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).

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.
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. Our innovation focuses on three targets within OMPTA class exclusively targeting WHO priority 1 pathogens.

  1. LptD/E: Inhaled Murepavadin Entering Phase I (IMI funding)
  2. LPS and BamA: Hit to Lead (CARBX funding)
  3. LptA Thanatin Derivatives: Hit to Lead (CARBX funding)

 

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

“Chimeric peptidomimetic antibiotics against Gram-negative bacteria”, published on Nature, October 2019 (PDF)
“Protein epitope mimetic macrocycles as biopharmaceuticals”, published on  Sciencedirect.com, June 13, 2016 (PDF)

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.

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 was supervised jointly by Prof. John A. Robinson and Dr. Daniel Obrecht and has successfully completed in July 2018.

In February 2019 Polyphor has been awarded a non-dilutive award of up to $5.6 million from CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) to support the development of a novel OMPTA BamA candidate until the completion of the Phase I clinical trial. The OMPTA BamA candidate addresses the deadliest and most resistant Gram-negative bacterial pathogens, including those designated as a critical concern by the World Health Organization.

In May 2019 Polyphor received an award from Innosuisse to accelerate the development of a new class of antibiotics, the antimicrobial peptide thanatin. The new antibiotic which is being developed in collaboration with the University of Zurich, inhibits the lipopolysaccharide (LPS) transport pathway.

In October 2020 Polyphor received a CARB-X award of up to USD 18.44 million to support development of new antibiotic program, Thanatin Derivatives belonging to Polyphor’s novel Outer Membrane Protein Targeting Antibiotic (OMPTA) class of antibiotics to potentially treat life-threatening infections caused by difficult-to-treat Gram-negative bacteria. CARB-X will provide Polyphor with initial funding of up to USD 2.62 million to complete the hit-to-lead stage and up to USD 15.82 million if certain project milestones are met. This funding is the second major support for Polyphor’s antibiotics program and follows a previous grant in 2019. The thanatin-derivative antibiotics discovered by Polyphor and the University of Zurich are part of Polyphor’s new Outer Membrane Protein Targeting Antibiotic (OMPTA) class of antibiotics and target the lipopolysaccharide (LPS) transport protein A (LptA), a novel essential target in the LPS transport mechanism of Gram-negative bacteria. Most importantly, these new types of antibiotics show potent and specific antimicrobial activity against Enterobacteriaceae, including extremely drug resistant strains, which are among the WHO priority-1 pathogens.

Outlook
The search for broad-spectrum antibiotics was built upon applying the PEM technology to discover novel peptidomimetics targeting a broad range of important Gram-negative pathogens. Polyphor currently plans to move inhaled Murepavadin into clinic for cystic fibrosis to treat chronic Pseudomonas A. infections while continuing preclinical efforts of its other two programs.

Swiss TV Interview (in German) with Daniel Obrecht, Chief Scientific Officer Polyphor

Source: SRF Tagesschau of 23. October 2019