A sample of an innovative pharmaceutical company: the hardest road and the fastest way

Time to 2022, the road to domestic innovative pharmaceutical companies suddenly narrowed
.

Say "sudden" is not the case, the chess game is not a day to go down to this step, the change in the domestic payment environment has been opened since 5 years ago, although the policy has been determined early on, but the earliest "cold" is only in the pharmaceutical company executives among the word of mouth, the heart understands
.

Since last year, the coldness has gradually become obvious: in 2021, Biotech ushered in a wave of IPO breaking, 24 biopharmaceutical companies declared the listing of the science and technology innovation board, and by the beginning of 2022, the secondary market pharmaceutical stocks have ushered in a sharp decline, and everyone can see that the pharmaceutical market is temporarily unable to create a myth of rapid wealth
.

But a way out has to be found, especially for Biotech's founders, who have signed a VAM deal
.
At the beginning, with their years of professional accumulation and experience in Europe and the United States, they have integrated dazzling astronomical figures, and it is a great thing to raise funds, and it is also the basis for many scientists to achieve their ambitions, but many founders also know how hot these money is
.

New drug research and development investment is huge, nine deaths on the road, some innovative pharmaceutical companies in the front of the water, it is difficult to survive the project, clinical road pass, to stay in the domestic listing, but found that the payment end can not undertake
.
Due to the pressure of the medical insurance fund, the national collection and procurement began to be implemented, and the circulation of generic drugs was squeezed layer by layer
.

For innovative drugs, there are also annual medical insurance national talks to frame the price ceiling, the case is in front: with the domestic wave of innovative drug hopes of PD-1 sales have been folded, the domestic payment system space has long been an indisputable fix, for the founder of Biotech, the expected commercial return rate has not arrived, but the research and development funds have been spent, in and out, this is a difficult game
.

Many people have set their sights on going to sea, but it is not easy to go to sea, the founders of Biotech returned from overseas to value the potential of domestic innovative drugs, at least they did not lay out to sea at the beginning - new drugs are listed and it is not easy, new drugs to go to sea for a pharmaceutical company's comprehensive strength requirements are more stringent, especially with Huang Pharmaceutical's sofantinib, Cinda / Eli Lilly and other well-anticipated star products have successively "broken through" the FDA after the frustration, China's innovative drugs "go to sea" The road seems to be exceptionally high and far away for a while
.

But China's innovative drugs are not impossible, the legendary biology of CAR-T was approved in the United States after the Johnson & Johnson cooperation, Rongchang Biology's ADC drug and Seattle gene's 2.
4 billion US dollars of large orders refreshed the domestic pharmaceutical company license-out record, from this point of view, going to sea is not impossible, the most fundamental thing is to grasp the clinical needs
of the destination to the sea.

At present, behind the successful pharmaceutical companies in the sea there are mature research and development, BD, pharmaceutical system support, before many Biotech did not put the sea on the agenda of the reason is "not to do, it is really difficult to do
.
" "But some sunk costs have to be paid, when the road ahead, a part of the Biotech has turned the bow of the ship, silently go to sea to do declaration and clinical, and in the early stage has successfully gone to sea, can become these Biotechs to provide some local experience
.
"

From this point of view, founded in 2010 Fuhong Henlius is a good sample, in the sea strategy, pharmaceutical declaration, BD direction, overseas clinical trials and other aspects, it has been cultivated for many years, when everyone began to turn the bow, it has been in this unfamiliar sea for a long time, but also hit some fish
.

The report card of the growth against the trend, how many points do the "battle results" account for at sea?

In August 2022, the high temperature that swept the world was so hot that the air seemed to freeze, but the conference room of Henlius Fuhong in Shanghai headquarters was full, and various media came out in the summer to listen to the company's 2022 interim report performance communication meeting
.

2022 is very important for Henlius, to use its internal tone, which is also the year
of its "From Biotech to Biopharma".
This slogan has been shouted out since last year, and this year it is time
to accept the results.

