A novel class of highly specific outer membrane protein targeting antibiotic to treat resistant Pseudomonas infections
Pseudomonas aeruginosa – a deadly threat
As one of the six most dangerous drug-resistant ESKAPE* pathogens, Pseudomonas aeruginosa is a significant and increasing global health concern1 and is responsible for many deaths.
Every year, Pseudomonas aeruginosa (PA) causes up to 250,000 hospital-acquired infections in the US and Europe alone; in the US, for example, it is responsible for 9% of all hospital-acquired infections.
PA is also the second leading cause of Nosocomial Pneumonia with a high mortality rate of 30-40%, e.g. from Ventilator-Associated Bacterial Pneumonia (VABP) 2.
Multidrug resistance (MDR) pathogens, including Carbapenem-resistant Pseudomonas aeruginosa (CRPA), has become a serious global health concern. Treatment of infectious diseases caused by MDR strains of PA is becoming more challenging over time, while treatment options remain limited.
Murepavadin, a pathogen-specific antibiotic, is being developed for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa.
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.
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.
Murepavadin has obtained QIDP (Qualified Infectious Disease Product) status and eligibility for priority review, with statutory exclusivity for an additional five years upon FDA approval.
* ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.
2. Micek Scott T et al. An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multi drug resistance. Critical Care. 2015;19:219
A precision weapon against resistant Pseudomonas pathogens
Murepavadin (POL7080) is the first of a novel class of antibiotics, known as OMPTA, that target the Gram-negative bacterias’ outer membrane proteins, and works against one of the most dangerous drug-resistant microbes, Pseudomonas aeruginosa. Murepavadin is derived from Polyphor’s proprietary chemistry platform and its effect is based on a new mechanism of action.
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.
The video shows the LPS export mechanism via LptD-LptE, which is inhibited by Murepavadin
In preclinical studies, Murepavadin was highly effective against Pseudomonas aeruginosa, without evidence of generating resistance.
- Murepavadin exerts a very potent, specific anti‑pseudomonal activity, supported by a good lung tissue penetration 3
- Is highly specific against Pseudomonas aeruginosa, including MDR (multidrug resistant) strains (precision medicine)
- Targets the essential outer membrane (OM) 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)
- 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
3. Magill Shelley S. et al. Multistate Point-Prevalence Survey of Health Care-Associated Infections. N Engl J Med. 2014;370:1198-1208
Murepavadin has been evaluated in 8 clinical studies. Murepavadin penetrates into lung tissue and showed encouraging results in a Phase II study when given on top of standard‑of‑care in patients with VABP 4.
Six Phase I/exploratory and two Phase II studies have been conducted. The two Phase II studies were done in patients with Ventilator-Associated Bacterial Pneumonia and Non-Cystic Fibrosis Associated Bronchiectasis.
- Following single i.v. dose administration, there are dose-dependent increases in Cmax and AUC within the dose range from 0.05 to 8 mg/kg, and t1/2 is approximately 5 to 7 hours independently of dose 5 , 6
- Steady-state concentrations were reached by 48 hours relative to the first dose*
- Rapid pulmonary penetration was observed after i.v. dosing with exposures in Epithelial Lining Fluid and Alveolar Macrophages similar to free plasma, which supports its use in the treatment of lower respiratory tract infections 7
- A drug-drug interaction study with Amikacin 8 indicated no relevant increase in Murepavadin & Amikacin exposures when administered concomitantly, and multiple doses of Murepavadin were considered to be safe and with acceptable tolerability
- The most frequently reported adverse events in patients and healthy volunteers were paresthesia, dizziness and infusion site reactions, all of which were fully reversible after discontinuation of the treatment*
- Murepavadin preliminary data from a Phase II trial in patients with Ventilator-Associated Pneumonia were encouraging and warrant the further exploration of this compound. Among the twelve patients in the microbiological intention-to-treat set the clinical cure rate at TOC was over 80% and the 28-day all cause mortality was 8%. There was no emergence of resistance related to Murepavadin therapy during this study 4
* Data on file
4. Armaganidis A, et al. Efficacy of Murepavadin co-administered with standard-of-care in a Phase 2 study in patients with ventilator-associated pneumonia due to Pseudomonas aeruginosa infection. 37th International Symposium on Intensive Care and Emergency Medicine, Brussels, 2017
5. Dembowsky K. et al. Phase 1 (multiple ascending dose) study with the novel Pseudomonas aeruginosa antibiotic POL7080 in healthy volunteers. ECCMID, London, 2012
6. Wilbrahama D. et al. Phase 1 study with the novel Pseudomonas aeruginosa antibiotic POL7080 in healthy volunteers. ECCMID, Milano, 2011
7. Winter E. et al. Penetration of POL7080/RO7033877 into Epithelial Lining Fluid and Alveolar Macrophages of Healthy Volunteers. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, 2015
8. Leidig M. et al. Pharmacokinetics of Murepavadin (POL7080) and Amikacin in a Drug-Drug Interaction Study in Healthy Subjects. ECCMID, Vienna, 2017