Proxalutamide, a new antiandrogen, improves COVID-19 outcomes in trials of men and women

Disclaimer: I am not a medical professional and this is not medical advice. The COVID-19 pandemic continues to be a rapidly evolving situation, and this information may be superseded by later findings. This article was last updated on February 28, 2021.

Since the worldwide outbreak of pandemic coronavirus last year, sex-specific patterns of infection and severity have offered tantalizing hints about the disease process and possible treatments. With those assigned male being significantly more likely than those assigned female to experience severe COVID-19 and death (Peckham et al., 2020), an explanation was sought. The cause of this bias appears to be multifactorial: two X chromosomes can code for a broader array of immune responses than only one, higher estrogen levels boost immune response to infection, and androgens such as testosterone can suppress immune function. This suggested the possibility of treating COVID-19 using estrogen, antiandrogens, or both.

Androgens can open the door for the coronavirus

Many publications on sex hormones and disease severity have been hypothetical or based on in vitro observations, noting that androgen receptor signaling can affect expression of ACE2 and TMPRSS2, which are both needed for the SARS-CoV-2 virus to enter cells (Qiao et al., 2021). If antiandrogen medications could lower ACE2 and TMPRSS2, this would make it more difficult for the virus to infect cells, treating the disease. Clinical trials are currently studying treatment of COVID-19 infection with a variety of antiandrogens: dutasteride, which inhibits the conversion of testosterone to the stronger androgen dihydrotestosterone (NCT04729491); degarelix, a GnRH antagonist that shuts off the body’s production of sex hormones (NCT04397718); and bicalutamide and enzalutamide, non-steroidal antiandrogens (NSAAs) that bind to the androgen receptor and block it directly (NCT04509999, NCT04475601).

Recent positive results from proxalutamide

As of this month, results from multiple trials have found that proxalutamide, an in-development NSAA, has a significant effect on severity and outcomes of COVID-19 infection. Cadegiani et al. (2021) reported that in both men and women with mild to moderate COVID-19, those given 200mg/day of proxalutamide either for 15 days or until “clinical remission” experienced a faster recovery than those who only received a placebo plus standard treatment. By the seventh day, the SARS-CoV-2 virus could no longer be detected in 82% of patients who received proxalutamide, compared to 31% of those who received placebo. Additionally, patients in the proxalutamide group reported no longer having any COVID-19 symptoms after an average of 4.2 days, compared to an average of 21.8 days for the placebo group.

An earlier preprint by Cadegiani et al. (2020) focused on clinical endpoints in men with mild COVID-19 who were given proxalutamide or placebo plus standard treatment. In this trial, 27% of patients in the placebo group were hospitalized, with 9% requiring a ventilator and 2% dying. Remarkably, in the proxalutamide group, no patients were hospitalized, needed ventilation, or died. An upcoming trial will study outcomes from 300mg/day proxalutamide in men and women who have been hospitalized with COVID-19 (NCT04728802).

More antiandrogen treatments could be on the way

Although dutasteride has not yet been studied in women or for outcomes such as ventilation or death, a trial of 0.5mg/day dutasteride for 30 days (or until remission) by Cadegiani et al. (2020a) found positive effects on disease progression. On the seventh day of treatment, 64.7% of the dutasteride group had no detectable virus compared to 11.8% of the placebo group. Those patients taking dutasteride also experienced remission of all symptoms by an average of 9.2 days compared to 16.3 days in the placebo group.

If the findings of these studies are confirmed by other research, the cost and availability of these medications could still pose a barrier to their wider use in routine treatment of COVID-19. Proxalutamide has not yet come to market, and other NSAAs such as enzalutamide, apalutamide and darolutamide are expensive and not yet generic. However, generic dutasteride is available at a much lower price, as is the generic NSAA bicalutamide; both have also sometimes been used as antiandrogens by trans women and transfeminine people. Cadegiani et al. (2021) have asserted:

In addition to direct AR antagonism, Proxalutamide has been shown to downregulate AR expression, a mechanism that is not present in bicalutamide or enzalutamide. Because of the dual mechanism of action, it is expected to be a more effective and less toxic second-generation anti-androgen drug therapy. Additionally, it has been reported that Proxalutamide lowers the expression of ACE2, which would be beneficial for preventing the entry of SARS-CoV-2 into lung cells.

But this does not therefore mean that any actions unique to proxalutamide are required for it to be clinically effective, or that bicalutamide or enzalutamide can be assumed to be clinically effective because they lack these specific mechanisms. Trials of bicalutamide and enzalutamide are still underway and the results have not yet been reported; it is not known that these are clinically inferior to proxalutamide. As mass vaccination programs slowly move forward, COVID-19 transmission, illness, and death will continue to be a significant presence in our lives for some time – even after the recent decline, daily case levels in the United States remain higher than the summer peak. Effective and accessible treatments will still be necessary, and more research on these medications is needed to clarify which particular mechanisms are required for an androgen-modulating drug to treat COVID-19. ■