Telmisartan for Treatment of COVID-19 Patients

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications
similar to those produced by the SARS coronavirus (SARS-CoV) in the 2002-2003 epidemic. This
new disease was named COVID-19 and the causative virus SARS-CoV-2 (Chen, Liu, & Guo, 2020; Li
et al., 2020).

Given that vaccines against COVID-19 are still in development and an effective treatment
against this new coronavirus is lacking, various pharmacological agents are being tested in
clinical trials designed by institutions such as the WHO or scientific entities in different
countries (C.-C. Lu, Chen, & Chang, 2020).

Taking into account the characteristics of the mode of entry of this coronavirus to human
cells through binding with Angiotensin Converting Enzime 2 (ACE2) and extensive scientific
and clinical evidence information on the Renin Angiotensin System, the hypothesis of the
involvement of this system in the pathophysiology of COVID-19 was born (Gurwitz, 2020;
Vaduganathan et al., 2020).

The SARS-CoV-2 virus, enters the airway and binds, by means of the S (Spike) protein on its
surface (after whose image the term coronavirus is coined), to the membrane protein ACE2 in
type 2 alveolar cells (R. Lu et al., 2020; Wan, Shang, Graham, Baric, & Li, 2020). The S
protein-ACE2 complex is internalized by endocytosis and facilitates the entry of each virion
into the cytoplasm. For each intracellular entry, the function of one ACE2 molecule is lost
leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar
cells of the lung directly related to the viral load of the air inoculum.

ACE2 catalyzes the transformation of angiotensin II into angiotensin 1-7. Angiotensin II
acting on AT1 receptors causes vasoconstriction, apoptosis, proinflammatory effects, and
fibrosis. Angiotensin 1-7 acting on Mas receptors causes opposite effects: vasodilation and
anti-inflammatory. Partial decrease or total loss of ACE2 function in alveolar cells results
in a deviation of the homeostatic balance of the Renin Angiotensin System in favor of the
angiotensin II-AT1 receptor axis (Paz Ocaranza et al., 2020; Tikellis, Bernardi, & Burns,
2011). Indeed, it increases the tissue concentration of angiotensin II by decreasing its
degradation and reduces the concentration of its physiological antagonist angiotensin 1-7(Liu
et al., 2020).

The clinical manifestations of COVID-19 disease will depend fundamentally on the degree of
alteration of the homeostatic balance of the Renin Angiotensin System in the lung and at the
systemic level (mainly at the heart).

Increasing the effects of angiotensin II on the lung interstitium can promote apoptosis,
which, in turn, initiates an inflammatory process with release of proinflammatory cytokines,
establishing a self-powered cascade (Cardoso et al., 2018). In certain patients this process
reaches such clinical relevance that requires external oxygen supply and in severe cases an
Acute Respiratory Distress Syndrome (ARDS) ensues (this correlates with an acute release
-storm- of cytokines) (Ware & Matthay, 2000).

Based on the aetiopathogenic hypothesis described, there are various pharmacotherapeutic
proposals to be evaluated through clinical trials: Recombinant ACE2 therapy, administration
of agents aimed at increasing ACE2 levels (e.g. estradiol), and administration of drugs that
decrease the elevated activity of angiotensin II including renin release inhibitors, classic
ACE inhibitors or Angiotensin Receptor 1 Blockers (ARBs).

Most patients who develop COVID-19 disease initially have fever, indicative ofan inflammatory
process with systemic release of pyrogenic cytokines. According to the hypothesis described,
this inflammation is induced by the inhibition of ACE2 and the imbalance of the renin
angiotensin system in the pulmonary interstitium in favor of the angiotensin II-AT1 receptor
axis. Faced with the onset of the inflammatory process, a rapidly effective treatment is
necessary to antagonize the cascading and self-sustaining phenomenon described. Of the
different types of drugs mentioned above, we consider that the most rapidly effective may be
ARBs.

Recently, Gurwitz (2020) proposed the tentative use of agents such as losartan and
telmisartan as alternative options for treating COVID-19 patients prior to development of
ARDS.

