In the indications of O medicine and K medicine folding, why does H medicine stand out? What is its hardcore?

New drug research and development is high-risk, high investment, there are still many explorers who are not afraid of difficulties, and it is precisely because of them groping in the dark that more and more light can gradually shine into reality, from scratch, from 0 to 1, stepping out of a road

New drug research and development is high-risk, high investment, there are still many explorers who are not afraid of difficulties, and it is precisely because of them groping in the dark that more and more light can gradually shine into reality, from scratch, from 0 to 1, stepping out of a road

On June 3-7, 2022, the annual meeting of the American Society of Clinical Oncology (ASCO), the world's largest, highest academic and most authoritative clinical oncology conference, was held

At the ASCO Annual Meeting, in terms of the indications for O drugs and K drugs to be folded, why did H drugs stand out? What is its hardcore? Domestic new drug research and development targets are piled up, the inner volume is serious, only the real Fast-in-class, Best-in-class drugs can go further, the rise of the tide of the sea, major pharmaceutical companies began to embark on internationalization, but internationalization is not so easy, FDA and other overseas regulatory agencies approval process, policy is not familiar, but also many pharmaceutical companies halfway back, or even prohibitive

In this process, for China's Biotech, Biopharma, etc.

ASTRUM-005 was selected as ANCO, what is the "hard core" of H drugs? ASTRUM-005 was selected as ANCO, what is the "hard core" of H drugs?

On June 6, 2022, Fuhong Henlin (2696.

On June 6, 2022, Fuhong Henlin (2696.

According to reports, the ASTRUM-005 study is the first international multi-center clinical study of the largest PD-1 inhibitor for widespread small cell lung cancer led by Chinese researchers, and subjects from 114 research centers around the world participated in the screening, enrolling more than 31.

From specific data, as of October 22, 2021, a total of 585 eligible patients (srullizumab group, n=389; placebo group, n=196) were enrolled in this study, with a median follow-up time of 12.
3 months
.
The median OS of the Slullimab and placebo groups were 15.
4 months (95% CI 13.
3–NE) and 10.
9 months (95% CI 10.
0–14.
3), respectively, and the risk ratio (HR) was 0.
63 (95% CI 0.
49–0.
82; p<0.
001).

The 24-month overall survival rates for the two groups were 43.
1% and 7.
9%,
respectively.
The median PFS of the Slullimonumab and placebo groups assessed by the Independent Imaging Evaluation Board (IRRC) according to RECIST v1.
1 was 5.
7 and 4.
3 months (HR 0.
48, 95% CI 0.
38–0.
59),
respectively.
Improvements
in efficacy were also observed in IRRC's orR (80.
2% vs.
70.
4%) and DOR (median DOR, 5.
6 vs.
3.
2 months) based on RECIST v1.
1.

In both trial groups, 129 (33.
2%) and 54 (27.
6%) patients experienced grade III or more treatment-related adverse events (TRAEs)
associated with slullizumab or placebo.
The incidence of immune-related adverse events (irAEs) was higher in the srullizumab group than in the placebo group and similar
to the approved PD-1/PD-L1 monoclonal antibody.

In both trial groups, 129 (33.
2%) and 54 (27.
6%) patients experienced grade III or more treatment-related adverse events (TRAEs)
associated with slullizumab or placebo.
The incidence of immune-related adverse events (irAEs) was higher in the srullizumab group than in the placebo group and similar
to the approved PD-1/PD-L1 monoclonal antibody.

In the development of small cell lung cancer drugs, it is important
to obtain statistical significance for OS and PFS in clinical trial data.
It can be seen that the median total survival of Slullizumab combined with chemotherapy in the first-line treatment of wide-range small cell lung cancer can reach 15.
4 months, the median PFS is 5.
7 months, the total population reduces the risk of death by 37%, and the 2-year total survival rate can reach 43.
1%, which basically opens up the gap
between the current treatment of SCLC drugs.

In the development of small cell lung cancer drugs, it is important
to obtain statistical significance for OS and PFS in clinical trial data.
It can be seen that the median total survival of Slullizumab combined with chemotherapy in the first-line treatment of wide-range small cell lung cancer can reach 15.
4 months, the median PFS is 5.
7 months, the total population reduces the risk of death by 37%, and the 2-year total survival rate can reach 43.
1%, which basically opens up the gap
between the current treatment of SCLC drugs.

From the perspective of lung cancer incidence, the incidence of small cell lung cancer (SCLC) is relatively low compared to that of non-small cell carcinoma (NSCLC), accounting for about 15% to 20%
of the incidence of lung cancer.
But in terms of treatment, the treatment options available for small cell lung cancer are far less than those for non-small cell lung cancer, and SCLC treatments have rarely made breakthroughs
in decades.

