Periodic Reporting for period 1 - GNA NOW (NOVEL GRAM-NEGATIVE ANTIBIOTIC NOW)
Periodo di rendicontazione: 2019-07-01 al 2020-06-30
Under the global umbrella of the AMR Accelerator, the Gram-Negative Antibacterials-NOW (GNA NOW) consortium pledges to a 6 years commitment bringing together key European academic and private experts in antibiotic discovery and development in order to support and manage a portfolio of novel mode of action drugs against Gram-negative bacteria. Starting with three initial compounds/series, dedicated project teams are work together to define and execute the most efficient project plans. The consortium have put in place robust governance and management structures to ensure that the most promising compounds are pursued diligently. Ultimately, the goal of GNA NOW is to progress one compound through completion of Phase I studies plus one compound reaching Investigational New Drug (IND) stage and/or up to two compounds reaching clinical development candidate stage.
The GNA NOW portfolio includes three natural-product derived assets all exerting a novel mechanism of action on the bacteria. As such they will be complementary to existing treatments and less susceptible for interfering resistance development. The most advanced asset is NOSO-502, a compound of the odilorhadbin class. In the first year, the work has focused on three areas: CMC (chemistry, manufacture and control), pharmacology and toxicology, and mechanism of action.
Process developments were conducted to scale-up the production of building-blocks from grams to kilograms scale. Synthesis of GMP-like preclinical batch of drug substance has started by the end of May 2020.
A strong effort was done to better characterize the pharmacological and toxicological properties of NOSO-502. These results, together with previous data, have led to the definition of an anticipated human dose (1g/day) and of safety margins.
Mechanism of Action:
Several mechanism of action studies were initiated aiming to understand the relationship between NOSO-502 antibacterial spectrum and mechanism of action.
The second programme is NOSO-2G, currently in lead optimisation phase aimed to produce a second generation odilorhadbin, with improved properties In the past period, in total 102 analogues have been designed, synthesized and evaluated through the screening architecture that integrates the expertise of the partners of the GNA NOW consortium.
- Antibacterial activity: 90 compounds tested
- Target inhibition: 62 compounds tested
- Bacterial uptake: 32 compounds tested
- ADME (absorption, distribution, metabolism and elimination), and plasma stability: 36 compounds tested
- Early toxicity profiling, including cytotoxicity: 82 compounds tested
- Haemolysis: 68 compounds tested.
The conclusion of this first year of synthesis is that we have in hands two subseries: the NOSO-502 analogues that are safe but whose antibacterial spectrum remains similar to NOSO-502, and the NOSO-95753 subseries that has a larger spectrum but for which tolerability needs to be improved.
The third asset is a compound derived from the natural product corramycin. The project activities in this reporting period have been focused on the mitigation of project-related risks which led to the suspension of several activities, in particular the large-scale synthesis of the compound. First estimations of efficacious doses in human were made and encouraging results supports the strategy of targeting both complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI).
• Contribute to the development of a vibrant AMR research environment in the EU and more specifically it will leverage public-private synergies: GNA NOW has put together a consortium of experts with complementary expertise, bringing experience from industrial partners in drug development with more specific experience in innovative technologies along the full length of the value chain. As such, beyond the goal of progressing compounds the EU will benefit from an improvement in expertise and knowledge on AMR.
• Enhance the overall pipeline of medicines for patients with infections caused by multidrug resistant Gram(-) bacteria and advance new and innovative agents, thus improving European citizens' health. Untreatable G(-) infections are predicted to lead to an increase in the number of deaths and a huge economical burden.
• Contribute to the EU’s ambition of being a ‘best practice region’ for addressing AMR, through the contribution, aggregation and reuse of appropriate data sets generated within our projects. These data will be combined with historical and project data from parallel AMR Accelerator projects leading to new scientific findings identified by colleagues in Pillar A and the wider network. The specific task of improving Quality Management of preclinical PK/PD is peculiarly addressing this need to contribute to EU’s ambition of being a “best practice region”
• Strengthen the competitiveness and industrial leadership of Europe in a key societal challenge: Two European companies are involved in this project. Moreover, the project is fully in line with the European plan on AMR - European One Health Action Plan against Antimicrobial Resistance (AMR) and with UN aim of “Sustainable Development Goal 3, ensure health and well-being for all, at every stage of life”
• Contribute to one of the key IMI2 objectives in Infectious Diseases by improving the current drug development process via dissemination of best-practices, developing new therapies against antimicrobial resistance and ensuring exchanges with regulators and patients via Patient and Public Involvment to bring new priority medicines to patients.
• Further strengthen the role of Patient and Public Involvement (PPI) in preclinical antibacterial research.