OMPTA – new antibiotics platform

OMPTA – new antibiotics platform

Potential for breakthrough infection treatment

Potential for breakthrough infection treatment

Polyphor has discovered a novel class of antibiotics, the Outer Membrane Protein Targeting Antibiotics (OMPTA). This new class has the potential to provide breakthrough treatment options for difficult to treat infections caused by Gram-negative bacteria (including MDR strains).

The current lead compounds demonstrate potent antibacterial activity against a broad range of pathogens, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter spp, Acinetobacter baumannii, Stenotrophomonas maltophilia and Pseudomonas aeruginosa – including the pandrug-resistant isolates where there are currently no treatment options available.

The potent in vitro activity has also been demonstrated in vivo. Significantly, the compounds have shown both potent in vitro and in vivo activity towards colistin-resistant isolates (colistin is considered as the treatment of last resort against Gram-negative ESKAPE pathogens). The first compounds are expected to reach the clinic in 2019, and it is foreseen that preclinical candidates for further development will be identified in the near future: extended spectrum, selective spectrum or narrow spectrum/precision.

Excellent activity of PEM antibiotic lead compounds against a broad spectrum of Gram-negative strains including MDR bacteria

Growing antibiotic resistance is a global health hazard

Growing antibiotic resistance is a global health hazard, partly because no new classes of antibiotics have been developed for several decades. Moreover, it is a global rather than a local issue, as antimicrobial resistance can now rapidly spread between countries or continents more than ever before. Consequently, the development and commercialization of efficacious new antibiotics are strongly supported by the regulatory authorities and health institutions around the globe.

Antibiotics of the OMPTA class combine high-affinity binding to both Lipopolysaccharide (LPS) and outer membrane proteins, resulting in high specificity towards Gram-negative bacteria and effective bactericidal activity. The video shows the LPS export mechanism by LptD-LptE which is inhibited by Murepavadin (POL7080).
Video Source: Dr. Kerstin Moehle, University of Zurich

Bacteria species grouped under the term “Gram-negative” (as they do not retain a stain developed by the Danish researcher Hans-Christian Gram) are of particular concern as they are especially well protected by an inner and outer membrane from the action of antibiotics. Gram-negative bacteria are a common cause of serious and often life-threatening infections including intra-abdominal infections, urinary tract infections, pneumonia and bacteremia (blood stream infections).

Polyphor started developing its innovative chemistry (“macrocycle”) platform more than a decade ago, resulting in a leading position in this emerging drug class. An important part of this platform and source of the novel antibiotics are macrocyclic “Protein Epitope Mimetics” (PEM), medium-sized (0.7-2 kDa), fully synthetic, cyclic peptide-like molecules that mimic secondary structures of proteins.

Polyphor’s PEM antibiotics form a new class: the Outer Membrane Protein Targeting Antibiotics (OMPTA). They are characterized by a low rate of resistance development and offer new treatment options for patients with difficult-to-treat infections caused by Gram-negative bacteria (including multidrug resistant or “MDR” strains).

Antibiotics of the OMPTA class combine high-affinity binding to both LPS and outer membrane proteins, resulting in high specificity towards Gram-negative bacteria and efficient bactericidal activity. Polyphor’s Murepavadin (POL7080) is the first antibiotic of the OMPTA class to reach the clinical development stage.

While Murepavadin (POL7080) is highly selective for Pseudomonas aeruginosa, the latest novel “PEM antibiotics” exhibit broad-spectrum activity against Gram-negative bacteria, amongst them Escherichia coli and bacteria belonging to ESKAPE.

Key properties of the Polyphor broad-spectrum OMPTA

  • Outer Membrane Protein Targeting Antibiotics (OMPTA): a novel class of antibiotics discovered at Polyphor
  • Highly efficacious towards a large panel of MDR-isolates of Gram-negative ESKAPE pathogens, including strains resistant to colistin (note: colistin is an antibiotic often considered as the last option for treatment of MDR Gram-negative bacteria)
  • Favorable safety profile in animals
  • Favorable resistance profile compared to known antibiotics
  • Excellent activity in animal systemic infection models

Overall, the OMPTA display an extremely promising broad and potent coverage against Gram-negative bacteria species belonging to the difficult-to-treat ESKAPE pathogens. So far, there has been very low cross-resistance observed with comparator antibiotics. OMPTA seem to overcome colistin resistance in all of the tested ESKAPE pathogens, including K. pneumoniae, well known to overproduce capsule polysaccharides (CPS) which serve as a protective shield and limit the killing effect of current antibiotics. No activity is observed against Gram-positive bacteria.

“Protein epitope mimetic macrocycles as biopharmaceuticals”, published on  Sciencedirect.com, June 13, 2016 (PDF)

Awarded and ongoing research

Polyphor continues to invest significantly in research on broad-spectrum Gram-negative PEM antibiotics of the OMPTA class. Currently, Polyphor is concentrating its efforts on further optimizing the potency and properties of the PEM molecules required for a development candidate.

The University of Zurich and Polyphor have been awarded a grant from the Swiss Commission of Technology and Innovation (CTI; project CTI-Nr.: 181146.1 PFLS; Swiss Government). The joint research focuses on expanded studies on the mechanism of action of the new class of antibiotics against Gram-negative ESKAPE pathogens. The project started in January 2016 and is supervised jointly by Prof. John A. Robinson and Dr. Daniel Obrecht. The project is also supported by the Wellcome Trust foundation, which granted a Seed Drug Discovery Award of CHF 2.3 million in February 2017.

Outlook

The search for broad-spectrum antibiotics was built upon the successful development of Polyphor’s first antibiotic, Murepavadin (POL7080), by applying the PEM technology to discover novel peptidomimetics targeting a broad range of important Gram-negative pathogens. The antibiotic program is on track to select a preclinical candidate by the first quarter of 2018 and start clinical Phase 1 in 2018.