A novel class of highly specific outer membrane protein targeting antibiotic to treat Pseudomonas infections in people with cystic fibrosis
Pseudomonas aeruginosa infections: A common and deadly unmet medical need in cystic fibrosis
Pseudomonas aeruginosa is the key pathogen of cystic fibrosis (CF) lung infections, and the most important pathogen in progressive and severe CF lung disease. It is the most common cause of chronic respiratory infections and the leading cause of morbidity and mortality in people with cystic fibrosis (CF). 1
P. aeruginosa is very common pathogen amongst people with CF. About half of all people with CF have Pseudomonas. More than 60 percent of adults with CF have Pseudomonas. 2
P. aeruginosa infections are difficult to treat, because it is resilient and often resistant to most antibiotics. Overtime, these infections usually become chronic and are particularly hard to eradicate. This leads to strong inflammatory response and resulting in rapid deterioration of lung function and a poorer prognosis.
Inhaled antibiotics are commonly used for the treatment of chronic lung infections. These antibiotics have a broad spectrum of bacterial coverage; while they are usually effective against Pseudomonas aeruginosa infections, they might have a negative impact on microbiome of the patients. Furthermore, the prevalence of antibiotic resistance is a cause of concern, and new options for treatment are needed.
1. Pseudomonas aeruginosa in cystic fibrosis: A chronic cheater Christopher M. Waters, Joanna B. Goldberg Proceedings of the National Academy of Sciences Apr 2019, 116 (14) 6525-6527; DOI: 10.1073/pnas.1902734116
Inhaled murepavadin: First targeted antibiotic being developed for treating Pseudomonas aeruginosa infections in people with cystic fibrosis
Inhaled Murepavadin, a precision antibiotic specifically targeting Pseudomonas aeruginosa, is being developed for the treatment of these infections in people with cystic fibrosis. It is a representative of the Outer Membrane Protein Targeting Antibiotics (OMPTA), a class of antibiotics with a novel mode of action discovered by Polyphor and the University of Zurich. Inhaled Murepavadin is highly potent and active against Pseudomonas aeruginosa including multidrug resistant strains, one of the most common and difficult to treat pathogens in people with cystic fibrosis. It is currently in the late preclinical stage of its development.
The concept of applying a pathogen-specific antibiotic has been developed with the aim to minimize the collateral damage of the microbiome and delay resistance acquisition through horizontal gene transfer, which is a common feature of all broad-spectrum antibiotics.
Inhaled Murepavadin fits well with the new trend in antibiotic use known as ‘antibiotic stewardship’ which, among other things, aims to reduce the excessive use of broad-spectrum products which generates resistance especially for patients who are using inhaled antibiotics chronically such as those with cystic fibrosis.
The video shows the LPS export mechanism via LptD-LptE, which is inhibited by Murepavadin.
Murepavadin, a 14-amino-acid cyclic peptide for intravenous administration, targets the lipopolysaccharide transport protein D (LptD). This outer membrane protein of Pseudomonas aeruginosa is critical for lipopolysaccharide (LPS) biogenesis. LPS is an integral part of the bacterium’s outer membrane and necessary for the pathogen to survive and proliferate. Through binding to LptD in the outer membrane of the bacterium, Murepavadin causes LPS alterations and ultimately kills the bacterium.
In preclinical studies, Murepavadin was highly effective against Pseudomonas aeruginosa, without evidence of generating resistance.
- Murepavadin exerts a very potent anti‑pseudomonal activity and shows a good lung tissue penetration
- Is highly specific against Pseudomonas aeruginosa, including MDR (multidrug resistant) strains (precision medicine)
- Targets the essential outer membrane (OM) β-barrel transporter protein LptD, which translocates LPS from the periplasm to the OM and is essential for outer membrane biogenesis
- Is highly active in vitro (MIC90≤ 0.25µg/ml; >1,500 strains tested worldwide)
- Retains potent activity on Pseudomonas aeruginosa CF clinical isolates (strains MIC90= 2µg/ml; >400 strains tested)
- Is highly effective in several animal infection models with high exposure in the epithelial lung fluid (ELF)
- Showed no cross-resistance with current standard-of-care antibiotics
- Inhaled Murepavadin is expected to complete its preclinical program in the near future
Collaborative and patient oriented approach in development
The development of Inhaled Murepavadin program is jointly funded by Polyphor and the European Innovative Medicines Initiative (IMI). It is also part of the iABC project, a Europe-wide program dedicated to the development of inhaled antibiotics run by a consortium of leading lung specialists and research institutions in various European countries.
Following the successful completion of the preclinical program suggesting efficacy and a broader safety margin compared to the I.V. formulation, a Clinical Trial Authorization (CTA) for inhaled murepavadin was granted in December 2020 by the MHRA leading to the initiation of the Phase 1 program. The start of subject enrollment in the the Phase 1 study, evaluating safety and tolerability of single and multiple ascending doses of the novel antibiotic in healthy volunteers, is expected in Q4 2021. Polyphor expects results of the Phase 1 study in 2022.
Following a successful Phase 1 study, Polyphor could start a Phase 1b/2 trial in 2023. In November 2020, we concluded a funding agreement with the Cystic Fibrosis Foundation to advance clinical development up to 3.3M $ to fund a Phase 1b/2a clinical trial of inhaled murepavadin further extending the potential funding for this program.