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Recently, with the surge in the number of new crown infections in China and the increase in the number of critically ill patients, Pfizer's new crown oral drug Paxlovid is arriving in many hospitals across the country, but the number is extremely limited
.
In the folk, this drug is still "hard to find"
.
In fact, as early as before the epidemic policy adjustment in December, the Ministry of Industry and Information Technology held a drug preparation meeting, including several domestic new crown oral drug companies
whose products were not yet on the market and were stuck in the CDE approval stage.
whose products were not yet on the market and were stuck in the CDE approval stage.
But no one thought that after the peak of infection, even ibuprofen and other drugs that reduce the symptoms of the new crown were out of stock
.
The new crown oral drugs that can "save lives" are only Pfizer's Paxlovid and Azvudine listed in China, and the situation of out-of-stock can be
imagined.
Several community hospitals in Beijing have been facing a large number of residents' inquiries
about Paxlovid for several days.
However, the vast majority of counselors are disappointed – most community hospitals have still not arrived, and when they do, there are usually only a dozen boxes, which is far from enough to meet the needs
of people over 65 years of age with underlying medical conditions in the jurisdiction.
Azvudine, as a "replacement", is also being snapped up by many people
.
The drug has been widely stocked in hundreds of hospitals and several online consultation platforms across the country, but many hospitals and platforms are often out of stock
.
Obviously, the market demand for anti-new coronavirus oral drugs is far from being met
.
.
On December 29, 2022, in addition to Paxlovid, another international mainstream anti-new coronavirus oral drug was finally approved in China - the State Food and Drug Administration conducted emergency review and approval in accordance with the special approval procedure for drugs, and conditionally approved the import registration
of MSD's monogravir capsules (trade name: Lizhuorui/LAGEVRIO).
"Emergency review and approval, with a certain period of time, is a relatively relaxed approval
.
" An industry insider believes
.
Because the effect of monoravir is not as good as Paxlovid, it is used relatively little in many countries such as the United States, and it is mainly used to provide people who are not suitable for taking Paxlovid due to physical conditions and daily medication conditions (unlike Paxlovid, taking monoravir does not need to consider so many drug interactions).
.
"
As of the last day of 2022, China has a total of three oral anti-new coronavirus drugs: Pfizer's Paxlovid, Merck's monoravir, and China's domestic azvudine
.
In fact, in addition to the three drugs that have been approved, there is still a long queue
of anti-new coronavirus oral drugs under research in China.
There is Junshi who is in the forefront, pioneering the pharmaceutical industry; There are also Simcere Pharmaceutical, Zhongsheng Pharmaceutical, etc
.
that entered the game later.
Some of them have already completed phase III clinical trials and are only waiting for approval by the Food and Drug Administration; Others are speeding up phase III trials; Many others have also entered the clinical trial stage
.
of anti-new coronavirus oral drugs under research in China.
Why is it that only one of azvudine, which started not too late, has been approved so far? Who will be the next approved anti-coronavirus oral drug?
-01-
-01-Why is only one domestic new crown oral drug approved?
Why is only one domestic new crown oral drug approved?Domestic new crown oral drugs are difficult to be approved, and in the eyes of many industry insiders, the key lies in the unchanged high standards
of CDE.
The strain of the new coronavirus changes rapidly, and the results of infection between different strains in different populations are very different, so drug reviews need to adjust and balance
the scale of "flexibility" and "no lowering of standards".
between "flexible" and "not lowering standards" scales.
Like the new crown vaccine, anti-new crown virus oral drugs are also an area
that many Chinese pharmaceutical companies are vying to invest in.
As early as March and April 2022, shortly after the State Food and Drug Administration approved Paxlovid, three Chinese pharmaceutical companies have entered phase III clinical trials of anti-new coronavirus oral drugs, namely: VV116 from Junshi Biologics, Proclomide from Pioneer Pharmaceuticals and azvudine
from Real Biologics.
Until the last day of 2022, there is still only one
domestic new crown oral drug that has been approved, and there is still azvudine.
A number of industry insiders believe that the approval progress of domestic new crown oral drugs has been slow for a long time, which is also related
to the clinical endpoint setting in the CDE guidelines.
Paxlovid
Emergency approval in the United States at the end of 2021 is based on the results of a clinical trial in which early use in infection can reduce hospitalization and mortality in high-risk adult patients by 89%.
The trial began in July 2021 and is the main strain that causes severe disease and death
.
In the era of the Omicron pandemic, it was very difficult for clinical trials to produce such results – even in the placebo group, the number of severe cases or deaths was very small, and the difference from the drug group was difficult to be statistically significant
.
Similarly, the long-term "improvement of severe disease and hospitalization rate" as the primary clinical endpoint is considered by the industry to be an important reason
for the lack of progress of domestic oral drugs in the past year.
the lack of progress of domestic oral drugs in the past year.
