On March 17, local time, the official website of the Geneva Medicines Patent Pool (MPP) announced that it had signed agreements with 35 companies to authorize them to produce generic versions of Pfizer’s oral new crown treatment drug nematevir, including 5 Chinese pharmaceutical companies, respectively. It is Shanghai Desano, Huahai Pharmaceutical (600521.SH), Puluo Pharmaceutical (000739.SZ), Fosun Pharmaceutical (600196.SH, 02196.HK), Jiuzhou Pharmaceutical (603456.SH), the top four One company produces naimatevir APIs and finished medicines, while Jiuzhou Pharmaceutical manufactures nematevir APIs.
These companies are licensed in 95 low- and middle-income countries such as India, Pakistan and Côte d’Ivoire, excluding China. Under the agreement, companies that have obtained generic production of raw materials and finished drugs of naimatevir will be able to simultaneously produce the combination packaging of naimatevir/ritonavir.
On March 18, Fosun Pharma, Huahai Pharmaceutical, etc. pointed out that the relevant products under this license need to complete the relevant technical handover before production, and the production facilities need to be approved by SRA or certified by WHO PQ. The production and sales of licensed products in the region are subject to the approval of the relevant competent authorities (including but not limited to marketing approval).
In terms of pricing, both Fosun Pharma and Huahai Pharma stated that according to the agreement, the company will supply the product according to the actual cost of the product (which can be verified through third-party audit) plus a reasonable price increase (to be determined). Given that this cooperation aims to help 95 low- and middle-income countries obtain the licensed product affordably, the price is expected to be lower than the original product or the price in high- and middle-income countries. As of now, the specific cost and pricing of the licensed product cannot be determined. .
It is also understood that at 22:30 on March 17, 21,200 boxes of the imported new coronavirus treatment drug “Nimatevir/ritonavir tablets” (Paxlovid) were inspected and released by the customs of Shanghai Waigaoqiao Free Trade Zone. All import customs clearance procedures are quickly shipped to the whole country. This is the first batch of imports of Paxlovid after it was included in the latest version of the new coronary pneumonia diagnosis and treatment plan.
The price is lower than the original drug price
MPP is a public welfare project that aims to supply special-needed medicines to low- and middle-income countries at more affordable prices, one of which is the oral medicine for COVID-19. Up to now, there are two new coronavirus oral small molecule specific drugs that have been approved for marketing in the world, namely Molnupiravir of Merck and Paxlovid of Pfizer.
In January of this year, MPP has announced the list of companies that are imitating the production of Molnupiravir by Merck. Fosun Pharma signed a sub-licensing agreement with MPP to manufacture and supply the oral drug Molnupiravir (MK-4482 and EIDD-2801) to 105 low- and middle-income countries or regions.
In addition to this MPP agreement, Pfizer and the above-mentioned 35 companies will provide 95 low- and middle-income countries around the world with affordable new crown oral drugs, which can cover about 53% of the world‘s total population.
Among the 35 companies, there are 5 Chinese companies, namely Shanghai Desano, Huahai Pharmaceutical, Puluo Pharmaceutical, Fosun Pharmaceutical, and Jiuzhou Pharmaceutical. Among them, Jiuzhou Pharmaceutical only produces APIs, and the other four can produce APIs and preparations at the same time. Fosun Pharma and Desano have obtained the “special imitation” rights of MSD and Pfizer’s new crown drugs.
On the morning of March 18, both Fosun Pharma and Huahai Pharmaceutical issued explanatory announcements. Both Fosun Pharma and Huahai Pharma stated that, based on the Pfizer-MPP agreement, MPP granted them the use of relevant patents and know-how to conduct research on “Nematavir” and the licensed product “Nematavir/ritonavir combination”. Production, in which the licensed product is a combination packaged oral small molecule new crown treatment drug, including the production of two antiviral drugs, namely nelmatevir and ritonavir, including the raw material (drug) and finished drug of nelmatevir (formulations), as well as the manufacture of the nematevir/ritonavir combination.
