Dr. Youzhi Tong
SARS-CoV-2 invades host cells via two proteins on the host cell surface, ACE2 and TMPRSS2, whose expression levels can be positively regulated by the human androgen receptor (AR). Proxalutamide inhibits the expression of ACE2 and TMPRSS 2 proteins by binding to AR and down-regulating AR gene expression levels, thereby preventing the virus from entering host cells.
Some experts have found that AR is also expressed in macrophages and that this pathway regulates macrophage activation, which is associated with a strong inflammatory response caused by viral infection in alveolar macrophages. This may be proxalutamide's therapeutic mechanism in serious COVID-19 patients.
After reviewing the statistics, Kintor found the rate of severe conditions is higher in adult male patients than in females, while children are less susceptible. This distribution of severity closely corresponds to the distribution of androgen concentrations in people of different sexes and ages.
Therefore, Kintor speculates that the infection of SARS-CoV-2 may be related to androgen.
In February and March 2020, Kintor conducted in vitro studies on both cancer and lung cells. Both found proxalutamide inhibited the expression of ACE2 and TMPRSS2 proteins. The studies confirmed the previous hypothesis and found that proxalutamide could regulate the expression of AR receptors in the lung cells. However, by that time, the COVID-19 epidemic was under control in China and the study was suspended.
The COVID-19 outbreak then spread globally. A retrospective study of 4,532 patients in Europe published in May 2020 found that male patients had more severe symptoms than women and that cancer patients' health was more likely to deteriorate. However, prostate cancer patients who received androgen deprivation therapy were able to withstand the infection's progression.
Later, Dr. Andy Goren, professor at Brown University and president and chief medical officer of Applied Biology, published findings on the potential association between androgenetic alopecia and the pathogenesis of COVID-19, pointing out that patients with androgenetic alopecia were more susceptible to the disease and deterioration.
These supportive clinical observations and in vitro evidence began to strengthen Dr. Tong's belief in a possible relationship between AR and SARS-CoV-2 infection. It eventually led to a collaboration between Kintor and Applied Biology to conduct a clinical study in Brazil, resulting in these findings.
MRCT clinical study to start soon
For its next steps, Kintor plans to conduct several global multi-center Phase III registrational clinical trials in the US, China, Brazil, and other countries.
The Phase III clinical trial application for proxalutamide in the treatment of male mild-to-moderate COVID-19 patients was formally approved by the FDA on March 5. The study is expected to start in April.
Dr. Tong told PharmaDJ that Kintor had been in discussions with the FDA regarding the study during its Pre-IND phase.
At that time, only the results of the study for male mild-to-moderate COVID-19 patients were published, so the protocol of this US registration study was also designed for the same population. According to Dr. Tong, the FDA considered expanding the study to female patients in the future.
Kintor plans to submit to the FDA another Phase III application for serious patients based on the newly published results.
There is more competition in the US to conduct clinical studies for COVID-19 compared to Brazil, and our studies may be accelerated if US physicians see the advantages of proxalutamide over other products, Dr. Tong explained.
In the Brazil study, 590 hospitalized patients were enrolled in just 21 days in 12 hospitals in Manaus, a city in the Amazon region, where the outbreak was particularly severe. Previously, the enrollment of nearly 300 mild-to-moderate patients took two months.
Pioneer is also preparing to apply for a registrational MRCT clinical study of proxalutamide for COVID-19 treatment in China.
This study will enroll patients from China, Brazil, the Philippines, and other countries. The study's main goal is to obtain market approval of COVID-19 in China. With fewer patients in China now, more patients from other Asian countries will be included in the study.
Patients with COVID-19 in Asian countries such as China are all admitted in the hospital, so the study endpoint may be changed to the need for oxygen or mechanical ventilation, etc., said Dr. Tong. Discussion on the study protocol with China CDE (Center for Drug Evaluation) is still ongoing.
Currently, Kintor is in discussions with multiple governments to apply for emergency authorization for treating COVID-19 with proxalutamide. I hope proxalutamide will be the therapy for COVID-19. A vaccine alone is not enough. We need drugs that can provide effective treatment and be a barrier to battle viral mutations, said Dr. Tong.
Confidence in the drug's safety as a COVID-19 treatment
As for the safety of proxalutamide, Dr.Tong is quite confident.
AR receptor antagonists are also used clinically to treat diseases such as androgenetic alopecia and prostate enlargement. Nearly 2,000 patients with cancer or COVID-19 have been treated with proxalutamide worldwide. Some with prostate and breast cancer are on long-term use.
Dr.Tong told PharmaDJ that the duration of treatment for COVID-19 patients is only two weeks, and no significant safety issues were identified. No serious adverse events (SAEs) occurred in the several clinical studies involving nearly 800 patients in Brazil.
Serious and mild-to-moderate patients received dosages of 300 mg/day and 200 mg/day respectively. Because of its safety, dosages can be increased as well. In previous studies, for instance, cancer patients received 600 mg/day.
More indications and more pipelines
These proxalutamide studies point to other indications and several other possible applications for the drug are in the pipeline.
Two Phase III proxalutamide studies on castration-resistant prostate cancer are underway in China. One is a monotherapy for endline patients. The other is being conducted in combination with abiraterone as a first-line therapy.
The former study has completed enrollment and is awaiting overall survival (OS) data. It is expected that the analysis will be complete in the third quarter of this year. The study has been going on for three years and enrolled 330 patients. The latter study is expected to complete enrollment this summer. The results will be available by the end of the year.
Additionally, proxalutamide is being evaluated as a treatment for triple-negative and estrogen receptor-positive (ER+) breast cancer.
Pyrilutamide (KX-826), another AR receptor antagonist in Kintor’s pipeline, is being developed as a topical drug for androgenetic alopecia and acne. It has already completed enrollment in a Phase II study in China.