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On October 25, Novartis released its third quarterly report for 2022, which disclosed the progress of
its own pipelines and cooperative pipelines.
It vaguely revealed that BeiGene's PD-1 tislelizumab for the treatment of nasopharyngeal carcinoma has no US marketing application submission plan, and will be submitted
for the first time in the EU in 2023.
This also means that tislelizumab may have canceled its marketing plan in the FDA this year, but it may be the first domestic PD-1
to submit a marketing application for nasopharyngeal carcinoma in the European Union.
、
Image source: Novartis Third Quarterly Report 2022
For China's innovative drug industry, if domestic PD-1 products are successfully exported to the EU, their approval path can also directly reflect the review and approval standards of EU regulators for PD-1, as well as the necessity of
PD-1 international multicenter clinical data in marketing approval by European and American populations.
According to the US Clinical Trials Register (ClinicalTrials.
gov), the three domestic pharmaceutical companies that have planned to market the indications for PD-1 nasopharyngeal carcinoma in the United States - BeiGene, Junshi Biologics and Akeso Biologics are based on almost all clinical trials that lack European and American data
.
Today, BeiGene and Junshi Biologics' PD-1 applications have been extended in the FDA's BLA applications (Biologics License Application) for different reasons, and if tislelizumab is successfully approved in the EU, perhaps the EU will become another channel
for domestic PD-1 to go overseas.
01 Are all missing multi-region data?
Missing multi-region data? In the first half of this year, Innovent Biologics disclosed the FDA's failure to approve the complete response to the sindilimab BLA application: it recommended that the standard therapy of sindizumab in combination with chemotherapy and first-line metastatic NSCLC be conducted in a multi-regional, non-inferiority clinical trial
with overall survival as the endpoint.
In other words, "multi-regional" may be one of
the "hard indicators" of overseas review.
However, observing several clinical trials of domestic PD-1 with indications for nasopharyngeal carcinoma, almost all of them lack data from
European and American populations.
According to the US Clinical Trials Registry (ClinicalTrials.
gov), most of the Phase III clinical trials for first-line nasopharyngeal carcinoma indications of BeiGene, Hengrui Pharma and Junshi Biologics are mainly
in China or other Asian regions.
The marketing application of Payamprilimab in cooperation with CP Tianqing in the United States for the third-line treatment of metastatic nasopharyngeal carcinoma is also based on clinical trial data
mainly from China.
On the other hand, public data show that nasopharyngeal carcinoma is rare in Europe and the United States, with an annual incidence of about 1/100,000, and most nasopharyngeal carcinoma occurs in China, which may be the reason why
many companies have generally carried out clinical trials related to nasopharyngeal carcinoma in China or Asia.
BeiGene disclosed in its 2021 annual report that the study of tislelizumab for nasopharyngeal carcinoma during the reporting period included a Phase 3 clinical trial in China and Thailand (NCT03924986)
in combination chemotherapy versus placebo combined chemotherapy for first-line treatment of patients with nasopharyngeal carcinoma.
The registration information on the ClinicalTrials.
gov of NCT03924986 also shows that the overseas study is only in Thailand
.
According to the previous announcement issued by Junshi Biologics, the BLA application for trepilimab was again accepted by the FDA in July this year, based on the data results
of the POLARIS-02 study (NCT02915432) and the JUPITER-02 study (NCT03581786).
The POLARIS-02 study is a multicenter, open-label, Phase II pivotal registration clinical study
.
The JUPITER-02 study is a randomized, double-blind, placebo-controlled, international multicenter Phase III pivotal registration clinical study
.
However, all 23 study locations of the NCT02915432 study were located in China; Only one of the 32 study locations in the NCT03581786 study was from Singapore, and the rest were all domestic.
It is reported that trepilimab is the first domestic PD-1 monoclonal antibody
approved for marketing in China.
In August 2021, trepilimab combined with gemcitabine/cisplatin received FDA breakthrough therapy designation
as first-line treatment for patients with advanced relapsed or metastatic nasopharyngeal carcinoma.
In July 2022, FDA accepted the resubmitted BLA for teruplimab in combination with gemcitabine/cisplatin as first-line therapy for patients with advanced relapsed or metastatic nasopharyngeal carcinoma and monotherapy for second-line and above treatment following platinum-based therapy for relapsed or metastatic nasopharyngeal carcinoma, with a target review date of the Prescription Drug User Pay Act (PDUFA) set for December 23, 2022
.
