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This article comes from WeChat WeChat official account:With freehand brushwork biotech (Biotech(ID：TXYBiotech), Author: Yang Yi, original title: "Anti-influenza drugs and market analysis", title map from: vision china.

The ugly SARS-CoV-19 has not been completely conquered by human beings, and the lingering influenza virus has begun to wreak havoc again. The struggle between human beings and viruses is like this."Scientific Progress-Virus Variation and Drug Resistance"It spirals up in this cycle. The periodic spread of seasonal influenza virus makes the importance of anti-influenza drug development stand out again.

Oseltamivir, which went on the market 24 years ago, is still the mainstay of anti-influenza drugs. Although the first new drug, Baloshavir, enriched the team of anti-influenza drugs, it went on the market five years ago. After learning the cruelty of SARS-CoV-19 virus, people need to make a breakthrough in the development of influenza drugs.

I. Classification of seasonal influenza

Seasonal influenza（Seasonal influenza）It is an acute respiratory infectious disease caused by influenza virus prevalent all over the world. There are four types of seasonal influenza viruses, A, B, C and D.(Chinese corresponds to influenza A, B, C and D). Influenza A and B viruses spread and cause seasonal epidemics.（seasonal epidemics）.

According to the hemagglutinin on the surface of the virus（HA， hemagglutinin）And neuraminidase（NA， neuraminidase）The combination of influenza A virus is further divided into different subtypes. At present, subtype A is transmitted among humans.（H1N1）And a（H3N2）Influenza virus. A（H1N1）Influenza virus is also written as A.（H1N1）Pdm09, because it caused a pandemic in 2009, replaced the seasonal influenza A spread before 2009.（H1N1）Viruses.

Only influenza A virus is known to cause a pandemic at present. Influenza B virus is not classified into subtypes, but can be classified into lineages. The currently popular influenza B virus belongs to B/Yamagata or B/Victoria pedigree. The detection frequency of influenza C virus is low, which usually causes mild infection, so it is not of public health importance. Influenza D virus mainly affects cattle and does not infect or cause human diseases.^[1]

Second, influenza treatment

Seasonal flu patients without complications, if they have symptoms, stay at home and do their bit to reduce the spread of the virus. By means of self-monitoring, we can decide whether to seek medical treatment.

Patients suffering from serious or progressive clinical diseases related to influenza, that is, pneumonia, septicemia or clinical syndrome aggravated by chronic basic diseases, should receive antiviral drugs as soon as possible. The most common anti-influenza drugs are neuraminidase inhibitors.（Neuraminidase inhibitors）Oseltamivir（oseltamivir）. Ideally, it should be taken within 48 hours of symptoms to maximize the curative effect. It is recommended to treat for at least 5 days, but it can be extended until the clinical improvement is satisfactory.

It should be noted that corticosteroids should not be used for influenza.(corticosteroid, such as prednisone, cortisone, hydrocortisone, etc.)Unless there are other reasons.(e.g. asthma and other specific conditions)Because corticosteroids may lead to prolonged virus clearance time and double infection of bacteria or fungi caused by immunosuppression.

At present, all popular influenza viruses are resistant to adamantane antiviral drugs.(Adamantane antivirals, such as amantadine and rimantadine)Because of their drug resistance, these drugs are not recommended for monotherapy.^[1]

Third, anti-influenza drugs

The main anti-influenza drugs are divided into adamantane, neuraminidase inhibitors and polymerase inhibitors.(Table 1).^[2]There are four kinds of anti-influenza drugs approved by FDA recommended by the Centers for Disease Control and Prevention: Rapivab. （peramivir），Relenza（zanamivir），Tamiflu （oseltamivir phosphate）And Xofluza（baloxavir marboxil）.^[3]

Table 1. Antiinfluenza drugs

1. Neuraminidase inhibitors（Neuraminidase inhibitors）　

Neuraminidase inhibitor（NAI）Targeted neuraminidase（NA）Glycoprotein, which is second only to hemagglutinin in human body.（HA）The most abundant surface glycoprotein. Neuraminidase inhibitors can achieve antiviral effect by inhibiting the emergence of new virus particles in host cells and preventing the enzyme activity necessary for virus transmission.^[4]

The four most common neuraminidase inhibitors are oseltamivir, zanamivir, peramivir and laninamivir.(Figure 1).