Due to the influence of external factors of the epidemic, Shanghai Pharmaceutical has had a difficult life this year, and the company's achievements are particularly prominent: in the first half of 2022, the operating income was about RMB1.
289 billion, an increase of about 103.
5% over the same period last year, and the gross profit was 984 million yuan, an increase of 138.
7% year-on-year; The loss for the period was approximately $252 million, a decrease of $142 million
year-on-year.

Since last year, from the perspective of the results of the middle report and the annual report, the loss of Henlius has narrowed year by year, and for an innovative pharmaceutical company, the continuous narrowing of losses is a positive signal
when turning.
In the announcement of the interim report, the company attributed this to "sales revenue and licensing income brought about by the successive commercialization of a number of products", and at the performance communication meeting, its chairman, executive director and CEO Zhang Wenjie described it in more detail as a "comprehensive upgrade
of commercialization capabilities.
" ”

By August this year, Fuhong Henlius has a total of 5 products approved for listing, namely Hanlikang, Hanquyou, Handa Yuan, Hanbeitai and Hansi, Hansi-like is the company's independent research and development of a PD-1, the first indication approved is microsatellite highly unstable (MSI-H) solid tumor, listed in March this year, the semi-annual report performance of Hansi-like sales revenue of about 76.
9 million yuan, in the red sea of PD-1, this indication differentiation strategy worked
.

Henlius Fuhong this year's commercialized key product is trastuzumab Hanquyou, its sales performance in the first half of the year in China was 800 million yuan, up 178.
2% year-on-year, "has built a very sound channel, including first-level secondary distributors, DTP pharmacies, sales team in 7 regions more than 500 professionals, covering more than 3,500 domestic hospitals, more than 20,000 oncologists
.
" Zhang Wenjie said
.

In the past three years, the company has made remarkable achievements in channel construction, market access breakthroughs, sales and academic promotion in the market, and these systems and experiences can be copied to the commercialization of products other than Hanquyou, including breakthroughs
in production capacity.

Henlius, which was once trapped in production capacity, has won the Songjiang base this year, with production capacity jumping from 24,000 liters last year to 48,000 liters, and will reach 144,000 liters in 2026
.

In addition to domestic performance, another important performance of this company comes from overseas licensing and sales
.
According to the official website of Fuhong Henlius, Hanquyou was approved for listing in Europe and China in 2020, becoming the first "Chinese" monoclonal antibody biosimilar to land in Europe, opening up a precedent for domestic biosimilars to go out of the "country"
.
Up to now, Hanquyou has been approved in more than 30 countries such as the European Union and Australia, and has been successfully listed and sold in 20 countries, and the external authorization has covered about 100 countries and regions around the
world.

Hanquyou's BD cooperation is not only limited to License-out and getting a down payment, but with the approval of Hanquyou in many countries, Henlius has also received many regulatory milestone payments
from related BD cooperation.
In 2021, Henlius obtained 30.
2 million yuan of overseas licensing income from Hanquyou, and in the first half of 2022, the overseas sales revenue of Hanquyou was about RMB12.
5 million, and the overseas licensing income reached 2.
4 million yuan
.

The above income, based on the cooperation between Henlius and Accord, was achieved in 2018
.
In fact, this company takes the international route is not only Hanquyou, in the first half of 2022, it completed 4 license-out transactions, respectively, signed licensing agreements with Getz Pharma, Eurofarma, Abbott, Organon, BD transaction number and amount are leading in China, is the first in the number of domestic biological drug overseas transactions, of which the License-out large order signed with Organon during the epidemic, The transaction had a down payment of $73 million and potential revenue of $541 million
.

Why choose the hard road?

In recent years, on the way to the sea, Henlius Fuhong has sprinted into the European and American markets on the one hand, and on the other hand, it has also covered Indonesia, Brazil and other Asian, African and Latin American countries, which can be regarded as a unique path
among innovative pharmaceutical companies in the same period.

