Addressing the threat of bad bugs

Compound summary

EV-035 is a novel bacterial type II topoisomerase inhibitor, belonging to the chemical class of 2-pyridones. EV-035 shows excellent broad-spectrum activity, including pathogens such as Staphylococcus, Streptococcus, Enterococcus, Escherichia, Pseudomonas, Acinetobacter and Haemophilus. Most importantly, EV-035 shows activity not only on drug-sensitive strains, but also on those resistant to marketed antibiotics (including quinolones) and has a very low propensity of developing new resistance. EV-035 has a very favourable in vitro safety profile and its pharmacokinetic properties allow for intravenous as well as oral dosing. The spectrum of EV-035 also extends to potential biothreat agents such as Burkholderia pseudomallei, Burkholderia mallei, Yersinia pestis, Bacillus anthracis, Francisella tularensis and Brucella abortus, work which was part-funded by the US Department of Defense. Evolva owns all rights to EV-035 and has patent applications covering this portfolio.

The medical need, and the market potential

The current antibiotic market generates sales of around USD 42 billion. Beta-lactams, quinolones and macrolides are the top-selling products.

Marketed antibiotics are increasingly losing their power and new antibacterial agents are urgently needed to close this widening gap in medical practice. Particularly, multidrug-resistance among potentially lifethreatening pathogens calls for discovery and development of novel products and novel classes of antibiotics for both hospitalacquired and community-acquired bacterial infections. However, large pharma companies have been curtailing or eliminating anti-bacterial research over the last two decades, leading to a drastic shrinkage of the development pipeline for new antibiotics.

Progress

In 2011 Evolva continued SAR (Structure- Activity Relationship) work around the EV- 035 series in order to select the final lead compound. More than 120 analogs were tested against a large panel of bacterial pathogens, including multidrug-resistant strains. Superior activity over reference antibiotics was observed in vitro, in particular against a large collection of quinolone-resistant strains. Spontaneous resistance experiments showed a very low rate of resistant mutants with amino acid changes in a different site than the classical quinolone site.

In early in vivo infection models, EV-035 showed an efficacy comparable or better than gold standard drugs against both Gram-positive and Gram-negative strains, including E. coli and MRSA as well as other multidrug-resistant pathogens. The final selected lead compound has good oral bio-availability and exhibits a favourable safety profile. Data generated to date indicate that EV-035 is an excellent candidate for further characterization and promotion as broad-spectrum, first-line antibiotic in the hospital as well as the community.

In the first half of 2012, further biochemical and microbiological profiling of the selected lead compound confirmed its broad range of activity on multidrug-resistant pathogens, in combination with excellent tolerability. In September 2012, the compound will be presented at ICAAC in San Francisco, the world’s leading conference on antimicrobial agents and infectious diseases.

Scientific Presentation

Safe drugs for bad bugs; EV-035, a new topoisomerase inhibitor

• Download presentation 5 March 2012

Poster ICAAC 2012 F-2030 EV-035: Novel 2-pyridone based topoisomerase inhibitors with broad-spectrum activity against MDR pathogens, including quinolone resistance

Poster ICAAC 2012 F-2031 EV-035: Synthesis and in vitro antibacterial activity of a new series of 2-pyridone based topoisomerase inhibitors

Poster ICAAC 2012 F-2032 EV-035: in vitro ADMET, mouse PK and efficacy in murine infection models of a new orally available class of antibiotics

Poster ICAAC 2012 F-2033 EV-035: Potent antibiotic series against biothreat agent Burkholderia pseudomallei

Presentation ICAAC 2012 EV-035: 2-Pyridone-based Topoisomerase Inhibitors