Fig. 1. Common neuraminidase inhibitors and their molecular structures.

Although their structures are similar, there are obvious differences in treatment schemes, routes of administration and drug resistance. The most widely used neuraminidase inhibitor is oseltamivir.(Trade name: Tamiflu)The treatment plan for adults is 75mg twice a day for 5 days. Due to zanamivir(trade name Relenza)The oral bioavailability of is low.（<5%）Therefore, it is approved as an inhalation drug, 5mg each time, twice a day for 5 days.

In 2019, intravenous zanamivir(trade name Dectova)Authorized by the European Union to be used under special circumstances.(e.g. in case of resistance to other anti-influenza drugs). Efforts to increase bioavailability and half-life have led to peramivir.(Trade name: Rapivab/Rapiacta/PeramiFlu)Development of, by intravenous infusion with a single dose of 600mg; And ranimivir (trade name Inavir), a more persistent neuraminidase inhibitor, showed therapeutic effect after a single nasal inhalation dose.^[5] Paramivir and Ranimivir are allowed to be used in a few countries around the world, while oseltamivir and zanamivir are more widely approved geographically.

Different neuraminidase inhibitors show different efficacy, which mainly depends on the subtype/pedigree of influenza virus that infects patients.For example, oseltamivir versus A（H1N1）, a（H3N2）And the seasonal uncomplicated influenza caused by influenza A and B virus is more effective. However, the effect of antiviral therapy may be limited by the resistance of influenza virus to neuraminidase inhibitors. Different neuraminidase inhibitors have different drug resistance.

In view of the drug resistance of common neuraminidase inhibitors, people are now focusing on emerging drugs in research. At least two new neuraminidase inhibitors and one neuraminidase blocker are in the first and second development stages.

HNC042(Guangzhou Hengnuokang Pharmaceutical Technology Co., Ltd. and Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd.)In preclinical studies, it showed effective inhibitory activity against wild-type and oseltamivir-resistant NA-H274Y virus. HNC042 showed good safety, tolerability and linear pharmacokinetics in phase I trials in the United States.Learning (NCT04603989). HNC042 is used to prevent and treat influenza, especially for critically ill patients who need hospitalization.

AV5080(ChemRar, Russia, Viriom, USA, Figure 2)The preclinical evaluation revealed the activity against a variety of influenza viruses, including oseltamivir-resistant strains. Oral AV5080 shows good physicochemical and metabolic characteristics and good pharmacokinetic characteristics in animals.^[6]

Fig. 2. chemical structure of a new neuraminidase inhibitor drug candidate AV5080.

CD388 (Cidora Therapeutics Inc., USA)It is a long-acting neuraminidase blocker, and its structure is obtained by coupling neuraminidase of influenza virus to human antibody fragment.(Fc）Proprietary variants of the domain, so as to achieve two completely different and complementary mechanisms.(Figure 3). This new method of preventing and treating virus infection is expected to provide universal protection throughout the flu season. By targeting highly conserved virus areas, CD388 can potentially protect individuals from all influenza strains, including seasonal and pandemic influenza A, influenza B and major drug-resistant viruses with clinical characteristics.（NCT05523089）.

Figure 3. Schematic diagram of CDD components. (Source: CIDARA Therapeutics)

2. Polymerase inhibitors（Polymerase Inhibitors）　

Influenza virus RNA polymerase is very important for virus gene transcription and genome replication, which makes it the main goal of targeted drug design. They are highly conserved among influenza A, B, C and D viruses.^[7] Influenza virus RNA polymerase consists of three subunits: polymerase basic protein 1 in influenza A and B viruses. （PB1）Polymerase basic protein 2（PB2）And polymerase acidic protein.（PA）Or polymerase 3 protein in influenza viruses C and D.(P3) (Figure 4).

Fig. 4. Virus ribonucleoprotein (vRNP) complex model. In vRNP, the 5′ and 3′ ends of genomic antisense virus RNA (vRNA) fragment are bound by heterotrimeric RNA-dependent RNA polymerase, and the rest of vRNA is wrapped by nucleoprotein (NP). The complex is twisted into an antiparallel double helix structure, and its structure is maintained by the contact between NP monomers. The vRNA forms a loop opposite to the polymerase binding end 6. (Source: Nature)

The active sites of polymerase that bind, cleave and extend RNA are conserved in various types of influenza viruses, which is why RNA-dependent RNA polymerase is considered as the target of antiviral agents. Recently, several polymerase inhibitors have been developed for each subunit, including PB1 inhibitor favipiravir, PB2 inhibitor pimodivir and PA inhibitor baloxavir marboxil (Figure 5).