History is difficult to predict, and it is difficult to choose the right path at a threshold, so often when a definite result appears, people will pursue the cause
.
Even a few years ago, Henlius's "Biosimilar" route was not optimistic about too many insiders, and when the entire industry was booming, people were staring at the fastest and most "First in class"
.
The company chose a path that few people took, and the hardest path — from the beginning of the business, the two co-founders decided to "base themselves in China and look at the world
.
"

The determination and strategy to go overseas at the beginning is also related to its own product business logic, as long as the quality of biological drugs is good, it should be a global market itself," one of the advantages of Henlius Fuhong going overseas is that the company has built a benchmark with the regulatory standards of the mature biological drug market through the early development of biosimilars, and at the same time explored a set of successful experience in operating international multi-center tests," said
Zhu Jun, president of Henlius Fuhong.

The focus of biosimilars is that there is no clinical difference between drug quality, safety and efficacy and the original drug, and quality is also the core competitive advantage of Henlius, and its Xuhui production base is the only factory
in China that has been certified by EMA GMP to produce self-developed products.

The pharmaceutical payment system in Europe and the United States is also different, the mature market of biosimilars is in the European Union, and the first-class production quality system in the international mature markets such as the EU has also created the advantage of
Henlius Fuhong entering the international market.
Before 2014, technical standards for biosimilars in the United States and China had not yet been introduced
.
At the beginning of the establishment of the company in 2010, Henlius Fuhong developed biosimilars in accordance with EU standards, which is why it has the confidence to go to the EU to declare biosimilars for listing
.

In addition to achieving high-quality "me too", differentiation outside of "too" is also very important, and details are often decisive
.

Hantrazumab is now the only one on the market that competes with the original research, the famous Herceptin
.
Herceptin in the dosage form listed in China is 440mg and with preservatives, according to the average weight of Chinese patients, 440mg is usually disposable can not be used, which means that the remaining liquid needs to be preserved by refrigeration and other means, improper preservation is easy to cause waste
.

Hanquyou does not contain preservatives and the dosage form is 150mg, and later listed 60mg, "We solved the problem of inconvenient and non-standard clinical use, double specifications that are ready to use, no need for residual liquid preservation, for patients of different weights can be just right, this is our advantage
.
" Zhang Wenjie said
.

Back to the essence of drugs, even if there are differences between different ethnic groups, drugs that truly meet clinical needs should be unimpeded in the world, and then consider the research and development efficiency of drugs, for what kind of drugs to choose to go to sea, Zhu Jun concluded, "For products that target global clinical needs, if there is any birth defect that is not suitable for internationalization, I think this product should not be hastily pushed to the clinic in theory
.
" ”

This year, Henlius plans to file a Biologics Licensing Application (BLA)
for Hantrayou in the United States.
At present, the company has 13 products and 11 combination treatment options in more than 20 clinical trials around the world, due to the newly launched PD-1 Hansi-like clinical data on small cell lung cancer, Henlius also intends to send it to sea
.

"Our communication with the FDA is very smooth," Zhu Jun said, "although Hans-like has not enrolled clinical subjects in the United States, but because the FDA believes that in recent years, the United States or no new drugs for this indication have been approved, considering the clinical needs, the FDA is very interested in Hans-like combinations of chemotherapy for generalized small cell lung cancer, "Hans-like combination chemotherapy for generalized small cell lung cancer bridging trial will be launched in the second half of this year, is expected to submit a marketing application
to the FDA in 2024.
"

What is the most important thing about going to sea success?

International multi-center clinical trials are an important source of new drug registration data, whether the product can be successfully listed in the world is closely related to it, at the same time, different innovative pharmaceutical companies have different product logic, research and development routes, in the experience of Henlius Fuhong overseas, the most replicable part is how to declare locally and communicate
with the local pharmaceutical department.

