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In the past year, the popularity of domestic new crown oral drugs was almost entirely supported by the concept of 3CL protease inhibitors
.
Clear drug mechanism, this road is feasible is the premise; Pfizer's success makes expectations visible
.
In these two points, 3CL protease inhibitors have unrivaled logic
.
However, the antiviral pathway of small molecule drugs is not only 3CL protease
.
From a mechanism point of view, it is potentially possible
to interfere with replication-related host factors, inhibit the production of new viral particles, inhibit virus-encoded enzymes, or prevent viruses from entering host cells.
Some of the correct answers have already been written, such as the RdRp (RNA-dependent RNA polymerase) pathway
.
As the first FDA-approved small molecule drug, the success of remdesivir has confirmed the feasibility
of this pathway.
It's just that remdesivir, which is used as an injection, gave up the C position to the latecomer Paxlovid
because of the disadvantage of compliance.
At present, a small number of risk-takers are trying to justify remdesivir by "taking risks": they hope to get multiple upgrades of oral drugs such as efficacy and compliance through innovative upgrades to stand on the center
stage.
This is a challenging direction, and it has great uncertainty
.
But fortunately, some adventurers have already walked through the hurdles and are getting closer
and closer to "going ashore".
On December 28, Junshi published the clinical data
of VV116 head-to-head PAXLOVID in the New England Journal of Medicine, a top medical journal.
The results show:
The efficacy of VV116 is not inferior to PAXLOVID, and the safety is more dominant
.
This may also indicate that the battle for new crown oral drugs is evolving
towards the situation of "bipolar hegemony".
/ 01 /
/ 01 /A path that cannot be ignored
A path that cannot be ignoredFrom the beginning, the medical community believed that RdRp was a promising target
against the new coronavirus.
There are many reasons, and the clear mechanism of action and the highly conservative characteristics of RdRp are the core
.
In terms of mechanism of action, RdRp is a key enzyme for the replication and transcription of genetic material of RNA viruses, and its loss of function means that it is difficult for viruses to "reproduce"
.
Therefore, RdRp is considered one of the most promising targets against RNA viruses, and the new coronavirus is no exception
.
At the same time, RdRp is more "conservative" than imagined, not to mention that different strains of the new coronavirus, even different types of RNA viruses, have shown similar binding sites
.
For example, the structure of RdRp in the new coronavirus and the SARS virus is 96%
similar.
This feature can bring two potential benefits
to drug development.
On the one hand, an effective RdRp inhibitor is not afraid of new coronavirus mutations
.
You also know that the biggest feature of the new crown virus is that it continues to mutate;
On the other hand, old drugs may be able to be used in new ways, shortening the research and development process
.
Referring to the past history, many RdRp inhibitors have certain pan-strike capabilities
.
That's true
.
Remdesivir, who was the first to enter the public eye, is a "veteran"
who turned around.
10 years ago, remdesivir was hoped to be used against Ebola; But since 2020, with the advancement of many studies, people have gradually found that remdesivir is a "sharp blade"
against the new crown virus.
As an RdRp inhibitor, remdesivir acts like a "terminator":
During the replication process with the viral genetic material chain, it introduces a component NTP that stops viral replication, and this erroneous component competes with ATP to bind RdRp and inhibits RdRp enzyme activity to terminate the viral replication process
.
On December 26, 2021, the New England Journal of Medicine published clinical data showing that remdesivir reduced the risk of hospitalization or death by 87%
compared with placebo in symptomatic and unhospitalized COVID patients at high risk of disease progression.
For the same group, Paxlovid is recognized as the best in the world, with a figure of 89%.
In the case of non-head-to-head studies, remdesivir and Paxlovid showed a close match
.
This may be unexpected
.
In fact, in the subsequent confrontation with the Obikron strain, remdesivir seems to perform better
.
As shown in the figure below, according to the in vitro test IC50 data, remdesivir activity is minimally affected against multiple Mysterious Keron
strains.
strains.
In view of its outstanding anti-coronavirus capabilities, as early as May 1, 2020, remdesivir received FDA emergency use authorization for the treatment of critically ill hospitalized patients, and was subsequently extended to non-severe patients
.
On October 22, 2020, the FDA approved remdesivir for marketing, making it the first drug officially approved for the treatment of the new crown, which shows its status
.
/ 02 /
/ 02 /The direction in which the army is prominent
The direction in which the army is prominentHowever, the battle of new crown oral drugs is not only a competition of efficacy, but also involves a confrontation of comprehensive dimensions such as safety and
accessibility.
Remdesivir, which requires intravenous injection, is at a disadvantage in terms of accessibility
.
Remdesivir requires outpatient administration for 3 consecutive days of infusion
.
Although this is shorter than the course of treatment for hospitalized patients, remdesivir is much
more cumbersome than oral medications.
Therefore, compared with Pfizer's Paxlovid, remdesivir is the first to break through but its "presence" is not high, and its popularity is not even as good as its own Molnupiravir
.
However, this does not mean that remdesivir cannot fight
back.
Although remdesivir is not suitable as an oral drug, its metabolite in humans, the parent nucleoside (GS-441524), has "oral" potential and has better antiviral capacity
.