In the first half of 2022, a number of industry insiders said that if the clinical endpoints were not made according to the above indicators, they would basically not be approved for phase III clinical trials
.
At that time, the epidemic strain was dominated by Omicron, and there were very few cases of severe progression in new crown infections, so that many new crown drugs at that time were difficult to make positive data
on the clinical endpoint of "preventing severe progression".
Therefore, in the head-to-head experiment with Paxlovid published by Junshi Biologics recently published in the journal NEJM, no subjects
progressed to severe disease in either group.
progressed to severe disease in either group.
At that time, some drug regulators pointed out that based on the requirements of "improving the rate of severe disease and hospitalization", the vast majority of new crown oral drugs under development are difficult to meet the standard
.
On August 1, 2022, the Evaluation Center of the State Food and Drug Administration issued a "Q&A on the Non-clinical and Clinical Evaluation Standards of Antiviral New Drugs Infected with New Circulating Strains of the Novel Coronavirus" (hereinafter referred to as "Q&A"), revealing that the evaluation criteria for new coronavirus oral drugs have changed: "clinical efficacy index" is listed as the primary endpoint, and "reducing viral load" is elevated to the secondary endpoint level
.
This is a major change that allows the industry to see the possibility of
rapid approval of domestic new crown oral drugs.
However, after the approval of azvudine in July, there has been no new progress
in the approval of domestic new crown oral drugs.
One possible question is how to determine
clinical efficacy.
It is reported that CDE's indicators for the reduction of new crown symptoms were once strictly in accordance with WHO regulations, and later reduced several
after communicating with professionals.
But even so, the industry still generally believes that the existing more than ten symptom reduction goals are difficult to achieve
.
An industry insider explained: "The reduction of new crown symptoms is not a detection indicator, but a subjective indicator
.
Moreover, Omicron has different symptoms in mild, moderate, and severe people, and the clinical endpoints that can be achieved in severe people are likely not to be made in mildly ill people - compared with placebo, there is no statistical difference
.
”
Even the international mainstream first-line anti-new coronavirus oral drug Paxlovid has not been successful in the clinical endpoint of improving symptoms
.
At this moment, how to design the most scientific and realistic review indicators is the key
to the approval of the next new crown treatment drug.
the approval of the next new crown treatment drug.
-02-
-02-Merck Monoravir approved: emergency approval system
Merck Monoravir approved: emergency approval systemChina's peak infection base for this round of new crown infections is huge, and the severe disease and mortality rate of high-risk groups have made many people realize that drugs that only reduce symptoms will not reduce severe disease and mortality, but will cover up hidden dangers
that need attention.
"Some elderly people have symptoms that are not severe a week before they are infected with the virus, but they suddenly get sicker later, and once they worsen, the situation is more critical
.
" A doctor in Beijing who participated in frontline treatment reflected
.
Therefore, it is still extremely necessary
to reduce the viral load and clear the virus of the new crown oral drugs.
This time, Merck's monoravir is subject to emergency review and approval in accordance with the special approval
procedure for drugs.
In response to the global new crown epidemic crisis, the United States, Japan, and the European Union have successively launched rapid review measures
for new crown prevention and treatment products.
for new crown prevention and treatment products.
For example, the EUA initiation in the United States is generally determined by the safety and health department to enter a state of emergency, and after the declaration of determination, the FDA initiates a technical review of the application for related drugs, and finally the Department of Health and Welfare (HHS) issues the approval or rejection of the EUA request
.
Compared to conventional drug applications, the review speed is much
more efficient.
However, the FDA makes it clear that such reviews require at least one high-quality Phase III clinical trial result
in terms of safety and efficacy data.
That is, it can be accelerated, but it cannot be uncaused
.
Japan's accelerated review of new coronavirus treatment products is divided into two types, namely special case recognition and priority review
.
This process simplifies product evaluation procedures and data requirements, and also significantly reduces approval time
.
Priority review, on the other hand, is a "skip-the-line strategy"
compared to regular review.
China's accelerated review regulations for large-scale public health events are mainly of two types
.
.
One is the Special Drug Approval Procedure of the State Food and Drug Administration (Order No.
21) promulgated in 2005, the core content of which stipulates the response time for specific product review and official response applications, and proposes that drug approval
can be accelerated through early intervention and early communication.
The other is the newly revised Measures for the Administration of Drug Registration in 2020, which has three methods
to accelerate the marketing of drugs with conditional approval, priority review and approval and special approval procedures.
Previously, the State Food and Drug Administration has conditionally approved 5 new crown vaccines, and 8 vaccines have been included in emergency use, and 11 therapeutic drugs have been urgently approved, including Pfizer's Paxlovid and Tengsheng Bo Pharma's ambavirumab injection and romisivimab injection, as well as Merck's monogravir
.
The indication of azvudine for the use of COVID in adults was conditionally approved
.