"It is best to communicate with the regulatory authorities as soon as possible," Zhu Jun said, from their experience, for pharmaceutical companies that expect to go to sea, the sooner the better, "If you want to organize an international multi-center clinical trial, it is recommended to start from the
United States.
" "On the one hand, in China's declaration for pharmaceutical companies is the home battle, culture, language and habits are familiar, communication is easy to master, on the other hand, FDA has enough authority and professionalism, in the process of communication, FDA will give pharmaceutical companies some advice, pharmaceutical companies themselves will also gain a lot of experience, and these experiences can also be transferred to the market declaration
in other countries.
"

Another reason is that in the United States to declare and carry out clinical can be used as the highest touchstone for the effectiveness and safety of new drugs, due to the large number of drugs in the US market, many patients enrolled in the clinical treatment of new drugs have gone through multiple rounds of treatment, exhausting all the drugs on the market, if the new drugs can see the effect at this time, especially if the single drug is effective, the gold content of the new drug itself is self-evident
.

"Doing clinical work overseas, to cope with the different requirements of different regulatory parties, but also to deal with a variety of different situations," Zhu Jun said, often there are various emergencies, such as in the domestic clinical data recovery cycle is short, but in some countries there are various holidays, data collection is often delayed, in order to shorten the overall cycle, the need to adapt to the development of different strategies, the advantage of going to sea earlier is that there is now enough experience to deal with the regulatory requirements and various situations in different countries, "after doing more, We've relied on our own teams to do R&D and pharmaceutical communications, and we've calculated that the overall cycle of outsourcing to the CRO is twice as
fast.
”

Innovative drugs overseas is generally divided into license-out and overseas direct declaration and listing, in the development process of Henlius from biotech to biopharma, license-out is only the first step, Zhang Wenjie said, as a small-scale company if you want to go to sea, may not have enough resources, lack of experience, the product may not be particularly strong at the beginning, so usually through external authorization to go overseas transactions
.

With the overall upgrading and development, the layout of Henlius Fuhong to go overseas has entered the next stage, "now to next year, the focus of our overseas layout is the research and development and pharmaceutical management team
.
" Zhang Wenjie introduced that Hans-like is an excellent opportunity for this company to go to sea, "the product itself is very unique, especially in the indications for small cell lung cancer clinical data is also very good," even if Hans-like in the United States in 2024 to submit BLA, the post-marketing Hans-like may also be the only one in the United States approved for small cell lung cancer PD-1, "This is a good entry point for us to enter the U.
S
.
market.
" ”

This is indeed a good entry point, in September 2022, more specific good news came, Hansi-like treatment of small cell lung cancer in the third phase of the international multicenter study published in the Journal of the American Medical Association, Hansi-like combination chemotherapy in the overall population and the Chinese subgroup can extend OS (Overall Survival) (overall survival), Hansi-like group of the total population of the OS reached 15.
4 months, compared with chemotherapy can extend survival
by 4.
5 months.

Lung cancer is the second highest incidence of cancer in the world, lung cancer accounts for about 11.
4% of the global cancer incidence in 2020, and there are about 810,000 new lung cancer cases in China, ranking first in tumor incidence and mortality
.
Small cell lung cancer accounts for 15%-20% of the total number of lung cancers, is the most aggressive subtype of lung cancer, tumor growth is rapid, clinical deterioration is fast, the overall prognosis is poor, and the five-year survival rate is only 7%.

In April 2022, the listing application for the first-line treatment of small cell lung cancer with hansi-like combination chemotherapy was accepted
by the State Food and Drug Administration.
Since no first-line anti-PD-1 monoclonal antibody for small cell lung cancer has been approved worldwide, Hans-like may become the world's first first-line anti-PD-1 monoclonal antibody
for small cell lung cancer.

At this year's ASCO annual meeting, the lead researcher Professor Cheng Ying first reported the results of Hansi-like in small cell lung cancer, which attracted the attention of global peers, and the clinical results were listed in the world's four top medical journals, which is a great blessing
for Henlius's innovative reputation and journey to the sea.

When looking around at the unfamiliar expanse of the sea, it is difficult to choose which path will lead to a great victory
in the moment.
When looking back at the journey when it was back, Henlius Fuhong did research and development step by step, did overseas clinical practice solidly, let professional people do professional things, did not take shortcuts, there was no shortcut, more than 10 years later, the most difficult road that looked like it at the beginning became the fastest road
.