The first domestically produced small-molecule oral drug for COVID-19 is about to come out. What new opportunities are ushered in for the relevant industry chain?

Recently, the progress of domestic new crown small molecule oral drugs has been intensively disclosed, and drug research and development has ushered in a key node

On the evening of April 17, Junshi Bio released the latest research results of the new crown oral drug VV116: in the mouse model, the antiviral effect is significantly better than that of ribavirin, and it can alleviate the pathological damage of lung tissue

On April 6, Kintor Pharma announced the key data results of the Phase III global multicenter clinical trial of proclutamide in the treatment of non-hospitalized COVID-19 patients with mild to moderate symptoms

On April 2, the website of the Center for Drug Evaluation showed that Real Biology submitted an application for a Class III communication meeting, and the current status column has been changed from "Processing" to "Feedback"

The first domestically produced small-molecule oral drug for COVID-19 is about to come out, and it may be born in the above three drugs

Junshi - VV116

VV116 is a novel oral nucleoside anti-COVID-19 drug that can inhibit the replication of the new coronavirus

Preclinical studies have shown that VV116 exhibits significant anti-coronavirus effects both in vitro and in vivo.

Pioneering Pharmaceuticals - Prokalutamide

Kintor's proclutamide is an ACE2 and TMPRSS2 degrader, which has a good effect on the entire cycle of new crown infection (including early and middle and late stages)

On April 6, Kintor Pharma announced the final analysis results of the global multi-center Phase III clinical trial (NCT04870606) of its self-developed oral drug proclutamide for the treatment of mild to moderate diseases

The data show that proclutamide is effective in reducing hospitalization/mortality in patients with COVID-19 (mainly infected by Delta and Omicron variants), especially for all patients taking the drug for more than 7 days, and for middle-aged and elderly patients with high-risk factors.

As soon as the data came out, the share price of Kintor Pharmaceutical soared nearly 2 times in one day

Real Life - Azvudine

Azvudine is the new crown oral drug that has received the most public attention recently

On April 2, the three types of communication meeting for real biological applications

On April 16, at the China Medical Development Conference, Jiang Jiandong, a member of the Chinese Academy of Medical Sciences and academician of the Chinese Academy of Engineering, said when reporting on the research and development and progress of Azvudine in the treatment of new crown indications, Azvudine is a new type of nucleoside.

New crown small molecule oral drugs drive the development of domestic related industry chains

Globally, there are currently two new crown oral drugs that have been approved for marketing, namely Merck's Molnupiravir and Pfizer's Paxlovid

In November 2021, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) approved monupiravir for the treatment of adults with mild to moderate new coronary pneumonia, priced at $709 per course of treatment

Monupavir, developed by Merck in cooperation with Ridgeback Biotherapeutics, is an oral polymerase (RdRp) inhibitor
.
Monupavir can bind to the RNA polymerase of the new coronavirus and introduce wrong nucleotides into the newly synthesized RNA molecule, causing the virus's RNA to make mistakes and die
.

On December 22, 2021, the FDA granted an Emergency Use Authorization (EUA) for Pfizer's Paxlovid for the treatment of non-hospitalized adults with 2019-nCoV infection at high risk of developing severe disease
.
Paxlovid sells for $530 per session
.

Paxlovid is a compound preparation of 3CL protease inhibitor nirmatrelvir (PF-07321332) and ritonavir.
Nirmatrelvir can inhibit the replication of the new coronavirus protein, and ritonavir can slow down the decomposition of nirmatrelvir, so that the effective concentration in the body can be maintained for a longer time.
time
.

At present, Paxlovid has been completely introduced into China as a first-line drug for the treatment of patients with COVID-19
.
The introduction of new crown oral drugs has attracted much attention from related industry chain companies, mainly including CDMO companies, APIs, and intermediates
.

Benefit CDMO Enterprises

The first companies to benefit are CDMO companies that directly provide contracted custom R&D and production services for new crown oral drugs
.
Some domestic top small-molecule CDMO companies have already occupied an important position in the new crown industry chain with their strong capacity supply, cost advantages and delivery capabilities
.

On February 20, 2022, Asymchem announced that the company has recently signed a new batch of related products with customers in the process of continuing to provide contract custom development and production (CDMO) services for a small molecule chemical innovative drug of a pharmaceutical company.
The "Supply Contract", the contract value is equivalent to about 3.
542 billion yuan, and the supply time is 2022
.

On November 17, 2021, a small molecule drug supply contract equivalent to RMB 3.
1 billion was signed.
The contract supply time is from 2021 to 2022
.

On November 28, 2021, a new supply contract was signed, with a contract value equivalent to about 2.
72 billion yuan, and the delivery time is 2022
.

Coincidentally, Proton shares also announced a "mysterious big order" that month, indicating that it received a service order for a small molecule drug from a large pharmaceutical company in the United States
.
Proton shares will provide CDMO services for it, with a total order value of 681 million US dollars.
The announcement stated that the relevant purchase order is currently in effect, and the order delivery time is 2022
.

On November 30, 2021, Proton also issued a major order announcement
.
According to the announcement, the cumulative order value of the drug in the past 12 consecutive months has reached 217 million US dollars
.
The order is fully delivered in 2021-2022
.

