Reorganising research into new anti-COVID molecules

Since the start of the pandemic, biomedical research has made unprecedented efforts to improve patient health and halt the progression of SARS-CoV-2. The incredible levels of incidence of COVID-19 has facilitated the carrying out of enormous numbers of clinical trials to try and evaluate the effectiveness of new molecules and old (repositioning). However, few of the drugs developed have had a real impact on mortality levels. How can this be explained?

We understood early on that the symptoms of COVID-19 resembled other acute respiratory distress syndromes and that serious illness occurred when the inflammatory response was out of control. Patients were soon treated with immunomodulators and anti-viral drugs. In these exceptional circumstances, rules and regulations of clinical testing were not always adhered to: some pre-clinical steps were neglected and proof of efficacy was often absent (Hydroxychloroquine, Ivermectin). Action mechanisms and the bioavailability of the majority of molecules were unknown.

So there were multiple risks: for the health of patients, for popular confidence in biomedical research, and for the opportunities of treating patients with better medicines.

With regard to anti-virals, only Remdesivir proved to be really effective, but it is not even sure that it reduces mortality. Numerous specific immunomodulators with known means of operation were repositioned (Anakinra, Tocilizumab), but in severe cases they were less effective than broad-spectrum molecules (Dexamethasone, Baricitinib). Our anticipation might have been better, and we might have saved time: we already knew that multiple inflammatory pathways were dysregulated in severe cases.

What lessons can be learned from these mistakes? We now see that our arsenal of immunomodulating and anti-viral drugs may well prove to be inadequate if new pathogens emerge. Over the last decades, political and economic decisions have severely slowed the development of new drugs. Even beyond the context of the pandemic, we need to prepare for the emergence of new viruses by reinforcing:

• the referencing of emerging viruses
• the development of in vivo and in vitro models to study infectious diseases
• the identification of new drugs against orphan viruses
• efforts to reposition known molecules
• the prioritising of molecules that are easy to administer (oral)

In the context of the pandemic, repositioned drugs need to be better targeted for clinical testing, in order to reduce patient risk, time and cost. It is therefore imperative to have:   

• effective preclinical proofs of effectiveness in a similar situation (Remdesivir)
• a safety profile already established and accepted
• already defined pharmacokinetics
• evidence of pharmacodynamic activity on the target.

It is clear that clinicians, virologists, immunologists and pharmacists need to collaborate to select which molecules should be tested.

Recently, many research projects have turned out to be redundant and unhelpful due to a lack of coordination between different laboratories. It is therefore necessary that States get more involved so as to promote the use of generic drugs, to reduce costs and to encourage fairer global distribution. One of the major lessons of this pandemic has been that unequal distribution of medicines benefits no-one in the long-term (see article on vaccinal nationalism).

In addition, regulatory agreements should be established beforehand so that authorities can rapidly review the situation if a molecule is of interest and needs looking at urgently.

Finally, an institute of international cooperation for scientists and clinicians as well as an international regulatory authority should be created to coordinate trials (as is the case with nuclear and climate threats). This would limit experimental therapies that put  patients at risk, optimise global efficiency in terms of research (sharing of tasks and costs), reduce disinformation, and regulate questions of cultural, social or racial influences. Currently, authorisations are issued by national agencies, which slows down the distribution of medicines to the communities that need them most.