Among them, baloxavir marboxil is a relatively new drug, which belongs to hat-dependent endonuclease inhibitor.（cap-dependent endonuclease inhibitor， CENI）, a new anti-influenza drug with a new mechanism of action initiated in recent 20 years, was developed by Shionogi.（Shionogi）First developed by Pharmaceutical Co., Ltd., there is no equivalent generic drug, which has been proved to have similar symptom relief time and greater viral load reduction for healthy adults and oseltamivir.^[8]A retrospective study shows that baloxavir marboxil may reduce the hospitalization rate compared with neuraminidase inhibitors.^[9]

Fig. 5. Chemical structure of anti-influenza drugs of RNA polymerase inhibitors.

The drug resistance of Baloxavir marboxil, Favipiravir and Pimodivir and other defects highlight the need to develop other polymerase targeting molecules that can widely inhibit influenza A and B viruses.

Pre-clinical studies on various PB2-targeted small molecules are under way.^[10]At least one of them（CC-42344） In the first stage（NCT05202379）, the other one（ZSP1273）In the third stage of research(NCT04024137) (Figure 7). Substitutes for nucleoside inhibitors of Favipiravir, such as molnupiravir.(Figure 6)Because it is effective against various RNA viruses, it may be beneficial to the treatment of influenza, but they may also have teratogenic side effects similar to Favipiravir, so Merck, its developer, finally gave up the development of influenza viruses and turned to Covid-19 for treatment.The development of PB1 inhibitors based on nucleoside and non-nucleoside is in preclinical stage.^[11]But there is no clinical trial at present.

Baloxavir marboxil obviously provides a broad idea for developing polymerase inhibitor anti-influenza drugs, and many patents and in vitro studies focus on compounds or variants of Baloxavir marboxil skeleton.^[12] Although some of them have shown promising in vitro efficacy and pharmacodynamics in mice,^[13]However, candidate drugs such as AL-749 did not pass the Phase I test.

Cap-dependent endonuclease inhibitor TG-1000 (Dongyangguang Pharmaceutical)And GP681(Jiangxi Qingfeng and Yinxingshu Pharmaceutical Co-developed)Recently completed the second phase of the experiment.（NCT04706468、NCT04736758), and the recruitment of ZX-7101A phase 1 research is under way.（NCT05217732）. Various small molecules and peptides that disrupt the important protein-protein interaction between components of polymerase complex, including the key contact between PA and PB1 or between PB1 and PB2, are in the preclinical development stage.^[14]

Fig. 6. Chemical structure of a new polymerase inhibitor molnupiravir.

Fourth, the global market of anti-influenza drugs

According to the latest report released by Growth Plus Reports, the global influenza drug market is expected to reach US$ 1.51 billion by 2030, and it will grow at a compound annual growth rate of 4.8% during the forecast period. The number of influenza cases increases sharply every year, which is expected to promote the sustained growth of the influenza drug market.^[15]

North America accounts for most of the global influenza drug market.The high diagnosis rate of influenza, the wider basis of drug discovery and development, the wide availability of treatment methods, and the more significant medical expenditure contribute to the dominant position of influenza drugs in the North American market. The Asia-Pacific region has the second largest market share of influenza drugs in the world. The high prevalence rate, the government’s measures to control diseases, and the increase in health care expenditure have affected this growth.

Due to the increasing incidence of diseases and the existence of considerable influenza-related risk factors in the general population, it is expected that the European market will also see significant growth. NCBI(National Biotechnology Information Center)According to a new study, there are 27,600 respiratory deaths related to seasonal influenza in 28 EU countries every winter, of which 88% are people over 65. The mortality rate of this age group is about 35 times that of people aged 65 and under.

The main participants in the development and sales of influenza drugs include: Sanofi, Lupin, Teva, Shionogi, Macleods, Alvogen, AstraZaneca, BioCryst, La Roche, Novartis, Vitaris, etc.

