4a. Observational data based upon administrative records.
The key question here is not just around the evidence that the agents
that inhibit the RAS improve patient outcomes in COVID-19 disease but at
what doses – both for efficacy and for toxicity.
Over the last several months in
2020 we are aware of four clinical observational based studies, (42-45)
all derived from medical records of patients hospitalised for COVID-19.
As indicated above these studies did not indicate a deterioration of
patients with RAS inhibition and conversely to varying extents an
improvement in outcomes when compared to patients with COVID-19 disease
not treated with RAS inhibitors.
By inference these patients were
likely being treated prior to hospitalisation for hypertension or
diabetes on the standard drug
regimens. Based on observational
data there would be an argument to explore further the possibility of a
new indication for RAS inhibitors as repurposed drugs in COVID-19.
4b. The relationship between the existing Cmax and EC50
for new indicatio n.
The specific question of interest here is whether there is evidence that
RAS agents are effective at doses below the approved Cmax in attenuating
pulmonary responses and preventing or reversing the aberrant
inflammatory pathophysiology. This is also important dosing knowledge to
reduce toxicity.
In a comprehensive review on repurposing (10) potential differences in
dosing amounts and schedules in the area of repurposing. Our experience
has indicated that if the ED50 for the new indication for the repurposed
drug is equal to or less than the Cmax achieved by the drug in
registered dosing schedules for its original indication then dosing
issues become less complex and the arguments for registration of the
repurposed drug for a new indication much easier. The point being that
the bioavailability, toxicology and pharmaco-surveillance of the drug at
that dose, is well established as part of the original drug approval
process, albeit the disease being treated is different. This latter
point may introduce issues around dose-response and also dose-toxicity,
but they can be surveyed from an a priori basis rather than from
no knowledge.
By inference in the studies based upon observational data described
immediately above (4a) the COVID-19 patients were likely being treated
prior to hospitalisation for hypertension or diabetes on the standard
drug regimens. If that were the case then it could be assumed that the
RAS inhibitors would have been employed at or below their approved Cmax
obtained from the top of the dosing range for the RAS inhibitors.
As there is no human information to date on these preclinical aspects,
we need to analyse known pharmacological data from cellular systems and
animals; and use supporting data from human studies of other viruses
that cause ARDS in a pathophysiological process resembling COVID.
Based upon the observational data there would be an argument to explore
further the possibility of a new indication for RAS inhibitors as
repurposed drugs in COVID-19 initially within the existing approved Cmax
of the drugs