BEIJING – Androgen receptor (AR) antagonist developer Kintor Pharmaceutical Ltd., of Suzhou, China, is going to provide its proxalutamide (GT-0918) to an ongoing clinical trial in male patients, led by U.S. firm Applied Biology Inc., in Brazil for COVID-19, after preliminary clinical research suggested a potential link between androgenetic alopecia and COVID-19 pathogenesis.
The main point of the collaboration is to see if proxalutamide can slow progression in male patients, when men are found more vulnerable to COVID-19 as androgens appear to help the coronavirus get inside cells more easily.
“We focus on early stage patients who tested positive but do not need hospitalization. Our proxalutamide may have a therapeutic effect to help slow progression,” Kintor’s chief financial officer, Lucy Lu, told BioWorld.
In the Brazil study, Applied Biology will study proxalutamide, plus standard of care, as an additional arm to the trial with around 120 male participants. The overall study aims to enroll 254 male subjects, 50 or older, with androgenetic alopecia. It aims to explore the possible protective role of anti-androgens in SARS-CoV-2 infections, to see if they are effective in reducing the rate of COVID-19 hospitalization. The primary endpoint is the percentage of subjects hospitalized due to COVID-19 within 30 days.
“The current trial started in June. The plan is to finish the trial by end of this year or January next year,” said Lu. “It’s a very short dosing period. The patients will take the drug for 14 days, then we will check the percentage of hospitalization. Hopefully, we will receive the data by the end of this year.
“We’ll see how the data goes. If the collaboration goes well, we won’t rule out any collaboration opportunities to roll out clinical trials in the U.S.,” she added.
Kintor CEO Youzhi Tong said it is critical to find a treatment that helps COVID-19 patients slow the progression, even as the general global biotech community pursues therapies to prevent or treat COVID-19.
“By doing so, the human immune system may have sufficient time to generate antibodies to fight against the novel coronavirus. We believe this research study demonstrates the possible therapeutic effect of proxalutamide as an anti-androgen therapy to treat COVID-19,” he said.
A lead drug candidate for Kintor, proxalutamide is a second-generation AR antagonist that is in phase III trials in China and phase II studies in the U.S. for metastatic castration-resistant prostate cancer. Kintor said it is a potential best-in-class small-molecule AR antagonist with a novel chemical structure that enables it to down-regulate AR expression.
Link between androgens and COVID-19?
Kintor discovered the potential of proxalutamide in treating COVID-19 through a preclinical research collaboration with Soochow University in China earlier this year.
With data collected from 1,339 COVID-19 patients, the collaboration explored potential mechanisms of COVID-19 gender disparity and found that blocking AR signaling could reduce the expression of ACE2 and TMPRSS2 in normal lung cells and cancer cells derived from prostate and lung cancers.
The study also found that proxalutamide inhibited the expression of inducible nitric oxide synthase and TNFα, the macrophage-activation markers, in mouse macrophage cells. Researchers believe androgen-AR signaling plays a role in disease progression and the mortality in male patients with COVID-19, and that suppressing the AR-ACE2/TMPRSS2 axis by AR antagonists may help.
Separately, Applied Biology also investigated the link between androgens and COVID-19 pathogenesis, emphasizing the role of ACE2 and TMPRSS2.
It explained that SARS-CoV-2 primarily infects type II pneumocytes in the human lung and it enters pneumocytes by anchoring to the ACE2 cell surface receptor.
Prior to receptor binding, viral spike proteins undergo proteolytic priming by TMPRSS2. TMPRSS2 inhibition or knockdown reduces ability of SARS-CoV-1, a related virus to SARS-CoV-2, to infect cells in vitro. 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, TMPRSS2 mRNA expression increase was mediated by the AR.
Andy Goren, chief medical officer of Applied Biology, said the company looks forward to studying proxalutamide, a novel molecule that reduces the expressions of both TMPRSS2 and ACE2, the two molecules implicated in SARS-CoV-2 infectivity.
“Provided our study demonstrates efficacy and safety, proxalutamide could potentially be used as a first-line treatment for COVID-19 male patients at the early stage of infection,” he added.