Source 丨21 Healthnews21 original work
Author 丨Ji Yuanyuan
Editor 丨Xu Xu
Picture | figure worm
Recently, new crown oral drugs have become the focus, and the research and development of domestic new crown oral drugs has received widespread attention.
On February 13, Hong Kong-listed company Celees pharma announced that it had submitted an application for marketing authorization for ritonavir (100 mg film-coated tablets) to Germany, France, Ireland and the United Kingdom through its European agents. Ritonavir listing authorization applications in other countries in Europe, North America and Asia Pacific are also expected to be submitted in the near future. Oral ritonavir tablets are pharmacokinetic enhancers of multiple oral antiviral drugs against viral proteases and are one of the components of Pfizer oral antiviral Paxlovid (combination packaging of nematvir tablets + ritonavir tablets).
At present, according to the incomplete statistics of the 21st Century Business Herald reporter, the domestic layout of new crown oral small molecule drugs enterprises mainly include Pioneering Pharmaceutical, Junshi Biological/Wangshan Wangshui, Real Biology, Simcere Pharmaceutical, Guangshengtang Pharmaceutical, Andey Pharmaceutical, etc. Among them, Junshi Bio/Wangshan Wangshui new crown oral drug VV116 has been authorized for emergency use in Uzbekistan; real bio Azvudine is currently carrying out Phase III clinical trials in China, Brazil and Russia.
On February 12, according to Junshi Biology, VV116 has completed all 3 Phase I clinical trials in China, and the results may be published through the article within 2 weeks. Previously, the market expected VV116 to submit a listing application in the second half of 2022.
"COVID-19 vaccine + specific drugs" is considered to be the best combination of prevention and control to end the global pandemic. At present, the new crown vaccine has achieved great success and played a huge role in the world, while the new crown oral drug has yet to be applied on a large scale.
According to the analysis of Southwest Securities, the listing of new crown oral drugs is expected to make the treatment of new crown as convenient as the treatment of influenza, and the popularity of new crown oral drugs will be significantly higher than that of injectable drugs. It is also based on the large number of new crown oral drug layouts, and the global new crown oral drug market size is expected to be billions to tens of billions of dollars.
The research and development of domestic new crown oral drugs has been promoted in an orderly manner
Previously, the fastest progress in the research and development of new crown oral small molecule drugs by domestic enterprises was to develop the pharmaceutical industry.
As early as July 16, 2021, Pioneering Pharmaceuticals announced that paraguay's Ministry of Public Health and Social Welfare (MSPBS) had granted an emergency use authorization (EUA) for the treatment of hospitalized patients with covid-19. However, a Phase III clinical trial of pkrutamine in the United States suffered a major setback. On December 27 last year, Pioneering Pharmaceutical issued an announcement announcing the progress of the phase III clinical trial of the research new crown treatment drug pkrutamine for non-hospitalized patients with mild and moderate covid-19, saying that according to the interim analysis data of 348 new crown patients, the company plans to adjust the clinical trial plan for patient recruitment due to the small number of events that have not reached statistical significance.
According to the public information disclosed by pioneering pharmaceuticals, this randomized, double-blind, placebo-controlled, global multicenter Phase III clinical trial aims to explore the efficacy and safety of pruneutamine in the treatment of mild and moderate disease in men with new crown. Nearly 200 participants have been enrolled in the trial in countries such as Brazil, the Philippines and Malaysia. China is one of the main participants in this Phase III clinical trial, which was approved by the State Drug Administration on September 1, 2021. The centers participating in the clinical research include Beijing Ditan Hospital, China-Japan Friendship Hospital, Shenzhen Third People's Hospital, Shanghai Public Health Clinical Center, Hangzhou Xixi Hospital, Chengdu Public Health Clinical Center and Suzhou Fifth People's Hospital.
As for the effectiveness of pkrutamine for a mutated strain in the context of the Omicron epidemic, the relevant person in the pioneering pharmaceutical industry said in an interview with the 21st Century Business Herald reporter that we are asking an academician in the United States to help us do experiments, and we are still waiting for data. "Judging from the approval of the new crown oral drug, it is also good for our small molecule new crown drug research and development, and we are also actively accelerating the domestic clinical progress and including more clinical centers to promote the clinical process." the person concerned said.
Also following the disclosure of the latest developments in pkrutamine, Golee Pharmaceuticals announced that it had submitted a marketing authorization application for ritonavir (100 mg film-coated tablets) to Germany, France, Ireland and the United Kingdom through its European agents.
Cerley Pharma's ritonavir is a pharmacokinetic enhancer of multiple oral antivirals against viral proteases, originally researched by AbbVie, and low-dose ritonavir (100 mg) is one of the components of Pfizer's COVID-19 oral drug Paxlovid (Nirmatrelvir + ritonavir). In September 2021, the oral tablets of ritonavir, first imitated by Golebi Pharmaceuticals, were approved for marketing by the State Food and Drug Administration for the treatment of AIDS. On January 3, 2022, Golee Pharmaceuticals announced that the annual production capacity of ritonavir oral tablets has been expanded to 100 million tablets, and it can be further expanded rapidly according to market demand in the future. On January 19, 2022, Cerley signed a purchase agreement with Phonam Pharmaceutical Import-Export Co., Ltd. in Laos.