ARBs are widely used to treat hypertension and there is an abundant clinical experience with
its use, all representatives of this group being characterized by their excellent tolerance;
Furthermore, its adverse effects profile has been described as "placebo like(Schumacher &
Mancia, 2008; Sharpe, Jarvis, & Goa, 2001).

The most suitable ARB to antagonize the proinflammatory effects of angiotensin II in a
patient with a recent positive COVID-19 test should be the compound with the best
pharmacological properties for this indication. From the comparative analysis of the
available ARBs, telmisartan gathers properties that make it the best pharmacological tool to
evaluate the hypothesis under discussion in a clinical trial.

Liposolubility is relevant for absorption after oral administration and for tissue
penetration. Telmisartan stands out among all the representatives of the ARBs for being
markedly more lipophilic, expressed both in partition coefficients (octanol / neutral pH
buffer), distribution coefficients and distribution volumes (Vd). Telmisartan has a Vd of
approximately 500 L, irbesartan 93 L, and both valsartan and olmesartan, candesartan and
losartan, approximately 17 L.

The affinity of ARBs for the AT1 receptor has been measured by multiple studies, mainly using
radioligand binding studies. All AT1 receptor blockers are characterized by having similar
affinity values (pKi or pIC50, between 2 and 19 nM), with losartan and its active metabolite
EXP3174 being the lowest and irbesartan, candesartan and telmisartan the highest (Kakuta,
Sudoh, Sasamata, & Yamagishi, 2005).

Using isolated organ technique on blood vessels from different tissues and from different
animals, these AT1 antagonists have a blocking power (pA2) against angiotensin II in the nM
range (losartan, 8.15; irbesartan, 8.52; valsartan, 9.26; telmisartan 9.48; candesartan,
10.08). Telmisartan has a 10-fold higher blocking potency than losartan (Kakuta et al.,
2005).

Functional as well as biochemical studies determining the dissociation rates of the ARBs have
shown that these drugs have a slow dissociation rate that gives them characteristics of
pseudo-irreversible blocking agents. In the only comparative study using cloned human AT1
receptors, the half-lives of receptor dissociation were: telmisartan, 213 min; olmesartan,
166 min; candesartan, 133 min; valsartan, 70 min; losartan, 67 min (Kakuta et al., 2005).
Telmisartan is the AT1 blocker that dissociates more slowly from the receptor. This property
may be clinically relevant as it maintains a longer lasting blockade difficult to reverse by
the endogenous agonist angiotensin II.

Furthermore, telmisartan causes downregulation of AT1 receptor at the mRNA and protein level
apparently due to its action as a partial agonist of PPAR-gamma (Peroxisome
Proliferator-Activated Receptor gamma). This action can contribute to the effects of
telmisartan by producing a decrease in the number of AT1 receptors (Imayama et al., 2006).

In summary, telmisartan, which is well absorbed after oral administration, is the ARB with
the longest plasma half-life (24 h), it reaches the highest tissue concentrations due to its
high lipid solubility and high volume of distribution (500 L), and dissociates more slowly
after binding to the AT1 receptor, causing an apparently irreversible block (Kakuta et al.,
2005; Michel, Foster, Brunner, & Liu, 2013).

The present study is an open-label randomized phase II clinical trial for the evaluation of
telmisartan in COVID-19 patients. Briefly, patients with confirmed diagnosis of SARS-CoV-2,
will be randomized to receive 80 mg/12h of telmisartan (Bertel®, Laboratorio Elea Phoenix,
Buenos Aires, Argentina) plus standard care or standard care alone will be monitored for
development of systemic inflammation and acute respiratory distress syndrome. Other variables
regarding lung function and cardiovascular function will also be evaluated.

Clinical studies to evaluate the safety of Telmisartan in healthy individuals or in
hypertensive patients with daily doses of up to 160 mg, found no difference between those
treated with telmisartan and the placebo group in frequency and intensity of adverse effects
(Schumacher & Mancia, 2008; Sharpe et al., 2001; Stangier, Su, & Roth, 2000).