text | Dun Yuting
Since the release of the "Ten National Regulations" on December 7, many cities across the country have experienced the first wave of the epidemic, and cold and antipyretic medicines were once out of stock. Now, the peak of severe cases is approaching, and oral drugs for COVID-19 are even more difficult to find. On this occasion, local pharmaceutical companies have launched a general offensive against new coronavirus drugs, taking advantage of this opportunity to quickly complete the clinical enrollment of patients and accelerate the launch of products.
Putting aside , new crown , in fact, it was difficult for us to see such a lively scene in the anti-virus field before. Especially as hepatitis C can be clinically cured and HIV has been brought under control, global investment in the research and development of antiviral drugs has continued to decrease in the past few years, and anti-HIV drugs and anti-hepatitis drugs are still the mainstay.
In terms of market size, global antiviral drugs have slowly declined after reaching a peak of US$61.4 billion in 2016. The market size in 2019 was US$56.4 billion, which is in sharp contrast to the US$100 billion scale of anti-tumor drugs. Is
antiviral a good track?
On the supply side, despite having experienced SARS, MERS, and Ebola before, there are still very few backup antiviral drugs for people to choose from. However, due to the increasing incidence of pandemic diseases caused by the spread of virus , in addition to the new crown, there is also the monkeypox virus that has been hotly discussed this year, RSV (respiratory syncytial virus) and influenza that are currently raging in Europe and the United States...all putting further pressure on the medical system. In the long term, as ecosystems become more fragile and populations move more frequently, viral infectious diseases may break out in stages, which will usher in new opportunities for antiviral drugs.
Image source: IC Photo
When faced with this "gap" between antiviral drugs and anti-tumor drugs, Tan Wenlong, a senior partner of Langmax Ventures who has worked in the hospital's tumor center, said that the real situation is not necessarily like this. He told 36氪 that tumors may be big, but due to medical insurance negotiations and centralized procurement, the scale of individual drug types is actually quite small. Taking some targeted drugs as an example, the number of patients covered by drugs for each indication (specific genetic mutations) is actually very small. "It would be good if it can reach tens of thousands." Moreover, tumor patients are special and their medication cycles are relatively short.
In the field of antiviral drugs, "If we bring the best overseas drugs to China and make them at Chinese prices, and there are enough patients in China, coupled with relatively low manufacturing costs, China will have a very big advantage."
It is reported that antiviral drugs can be divided into two major categories: small molecule drugs that interfere with virus replication and neutralizing antibodies that target viral capsid proteins. Because most small molecule drugs can be taken orally, are less prone to drug resistance and are priced relatively low, their market advantages are even more significant. "If a small molecule drug is used for CMC, 15 million to 20 million yuan is enough. For antibodies, 30 million to 40 million yuan is enough. Biological agents such as CGT are far more than that."
Nowadays, the field of antiviral drugs is also in full swing. Research and development: For different types of viral infectious diseases, in addition to traditional polymerase and protease inhibitors, there are also nucleic acid drugs, inhibitor , and host cell-targeting drugs. They are increasingly appearing in the R&D pipelines of major pharmaceutical companies.
Which will become the most promising antiviral drugs? Tan Wenlong said that some areas can be excluded first: areas where there is no breakthrough in technology, such as anti-AIDS , adenovirus , coxsackie virus and other drugs that have not yet had major breakthroughs in scientific research; existing technology has reached a very high level, such as anti-hepatitis C drugs, and patients can be cured. The remaining areas that have made significant progress in technology or scientific research, such as influenza, RSV, hepatitis B, etc., are many areas that are easily transmissible and highly pathogenic but "lack of drugs" or "lack of good drugs". They are worth exploring, and the market is also very clear. "It depends on whether scientists and companies can provide good solutions in these areas."
The market prospect of a single drug depends on multiple factors: First, it depends on the base of the patient population, mainly referring to epidemiological data ; Secondly, it depends on the dosage form and efficacy , "For example, the cost of injections will be much higher and the price is generally more expensive." A drug with good efficacy is worth a higher price, just like Mabaloxavir is to oseltamivir; Finally, see if there is a fast and economical detection method , "Take influenza as an example. The short course of the disease requires rapid identification, and the overall cost of diagnosis and treatment is weighed on people's minds, so the diagnostic cost cannot be too high." 36Kr learned that many companies at home and abroad are focusing on the development of respiratory tract multiple detection products, which may be able to meet this demand. Below
, this article attempts to conduct a simple inventory and analysis of market segment prospects, basic development logic, benchmark products, and innovative companies entering the market.
