C. Wainwright analyst Ed Arce wrote of "a significant advantage" for Xenleta on the out-patient front, citing the typical hospitalization costs associated with CABP patients at $2,500 per day. "We project lefamulin to begin U.S. sales soon after its approval, and [to] reach peak sales of $460 million in the U.S. market by 2026," he said.

Nabriva CEO Ted Schroeder told BioWorld his company has had a market access team, a medical science liaison team and regional sales directors in place for more than 18 months. Together, the latter two have been profiling accounts to understand potential needs and readmissions patterns. "Beyond just targeting hospitals based on the volume of antibiotics they buy, we're also looking at their preparedness to add a product like lefamulin to their formulary," he said.

Meanwhile, the company's market access team has been engaged with payers, outlining the pharmacoeconomic benefit of an I.V.-to-oral step-down therapy and the overall antibiotic resistance trends nationally. They have also been laying the groundwork for the specialty pharma distribution infrastructure that would support getting oral lefamulin to patients upon hospital discharge, he said.

The NDAs for Xenleta were supported by two pivotal phase III trials, LEAP 1 and LEAP 2, that evaluated the safety and efficacy of both formulations of the antibiotic vs. moxifloxacin with or without linezolid in the treatment of 1,289 adults with CABP. LEAP 1 was designed with the option to switch participants from I.V. to oral administration, while LEAP 2 was designed as a short-course, five-day, oral-only treatment with Xenleta.

The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid, the FDA said. In LEAP 1, Xenleta demonstrated noninferiority compared to moxifloxacin, with or without linezolid, for the FDA primary endpoint of early clinical response (ECR) assessed 72 to 120 hours following initiation of therapy in the intent-to-treat (ITT) patient population (ECR rate = 87.3% for Xenleta and 90.2% for moxifloxacin, with or without linezolid). In LEAP 2, five days of oral Xenleta also demonstrated noninferiority to seven days of oral moxifloxacin for the ECR endpoint in the ITT population (ECR rate = 90.8% for Xenleta and 90.8% moxifloxacin). High-risk patients 65 and older achieved a similar ECR rate as those under 65.

The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting.

A novel MOA

Xenleta kills bacteria by interfering with the production of proteins on ribosomes. While that aspect in itself isn't novel, what's different about lefamulin is that it attaches to a different binding site that's not shared by any other class of antibiotic, Schroeder explained. The difference supports "a fundamentally lower risk of developing resistance, and importantly, cross-resistance to most other classes of antibiotic," he said.

Designed to be both an I.V. and a bioequivalent oral medication, it's intended to offer the same flexibility as fluoroquinolones without the risks of mental health side effects and serious blood sugar disturbances that have been flagged for quinolones.

Just one other pleuromutilin is approved for human use in the U.S., Almirall Prodesfarma SA's retapamulin. It's indicated for the treatment of impetigo in adults and children caused by methicillin-susceptible strains of Staphylococcus aureus and Streptococcus pyogenes. In the EU, retapamulin is indicated for the treatment of impetigo and infected small lacerations, abrasions or sutured wounds.

In March 2018, Nabriva licensed rights to Roivant Sciences Ltd. affiliate Sinovant Sciences Ltd. to develop and commercialize lefamulin in the greater China region. Nabriva received $5 million up front for the agreement and is eligible to receive up to an additional $91.5 million in milestone payments. China's NMPA accepted a clinical trial application for registration trials in CABP to start in the second half of this year.

Separately, Nabriva said Aug. 16 that, following receipt of a complete response letter for its complicated urinary tract infection therapy, Contepo (fosfomycin), in April, its team anticipates resubmitting its NDA for the medicine early in the fourth quarter of this year. (See BioWorld, May 2, 2019.)

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