V. Summary　

Although it is not as ugly as SARS-CoV-2 virus, influenza virus also kills many people, and treating influenza is still an arduous challenge for human beings. Like other antiviral drugs, the development of influenza drugs faces the difficulty of virus resistance. Baloxavir marboxil is the first new drug, which shows activity against some oseltamivir-resistant strains, and there is no significant difference in safety and effectiveness from the recently known drugs used to treat influenza. The listing of Baloxavir marboxil also brings new opportunities for combined treatment with two drugs with different mechanisms of action. Although this kind of research has not been carried out systematically, it provides a valuable new direction for influenza treatment.

In addition to Baloxavir marboxil, there are many drugs under research at different clinical stages.(Figure 7)They will be optimized in pharmacology, drug resistance, pharmacokinetics, etc., and stand on the shoulders of a few influenza drugs at present to launch a unremitting struggle against influenza virus.

Fig. 7. Overview of anti-influenza drugs in development. (Source: Antiviral Research)

References:

[1] WHO. Influenza (Seasonal). 12， 01， 2023. ↑[] Jones， J. C. et al. Influenza antivirals and their role in pandemic preparedness. Antiviral Research. 2023， 210， 105499.　

[2] Influenza (Flu) Antiviral Drugs and Related Information. FDA. 08， 12， 2022.　　

[3] Monto， A. S. et al. Influenza pandemics: history and lessons learned. Webster， R. G. et al (Eds.)， Textbook of Influenza (2 ed.)， Wiley Blackwell， West Sussex， United Kingdom (2013)， pp. 20-36　　

[4] Sugaya， N. et al. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob. Agents Chemother. 2010， 54， 2575-2582

[5] Ivachtchenko， A. V. et al. Novel oral anti-influenza drug candidate AV5080. J. Antimicrob. Chemother. 2014， 69， 1892-1902.　　

[6] Peng， Q. et al. Structural insight into RNA synthesis by influenza D polymerase. Nat Microbiol. 2019， 4， 1750–1759.　　

[7] Hayden， F. G. et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescentsN. Engl. J. Med. 2018， 379， 913-923.　

[8] Komeda， T. et al. Comparison of hospitalization incidence in influenza outpatients treated with baloxavir marboxil or neuraminidase inhibitors: a health insur ance claims database studyClin. Infect. Dis.， 2021， 73， e1181-e1190.　

[9] Chen， W. et al.　 Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit. Drug Discov. Today. 2022， 27， 1545-1553.　

[10] Hou， L. et al. Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins. Acta Pharm. Sin. B. 2022， 12， 1805-1824.　　

[11] Stevaert， A. et al. The influenza virus polymerase complex: an update on its structure， functions， and significance for antiviral drug design. Med. Res. Rev. 2016， 36， 1127-1173.　

[12] Ivashchenko， A. A. et al. Synthesis， inhibitory activity and oral dosing formulation of AV5124， the structural analogue of influenza virus endonuclease inhibitor baloxavir. J. Antimicrob. Chemother. 2021， 76， 1010-1018.　

[13] Massari， S. et al. Inhibition of influenza virus polymerase by interfering with its protein-protein interactions. ACS Infect. Dis. 2021， 7， 1332-1350.

[14] Influenza Medication Market – Global Outlook & Forecast 2022-2030. Growth Plus. 11， 10， 2022.　

This article comes from WeChat WeChat official account:With freehand brushwork biotech (Biotech(ID：TXYBiotech), author: Yang Yi

Special feature of 1905 film network In the first week of its release, the movie "The Man Caught by Light" did not exceed 60 million at the box office.

In the case of the first day of filming accounting for 28.6%, it was still upstaged by Sky Fire and Sheep Without A Shepherd. The single-day box office on December 15th was even surpassed by Frozen, which was released for three weeks, and Game of the Brave 2, which was released for 10 days.

On the fourth day of the release, the single-day box office had no momentum, and the number of films dropped lower and lower, which had dropped to 16.8% on the 17th. The industry’s latest box office forecast for this film is only 84.534 million.

　

Starring Bo Huang, Wang Luodan, Tan Zhuo, Ke Bai, Huang Lu and others, it is also the first work of Huang Bo’s new director support plan. It has been highly anticipated since it was set up. Even because of its high-concept overhead setting of soft science fiction, many people compare it with The Island directed by Bo Huang. Even if it doesn’t reach 1 billion box office, it should get a relatively good result. Obviously, today’s results do not meet the expectations of the public in the early stage.