Seeking domestic super “flu medicine”
In 2018, the long article “ Middle-aged Beijing Under the Influenza ” that swept the social media screen once served as a popular science at the social level-influenza can kill. Influenza is mainly influenza A and B. Patients may develop complications such as pneumonia, bronchitis, sinusitis, etc., resulting in hospitalization or even death. It is a highly contagious "nationally legal infectious disease".
According to World Health Organization (WHO) estimates, seasonal influenza epidemics can cause more than 600,000 deaths globally every year, which is equivalent to one death from influenza every 48 seconds. A global influenza pandemic, such as the Spanish Flu of 1918, may even kill millions of people. The global annual influenza attack rate in adults is 5%-10%, and in children it is as high as about 20%. This means that during the high influenza season, one in 10 adults will be infected with influenza; one in 5 children will be infected with influenza.
In terms of innovative development in the field of influenza drugs, with the advent of a new generation of "flu miracle drug" - Mabaloxavir (jointly developed by Japan's Shionogi Pharmaceutical Company and Roche), it is the first new anti-influenza virus drug with a new mechanism of action in the past 20 years - by inhibiting The cap-dependent endonuclease of the influenza virus inhibits viral replication. The entire course of treatment only requires one dose, which can stop viral detoxification within 24 hours, shorten the infectious period and significantly reduce the duration of influenza symptoms. "One tablet is worth 10 oseltamivir tablets", which has been given high expectations.
Image source: IC Photo
With the above-mentioned obvious advantages in drug delivery and efficacy, especially in the context of the China-US trade war, it is currently difficult for China to obtain a new patent compulsory license for mapaloxavir like Tamiflu. China must rely on self-research. Entrepreneurs also see the hope of domestically produced "super flu drugs" and focus on this innovation that "only needs to be taken once".
In this direction, ZSP1273, a small molecule RNA polymerase inhibitor for the treatment of influenza A, is currently making rapid progress in China. It has entered Phase III clinical trials; there is also Qingfeng Pharmaceutical Ginkgo Pharmaceutical’s endonuclease inhibitor GP681, which has been registered for a Phase 3 trial in July this year Clinical trials ; Zhengxiang Pharmaceutical's RNA polymerase inhibitor ZX-7101A is also in the Phase II/III clinical stage - according to an investor, "some pharmaceutical companies are grabbing BD recently"; in addition, Andikang Biotech, which is developing a domestic influenza miracle drug that benchmarks Mabaloxavir, also entered Phase II/III clinical stage in October this year.
An Dikang Biotech CEOZhu Xiaoyun said in an interview with 36Kr that influenza drugs are important materials needed in the field of public health security and are of strategic significance; the available drug options for severe influenza worldwide are extremely limited; there is also an urgent clinical need for drugs that can reduce the scope and scale of influenza virus epidemics in society. "These are its core values." Hao Xiaolin, co-founder of
Zhengxiang Pharmaceuticals, said that the research and development cycle of new anti-influenza drugs is short, especially the clinical time is short. "It only takes one influenza season to complete" and can become the first variety to be commercialized.Tan Wenlong also said, "It may only take about a week from entry to exit for an influenza patient, and the longest will not exceed 14 days; but it will take at least a year for a tumor patient from entry to exit."
Moreover, in the field of influenza, in fact Oseltamivir (targeting neuraminidase), which has dominated the market for nearly 20 years, has already appeared in the field. Its original drug is Roche's "Tamiflu". In China, Dongguang Yang Pharmaceutical's "Kewei" sales even surpassed "Tamiflu", becoming the "magic flu drug". It is reported that in 2019 alone, with the help of oseltamivir, Dongguang Pharmaceutical’s revenue reached 5.93 billion yuan, accounting for 95% of the company’s total revenue.
Tan Wenlong believes that in the field of influenza and new drug mechanisms, popular influenza drug products like "Kewei" will appear in China, especially with the effect of "preventing infection." Of course, the entry threshold for anti-influenza drugs is not low, especially the safety inspection requirements. This also means that in addition to target discovery, it is very difficult for companies to innovatively design and transform molecular structures. "Many anti-tumor drugs can be marketed even if they cause hematological toxicity; but if they are drugs in the non-tumor field, if there are safety incidents such as a decrease in white blood cells after taking them, they will definitely be killed."
RSV infection with "no drug available"?
