Prokalutamide on a roller coaster, Zirissovir in a marathon Industry Observation

A few weeks ago, two antiviral drugs developed by domestic biotechnology companies successively released positive results from phase III studies

In the early days of the new crown epidemic, Chinese scientists discovered that the new coronavirus enters human cells through the ACE2 receptor protein, but the ACE2 (angiotensin-converting enzyme 2) inhibitors that have been marketed have been used for the new crown treatment, and no obvious disease has been seen.

Another product, chiresovir, was mentioned in the press release published by ARK Baifa, which is the first RSV antiviral drug in the world to successfully complete a pivotal Phase III study in a pediatric patient population

RSV infection is a common disease in infants and young children, and it is also an important cause of death in children under 5 years of age

It can be predicted that once these two drugs with published data are approved for marketing, as the first innovative drugs, they will change the treatment pattern of the corresponding diseases

The difficult and wonderful road to clinical transformation

The research and development of the above-mentioned products also reflects the exploration ability of Chinese biotechnology companies in translational medicine

The development process of these two antiviral drugs broke the original stereotyped thinking

Subsequently, Tong Youzhi noticed that some literature mentioned that the expression of ACE2 and TMPRSS2, the key proteins involved in the entry of new coronavirus into cells, are positively regulated by androgen receptors, and proclutamide happens to bind to AR receptors and down-regulate the expression of AR genes

Afterwards, the results of in vitro studies on cancer cells and lung cells with proclutamide confirmed his conjecture

But this is just the beginning

As soon as the research started, it encountered the phased end of the new crown epidemic in China, and the research could only be delayed

Afterwards, prokalutamide first achieved preliminary positive results in the IIT study initiated by Brazilian researchers, suggesting that prokalutamide can reduce the risk of death in severe new crown patients by 92% (3.

However, new difficulties also followed

However, the development in the whirlpool is still insisting, and the in-depth research in the early stage has made it confident in the mechanism of drug action

At this point, Pioneer did not copy the clinical design of foreign antiviral drugs for new crowns, and it also potentially expanded the scope of the applicable population of proclutamide for the treatment of new crowns

The research of Prokluamide is like riding a roller coaster, experiencing various ups and downs in less than two years
.
The development of ziresovir is more like running a marathon - a clinical study of antiviral drugs for 8 years
.

Chirissovir was introduced from Roche at the beginning of AGCO Baifa's establishment.
Dr.
Wu Zheng, the founder of AGCO Baifa, is the co-inventor of the chemical structure of the drug.
of
.
Unfortunately, at that time, Roche's strategy was adjusted, and product development was facing a shutdown.
For this reason, he decided to set up a company to start the research and development relay.
At that time, Qiressovir had just completed preclinical research
.

Therefore, after AGCO Baifa took over, it was the first time to plan and carry out the first human study (FIH) of the product
.
At this time in 2014, the domestic drug review reform has not yet started, and the research experience of FIH is even lacking, which has become a major problem for AGCO Baifa
.
Wu Zheng had to choose the curve to save the country and go to Australia to start the Phase I clinical trial
.
At the end of 2014, the FIH study of zelisovir was launched, and the first doses of adults and infants were completed in Australia
.
Then in September 2016, the clinical research application of cilesovir in China was also approved
.

However, the product development also faces another difficulty, that is, how to make the research successfully completed in infants and young children
.
The recently released phase III data of cilisovir were aimed at hospitalized infants and young children with RSV infection
.
According to Aikebaifa, the unmet clinical needs of RSV in infants and young children are greater than that in adults, so the first phase III study of infants and young children is carried out, but there are many preconditions for infant and young children research.
Toxicology studies,
etc.

In addition, infant research also has many difficulties in practice
.
Some literature mentions that the number of clinical studies on children in China is sparse and inexperienced.
In 2020, there are only 145 clinical studies related to children registered in China
.
The number of domestic institutions that can carry out clinical research on unmarketed new drugs for children is relatively small, and it is relatively difficult to recruit children.
Their participation in clinical trials requires the consent of their guardians
.