As for Its part, Cerise Pharmaceuticals said that the company continues to negotiate cooperation between domestic and international companies on the commercial supply of ritonavir in China and around the world. According to a January 3 announcement by Gorese, it also has two candidates for COVID-19: the oral polymerase (RdRp) inhibitor ASC10 and the oral protease (3CLpro) inhibitor ASC11.
ASC10 is a candidate drug fully independently developed by Clarion, and it is planned to submit clinical trial applications to China, the United States and other countries in the first half of 2022. ASC11 will be used in combination with marketed ritonavir oral tablets to treat novel coronavirus infection. It is planned to submit clinical trial applications to China, the United States and other countries in the second half of 2022.
Systematic layout of domestic new crown oral medicines
In addition to pioneering pharmaceuticals and Geli Pharmaceuticals, Junshi Bio and Wangshan Wangshui Bio have cooperated to develop two new crown oral drugs VV116 and VV993.
On January 26, Junshi Biotech announced that it has reached a cooperation with Wangshan Wangshui to jointly undertake the research, production and commercialization of VV993, an oral anti-coronavirus candidate new drug targeting 3CL protease, in addition to Uzbekistan, Kyrgyzstan, Kazakhstan, Turkmenistan and Tajikistan (five Central Asian countries). 3CL protease (3C-likeprotease, 3CLpro) is an indispensable proteolytic enzyme in the replication process of the new crown virus, and its amino acid sequence has hardly changed in the multiple new coronavirus variants that have emerged so far, which is an important target for the development of highly conservative anti-virus drugs.
On February 12, Dr. Li Ning, CEO of Junshi Biotech, introduced at the company's conference call that VV116 has completed all 3 Phase I clinical trials in China, and the results may be published through the article within 2 weeks. The safety of the drug is very good, no adverse reactions of grade 2 or above have been seen, and international multicenter Phase II/III clinical trials are underway. It is planned to enroll 1800-2000 patients, 2-3 months to complete the enrollment, because many countries in the world under the epidemic already have a considerable patient reserve, so the patient enrollment speed will be relatively fast. In contrast, because there are relatively few patients in China, they will try to enroll as many groups as possible. Junshi Bio and CDE have communicated that the results of overseas data can support domestic declaration, while the research focus of VV116 will be overseas, and the US IND is also actively communicating, and will be declared in the near future.
"Clinical trials of VV116 are based on who and individual country-specific definitions of severity. The programme has been approved by the CDE and various national regulatory authorities. Another Phase 3 is an international multicentre clinical study of moderate to severe patients based on the positive results of 450 moderate to severe clinical studies in Uzbekistan, expanding the sample size to 650 cases for moderate and severe diseases. The sample size for the entire Phase 3 was around 2600. For the design scheme of VV116 clinical trials, Dr. Li Ning introduced.
Zheshang Securities said in the research report that Junshi Bio VV116 is optimized and designed according to the parent nucleoside structure metabolized by remdesivir in the human body, prolonging the metabolic time in vivo through the isotopic effect brought by deuterium generation, and adding multiple hydroxyl groups to enhance the water solubility of the drug, thereby improving oral bioavailability, and it is expected to obtain a better clinical treatment effect than remdesivir.
According to Minsheng Securities, the listing and stable supply of domestic new crown oral drugs are expected to drive the prosperity of the upstream API industry chain. VV116 is the world's third and first domestic emergency use authorization of the new crown oral drug, the future of the domestic approval of the market is more likely, and other domestic drugs with the same mechanism as Pfizer are currently in a preclinical state. In addition, the new crown treatment will still drive a lot of peripheral demand, such as the application of symptomatic treatment drugs such as hormones.
According to the 21st Century Business Herald reporter, VV116 and VV993 are drugs or drug candidates developed for different key and conservative targets of the virus life cycle, in addition to being used alone to exert their respective clinical advantages or characteristics, they also have the development prospect of "combined drug antiviral, complementary efficacy".
For the issue of production capacity, Dr. Li Ning said that VV116 has basically been satisfactorily solved under the coordination of multiple departments in the country. Two CDMO production bases have reached a cooperation plan with us, and the necessary large-scale production capacity layout will be completed by the end of March, and 2 CDMO are in line with the US GMP standard. According to the preclinical studies of partners, 3CL and VV116 have broad prospects for combination and monotherapy, not only for COVID-19, but also for other indications. It is not only necessary to establish a new crown product system, but also to accumulate reserves for the pipeline system of anti-virus products behind it. Preclinical and indications for extended studies are actively conducted.