Preclinical Data Supports Development of Inhaled Form of Murepavadin to Fight P. Aeruginosa Infections

Preclinical Data Supports Development of Inhaled Form of Murepavadin to Fight P. Aeruginosa Infections

A new experimental antibiotic named murepavadin is both safe and effective at fighting bacterial lung infections caused by Pseudomonas aeruginosa when given via inhalation, a study in mice shows.

These findings were discussed earlier this month at the 42nd European Cystic Fibrosis Conference in Liverpool, England, in a presentation titled, “Pharmacokinetics and pharmacodynamics of murepavadin (POL7080) in neutropenic lung infection models when evaluated by aerosol administration.”

Murepavadin, also known as POL7080, is being developed by the pharmaceutical company Polyphor. It belongs to a new class of antibiotics called Outer Membrane Protein Targeting Antibiotics (OMPTA) that are believed to effectively fight bacteria that are resistant to other antibiotics.

“Respiratory infections, especially those caused by drug-resistant bacteria, are the main cause of disease and death in people with cystic fibrosis and bronchiectasis. New treatment options are urgently needed to fight resistant pathogens, especially resistant Pseudomonas strains,” Daniel Obrecht, PhD, chief science officer of Polyphor, said in a press release. “Murepavadin is a precision antibiotic specifically targeting Pseudomonas aeruginosa, the main cause of chronic lung infection in cystic fibrosis [and bronchiectasis].”

In the most recent preclinical studies, researchers infected mice with P. aeruginosa, and then treated them with murepavadin at doses ranging from 0.156 to 15 mg/kg. The antibiotic was administered intratracheally, meaning it was pumped directly into the trachea (windpipe). This administration route is more invasive than simple inhalation, but it allows more precise control over dosing.

The research team was particularly interested in understanding the stability and dynamics (pharmacokinetics) of murepavadin inside the body when given intratracheally.

They found that murepavadin levels in mice’s blood and epithelial lining fluid (ELF, the fluid around the lungs) increased linearly with increasing dosage, meaning that an increase in dose was met by an increase of the same magnitude in the amount of the medicine detected in the blood and ELF. Importantly, ELF exposure to murepavadin was approximately 1,000-fold greater than that of blood. This suggests the antibiotic will have less systemic effects, and its activity will be concentrated in fighting infections in the lungs.

Also, the antibiotic significantly reduced the numbers of bacteria in the lungs, with the most resistant strain of P. aeruginosa tested being reduced in number by more than 10-fold at a dose of 1.25 mg/kg.

Murepavadin’s antibacterial activity was found to be stronger than that of one commonly used antibiotic called Polymyxin B, which, in contrast, failed to effectively reduce the numbers of the most resistant strain of P. aeruginosa.

Researchers also evaluated the safety of murepavadin when administered by inhalation to male mice. With an estimated dose of 7.26 mg/kg of murepavadin no new signs of toxicity or adverse side effects reported.

Collectively, these preliminary results demonstrate that murepavadin holds “potent activity towards P. aeruginosa” and that “is well tolerated when administered by inhalation route.”

To expedite the development of a new inhaled formulation of murepavadin, Polyphor is taking advantage of a European program dedicated to the development of inhaled antibiotics.

The iABC (inhaled Antibiotics in Bronchiectasis and Cystic fibrosis) project is being conducted by a consortium of leading lung specialists across 18 hospitals and research institutions in eight European countries.

The program is being supported by the Innovative Medicines Initiative, the largest public-private partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations.

“The in vivo data presented are encouraging and we are looking forward to further developing the inhaled formulation of murepavadin within the iABC project, which will be an important step to find a new treatment option to improve the quality of life and increase life expectancy of these patients,” Obrecht said.