　

Perhaps the greater the expectation, the greater the disappointment. The Douban score of "The Man Taken Away by Light" dropped from 7.8 points to 7.1 points, and the score of the ticketing platform was not satisfactory, so it was difficult to drive the follow-up box office.

Coincidentally, a similar situation occurred in the movie The Whistleblower, which was released last week. Compared with Xue Xiaolu’s previous films, the film has the same lineup and is also a transnational theme. However, compared with the 520 million and 780 million achievements of the first two "Seattle", this one obviously failed to meet everyone’s expectations.After 11 days of release, the box office totaled 48.55 million, and it is expected to stop before 50 million.

　

According to the marketing data, as of December 15th, Whistleblower has released 41 video materials, which have been played for 3.25 million times. A total of 26 video materials were released in "The Man Caught by Light", which was played 5.931 million times. In addition, the creators of the two films also actively participated in roadshows, which won enough exposure for the films.

Why do these two commercial films, which have such a luxurious lineup and top publicity, collectively fall short of expectations?

　

Is there a threshold for watching movies?

On the eve of the release, when the directors of the two films were interviewed, they seemed to have expected the market reaction today.

　

Xue Xiaolu once said,"The audience will look not to understand? I am also quite embarrassed, but in fact this type of movie is really not the first one. "Run Nian Dong told us directly,"I don’t really expect much from the market. I hope the audience can go to the cinema to see this movie, but" The Man Caught by Light "is not a movie to please the audience."

It can be seen from the words of the two directors that these two films have certain thresholds for the audience.

　

After The Whistleblower was released, many people were curious about its title. What exactly is a "whistleblower"? Tan Fei, a film critic, spoke on Weibo. "The English of Whistleblower is estimated to be known by many people in the English context, but it is almost a completely unfamiliar vocabulary in the Chinese context. It is too difficult for the audience to understand it at a glance."

"Whistleblower" refers to the disclosure system of insiders, and a person has to fight against a huge organization alone. In September this year, the State Council first proposed to establish a "whistle blower" system in China.

　

Faced with such a brand-new concept, the film failed to make the audience understand from the initial publicity, and the synopsis of the follow-up film was also unclear, which eventually led to the audience never finding a position for the film.

　

In fact, in recent years, there have been many similar incidents in China. Ordinary people reported their voices through real names or through the Internet, which finally led to some investigations. From this perspective, The Whistleblower should be a film with realistic theme. If it is put in the present, it can completely benchmark Dying to Survive and other films, and it has the opportunity to make the audience empathize.

　

However, in her creation, director Xue Xiaolu seems not only to tell a simple story, but to fulfill her own ambition as much as possible."The Whistleblower is a crime suspense movie with a classic Hollywood narrative in the 1990 s, and now even Hollywood doesn’t make such a movie."

　

In the end, the two leading actors, as "whistleblowers", have many flaws in their settings. In order to help them "wash the white", the plot is constantly reversed for the sake of reversal. The whole film is like a ball of wool, which is getting more and more chaotic, making it difficult to find a clue. More importantly, the film also integrates many types of elements such as crime, suspense, action and love.

　

Obviously, this book will not be a relaxing and entertaining cool film.

The same is true of the movie "The Man Caught by Light". The story tells "After a white light, all the people who have love are taken away. What should those who stay do?" From the story level, there are not many problems. Many viewers said after the screening that "the story is good" and "the concept is good".

　

How should this film be defined from the genre level? Science fiction is inappropriate, and love seems to be insufficient. It is more like a type mentioned by Chen Kexin &mdash; &mdash; A "relationship film" is a film about the relationship between people. Run Nian Dong also indicated in the interview that,"In addition to love, a large part of the film wants to discuss the relationship between people and between people and society. I feel that the emotions before people are not so simple, and they are largely influenced by family and social concepts. "

　

Obviously, this is a work that I hope can arouse the audience’s post-reflection thinking. "I actually don’t know if this kind of thinking will make the young audience uncomfortable or stimulate them." Run Nian Dong tried to put his sincerity into the film. "The film is 130 minutes long, and I began to worry a little, but considering that all the emotions inside it need to have such a length to digest."

　

What the director was worried about happened after all. The emotional content that the film hoped to convey did not introduce extensive thinking. On the contrary, many people thought that the whole was just "concept first", which led to the continuous decline of the film rating.