After the first dose of cilisovir in infants and young children in Australia, an international multi-center clinical phase II study called VICTOR was carried out in 8 different countries or regions around the world.
This study enrolled 72 children.
Launched in August 2016 and completed in November 2019, it took over 3 years
.

After that, the Phase III study in China was launched.
From the approval in December 2019 to the announcement of the results, it took nearly two and a half years to enroll more than 300 infants and young children
.
ARK Baifa has completed this protracted battle.
In October 2020, Zirisovir was recognized as a breakthrough therapy product by the State Food and Drug Administration
.
From the time when the compound molecule was designed, it can be said that it has been a sword for ten years
.

Completing the global listing registration still needs to overcome obstacles

Both products will then enter the market application process
.
According to the press release, Pioneer is actively advancing the Emergency Use Authorization (EUA) license of Prokluamide in China, the United States and other countries and regions
.
AGCO Baifa mentioned that it will first submit a new drug marketing application to Chinese regulators in mid-2022
.

As the first innovative drugs, the products are usually aimed at the global market, and the clinical research layout of the two products is indeed focused on this
.
There are still two Phase III studies of prokalutamide for the treatment of new crowns, one of which is for severe patients and the other for mild patients in countries outside the United States, including China and other regions
.
ARK Baifa also mentioned on its website that cilisovir started a phase I clinical study in the United States last year
.

It is only for Chinese biotechnology companies that develop first-in-class drugs, it is not easy to achieve simultaneous domestic and foreign listing of products.
So far, very few domestic companies have achieved this goal.
After all, the clinical practice and drug registration regulations of different countries are different
.
Ziresovir has been recognized by the NMPA as a breakthrough therapy, and it is more likely that domestic regulatory agencies will accept its listing application in the future, but it is difficult to predict when it will land in foreign markets
.
Prokalutamide has obtained EUA authorization in China and the United States with current data, and both places may need further communication with regulatory agencies
.

The uncertainty of the overseas listing of chirissovir may mainly come from the competition of similar products of multinational companies
.
Ziresovir is a small molecule inhibitor of RSV fusion protein.
It binds to the viral F protein to prevent the virus from invading human cells, and can also block the virus from infecting cells through cell-to-cell fusion
.
It is currently far ahead in the research and development of drugs with the same mechanism in China, and investment institutions predict that it will have a market exclusivity period of 3 to 4 years if it is launched
.

However, the situation abroad is different.
Just less than a week after the results of the phase III study of cilesovir were announced, Pfizer introduced the RSV research product sisunatovir through the acquisition of ReViral.
The mechanism of action of this product is similar to that of cilesovir.
Phase II clinical studies have been carried out in infants and young children, and the FDA has granted it Fast Track status
.
During the new crown epidemic, we have witnessed Pfizer's ability to promote clinical research of new products, and sisunatovir may next compete with cilisovir for foreign research resources
.
However, the Chinese rights of the simulator were licensed to Liantuo Biotech last year
.

In addition, the registration and application of first-in-class drugs developed by Chinese companies in the international market will also be hindered by the lack of international reputation accumulated in the development of first-in-class drugs
.
Prokalutamide may now need to convince foreign regulators that the positive Phase III data it has obtained is not an accident
.
Recently, Veru in the United States also announced the results of the phase III clinical interim analysis of its new crown candidate drug sabizabulin.
The data showed that it can reduce the risk of death in high-risk hospitalized patients by 55%.
The mechanism of action of the drug is also related to androgen receptor blockade.
Also advanced prostate cancer
.
Unlike prokalutamide, not many people questioned sabizabulin's data too good to be true this time around
.

At present, it is not known whether such recognition is good or bad for the listing and registration of Prokluamide in foreign countries
.
In the future, China needs more first-in-class new drugs to come out and jointly use data to prove their strength
.
If several other clinical studies of proclutamide for the treatment of new crowns also achieved positive results, will the attitude of foreign academic circles and regulatory agencies change immediately?