Anti-Androgen Treatment for COVID-19

During the continuing SARS-CoV-2 (COVID-19) pandemic, several studies have reported a
significant difference in the rate of severe cases between adult females and adult males (42%
vs 58%).Among children under the age of 14, the rate of severe cases was reported to be
extremely low. To explain this difference, several theories have been proposed including
cigarette smoking and lifestyle habits. However, no theory fits both the gender difference in
severe cases as well as reduced risk in pre-pubescent children. Our past research on male
androgenetic alopecia (AGA) has led us to investigate an association between androgens and
COVID-19 pathogenesis. In normal subjects, androgen expression demonstrates significant
variation between men and women as well as between adults and pre-pubescent children.

SARS-CoV-2 primarily infects type II pneumocytes in the human lung. SARS-CoV-2 enters
pneumocytes, by anchoring to the ACE2 cell surface receptor. Prior to receptor binding, viral
spike proteins undergo proteolytic priming by the transmembrane protease, serine 2 (TMPRSS2).
TMPRSS2 inhibition or knock down reduces ability of SARS-CoV-1 (a related virus to
SARS-CoV-2) to infect cells in vitro. Additionally, TMPRSS2 also facilitates entry of
influenza A and influenza B into primary human airway cells and type II pneumocytes.

The human TMPRSS2 gene has a 15 bp androgen response element and in humans, androgens are the
only known transcription promoters for the TMPRSS2 gene. In a study of androgen-stimulated
prostate cancer cells (LNCaP), TMPRSS2 mRNA expression increase was mediated by the androgen
receptor. Further, the ACE2 receptor, also critical for SARS-CoV-2 viral infectivity, is
affected by male sex hormones with higher activity found in males.

Androgenetic alopecia (AGA), often referred to as male pattern hair loss, is the most common
form of hair loss among men. The development of androgenetic alopecia is androgen mediated
and is dependent on genetic variants found in the androgen receptor gene located on the X
chromosome; thus, it is hypothesized that men with AGA would be more prone to severe COVID-19
disease. The investigators conducted a preliminary observational study of hospitalized
COVID-19 patients at two Spanish tertiary hospitals between March 23-April 6, 2020 to test
this theory. In total, 41 Caucasian males admitted to the hospitals with a diagnosis of
bilateral SARS-CoV-2 pneumonia were analyzed. The mean age of patients was 58 years (range
23-79). Among them, 29 (71%) were diagnosed with AGA (16 (39%) were classified as severe AGA
(Hamilton IV or above)) and 12 (29%) did not present clinical signs of AGA. The diagnosis of
AGA was performed clinically by a dermatologist. The precise prevalence of AGA among
otherwise healthy Spanish Caucasian males is unknown; however, based on published literature,
the expected prevalence of a similar age-matched Caucasian population is approximately
31-53%.

Based on the scientific rationale combined with this preliminary observation, the
investigators propose to test an anti-androgen as a treatment for patients recently diagnosed
with COVID-19.

We have chosen the use of the novel second generation androgen receptor (AR) antagonist
proxalutamide as a means for rapid reduction in AR activity. Proxalutamide (GT0918)
demonstrates a dual mechanism of action. It is highly effective in inhibiting AR as well as
exhibiting pharmacological effects of inducing the down-regulation of AR expression; the
mechanism that is not present in bicalutamide and enzalutamide. Additionally, it has been
reported that Proxalutamide lowers the expression of ACE2. Both would be beneficial for
preventing SARS-CoV-2 entry into lung cells.

This study is intended to explore the possible protective role of anti-androgens in
SARS-CoV-2 infection. Provided anti-androgens are effective in reducing the rate of COVID-19
hospitalization, subjects enrolled in this study may experience a lower rate of
hospitalization.