Periodic Reporting for period 2 - Signia (An innovative drug development and repurposing platform for rapid identification and validation of antimicrobial therapeutics)
Reporting period: 2021-06-01 to 2023-05-31
Acute respiratory tract infections (ARTIs) caused by over 200 viruses and a number of virus-bacteria coinfections, are the main source of acute diseases worldwide, with over 17.5B cases and 2.4M deaths per year, notably killing newborns and young children. Yet today we only have vaccines and a limited number of treatment options for Influenza and just one monoclonal antibody treatment for respiratory syncytial virus (RSV). Even so, influenza has a big impact in today’s society. With the high viral mutation rates, the antiviral options are losing efficiency quickly. Influenza is responsible for:
-Over 48.8M illnesses, over 22.7M medical visits and 959T hospitalizations in the US (2017-2018 season).
-Over $3.2B medical expenses and $8.0B anual loses in US and in the EU, we estimate approximately €11.4B of medical expenses and €17.9B of lost earnings every year.
-The growing resistance to current agents such as Oseltamivir (Tamiflu®) or even the newly licensed Baloxavir (Xofluza®) and the rising the annual mortality (30% from 2016 to 2017 as registered by WHO).
The situation is much worse for high-morbidity infections caused by human pneumoviruses (hRSV and hMPV) or newly emerging viruses with pandemic potential, as the highly lethal Middle East coronavirus (MERS-CoV), for which no specific/efficient therapeutic treatment is available. In addition, globalization and human migration spread drug-resistant pathogens. Globally, 700K patients die annually infected by resistant microorganisms.
In that context, our project aims at offering a disruptive solution to fight difficult-to-treat and emerging infections globally: a drug development platform allowing the quick expansion of the current limited range of antimicrobial treatments targeting ARTIs. Our Signatura platform capitalizes from two approaches increasingly adopted by the pharma industry: (1) Repurposing, i.e. the use of already-marketed drugs for new therapeutic indications (2) Repositioning, i.e. use of investigational drugs outside the scope of the original therapeutic indication. This strategy decreases the risk of failure (the safety and bioavailability of the drug candidates have been previously assessed) and reduces both drug development time and the investment needed for market entry.
In just 2 years, our technology has led to the identification of 8 molecules with confirmed antiviral activity (protected by international patents) against Influenza viruses (common flu) and the creation of an extensive proprietary library of transcriptional data from patients infected with respiratory viruses. Our strategy is set to revolutionize the current process of drug development, because it involves a paradigm shift. We target the global response of the host cell during infection (the most relevant gene expression changes induced by the pathogen), instead of focusing on specific (and more variable) molecular determinants of the pathogen. This pioneer approach currently allows the identification and validation of effective and broad-spectrum antimicrobial agents to fight respiratory pathogens and will allow in the future to rapidly and effectively respond to (re-)emerging infectious threats and aggressive pathogen outbreaks, even when the exact nature of the pathogen is unknown.
-Over 48.8M illnesses, over 22.7M medical visits and 959T hospitalizations in the US (2017-2018 season).
-Over $3.2B medical expenses and $8.0B anual loses in US and in the EU, we estimate approximately €11.4B of medical expenses and €17.9B of lost earnings every year.
-The growing resistance to current agents such as Oseltamivir (Tamiflu®) or even the newly licensed Baloxavir (Xofluza®) and the rising the annual mortality (30% from 2016 to 2017 as registered by WHO).
The situation is much worse for high-morbidity infections caused by human pneumoviruses (hRSV and hMPV) or newly emerging viruses with pandemic potential, as the highly lethal Middle East coronavirus (MERS-CoV), for which no specific/efficient therapeutic treatment is available. In addition, globalization and human migration spread drug-resistant pathogens. Globally, 700K patients die annually infected by resistant microorganisms.
In that context, our project aims at offering a disruptive solution to fight difficult-to-treat and emerging infections globally: a drug development platform allowing the quick expansion of the current limited range of antimicrobial treatments targeting ARTIs. Our Signatura platform capitalizes from two approaches increasingly adopted by the pharma industry: (1) Repurposing, i.e. the use of already-marketed drugs for new therapeutic indications (2) Repositioning, i.e. use of investigational drugs outside the scope of the original therapeutic indication. This strategy decreases the risk of failure (the safety and bioavailability of the drug candidates have been previously assessed) and reduces both drug development time and the investment needed for market entry.
In just 2 years, our technology has led to the identification of 8 molecules with confirmed antiviral activity (protected by international patents) against Influenza viruses (common flu) and the creation of an extensive proprietary library of transcriptional data from patients infected with respiratory viruses. Our strategy is set to revolutionize the current process of drug development, because it involves a paradigm shift. We target the global response of the host cell during infection (the most relevant gene expression changes induced by the pathogen), instead of focusing on specific (and more variable) molecular determinants of the pathogen. This pioneer approach currently allows the identification and validation of effective and broad-spectrum antimicrobial agents to fight respiratory pathogens and will allow in the future to rapidly and effectively respond to (re-)emerging infectious threats and aggressive pathogen outbreaks, even when the exact nature of the pathogen is unknown.
In the first year of the project, we have successfully:
1) Developed an improved and enhanced version of our proprietary Data Bank by upgrading the core computational architecture, developing novel AI based algorithms and tailored bioinformatics tools for signature comparation and selection and expanded the screening capacity and autonomy of the platform.
