更多栏目
搜索
Kintor‘s Cancer Drug Reduces COVID-19 Mortality Risk by 92% in Phase III Trial
储旻华·2021-03-22
PharmaDJ
Its nonsteroidal antiandrogen candidate proxalutamide reduced mortality risk by 92% and shortened the median length of hospital stays by nine days, according to an investigator-initiated trial conducted in Brazil.

Kintor‘s Cancer Drug Reduces COVID-19 Mortality Risk by 92% in Phase III Trial


Writer: Minhua Chu, Yingzi Shi

Editor: Justin Fischer


Kintor Pharmaceuticals (HKEX: 9939), a Chinese clinical-stage biotechnology company recently announced that its nonsteroidal antiandrogen candidate proxalutamide reduced mortality risk by 92% and shortened the median length of hospital stays by nine days, according to an investigator-initiated trial conducted in Brazil.


“The positive data astonished me with unexpected big differences between two arms”, Dr. Youzhi Tong, Founder and CEO of Kintor Pharmaceuticals, told PharmaDJ. He noted that the Phase III trial in male COVID-19 patients with mild or moderate symptoms just got the FDA’s nod of approval and will enroll its first patients in April.



Kintor is also preparing to apply to China's regulatory authority for a registrational Multi-Regional Clinical Trials (MRCT) to enroll patients from China, Brazil, and the Philippines. An application for emergency use authorization (EUA) for proxalutamide will be discussed with several governments as well.


Promising results in both serious and mild-to-moderate COVID-19 patients


The preliminary analysis conducted on March 9, 2021 showed the study (NCT04728802) met the primary endpoint on day 14, demonstrating a reduction of 4.01 (5.663 to 1.653) in the WHO COVID-19 ordinal scale from a baseline in the proxalutamide arm versus a reduction of 0.25 (5.618 to 5.368) in the control arm (p<0.0001).


Proxalutamide also demonstrated a reduction in mortality risk by 92% (3.7% vs 47.6%) and shortened the median length of hospital stays by nine days (median hospital stays of five days versus 14 days). 89.1% of the hospitalized patients' symptoms became mild. They were discharged after 14 days of proxalutamide treatment, and the prognostic indicators such as C-reactive protein (CRP), inflammatory factors, and D-dimer decreased.



Only a few studies have been conducted on serious COVID-19 patients thus far. Very few drugs (Remdesivir, for example) have gotten EUAs for treatment.


It is not the first time proxalutamide has yielded unexpectedly positive results in treating COVID-19 patients. On January 7 of this year, Kintor published data on proxalutamide in men with mild-to-moderate symptoms, which showed a 0% hospitalization rate, compared to 27% in the control group, significantly reducing the disease's rate of progression.


The study was later expanded to 95 female patients and obtained similar results.



The drug is believed to prevent the virus from invading host cells


Proxalutamide is is an orally selective high-affinity silent antagonist of the androgen receptor.  It is under development for the potential treatment of COVID-19, prostate cancer, and breast cancer.


Dr. Tong believes proxalutamide works by blocking the pathway of SARS-CoV-2 invasion into host cells.


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.



Kintor is also optimistic about the prospects of the ALK-1 inhibitor GT90001 licensed from Pfizer.


Dr. Tong mentioned that GT90001 in combination with Opdivo as the second-line therapy for liver cancer has yielded positive results in a Taiwan study, and a Phase II global multicenter registrational clinical study, approved by the FDA last month, will soon commence.


This product can achieve better therapeutic results when combined with immunotherapy and could expand to many possible indications in solid tumors other than liver cancer in the future. This is also the first large-molecule drug from Kintor to enter a clinical study. We look forward to the future development in both small molecules and large molecules, Dr. Tong said.


文章关键字:Kintor Pharmaceuticals,COVID-19,Tong Youzhi,emergency use authorization (EUA),MRCT
6720
谁阅读了此文章?
回复评论0
登录后回复评论,不超过1024个字(当前剩余字数:1024)
储旻华 个人用户

热衷收罗医药圈从研发到上市的各种“八卦”,然后基于事实和数据加以分析

联系方式

联系电话

电子邮箱

chu.minhua@pharmadj.com

公司名称

研发客

公司网站

公司地址

进入主页
Copyright © 2016-2020 研发客.All Rights Reserved.
建议反馈: Support@PharmaDJ.com
备案/许可证编号: 沪ICP备17054709号-1
联系电话:021 - 88194359