Proxalutamide Improves Inflammatory, Immunologic, and Thrombogenic Markers in Mild-to-Moderate COVID-19 Males and Females: an Exploratory Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial Early Antiandrogen Therapy (EAT) with Proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial)
Flávio Adsuara Cadegiani, MD Andy Goren, MD, PhD Carlos Gustavo Wambier, MD Ricardo Ariel Zimerman
doi:10.1101/2021.07.24.21261047
Background: The androgen theory on COVID-19 is based on the fact that males, in particular when affected by androgenetic alopecia, and females with hyperandrogenic states are more severely affected by COVID-19, while chronic users of antiandrogens experiment lower rates of COVID-19 complications. The theory finds plausibility on the androgen-mediated transmembrane protease serine 2 (TMPRSS-2), a key protein for SARS-CoV-2 cell entry. We demonstrated reduction of hospitalization rate using a potent non-steroidal antiandrogen (NSAA), proxalutamide, in both females and males COVID-19 outpatients. In this joint exploratory analysis, we aimed to demonstrate whether the efficacy of proxalutamide on mild-to-moderate COVID-19 could be justified by improvements in inflammatory, immunologic, and thrombogenic responses. Methods: This is a joint post-hoc analysis of two double-blind, placebo-controlled twoarm randomized clinical trials (RCTs) on proxalutamide 200mg/day for seven days for female and male COVID-19 outpatients, respectively, compared to standard of care (SOC), of hematocrit, neutrophils lymphocytes, eosinophils, platelets, neutrophil-tolymphocyte (N/L) ratio, ferritin, fibrinogen, D-dimer, ultrasensitive C-reactive protein (usCRP) lactate 1-hour erythrocyte sedimentation rate (1hESR), total testosterone, estradiol, sex hormone binding globulin (SHBG), oxygen saturation and heart rate measured on days 0, 1 and 7. Results: A total of 445 subjects were enrolled (268 males and 177 females) between October 21 th 2020 and February 28 th 2021, with similar baseline characteristics. Neutrophils were lower in proxalutamide group in Day 1 (p = 0.005) and Day 7 (p < 0.0001). Lymphocytes were higher in the proxalutamide group in Day 7 (p = 0.0001). Eosinophils were higher in the proxalutamide arm in Day 1 (p = 0.04) and Day 7 (p < 0.00010. In Day 7, platelets were higher in proxalutamide arm (p = 0.03). Ferritin levels were lower in proxalutamide arm in Day 7 (p = 0.03) Fibrinogen levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). D-dimer levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). UsCRP levels were reduced in proxalutamide group in Day 7 (p < 0.0001). 1hESR) was reduced in proxalutamide arm in Day 1 (p = 0.0009) and Day 7 (p < 0.0001). In males, testosterone levels were higher in proxalutamide group in Day 1 (p = 0.048) and Day 7 (p = 0.0001). In females, testosterone levels were higher in proxalutamide group in Day 7 (p = 0.018), .
24, 25 The use of antiandrogens as a promising therapy for COVID-19 is based on the androgen theory on COVID-19. We have previously shown that males, particularly those exhibiting AGA, BPH and or genetic polymorphisms in AR, were more severely affected by COVID-19 1,2-5 . Women with hyperandrogenism phenotypes have also been associated with worse prognosis. 7, 8 Finally, we have recently shown that athletes abusing DHT derived AAs may be predisposed to more severe SARS-CoV-2 infections and complications. 12 Males under androgenic deprivation therapy (ADT) for castrationresistant prostate cancer were linked to lower risk of severe COVID-19, which is unexpected, since ADT may lead to immunosuppression and increased frailty, compared to non-ADT. [9] [10] [11] In an early report of two of our randomized, placebo controlled, double blind clinical trials on Early Anti-androgenic Therapy (EAT) for COVID-19 with two antiandrogens, dutasteride and proxalutamide, we were able to prove the concept that anti-androgenic therapy has a definitive antiviral effect. 17, 26 In the case of proxalutamide, this effect was consistent for both male and females. Proxalutamide antiviral effects may be ascribed both to ACE-2 and TMPRSS-2 down regulation. 21 The importance of viral load as a surrogate marker has being increasingly recognized, as it directly relates to critical clinical outcomes, such as mechanical ventilation use and death. Unfortunately, because dependence on availability..
