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CORDIS - Forschungsergebnisse der EU


Periodic Reporting for period 2 - GNA NOW (NOVEL GRAM-NEGATIVE ANTIBIOTIC NOW)

Berichtszeitraum: 2020-07-01 bis 2021-06-30

AntiMicrobial Resistance (AMR) is a global and serious threat to human health. Gram-negative bacteria are widely regarded as the culprit representing one of the gravest dangers. Indeed, there is a dearth of new agents able to address AMR in Gram-negative bacteria, especially compounds with novel modes of action. Finding and developing such compounds represents a huge scientific challenge, one that requires the collaboration of stakeholders bringing many different kinds of expertise. The world is coming together to tackle this issue and public-private partnerships represent an attractive way to hasten the pace and increase the probability of successfully identifying and developing novel antibiotics. 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 working together to define and execute the most efficient project plans. The consortium has put in place robust governance and management structures to ensure that the most promising compounds are pursued diligently, with clear stage gate criteria, and processes for suspending, replacing and recruiting programmes. Ultimately, the goal of GNA NOW is to progress one compound through completion of Phase I studies plus one compound reaching Investigational New Drug stage and/or up to two compounds reaching clinical development candidate stage.
Whereas the first year of the project was used to establish the infrastructure needed to drive three AMR drug development projects by forming all governance bodies, electing external advisors and identifying and consulting a public-patient interaction panel, this infrastructure was maintained in the second year. The original GNA NOW portfolio included 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. In the second year, it was identified that one of the three programmes was unlikely to reach the set objective within the GNA NOW project term and budget. As a measure to de-risk the GNA NOW portfolio, the programme was suspended and a process to identify an additional programme was developed and deployed.

The most advanced asset is NOSO-502, a compound of the odilorhadbin class. In the first year, the work focused on CMC (chemistry, manufacture and control), pharmacology and toxicology, and mechanism of action to understand the relationship between antibacterial spectrum and mechanism of action. In the second year CMC activities were pursued, the formulation of the compound has been defined and the analytical method for drug substance and drug product has been developed. Furthermore pharmacology activities, in vitro efficacy experiments and preclinical safety studies were performed.

The NOSO-2G project has been built to provide a second generation of odilorhabdins with an enlarged antibacterial spectrum, and therefore to target other clinical indications such as respiratory infections (HAP/VAP: hospital acquired and ventilator associated infections). In the first year, a total of 102 analogues were designed, synthesized and evaluated through the screening architecture that integrates the expertise of the partners of the GNA NOW consortium. At the beginning of Year 2, the Team reached a strategic decision based on the medical need. The project was refocused on one of the two subseries and the means to improve the tolerability without losing the spectrum. A total of 341 analogues were synthesized during the second period and evaluated for their in vitro and in vivo properties. A first frontrunner with improved tolerability was rapidly identified and paved the way for the remainder of the program. The lead optimisation phase of this project is almost completed with the identification of several promising analogues. Of these, 1-2 will be selected to be characterized further.

The third asset is a compound derived from the natural product corramycin. The project activities
in the first year were 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. At the beginning of the second period, the project was restarted with a clear focus of activities on synthetic feasibility and on optimizing the final steps to assess the probability of success of future scale-up and production of batches for the in vivo toxicity studies. Considering the difficulties encountered, the team did not succeed in producing a 5g batch required for the anticipated preliminary toxicity study in rat. In February 2021, the Steering Committee and the General Assembly decided to discontinue the programme.
The GNA NOW consortium will have many important impacts:

• 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 Gram(-) 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 the 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, training early career researchers, developing new therapies against antimicrobial resistance and ensuring exchanges with regulators and patients via Patient and Public Involvement (PPI) to bring new priority medicines to patients.
• Further strengthen the role of Patient and Public Involvement (PPI) in preclinical antibacterial research.
GNA NOW Portfolio