1.2 Rationale for a small molecule approach
Multiple recent clinical studies have been evaluating different biological agents (“biologics”) that target specific cytokines. Therapeutics under consideration include tocilizumab and sarilumab, both monoclonal antibodies inhibiting the IL-6 pathway, as well as the TNFα targeting agent adalimumab. A study from China reported preliminary results showing that treatment with tocilizumab improved the condition of 21 patients such that 19 were discharged within two weeks following treatment, with the remaining patients “recovering well”. While these and other promising data are developing around the inhibition of cytokine production by biologics, these therapeutics come with multiple drawbacks for their application to COVID-19. Not only is the production of such large molecules time consuming and expensive and their storage may require facilities not always available in developing countries, but also their penetration into pulmonary tissue may not be sufficient; moreover, they target only one of the several cytokine pathways implicated in the immunopathic diseases processes of COVID-19. Finally, there is also the paradoxical concern that they may make patients prone to secondary infections or other toxicities (hepatotoxicity) when administered systemically. For all these reasons, the application of biological agents in a global pandemic, which also affects developing countries lacking the same resources as developed countries, has its limitations. Consequently, small molecule therapeutics are an attractive alternative, especially potentially “repurpose-able” known drugs that are safe, available in reasonable quantities worldwide, easily synthesized at low cost and easily handled and stored – such agents should be explored for their therapeutic utility in both developed and developing countries immediately.