References
Bhowmick, Oft, Dorff, Pal, Agarwal et al., COVID-19 and androgen-targeted therapy for prostate cancer patients, Endocr Relat Cancer,
doi:10.1530/ERC-20-0165Cadegiani, Fonseca, Correia, Proxalutamide Improves Lung Injury in Hospitalized COVID-19 Patients -an Analysis of the Radiological Findings of the Proxa-Rescue AndroCoV Trial, medRxiv,
doi:10.1101/2021.07.01.2125965Cadegiani, Lim, Goren, Mccoy, Situm et al., Clinical symptoms of hyperandrogenic women diagnosed with COVID-19, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17004Cadegiani, Lin, Goren, Wambier, Potential risk for developing severe COVID-19 disease among anabolic steroid users, BMJ Case Rep,
doi:10.1136/bcr-2021-241572Cadegiani, Mccoy, Wambier, Goren, Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial -Biochemical), Cureus,
doi:10.7759/cureus.13047Cadegiani, Mccoy, Wambier, Proxalutamide Significantly Accelerates Viral Clearance and ReducesTime to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial, Cureus,
doi:10.7759/cureus.13492Cadegiani, Zimerman, Fonseca, Correia, Mccoy et al., Proxalutamide (GT0918) Reduces the Rate of Hospitalization in mild-to-moderate COVID-19 Female Patients: A Randomized Double-Blinded Placebo-Controlled Two-Arm Parallel Trial medRxiv,
doi:10.1101/2021.07.06.21260086Dhindsa, Zhang, Mcphaul, Wu, Ghoshal et al., Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2021.11398Gebhard, Regitz-Zagrosek, Neuhauser, Morgan, Klein, Impact of sex and gender on COVID-19 outcomes in Europe, Biol Sex Differ,
doi:10.1186/s13293-020-00304-9Gordon, Mouncey, Al-Beidh, Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2100433Goren, Wambier, Herrera, Mccoy, Vaño-Galván et al., Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.16953Herold, Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19, The Journal of allergy and clinical immunology,
doi:10.1016/j.jaci.2020.05.008Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Mccoy, Cadegiani, Wambier, Herrera, Vaño-Galván et al., 5-alphareductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17021Mccoy, Goren, Cadegiani, Vaño-Galván, Kovacevic et al., Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial, Front. Med,
doi:10.3389/fmed.2021.668698Montopoli, Zumerle, Vettor, Rugge, Zorzi et al., Androgendeprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532), Ann Oncol,
doi:10.1016/j.annonc.2020.04.479Patel, Zhong, Liaw, Tremblay, Tsao et al., Does androgen deprivation therapy protect against severe complications from COVID-19?, Ann Oncol,
doi:10.1016/j.annonc.2020.06.023Peter W Horby, Pessoa-Amorim, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial,
doi:10.1101/2021.02.11.21249258Qu, Gu, Wang, He, Zhou et al., Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells, Invest New Drugs,
doi:10.1007/s10637-020-00901-wSalazar Arenas, Del Carpio-Toia, Galdos, Rodriguez-Morales, Alopecia and severity of COVID-19: a cross-sectional study in Peru, Infez Med
Sang, Wang, Zhong, Gu, Wang et al., Quantitative determination of proxalutamide in rat plasma and tissues using liquid chromatography/tandem mass spectrometry, Rapid Commun Mass Spectrom,
doi:10.1002/rcm.9003Subramanian, Anand, Adderley, Okoth, Toulis et al., Increased COVID-19 infections in women with polycystic ovary syndrome: a population-based study, Eur J Endocrinol,
doi:10.1530/EJE-20-1163Swiglo, Cosma, Flynn, Kurtz, Labella et al., Clinical review: Antiandrogens for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials, J Clin Endocrinol Metab,
doi:10.1210/jc.2007-2430Wambier, Mccoy, Goren, Male balding as a major risk factor for severe COVID-19: A possible role for targeting androgens and transmembrane protease serine 2 to protect vulnerable individuals, J Am Acad Dermatol,
doi:10.1016/j.jaad.2020.09.015Wambier, Vaño-Galván, Mccoy, Gomez-Zubiaur, Herrera et al., Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The "Gabrin sign, J Am Acad Dermatol,
doi:10.1016/j.jaad.2020.05.079