Looking at the accelerated listing of these new crown vaccines and drugs, they are basically proposed by the Joint Prevention and Control Office, the Food and Drug Administration does a technical review, and finally the Joint Prevention and Control Office decides whether to pass the application
.
Merck's monoravir was recently approved urgently, which may mean that the channel for more new crown drug approvals is opening
.
-03-
-03-Domestic new crown oral medicine queued
Domestic new crown oral medicine queuedAmong the domestic new crown oral drugs waiting to be judged, the most famous of them include Junshi Biologics' VV116
.
This drug is the same as Merck's monupivir as the RdRp inhibitor technology route and has been approved in Uzbekistan for moderate to severe disease
.
Junshi announced in May this year that its VV116 met the preset primary endpoint of the protocol in a phase III head-to-head trial with Paxlovid for the early treatment of mild to moderate novel coronary pneumonia, and has submitted an application
to CDE.
However, this head-to-head trial has been questioned, and even if the results of the Paxlovid trial are "not inferior", it still cannot meet the CDE's setting
of clinical endpoints.
Recently, the number of new crown infections has surged, and the number of critically ill people has increased
.
At the same time, VV116 began a clinical trial
.
On December 19, Junshi Biologics registered a Phase III clinical trial
of VV116 head-to-head compared with Paxlovid for the treatment of mild to moderate COVID-19 virus rebound rate.
The phase III clinical trial was presided over by Academician Ning Guang, President of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and 478 subjects
were planned to be enrolled.
This newly opened clinical trial, focusing on the "virus rebound rate", mainly tracks the proportion of relapse after treatment, which is considered "very meaningful"
by the industry.
Domestic Pioneer Pharmaceuticals and other industries are also doing similar tests
.
In May 2022, Pioneer Pharmaceuticals announced that its clinical trials for the treatment of severe or critical COVID patients (patients who developed a positive COVID after taking Paxlovid) showed that the virus cleared
after 7 to 12 days of treatment.
In the face of a huge market, even if the review is still very difficult, there are constantly companies that enter the game
.
On December 18, Simcere Pharmaceutical announced that the company cooperated with the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Wuhan Institute of Virology to cooperate with the anti-new coronavirus drug SIM0417
The Phase II/III clinical study has completed patient enrollment
.
.
Zhongsheng Pharmaceutical announced on December 28 that the company's RAY1216, a randomized, double-blind, placebo-controlled phase III clinical study protocol for the treatment of mild and common new crown infection patients, has obtained rapid review approval for clinical trials, and is currently conducting phase III clinical studies
.
Like Paxlovid, the drugs under study are also 3CL protease inhibitors
.
-04-
-04-Who will be approved next?
Who will be approved next?Compared with the domestic new crown oral drug stuck on the review, Pfizer and Merck have much better luck
.
In addition, the new crown oral drug of Shionogi Shiono, a well-known Japanese pharmaceutical company, was also trapped in clinical endpoints, and was finally approved for marketing in Japan in November 2022, and has submitted an application
to China's CDE.
to China's CDE.
The anti-new coronavirus oral drug Ensitrelvir developed by Hokkaido University and Shionogi in Japan is also a 3CL protease inhibitor
.
The approval of this drug in Japan has also been plagued
by the endpoint of clinical trials in the Omicron era.
As early as February 2022, Shionogi Pharmaceutical applied to the Japanese Ministry of Health, Labour and Welfare for approval with the results of the phase II trial, and subsequently submitted an emergency authorization application
.
However, the Ministry of Health, Labour and Welfare has always said that "more careful discussion is needed.
"
The problem is also with the clinical trial endpoint
.
.
The phase II trial showed a significant reduction in viral load reduction
in the treatment group compared to the placebo group.
However, in terms of clinical symptom improvement, the treatment group did not have a significant difference from the placebo group in the composite score of 12 related symptoms, and only improved the composite score
of respiratory tract and fever on 5 symptoms.
Shionoyoshi revised the primary endpoint in the phase III trial: improvement in five symptoms
: runny or stuffy nose, sore throat, cough, fever or fever, and fatigue (fatigue).
The trial showed that the disappearance time of five symptoms in the treatment group was shortened by 24 hours
compared with the placebo group.
By late November 2022, Ensitrelvir had finally received emergency use authorization approval from the Japan Medicines and Medical Devices Agency – and Japan's review criteria had changed
.
Previously, Shionogi had submitted the application materials
for this drug to China's CDE on a rolling basis.
However, according to the Shionogi approved by the Japanese review, there is only 5 symptoms improved, and there is still a certain suspense
to pass the clinical endpoint of more than ten symptom improvement of CDE.
to pass the clinical endpoint of more than ten symptom improvement of CDE.
If Shionogi finally passes the approval of CDE, does it mean that the review standards are relaxed, and will more domestic new crown oral drugs be approved in the future?
