Periodic Reporting for period 5 - GNA NOW (NOVEL GRAM-NEGATIVE ANTIBIOTIC NOW)
Okres sprawozdawczy: 2023-07-01 do 2024-06-30
Antimicrobial Resistance (AMR) is a global and serious threat to human health. Gram(-) 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(-) 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(-) bacteria. The Consortium is committed to developing completely novel compounds derived from previously unknown natural compounds with new modes of action.
Our approach is to leverage the support of a network of platforms with key expertise in the research and development of antibiotics, which is required for a new molecular entity to progress from Lead or pre-candidate/candidate stages up to the completion of Phase I studies. Moreover, GNA NOW aims to contribute significantly to preclinical antibacterial development in the widest sense with capacity and knowledge exchange. The project is committed to integrating Patient and Public Involvement (PPI) into compound development and will perform an evaluation of its impact. Finally, the Consortium is developing a quality management system for the use of PK/PD models in preclinical science for better predictions of clinical outcomes which will have clear benefits for the whole AMR community.
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(-) bacteria. The Consortium is committed to developing completely novel compounds derived from previously unknown natural compounds with new modes of action.
Our approach is to leverage the support of a network of platforms with key expertise in the research and development of antibiotics, which is required for a new molecular entity to progress from Lead or pre-candidate/candidate stages up to the completion of Phase I studies. Moreover, GNA NOW aims to contribute significantly to preclinical antibacterial development in the widest sense with capacity and knowledge exchange. The project is committed to integrating Patient and Public Involvement (PPI) into compound development and will perform an evaluation of its impact. Finally, the Consortium is developing a quality management system for the use of PK/PD models in preclinical science for better predictions of clinical outcomes which will have clear benefits for the whole AMR community.
The first year of the project was used to establish the infrastructure needed to drive three AMR drug development projects. The original GNA NOW portfolio included three natural-product derived assets all exerting a novel mechanism of action on the bacteria. These programmes were NOSO-502 – bringing an odilorhabdin derivative from Late Lead to completed phase 1 study, NOSO-2G – Lead optimisation to find a second generation odilorhabdin with a complementary microbiological profile and/or improved DMPK characteristics, and CORRA – bringing a corramycin derivative from Late Lead to Clinical Candidate stage.
In the second and third year, it was identified that two of the three original programmes, CORRA and NOSO-2G were unlikely to reach the set objective within the GNA NOW project term and budget. The programmes were suspended as a measure to de-risk the GNA NOW portfolio. In the fifth reporting period, a patent was submitted for NOSO-2G on “New odilorhabdins analogues as antibiotics against multi-resistant bacteria”
Spurred by the promising results of preclinical studies of NOSO-502, CMC activities and preparation of drug product for clinical trials were conducted. Unfortunately, two major deviations from the plan - the first batch of drug product being smaller than anticipated and delays and uncertainties in the synthesis of the second batch of drug substance – triggered a No-Go recommendation, which was endorsed by the NOSO-502 Steering Committee and the GNA NOW General Assembly.
At the end of the third reporting period, Evotec disclosed to the consortium that they intended to withdraw from their commitments as the GNA NOW Scientific Lead. A replacement industry partner, with a viable programme that would fit the GNA NOW objectives and which would benefit from the consortium's expertise, was sought. A match was found in one of GSK's Gram- antibiotic programmes. The change of scientific lead, the accession of GSK to the consortium, and the adoption of the partner and the associated new programme, Global Health Infectious Disease (GHID, WP7), was the focus in the fourth project year.
In the fifth year, activities in the GHID WP7 have started. The ultimate goal of this work package is to generate enough information through pre-clinical activities in GNA NOW to fully assess the suitability of novel compounds to treat severe bacterial enteric infections in LMICs, and primarily paediatric populations, to inform decisions on subsequent progression to clinical phases. To date, comparatively little research has been made on this indication and the related pathogens. Consequently, GNA NOW’s activities in the fifth reporting period has focussed on selection, collection, and characterisation of relevant strains and developing an antibiotic panel. Several microbiology and PK/PD experiments have been conducted to assess the profiles of standard of care antibiotics to use later as reference. This is preparatory work, to establish baselines and protocols, so that in the next reporting period work with the novel compound, Gepotidacin, can start,
In the second and third year, it was identified that two of the three original programmes, CORRA and NOSO-2G were unlikely to reach the set objective within the GNA NOW project term and budget. The programmes were suspended as a measure to de-risk the GNA NOW portfolio. In the fifth reporting period, a patent was submitted for NOSO-2G on “New odilorhabdins analogues as antibiotics against multi-resistant bacteria”
Spurred by the promising results of preclinical studies of NOSO-502, CMC activities and preparation of drug product for clinical trials were conducted. Unfortunately, two major deviations from the plan - the first batch of drug product being smaller than anticipated and delays and uncertainties in the synthesis of the second batch of drug substance – triggered a No-Go recommendation, which was endorsed by the NOSO-502 Steering Committee and the GNA NOW General Assembly.
At the end of the third reporting period, Evotec disclosed to the consortium that they intended to withdraw from their commitments as the GNA NOW Scientific Lead. A replacement industry partner, with a viable programme that would fit the GNA NOW objectives and which would benefit from the consortium's expertise, was sought. A match was found in one of GSK's Gram- antibiotic programmes. The change of scientific lead, the accession of GSK to the consortium, and the adoption of the partner and the associated new programme, Global Health Infectious Disease (GHID, WP7), was the focus in the fourth project year.
In the fifth year, activities in the GHID WP7 have started. The ultimate goal of this work package is to generate enough information through pre-clinical activities in GNA NOW to fully assess the suitability of novel compounds to treat severe bacterial enteric infections in LMICs, and primarily paediatric populations, to inform decisions on subsequent progression to clinical phases. To date, comparatively little research has been made on this indication and the related pathogens. Consequently, GNA NOW’s activities in the fifth reporting period has focussed on selection, collection, and characterisation of relevant strains and developing an antibiotic panel. Several microbiology and PK/PD experiments have been conducted to assess the profiles of standard of care antibiotics to use later as reference. This is preparatory work, to establish baselines and protocols, so that in the next reporting period work with the novel compound, Gepotidacin, can start,
- Contribute to the development of a vibrant AMR research environment in the EU and more specifically 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 economic 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.
- Strengthen the competitiveness and industrial leadership of Europe in a key societal challenge. 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 PPI to bring new priority medicines to patients.
- Further strengthen the role of PPI in preclinical antibacterial research.
- To develop a target product profile (TPP) and generate enough data through preclinical activities in WP7 to fully assess the suitability of (a) novel compound(s) to treat severe bacterial enteric infections in LMICs, primarily in paediatric populations, to inform a decision on subsequent progression to clinical phases.
- 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 economic 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.
- Strengthen the competitiveness and industrial leadership of Europe in a key societal challenge. 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 PPI to bring new priority medicines to patients.
- Further strengthen the role of PPI in preclinical antibacterial research.
- To develop a target product profile (TPP) and generate enough data through preclinical activities in WP7 to fully assess the suitability of (a) novel compound(s) to treat severe bacterial enteric infections in LMICs, primarily in paediatric populations, to inform a decision on subsequent progression to clinical phases.