Although both Boten and Asymchem have stated that it is inconvenient to disclose customer and product-related information because of the customer's trade secrets
.
However, combined with the pipeline layout and timing of small molecule drugs that can be seen in the industry, the market generally believes that these orders are related to Pfizer's Paxlovid
.
And Asymchem and Proton have had long-term cooperation with Pfizer before
.
However, the two companies did not respond more in-depth to this
.

In addition to CDMO companies, the second type of companies that benefit from the new crown oral drugs are the API industry chain companies
.
What is an API?

The broad API industry includes APIs and intermediates
.
API (Active Pharmaceutical Ingredient) in English
.
That is, the active ingredient of the drug is the basic substance that constitutes the pharmacological action of the drug.
The API cannot be directly used by the patient, and must be further processed into a preparation through the addition of excipients before the patient can take it
.
The intermediate is a material produced in the process steps of the API and must undergo further molecular changes or refining to become the API
.

Molnupiravir API Industry Chain

Molnupiravir (nucleoside inhibitor EIDD-2801/MK-4482) is an oral ribonucleoside drug jointly developed by Merck & Co and Ridgeback
.
On January 20, 2022, the Medicines Patent Pool (MPP) announced an agreement with 27 generic drug manufacturers to authorize the production of low-cost oral drug Molnupiravir for 105 low- and middle-income countries for free
.

(The full name of MPP is MedicinesPatent Pool, which is headquartered in Geneva.
It was established with the support of the United Nations, the international drug procurement agency UNITAID, and the Swiss Agency for Development and Cooperation (SDC).

The purpose of MPP was originally to promote and promote Popularization of high-priced new anti-AIDS drugs in developing countries
.

MPP itself does not produce and sell generic drugs.
He negotiated with the original pharmaceutical company for voluntary licensing of drug patents.
The original pharmaceutical company put its drug patents in the patent pool, and the generic drug company applied to MPP to obtain patents in the patent pool.
Licensing, production and supply of generic drugs to low- and middle-income countries
.
)

Five of the 27 companies are from China, including Fosun Pharma, Longze Pharmaceuticals (with Aidi Pharmaceuticals shares), Langhua Pharmaceuticals (Via Biotech Holdings), Borui Pharmaceuticals and Shanghai Desano Pharmaceuticals
.
Among them, Langhua Pharmaceutical is only authorized to produce APIs, and the other four can produce APIs and finished drugs at the same time
.

Uridine is the raw material for the production of EIDD-2801, which is the raw material for the production of Molnupiravir
.
Molnupiravir is a nucleoside analog, and suppliers of upstream API intermediates include Tuoxin Pharmaceutical and Tianyu
.

Paxlovid API Industry Chain

Paxlovid is made up of two main medicines, one is nirmatrelvir, which is designed to inhibit 3CL protease, thereby preventing virus replication; the other is ritonavir, which slows down nirmatrelvir to help it remain active in the body for longer at higher concentrations
.

On March 17, the MPP organization announced that it had signed agreements with 35 pharmaceutical companies to allow them to produce APIs and preparations for nematevir tablets, one of Paxlovid's ingredients
.
Among them, 5 Chinese companies were authorized, namely Shanghai Desano, Huahai Pharmaceutical, Puluo Pharmaceutical, Fosun Pharmaceutical, and Jiuzhou Pharmaceutical
.

According to the Baipe Health website, the combination of 300mg (150mg/tablet) of nirmatrelvir and one 100mg tablet of ritonavir is administered twice a day for 5 days
.
If Pfizer's forecast of 120 million courses of Paxlovid in 2022 is taken into account, that corresponds to the need for 360 tons of nirmatrelvir API
.

The upstream of Paxlovid mainly involves intermediates and APIs such as carronic anhydride, azabicyclo, SM1, SM2, and ritonavir
.
In terms of caron anhydride, the main manufacturers are Yaben Chemical and Jianfeng Group
.

In terms of SM1 and SM2, China's suppliers with sufficient supply capacity and sufficient production capacity include Minovar, Tianyu, Haichen Pharmaceutical, and Orient
.

In terms of ritonavir, Senxuan Pharmaceuticals, a subsidiary of domestic elite pharmaceutical companies, accounts for 70% of the market share of ritonavir intermediates, ranking first in the industry
.

Since the prevention and control of the new crown virus has been performed so far, vaccines alone cannot completely prevent the spread of the virus.
Oral specific drugs are the key to finally freeing people from the fear of new crown virus infection and the last piece of the puzzle to end the impact of the epidemic
.
As the new crown oral drugs gradually enter the commercialization stage from research and development, they will rapidly increase in volume under the catalysis of the epidemic, and the demand for intermediates and APIs will also show explosive growth, and the new crown industry chain is unprecedentedly hot
.
At the same time, many domestically produced new crown oral drugs keep pace with each other.
It is hoped that the leading pharmaceutical companies can withstand the many tests before listing and usher in the launch of the first domestically produced new crown oral drug as soon as possible
.

Reference source:

1.
Zhang, R.
, Zhang, Y.
, Zheng, W.
et al.
Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model.
Sig Transduct Target Ther 7, 123(2022).
https:// doi.
org/10.
1038/s41392-022-00963-7;

2.
"Nearly 9.
4 billion! New crown special medicine order, Aileying received a soft hand" Dandelion Ouryao;

3.
Zhang, R.
, Zhang, Y.
, Zheng, W.
et al.
Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model.
Sig Transduct Target Ther 7, 123(2022).
https:// doi.
org/10.
1038/s41392-022-00963-7.