In terms of price, both parties stated that according to the agreement, supply will be based on actual cost (verifiable through third-party audit) plus reasonable markup (negotiated), given that this license is designed to help 95 low- and middle-income countries to obtain affordable access. For licensed products, the relevant pricing is expected to be lower than the price of the original product or in other middle- and high-income countries. At present, the specific cost and pricing of the licensed products under this license cannot be determined for the time being.
This MPP authorization is to promote the availability of oral new crown medicines in low- and middle-income countries, thereby helping local epidemic prevention and control. Previously, Pfizer also stated that during the epidemic, it will conduct tiered pricing according to the income level of each country and region.
According to public information, the price of Pfizer Paxlovid in the United States is: a 5-day course of treatment, the US government needs to pay about 530 US dollars (about 3367 yuan).
At present, many countries and regions around the world have approved Paxlovid for emergency use or temporary authorization, and have established Paxlovid orders with Pfizer. In November 2021 and January 2022, Pfizer and the U.S. government signed two supply agreements for 10 million courses of treatment respectively; it is expected that Pfizer’s Paxlovid supply will reach 120 million courses of treatment in 2022.
According to the official website of the State Drug Administration, Pfizer’s new coronavirus treatment drug Paxlovid has undergone emergency review and approval in accordance with the special drug approval procedure, and was approved for import registration with conditions on February 11. On March 9, Sinopharm signed a supply agreement with Pfizer, responsible for the commercial operation of Paxlovid in the Chinese market.
On March 15, the main points of the revision of the “New Coronary Virus Pneumonia Diagnosis and Treatment Program (Trial Ninth Edition)” issued by the National Health Commission showed that PF-07321332/ritonavir tablets (Paxlovid) approved by the State Food and Drug Administration New coronavirus drugs are included in the diagnosis and treatment plan.
In addition, according to the Hong Kong Special Administrative Region Government’s March 15 bulletin, the first batch of the new crown oral antiviral drug Paxlovid arrived in Hong Kong, China on March 14, and was sent to the Hospital Authority for use on March 15.
There are still many hurdles to go through in the listing
The 21st Century Business Herald reporter found out that the above five Chinese pharmaceutical companies all have overseas layouts, but their focus is different.
For example, the financial report released by Puluo Pharmaceuticals on March 10 shows that the foreign markets of its APIs are mainly distributed in Europe, Russia, North America, East Asia, Japan and South Korea, South Asia, India and Pakistan, Southeast Asia, South America and other regions. CDMO (Contract Research and Development Services) foreign markets are mainly distributed in North America, Europe, Japan and other countries and regions, with foreign customers accounting for 53%.
According to the 2020 annual report of Fosun Pharma, it has formed an overseas commercialization team of about 1,000 people, mainly covering the United States, Africa and Europe. In Africa, it has long-term business cooperation with public drug procurement centers in major countries and international drug procurement agency groups, covering 35 English, French and Portuguese-speaking countries and regions south of the Sahara Desert.
Huahai Pharmaceutical’s 2020 annual report shows that it has companies in the United States, Europe, Japan, and offices in India, Russia and other places. It can handle international GMP certification, international registration, international cooperation and other businesses. , WHO, Australia, Japan and other international mainstream markets have obtained official certification.
Although authorized, Chinese pharmaceutical companies still have a long way to go to imitate the production of Pfizer’s oral new crown drugs.
Zhou Chaoze, chief analyst of the pharmaceutical industry of Minsheng Securities, pointed out that the synthesis route of Paxlovid is complicated, and the synthesis of core intermediates SM1 and SM2 has certain barriers. Considering the time and equipment issues, the short-term supply of core intermediates may be insufficient, and the prices of SM1 and SM2 are high and gross profit margin is high. , especially the synthesis of SM1 involves -120℃ ultra-low temperature cryogenic reaction and cyanide reaction, which has high production qualification barriers and is also an important intermediate with bottlenecks in short-term supply.