　

Audience-centered system?

We are used to talking about the director’s authorship, and even the creators flaunt themselves from time to time with Hou Xiaoxian’s idea that "the creation should be back to the audience". However, the bottom line of Hou Dao’s statement is that he is confident to recover the cost of the film through other channels, which makes him care about the box office income to some extent.

　

Are most directors ok now? Maybe you need to draw a question mark.

　

In the interview, we found that most directors would say, "First of all, make sure investors don’t lose money." Then, for any film operating under the business model, its basic attribute is commodity, box office is the most direct way to express its value, and the audience is the economic person who produces the box office. The so-called grounding gas when creating, "ground gas" refers to the preference of the public.

　

"Whistleblower" or "The Man Caught by the Light" are all good projects in terms of conception, and several leading actors have also contributed very brilliant acting skills, which are not inferior to the films of the same period.

These films are all under the banner of realism, but in the end, they didn’t make the audience empathize like Dying to Survive and Better Days, largely because they deviated from the audience from the director’s personal expression in creation.

　

On the other hand, Sheep Without A Shepherd, a film of the same period as The Man Caught by the Light, understood the audience’s watching rhythm, and grasped the audience’s emotions through the parents’ feelings for their children in the film, thus achieving a box office counterattack and becoming the first dark horse in this year’s Lunar New Year file.

　

Of course, we don’t blindly hope that the creators will pursue the audience-centered system in the future, but hope that they can be closer to the market, think more from the audience’s point of view and avoid self-satisfaction.

　 　 Director Niu Chengze’s new film held a press conference in Taipei on the 14th. Ruan Jingtian played a special tea room job from the withdrawal of sea dragon frog soldiers and distribution to relieving the physiological desires of soldiers. Not only was he tender, but he was also attacked by the waiter played by Miao Keli with a "peach" move. She laughed and said it was "a go". He laughed and said that he took three shots, "It’s very comfortable!" In Xiaotian’s film, he was in a gentle village but insisted on keeping his virginity. After leaving the army, he married his girlfriend. In real life, he was also close to a good thing with Xu Weining. Can smiled and responded: "Soon!"

　 　 Ruan Jingtian’s real-life alternative service, mainly paperwork, in the film is selected into the elite amphibious combat unit in Kinmen and undergoes rigorous military training of frog soldiers. He admits that in fact, he did not dare to take the role at first. From the real alternative service to the sea dragon frog soldier in the film, which is suffering in pain, is a unique experience in his life, which can be described as "painful and happy"! He did not expect the filming process to be so hard. After going through the ups and downs of the past year, including the early departure of the Golden Horse Awards ceremony, he said: "I have always been prepared to face the problems and pressures that will be encountered in the next publicity process, but I have partners along the way, so I am not afraid!"

　 　 In the film, Ruan Jingtian tells the chief that he has promised his girlfriend to maintain his innocence and return to Taiwan to get married and have two children, a man and a woman. Outside the movie, he and his girlfriend Xu Weining have been in love for seven years and publicly thanked her for her support over the years. The host of the press conference, Huang Zijiao, joked with him: "Will it not be the seven-year itch?" He generously said that he has already made a promise, "Soon! (Marriage) will be discussed with her, and my family is also a little anxious." Asked about the good friend Zhao Youting who started a family first, Xiao Tian smiled and said: "Mark is a little more anxious!" The bean guide of Yishi Yi brother added: "They dated on the premise of marriage, and their relationship has gone through ups and downs. He is now loyal. Everything will be discussed after the promotion in September."

　 　 Wang Bojie, an actor in the film, said: "I’ve heard of the director’s great achievements before. My hands would shake in the first week of entering the group, but I didn’t see him lose his temper this time." After the illegal boarding incident, the investors withdrew their hands, and the film resources and support disappeared. Doudao admitted: "Before the shooting started, I didn’t even know if this film could be shot, and I wanted to give up for a while. I will stick to it mainly for the team. I can’t live up to everyone’s expectations. I also thought that if I don’t shoot this time, I may not shoot in the future. This era and these people may be forgotten from now on." He repositioned his directorial role and function, treating himself as a carrier and channel, no longer clinging to the result and enjoying the process, and finally persisted until the film was completed. The process was like drinking water, and it also echoed the Sea Dragon team’s motto in the film: "Only yesterday is an easy life."

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