2) Performed an in silico screening and selection of a shortlist of 30 drug candidates with potential antiviral activity against SARS-CoV-2, influenza and/or RSV.
3) Advanced in the development and evaluation of nebulized formulations of drug candidates, better adapted to the treatment of respiratory infections.
4) Identified and pre-clinically validated the antiviral activity of one oral candidate against SARS-CoV-2.
In the second part of the project we have successfully:
1) Optimized the strategy to build up the signature database by building a predictive tool that allows us to identify the best conditions in which to perform the experimental treatment from single replicate in order to minimize the number of samples required to obtain an informative signature.
2) Implemented the key step of the signature database enrichment within Signia Therapeutics by mastering the RNA-Seq library preparation. The internalizing of know-how is an essential step for cost-reduction, bias control, and throughput.
3) Enriched the number of added signatures to 500 new compounds.
4) Performed an in silico screen to propose a list of candidates which were then screened in the wet lab to identify a restricted list of candidates.
5) Advanced preclinical validation of a restricted list of candidates with promising results against different respiratory viruses (SARS-CoV-2, influenza, RSV, HMPV).
1) Developed an improved and enhanced version of our proprietary Data Bank by upgrading the core computational architecture, developing novel AI based algorithms and tailored bioinformatics tools for signature comparation and selection and expanded the screening capacity and autonomy of the platform.
2) Performed an in silico screening and selection of a shortlist of 30 drug candidates with potential antiviral activity against SARS-CoV-2, influenza and/or RSV.
3) Advanced in the development and evaluation of nebulized formulations of drug candidates, better adapted to the treatment of respiratory infections.
4) Identified and pre-clinically validated the antiviral activity of one oral candidate against SARS-CoV-2.
In the second part of the project we have successfully:
1) Optimized the strategy to build up the signature database by building a predictive tool that allows us to identify the best conditions in which to perform the experimental treatment from single replicate in order to minimize the number of samples required to obtain an informative signature.
2) Implemented the key step of the signature database enrichment within Signia Therapeutics by mastering the RNA-Seq library preparation. The internalizing of know-how is an essential step for cost-reduction, bias control, and throughput.
3) Enriched the number of added signatures to 500 new compounds.
4) Performed an in silico screen to propose a list of candidates which were then screened in the wet lab to identify a restricted list of candidates.
5) Advanced preclinical validation of a restricted list of candidates with promising results against different respiratory viruses (SARS-CoV-2, influenza, RSV, HMPV).
Antimicrobial drug development strategies have been based on targeting single specific molecules/factors mainly from the pathogen or sometimes from the host cells. However, the emergence of drug resistance due to the high pathogen mutability and the redundancy of the host factor network have made these approaches mostly inefficient so far, leaving us with a scarce therapeutic arsenal. Despite the advent of new generation high-throughput screening methods, implementing such approaches using physiologically relevant preclinical models to reduce the very high false-discovery rate in a cost-effective manner remains a challenge, hence severely hampering their efficiency.
Our strategy is a shift from the ‘one-drug-one-target’ to the ‘one-drug-multiple-cell-targets’ paradigm. We prioritize the selection of those compounds that target the whole expression profile of infected cells instead of focusing on a specific factor or pathogen structure that may vary over time. This approach also allows us to establish the signature of coinfections (virus + bacteria), a frequent complication of viral infections, and potentially serious due to anti-microbial resistance. Moreover, since many pathogens use common cellular pathways and cause similar disease signature effects on the infected cells, our strategy can deliver drugs with broad spectrum antimicrobial efficacy along with long-term effectiveness, since they will remain effective despite pathogen mutations and emerging variants.
Finally, besides speeding the reaction force to propose therapeutic candidates against emerging pathogens, our strategy will drastically reduce the time and costs associated to the drug R&D process prior to market access. The breakeven point for already existing molecules is more easily reachable, de-risking the development process and creating value on repositioned molecules (generic or proprietary) in new indications, with new formulations and/or a new route of administration. This de-risked development at reduced costs can impact the price tag of the marketed drugs: keeping the same margin for companies, while reducing costs to the public healthcare reimbursement system and patients (reduced co-payments for end-users).
Our strategy is a shift from the ‘one-drug-one-target’ to the ‘one-drug-multiple-cell-targets’ paradigm. We prioritize the selection of those compounds that target the whole expression profile of infected cells instead of focusing on a specific factor or pathogen structure that may vary over time. This approach also allows us to establish the signature of coinfections (virus + bacteria), a frequent complication of viral infections, and potentially serious due to anti-microbial resistance. Moreover, since many pathogens use common cellular pathways and cause similar disease signature effects on the infected cells, our strategy can deliver drugs with broad spectrum antimicrobial efficacy along with long-term effectiveness, since they will remain effective despite pathogen mutations and emerging variants.
Finally, besides speeding the reaction force to propose therapeutic candidates against emerging pathogens, our strategy will drastically reduce the time and costs associated to the drug R&D process prior to market access. The breakeven point for already existing molecules is more easily reachable, de-risking the development process and creating value on repositioned molecules (generic or proprietary) in new indications, with new formulations and/or a new route of administration. This de-risked development at reduced costs can impact the price tag of the marketed drugs: keeping the same margin for companies, while reducing costs to the public healthcare reimbursement system and patients (reduced co-payments for end-users).