Addressing the threat of bad bugs
GC-072 is the lead compound of Evolva’s EV-035 series. It is a novel bacterial type II topoisomerase inhibitor, belonging to the chemical class of 4-oxoquinolizine. GC-072 has shown efficacy in both in vitro and in vivo studies against a wide range of bacterial pathogens, most notably Burkholderia pseudomallei. This bacterium causes the disease melioidosis and is regarded as a potential bio-threat agent. The preclinical development of GC-072 is funded by the Defense Threat Reduction Agency (DTRA) of the U.S. Department of Defense.
Evolva sold the EV-035 series to Emergent BioSolutions Inc. in December 2014. The lead compound in the EV-035 series is the broad-spectrum antibiotic GC-072, which is being developed with US government biodefense funding. For Evolva, this transaction is worth up to USD 70.5 million plus royalties.
Evolva has received from Emergent an upfront payment of USD 1.5 million and will receive an additional USD 4 million after the US government approves transfer of the GC-072 contract to Emergent. Furthermore, development milestone payments up to USD 65 million have been defined as well as tiered royalties up to a maximum of 10% on product net sales generated from the EV-035 programme.
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.
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 was presented at ICAAC in San Francisco, the world’s leading conference on antimicrobial agents and infectious diseases.
In September 2013, the US Defense Threat Reduction Agency (DTRA) announced selecting Evolva to enter into contract negotiations regarding possible preclinical funding for GC-072 (the lead compound in the EV-035 series) under the Transformational Medical Technologies Initiative (TMTI). The contract negotiations are expected to be concluded during 2014. The size of the award could be up to around USD 16 million.
In December 2014, Evolva sold the EV-035 series to Emergent BioSolutions Inc.
Safe drugs for bad bugs; EV-035, a new topoisomerase inhibitor
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