Although Hengrui Pharmaceutical did not disclose whether there is an overseas marketing plan for the treatment of carrelizumab for nasopharyngeal carcinoma, the registration information of the phase III clinical study NCT03707509 of this indication on the ClinicalTrials.
gov is all domestic research and there is no overseas clinical record
.
But it is not without domestic PD-1 clinical trials
in the United States.
ClinicalTrials.
gov showed that 3 of the 41 study locations in the phase III clinical trial of penpulimab for first-line nasopharyngeal carcinoma were located in the United States
.
02 Will the EU be the main position for the Baekje PD-1?
Will the EU be the main position for the Baekje PD-1? According to the current process of BeiGene advancing the marketing application of tislelizumab in Europe, Europe may be the "first stop"
for tislelizumab to go global.
According to BeiGene's 2022 interim report released on August 30, in Europe, the marketing authorization application (MAA) for tislelizumab for the treatment of non-small cell lung cancer (NSCLC) and second-line treatment of esophageal squamous cell carcinoma (ESCC) has been accepted by the European Medicines Agency (EMA) and is currently under review; The new drug application of tislelizumab for the treatment of first-line, second-line NSCLC and second-line ESCC has been accepted by the Australian Medical Products Administration (TGA); In cooperation with Novartis, the UK Medicines and Healthcare Products Administration (MHRA) has accepted a new drug application
for tislelizumab for the treatment of first-line, second-line NSCLC and second-line ESCC in the UK.
In the United States, the FDA has extended the BLA approval of tislelizumab for resectable recurrent locally advanced or metastatic ESCCs that are unresectable after prior systemic therapy, but BeiGene will continue to support Novartis' regulatory submissions for the use of tislelizumab for first-line gastric cancer, first- and topical ESCC, and first-line hepatocellular carcinoma (HCC),
which Novartis plans to submit in the U.
S.
in 2023.
It is worth noting that Novartis disclosed in its semi-annual report that it plans to submit a first-line nasopharyngeal carcinoma marketing application
for tislelizumab to the FDA for the first time in 2022.
Image source: Novartis 2022 Interim Report
However, BeiGene said in its semi-annual report that it has no plans
to submit marketing applications for other indications in the United States in 2022.
In addition, while the FDA is delaying BeiGene's BLA approval for esophageal squamous cell carcinoma, Novartis has decided not to proceed with the marketing
authorization application for tislelizumab for the second-line treatment of non-small cell lung cancer in the United States scheduled for the second half of this year.
According to foreign media ENDPOINTS NEWS, in the second quarter conference call, Novartis CEO Vas Narasimhan revealed that the FDA believes that BeiGene-led clinical studies do not fully reflect the characteristics
of the U.
S.
population in terms of patient numbers and standard treatments used.
So will Europe and Australia be BeiGene's PD-1's next stops?
According to the previous announcement disclosed by BeiGene, the indications for tislelizumab NSCLC declared in the EU mainly include:
Image source: BeiGene 2022 Interim Report
Based on results
from three clinical trials (NCT03358875, NCT03594747, NCT03663205).
The three trials included a total of 1499 patients, including a randomized, open-label, global phase 3 clinical trial RATIONALE 303 (NCT03358875).
The trial was designed to compare Bezean ® and docetaxel in patients
with second- or third-line locally advanced or metastatic NSCLC who have progressed to disease after prior platinum-based chemotherapy.
The trial enrolled a total of 805 patients in 10 countries in the Americas, Europe, Asia, and Oceania, who were randomized 2:1 to tislelizumab or docetaxel
.
ESCC's new indication marketing authorization application is based on the results of a randomized, open-label, multicenter global Phase 3 trial RATIONALE 302 (NCT03430843), which ClinicalTrials.
gov website shows that NCT03430843 is studied in the United States, Belgium, China, France, Germany, Italy, Japan, South Korea, Spain and the United Kingdom
.
In addition, in terms of commercialization and follow-up R&D, Zebrutinib paved the way, BeiGene officially opened a new regional office in Basel, Switzerland, and has established a commercialization and clinical development team in Europe, which will also serve as its regional operation center
in Europe.
03 Is Europe a good choice to go to sea?
Is Europe a good choice to go to sea? As the world's largest pharmaceutical market, it is understandable that the United States has become the preferred market for Chinese pharmaceutical companies to go global
.
However, the European market, which is second only to the United States and also has the characteristics of mature development, large size and stable growth, is often underestimated
.
According to the global innovative drug sales data in 2021, the five European countries (the United Kingdom, Germany, France, Spain, and Italy) have a market share of 16%, ranking second
in the world.
