Proxalutamide Improves Lung Injury in Hospitalized COVID-19 Patients – an Analysis of the Radiological Findings of the Proxa-Rescue AndroCoV Trial

Abstract

Introduction: Antiandrogen are good candidates against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) due to the inhibition of its entry into host cells by the suppression of TMPRSS2, an enzyme that primes the SARS-CoV-2 spike (S) protein and is key for its cell entry. Proxalutamide is a second-generation nonsteroidal anti-androgen (NSAA) with strong activities on androgen receptor (AR) antagonism, suppression of AR nuclear expression, and downregulation of the membrane-attached angiotensin converting enzyme-2 (ACE2). The efficacy of proxalutamide was previously demonstrated for early COVID-19 patients, and has now demonstrated efficacy to reduce deaths in hospitalized COVID-19 patient in a double-blind, placebo-controlled randomized clinical trial (RCT). Whether radiological changes would follow the improvement in clinical outcomes with proxalutamide is not established. The present post-hoc analysis aims to evaluate whether proxalutamide improves lung injury observed through chest computed tomography (CT) scans, in addition to the clinical improvement, thus providing further objective evidence of the drug response in COVID-19. Methods: This is a post-hoc analysis of the radiological findings of a double-blinded, placebo-controlled, prospective, two-arm RCT (The Proxa-Rescue AndroCoV Trial) with all enrolled patients from the three participating institutions of the city of Manaus, Amazonas, Brazil, that had at least two chest CT scans during hospitalization. The quantification of lung parenchyma involvement was performed by independent board-certified radiologists with expertise in analysis of COVID-19 images, that were blind to the assigned intervention in the RCT. A first chest CT scan was performed upon randomization and a second CT scan was performed approximately five days later, whenever patient transportation was feasible. Results: Of the 395 patients initially evaluated, 72 and 179 patients from the proxalutamide and placebo arms, respectively, were included (n=251). Baseline and clinical characteristics, interval between first and second chest CT scans, and percentage of lung parenchyma affected in the baseline chest CT scan were similar between groups. In the second chest CT scan, the percentage of lungs affected (Median - IQR) was 35.0% (25.0-57.5%) in the proxalutamide group versus 67.5% (50.0-80.0%) in the placebo group (p < 0.001). The absolute and relative change between the second and first chest CT scans (Median - IQR) were -15.0 percent points (p.p.) (-30.0 - 0.0p.p.) and -25.0% (-50.0 - 0.0%) in the proxalutamide group, respectively, and +15.0p.p. (0.0 - +30.0p.p.) and +32.7% (0.0 - +80.0%) in the placebo group, respectively (p < 0.001 for both absolute and relative changes). Conclusion: Proxalutamide improves lung opacities in hospitalized COVID-19 patients when compared to placebo. (NCT04728802)

Androgens’ Role in Severity and Mortality Rates of COVID-19

“…substantial improvements seen in immunological, inflammatory and thrombotic markers with proxalutamide can support reduction of hospitalization [129]. Proxalutamide also significantly improves lung injury in patients with COVID-19 [130]. Cadegiani et al in a double-blind, randomized clinical trial (DB-RCT), investigated the efficacy of proxalutamide 200 mg/day, compared to placebo group regarding viral clearance.…”

Proxalutamide for the treatment of COVID‐19 rebound following Paxlovid treatment: Report of four cases and review of the literature

“…Since TMPRSS2 is regulated by the androgen receptor, reduction of TMPRSS2 expression by inhibiting the androgen receptor would likely inhibit the entry of SARS‐CoV‐2 into human cells. Proxalutamide is a novel nonsteroidal anti‐androgen with strong antagonism to the androgen receptor 11 . It has been demonstrated to reduce the hospitalization rate in both COVID‐19 male 12 and female 13 outpatients.…”

“…Proxalutamide is a novel nonsteroidal anti‐androgen with strong antagonism to the androgen receptor. 11 It has been demonstrated to reduce the hospitalization rate in both COVID‐19 male 12 and female 13 outpatients. The final results from the Proxa‐Rescue Trial showed that proxalutamide increased the 14‐day recovery rate by 121% and reduced the 28‐day mortality rate by 78% when compared to the usual care in the treatment of hospitalized COVID‐19 patients.…”