In addition, this non-exclusive sublicense does not include the production of the drug ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, whose patent rights have expired, The drug does not require the permission of the original patentee, and the authorized enterprise needs to solve the supply of the drug ritonavir by itself.
If the product that the enterprise plans to apply for is a combination package of naimatevir and ritonavir, its marketing registration application must include two complete sets of registration information for naimatevir and ritonavir. On the basis of the license authorization of Pfizer’s nelmatevir, the license of the ritonavir (provided that it has passed the bioequivalence study and is approved for marketing) must also be obtained before the final submission of the combination package of nelmatevir and ritonavir. application for marketing authorization.
A senior person in the industry told the 21st Century Business Herald reporter that the original manufacturer of ritonavir is AbbVie, and it is not easy to copy the drug. Since the drug is a poorly soluble drug, it is difficult to obtain the same bioequivalence in humans as the original drug, and there are not many companies in the world that have imitated it and passed the bioequivalence study. According to information from the State Drug Administration, as of now, three companies have been approved to produce ritonavir, namely Desano Chemical Pharmaceuticals, Shanghai Xuankang Haimen Pharmaceuticals, and Wanquan Wante Pharmaceuticals; in addition, Lito of Ascletis Pharmaceuticals Navir tablets were approved for marketing by the China National Medical Products Administration in September 2021 (Drug Approval Number: Guoyao Zhunzi H20213698), and are the only ritonavir tablets approved for marketing through bioequivalence studies in China. On March 8, 2022, the marketing registration application for ritonavir tablets (generic drug registration classification: Category 4) submitted by Guangdong Sunshine Pharmaceuticals was undertaken by the Center for Drug Evaluation of the State Drug Administration.
China Medical Group previously announced that its affiliate Wanquan Pharmaceutical is the only company that owns both raw materials and preparations of ritonavir, and Microxin is the only approved ritonavir oral liquid in mainland China. In addition, Ascletis Pharma’s ritonavir tablets were approved for marketing by the China National Medical Products Administration in September 2021, and are the only ritonavir tablets approved for marketing through bioequivalence studies in China. For the above-mentioned companies that have obtained the imitation production of naimatevir/ritonavir combination packaging, how to solve the supply of ritonavir may face certain challenges.
To this end, Fosun Pharma and Huahai Pharma also emphasized in the announcement that the relevant products under this license still need to complete the relevant technical handover before production and the production facilities need to be approved by SRA or certified by WHOPQ. At the same time, the production and sales of licensed products in the region can only be implemented after approval by the relevant competent authorities (including but not limited to marketing approval). In addition, there is uncertainty as to whether the licensed product can obtain marketing approval from the local drug regulatory agency in the region, and the time to market in the region. As of now, the licensed products of the two companies have not yet had orders in hand and have not yet started formal production, so the impact on current and future performance is still unpredictable.
At the same time, public information on Pfizer’s new drug, nirmatrelvir, in combination therapies is relatively limited, and the manufacturer has had to wait for licensing and access to Pfizer’s original product. MPP executive director Charles Gore said there are unavoidable hurdles and complexities that will take time to resolve, including regulatory approval and proof that the Pfizer drug can retain its properties over time.
Fosun Pharma also pointed out that, globally, Pfizer’s combination packaged drugs of Nematevir Tablets/Ritonavir Tablets have obtained (mainly including) Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (U.S. FDA). ), conditional approval from the European Medicines Agency (EMA), emergency special approval from the Japanese Ministry of Health, Labour and Welfare, and emergency conditional approval from the State Drug Administration of China. However, clinical data for the licensed product are still limited, and unreported serious or unexpected adverse events may occur with the drug.
(Author: Zhu Ping Editor: Bao Fangming)