In fact, the European market seems to be more
receptive to new biotechnologies than in the United States.
Deloitte data shows that from 2015 to 2020, new products launched by emerging biotechnology companies have been dominant in the European Medicines Agency (EMA), accounting for an average of 33% of the total number of EMA approved drugs per year, of which the products launched by emerging biotechnology companies are orphan
drugs.
From a policy support perspective, the EMA grants Priority Drug (PRIME) status to drugs that provide potential clinical benefits, and through this program, the EMA proactively supports drug developers at an early stage, optimizes the generation of strong data on drug benefits and risks, and confirms the possibility
of accelerated review with companies when submitting marketing applications.
By working early with drug developers, PRIME supports the improvement of clinical trial schedules so that the data generated is suitable for evaluating new drug applications
.
From the perspective of disease area, oncology is the main therapeutic area approved by EMA, followed by hematology, metabolism and neurology
.
From the perspective of approval time, the average European market time is half a year to one year behind the United States, of which Germany and the United Kingdom are only about half a year later than the United States, and Spain, France and Italy are about one year
later than the United States.
Significantly ahead of the rest of the world
.
However, the reason that prevents pharmaceutical companies from entering Europe may be related to
the complex environment of the European pharmaceutical market.
Each country has a different system for drug registration and health insurance, and a single strategy may not solve the challenges
of different markets.
For most Chinese companies with little experience in the European market, dealing with the requirements of different regulatory authorities and payers is a self-evident
challenge.
Operating in a complex market requires a lot of effort and money
.
From the international experience of the world's leading biotech companies, in the United States, Europe and other global developed markets, highly innovative products can independently build commercialization capabilities in a variety of ways, and commercial licensing cooperation
can be considered in small or competitive markets.
According to BCG's "Innovative Drug Overseas Models", from 2020 to 2021, 63% of the new drugs listed in Europe by emerging biotech companies from the United States belong to the "hands-on" type of independent clinical + self-built commercialization team, including Seagen, Emergent Biosolutions, Ikena Oncology Insmed, AGC Biologics, etc
。 Companies that choose to expand into the European market through this model are all orphan drugs or FICs, and their own competitiveness is strong
.
At the same time, hands-on expansion also requires higher requirements for the company's own strength or backing the group, such as Seagen's market value of $23 billion, often with strong financial support companies can achieve independent overseas
expansion.
The second model is independent international clinical + authorized commercialization, and 25% of new products launched in Europe have chosen this cooperation method, such as Opko Health and Vifor Pharma; La Jolla with Paion
.
This type of cooperation model is generally manifested in the fact that the market competitiveness of listed products is not very prominent, and it requires the support of local leading pharmaceutical companies for commercialization expansion, and the company's market value is between
1 billion and 2 billion US dollars.
Another 13% of pharmaceutical companies will choose the full licensing model, granting international clinical and commercial to international big pharmaceutical companies or local pharmaceutical companies
.
For example, the product licensed by Ligand Pharma to Merck is a 15-valent pneumonia vaccine, which has high requirements for the commercialization and supervision of the product, so it is necessary to use the capabilities of international big pharmaceutical companies to open up overseas channels
.
For Chinese innovative pharmaceutical companies, they should choose the appropriate overseas expansion model
according to their own product characteristics, capability base and target market.
The industry generally believes that at the current stage, domestic pharmaceutical companies are still one of
the mainstream ways to cooperate in clinical development and commercialization to fully authorize clinical development and commercialization.
Especially for non-BIC/FIC products, when domestic innovative pharmaceutical companies are still shallow in capital, experience or capabilities, the use of full authorization is still an effective way to
reduce risks and quickly withdraw funds.
In addition, independently carrying out overseas clinical trials is one of
the ways that most domestic innovative pharmaceutical companies will choose.
Independently conducting international multicenter clinical trials has become a key link in the process of more and more domestic innovative drugs "going global", but BCG reports that this model requires pharmaceutical companies to build excellent clinical development and registration capabilities in order to win in speed and success rate
.
However, for many innovative drug companies, the challenge of conducting global trials, especially global phase III clinical trials, is still huge
.
In general, whether it is the United States, Europe or other markets around the world, the purpose of innovative drugs is to bring innovative and differentiated treatment options
to patients around the world.
The overseas and internationalization of innovative drugs has become one of the important keywords of China's pharmaceutical innovation, and for pharmaceutical companies that are bringing products to the sea or preparing to go global, differentiated products, solid clinical/registration capabilities, suitable commercialization models, and international talent reserves are the winning factors
for successful overseas expansion.