In the past month, the United States has encountered a "triple epidemic" - COVID-19, influenza, and respiratory syncytial virus (RSV), which has caused millions of people to become sick. The domestic supply of cold medicines in the United States exceeds demand, hospital emergency rooms are overcrowded, and the national medical system is overwhelmed. Among them, it goes without saying that the excitement of new coronavirus drugs, from the earliest Remdesivir, to Molnupiravir, to Nematvir/Ritonavir tablets (Paxlovid), the anti-epidemic battlefield is almost crowded with players; there are also specific drugs for influenza, but only RSV is "incurable" .
It is understood that RSV is a common RNA respiratory virus that spreads through the air. It enters the trachea and lungs through the mouth and nose, invades epithelial cells, causes airway damage, secretes respiratory mucus, blocks the lumen, and causes breathing difficulties. Common symptoms of RSV infection are runny nose, fever, cough and wheezing. In severe cases, it can cause respiratory distress and even blockage of the airway, leading to respiratory failure and even death.
Aike Baifa CEO Wu Zheng pointed out at the Qiming Venture Capital CEO Cloud Summit held today that in the post-epidemic era when society is reopened, RSV may explode together with the new coronavirus and influenza; and once RSV is infected, it will cause greater harm to vulnerable groups such as the "old and the young" and immunodeficiency .
According to statistics, in 2020, the number of severe RSV infections in children under 5 years old worldwide reached approximately 34 million, including approximately 3 million in China; the number of severe RSV infections in elderly people over 65 years old worldwide reached approximately 4.9 million, including approximately 1.2 million in China. WHO estimates that 160,000 children worldwide die from RSV infection every year, making it an important cause of childhood death . The elderly and people with chronic lung disease are also more likely to develop severe illness or even death after being infected with RSV.
Image source: IC Photo
However, there is currently no effective treatment for RSV in the world. The only RSV preventive drug, palivizumab (AstraZeneca Synagis), has not been approved in China and is mainly used for high-risk children and can only be used preventively. Even so, its sales peaked at $1.6 billion over the past decade. It can be said that among patients with RSV infection, especially children, there are still high unmet medical needs and there are also great "business opportunities" .
However, drug design and clinical trials for children are quite challenging, which makes the development of RSV treatment drugs difficult, and there are not many domestic entrants.
On the drug supply side, AK0529 (drug name: Elsevir®), an innovative anti-RSV drug from Ark, has recently submitted a marketing application in China. It has been included in the "priority review and approval" process and is expected to become the world's first anti-RSV small molecule therapeutic drug.
In addition, Shandong Danhong Pharmaceutical and Xianweida have entered the market. However, in June last year, Danhong Pharmaceutical’s RSV infection treatment drug BC0335 granules was ordered by the State Food and Drug Administration to suspend the Phase I clinical trial due to serious adverse reactions. In July last year, Xianweida disclosed that its XW001 inhalation solution, a broad-spectrum antiviral drug with anti-RSV efficacy, had good results in domestic Phase I clinical trials, but the current progress is unknown; Andikang Biotech also has a pipeline layout here.
Overseas, Johnson & Johnson and Pfizer (purchased from ReViral for US$520 million) are developing RSV fusion protein inhibitors with therapeutic effects on RSV virus infection. Among them, Johnson & Johnson's JNJ-678 has progressed to clinical phase III and has obtained breakthrough therapy designation from NMPA and FDA; Pfizer's RV521 has entered clinical phase II.
But a basic common sense in the field of infectious diseases is that prevention is far better than cure. Therefore, in the field of anti-RSV, more companies are focusing on prevention, especially the company that develops vaccine .
Aike Baifa has recently introduced another preclinical RSV antibody drug from the Institute of Microbiology of the Chinese Academy of Sciences for the prevention of RSV infection; TechnoMab Biotech's core product long-acting recombinant RSV antibody TNM001 is also intended to be used to prevent RSV infection in premature infants and infants. There are countless vaccine companies (see the figure below for details).
RSV vaccine company inventory (compiled by Guosen Securities Economic Research Institute)
In terms of domestic vaccine development, ADV110, the RSV vaccine product under development, is targeted at children 6 months to 5 years old and the elderly over 65 years old. It is currently in the Phase II clinical stage; Watson Bio Blue Que Bio's RSV mRNA vaccine, Zhifei Green Bamboo RSV combination vaccine, and CSPC RSV vaccine are in the preclinical stage. Overall, the patient base is huge, few people are joining the market, and it is still in the early stages of research and development, so there is still a certain window of opportunity.
