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.