Treating the Host Response via Protective Polypharmacy

Pending new vaccines, use Real World Data to evaluate the efficacy of already prescribed drugs in improving host response.

Dr. Luc Belmans, MD, CEO of Medaman BV in Belgium

The 1918/1919 influenza pandemic killed an estimated 50–100 million people worldwide. As of date 18th April 2021, the COVID-19 pandemic has already caused 3 million deaths worldwide (source WHO) . The emergence of a new, highly virulent and easily transmissible virus can also happen anytime and will spread rapidly, risking to overwhelm healthcare systems, as we have seen happening with COVID-19. It could be far worse than anything we will experience with COVID-19.  The proposed solution can be of value at the start of a new epidemic when new vaccines still have to be developed. It can be of value in developing countries prior to the arrival of the newly produced vaccines in those areas. Furthermore it can be of value when variants of the virus are emerging which are less well covered by already developed vaccines.

This corresponds with a subgroups of objectives among the 2c theme of Trinity challenges namely :

What drugs that we know today will have the best
chance to be effective therapeutics against the
most likely future pandemic threats (e.g. antiinfectives, immuno-modulators)?
Increases speed in developing therapeutic
(or preventive) responses to emerging infectious
disease, e.g. through better in silico modelling
tools

The identification of a Protective Polypharmacy host response efficacy early in a pandemic will have several possible strong value propositions:

Efficacy: It may serve to blunt the course of the pandemic by limiting susceptibility and transmissibility of a virus, by improving the host immune response.

Long Term Impact:  Given to ‘test-positive’ individuals before they develop symptoms or in the initial stages of illness, it might prevent the development of more severe illness or the chronic, persistent illness that has been seen in many survivors (the so-called ‘long-haulers’).Furthermore in patients already suffering from long-COVID it could help reduce remnant symptoms as these form already a huge strain on healthcare services.

Societal Impact:  Uncertainty about the disease might be greatly reduced and with it the devastating social, economic and political consequences experienced everywhere. By reducing lethality the need for social distancing measures could potentially be reduced. 

The project will generate analysis results, reports and publications which will generate hypotheses. This will allow existing medications or combinations of medications to become eligible for possible repurposing. This would be an ideal approach to help also developing countries where people have limited access to high level health care

The approach of exploring the possible medical advantages of treating the host response in viral pandemics can benefit all patients in principle. However, in view of the Real World Data search for possible roles of already existing medications and their combinations the benefits will be especially large for the patients in developing  countries where the health care systems are less well funded. (The eventually developed vaccines will first reach the richer countries.) An extra advantage of treating the host response to virus infections with repurposed existing medications is that medical doctors have already several years of experience with the administration of these established medications and the possible side effects are already well described. 

Based on the results of the Real World Data analyses, eligible existing medications for the treatment of the host response can be selected.  

The scaling with Trinity Challenge funding to larger, standardized Real World Data sets through the EU/EHDEN network, and the global OHDSI network, will allow signal detection to be done with increasing statistical power. 

The nature of viral pandemics and the mutational lability of the virus itself creates heterogeneity around the world in the actual disease process that patients are experiencing.  The geographic expansion of the Real World Data partners for the proposed Protective Polypharmacy Surveillance Network will allow the detection of regionally differentiated efficacy, which will facilitate tailoring of the possible drug candidates to improve host response.

Project reports and scientific manuscripts for publications can be prepared to present at conferences and to submit to interested companies to prepare repurposing approval dossiers of existing medications and their combinations to the regulatory authorities in many of the countries affected by the pandemic.

Repurposing of existing medications, based on analytic data mining, Machine Learning and artificial intelligence can help to protect and save the lives of millions of people across the world and especially in the developing countries. 

Each new virus infection has an overall hospitalization and an overall mortality rate which can be established after the first few hundred or thousand affected patients. The age corrected statistics can be measured at the start of a new pandemic. After the introduction and adoption of repurposed existing medications&combinations, the clinical  impact can be measured by the reduction of hospitalizations, ICU transfers, mechanical ventilation episodes, etc. as well as the all-important overall improvement in survival rates. 

Although ordinarily done under a prospective clinical trial, to save time in the face of a pandemic new models of clinical efficacy, inference can be evaluated using Real World Data information  collected by healthcare systems as part of patients’ care in all settings (general practice, hospital etc.).  The same Protective Polypharmacy Surveillance Network used for retrospective signal detection of beneficial drug combinations can also be applied to concurrently evaluate the efficacy and safety of extending the same candidate drug treatment over time in populations, analogous to the various proposals for Phase III/IV blurring, current practices in oncology with in-market surveillance of early therapeutics, the emerging concepts of adaptive licensing in EMA, and the current practice of releasing pandemic vaccines with emergency use authorization.

The main barrier at the moment is a starting budget. Major Pharmaceutical companies have not shown interest in this approach yet.  Generic Pharmaceutical companies have very little to no research budgets to envisage projects for studying and developing analytic tools for Real World Data exploration with the aim to clarify possible repurposing options of existing medications and their combinations to treat the host response in case of existing or future virus infection pandemics. 

Medaman BV, Belgium

University of Ghent-Department of Pharmacy, Belgium

Open Health UK

Steve Biko University Hospital, Pretoria, South Africa

DDO Strategic Services, Tucson, AZ 85737-8488, USA

To obtain essential funding to move the project forward. The exciting possibility to work with synergistic partners sharing a common mission as outlined by the Trinity Challenge in a subsection of category 2c namely "Establish feedback loops to improve response"

e.g. Bill and Melinda Gates Foundation and in particular the MRI-Medical Research Institute as they focus on providing help for better health programs solving pandemics