This means that by modifying GS-441524, remdesivir has the possibility
of "upgrading".
This process is not easy, but given the success of remdesivir, there are still a few strong institutions around the world to tackle tough problems
.
Gilead is one of them, which has developed an oral version of remdesivir GS-5245 to deliver GS-441524
to human cells.
At present, GS-5245 has entered phase III clinical trials and has obtained fast-track qualification
from the FDA.
Domestic enterprises have also not been left behind
.
Junshi Biologics' VV116 is also based on GS-441524, and "blue is better than blue"
.
Compared with remdesivir, VV116 has two potential advantages
while having oral advantages.
First, stronger anti-virus ability
.
As shown in the figure below, half of the maximum effective concentration (EC50) of VV116 and its metabolite (X1) is about 1/5 of remdesivir, even lower than GS-441524
.
.
The so-called EC50 refers to the concentration of the drug that can produce a maximum effect of 50%, and the lower the value, the better
the effect.
That is, VV116 has higher activity, stronger inhibition
.
Second, VV116 is more targeted
.
Remdesivir was originally designed to enhance antiviral activity
against hepatitis C virus.
Therefore, remdesivir has liver-targeted properties
.
However, the lungs of new crown patients are the most affected organs, and the efficacy of remdesivir, which has a slight deviation in the profession, may be "discounted"
.
.
In contrast, VV116 is specifically designed to fight the new coronavirus and is more targeted
.
Experiments in mice have shown that VV116 metabolite X1 is widely distributed in intestine, lung, kidney, liver, heart, brain and other tissues, most of which are the preferred targets for new coronavirus infection
.
This feature of VV116 will bring potential advantages
to its treatment of new crown infection.
More and more powerful players are gathering, a number of blockbuster clinical trials have also been on the road, and the door of oral RdRp inhibitors to the anti-epidemic market has long been pried open
.
Through the gap, many contestants can already see the scenery outside the door, but it seems that there is still something
short of stepping out of the door.
/ 03 /
/ 03 /Build a wall against the epidemic together
Build a wall against the epidemic togetherIn the eyes of many people in the industry, oral RdRp inhibitors are always short of a good enough data
to become the anti-epidemic responsibility.
Although a group of pioneers have disclosed the corresponding clinical data, they have not been able to tear off the "pending verification" label
.
The world's first new crown oral drug Molnupiravir opened high and low, with a final effectiveness of only 30%, and there is a mutagenic possibility; The domestic new crown oral drug Azvudine, which was the first to hit the line, has also been slow to produce data to prove itself, and the genetic and reproductive toxicity problems in animal experiments are also worrying
.
No one denies the potential of oral RdRp inhibitors, but the precursor data is not ideal and does not impress everyone
.
Fortunately, Junshi Biologics' VV116 finally brought good news
.
ON DECEMBER 28, JUNSHI PUBLISHED CLINICAL DATA
FOR VV116 HEAD-TO-HEAD PAXLOVID IN NEJM JOURNALS.
Results showed VV116 for adult patients with mild to moderate Covid-19 who were at high risk of progression to severe disease
The time to sustained clinical recovery in the treatment group was not inferior to Paxlovid
.
.
Specifically, the recovery time was shorter in the VV116 group, with a median symptom recovery time of 4 days, and the Paxlovid group had a symptom recovery time of 5 days
.
.
In terms of safety, VV116 has certain advantages
.
The incidence of AE was lower in the VV116 group than in the Paxlovid group (any grade of AE: 67.
4% vs.
77.
3%, Level 3 or 4 AE: 2.
6% vs.
5.
7%)
.
Higher safety and not inferior efficacy doom VV116 has the potential to join hands with Paxlovid to build an epidemic prevention wall
.
At present, Paxlovid is not enough
for the global pioneer in the fight against the epidemic.
The reason is that not all patient groups that fit the profile are suitable for Paxlovid
.
Ritonavine, one of Paxlovid's components, is metabolized by the CYP3A4 enzyme in the liver and interacts with numerous drugs, which in turn affects each other's efficacy
.
Paxlovid is more targeted at elderly
people with a variety of chronic diseases.
Many of the interacting drugs are many drugs that the elderly usually eat (including antihypertensive drugs, lipid-lowering drugs, etc.
).
Obviously, Paxlovid is very inconvenient
for some patients who cannot stop the basic medication.
VV116, on the other hand, does not inhibit or induce major drug-metabolizing enzymes or inhibit major drug transporters, so it is less
likely to interact with concomitant drugs.
This also means that the VV116 has the ability to reach people who are difficult to reach in Paxlovid
.
From remdesivir to VV116, the latest research data published in the top journal New England Journal of Medicine seems to be a legacy:
The former points the way for the development of RdRp inhibitors, while the latter injects confidence
into the development of oral formulations of this technology route.
On December 30, the Food and Drug Administration conditionally approved the listing of Merck's Molnupiravir, which further demonstrates the ability of oral RdRp inhibitors to contribute more to the "fight against the epidemic
".
With the disclosure of more and more clinical data of VV116, it will also bring strong support
for its domestic and even global listing.
This should be news to look forward to for people looking forward to oral RdRp inhibitors
.