From the perspective of lung cancer incidence, the incidence of small cell lung cancer (SCLC) is relatively low compared to that of non-small cell carcinoma (NSCLC), accounting for about 15% to 20%
of the incidence of lung cancer.
But in terms of treatment, the treatment options available for small cell lung cancer are far less than those for non-small cell lung cancer, and SCLC treatments have rarely made breakthroughs
in decades.

SCLC is a refractory, poor prognosis lung cancer, characterized by rapid growth and early spread, the vast majority of patients are already in stage IV or extensive (ES) at the time of diagnosis, ES-SCLC accounts for about 60% to 70% of small cell lung cancer, and its average 5-year survival rate is only 2%.

The disease is characterized by strong invasiveness, rapid disease progression, early distant metastasis, and high mortality
.

SCLC is a refractory, poor prognosis lung cancer, characterized by rapid growth and early spread, the vast majority of patients are already in stage IV or extensive (ES) at the time of diagnosis, ES-SCLC accounts for about 60% to 70% of small cell lung cancer, and its average 5-year survival rate is only 2%.

The disease is characterized by strong invasiveness, rapid disease progression, early distant metastasis, and high mortality
.

Prior to PD-(L)1, etoposide plus platinum (EP) had been the standard protocol for first-line treatment with ES-SCLC, with median OS of only 8 to 10 months
in advanced patients receiving first-line chemotherapy.

Prior to PD-(L)1, etoposide plus platinum (EP) had been the standard protocol for first-line treatment with ES-SCLC, with median OS of only 8 to 10 months
in advanced patients receiving first-line chemotherapy.

At present, there are only two imported PD-L1 inhibitors approved for immunotherapy drugs for SCLC, namely duvalliumab (I drug) and altelizumab (T drug).

The data showed that in the CASPIAN study of IMpower133 and duvalliumab of atenizumab, the experimental group of 4-cycle chemotherapy combined with PD-L1 monoclonal antibody was very consistent, with PFS being 5.
2 and 5.
1 months and OS 12.
3 and 12.
9 months
, respectively.

At present, there are only two imported PD-L1 inhibitors approved for immunotherapy drugs for SCLC, namely duvalliumab (I drug) and altelizumab (T drug).

The data showed that in the CASPIAN study of IMpower133 and duvalliumab of atenizumab, the experimental group of 4-cycle chemotherapy combined with PD-L1 monoclonal antibody was very consistent, with PFS being 5.
2 and 5.
1 months and OS 12.
3 and 12.
9 months
, respectively.

In the above two studies, the OS in the immunotherapy group was about 1 year, and the lengthening of OS was only 2 months
compared with chemotherapy alone.
In the horizontal comparison study data, the OS lengthening of slullizumab compared with the chemotherapy group alone was significantly better than that of atenizumab and duvalliumab
.
In terms of two-year survival rate, the listed PD-L1 products are about 20%, while year-on-year, Henlius' Slullimonumab almost doubled
the two-year survival rate.

In the above two studies, the OS in the immunotherapy group was about 1 year, and the lengthening of OS was only 2 months
compared with chemotherapy alone.
In the horizontal comparison study data, the OS lengthening of slullizumab compared with the chemotherapy group alone was significantly better than that of atenizumab and duvalliumab
.
In terms of two-year survival rate, the listed PD-L1 products are about 20%, while year-on-year, Henlius' Slullimonumab almost doubled
the two-year survival rate.

For ES-SCLC, one of the biggest breakthroughs in the ASTRUM-005 research on H drugs is that for the first time, the two-year survival rate of the disease has crossed 40%, which can manage the refractory tumor towards chronic disease in two years, and the extra time also makes follow-up treatment more possible
.

For ES-SCLC, one of the biggest breakthroughs in the ASTRUM-005 research on H drugs is that for the first time, the two-year survival rate of the disease has crossed 40%, which can manage the refractory tumor towards chronic disease in two years, and the extra time also makes follow-up treatment more possible
.

As for the clinical trial design that the outside world is concerned about, Zhu Jun explained that the ASTRUM-005 study is not flattering
.
In the design of the entire clinical trial, the ASTRUM-005 of H drug and the IMpower133 of atenizumab are similar in design, including enrolling patients
and performing immune cross-line therapy after disease progression.

As for the clinical trial design that the outside world is concerned about, Zhu Jun explained that the ASTRUM-005 study is not flattering
.
In the design of the entire clinical trial, the ASTRUM-005 of H drug and the IMpower133 of atenizumab are similar in design, including enrolling patients
and performing immune cross-line therapy after disease progression.

Ingenious construction, breaking through the impossible

Ingenious construction, breakthrough impossible ingenuity, breakthrough impossible

In the SCLC field, the development path of PD-1 inhibitors is not smooth
.
Bristol-Myers Squibb's Opdivo (O drug) and Merck's Keytruda (K drug) voluntarily withdrew after being approved for this indication
.

In the SCLC field, the development path of PD-1 inhibitors is not smooth
.
Bristol-Myers Squibb's Opdivo (O drug) and Merck's Keytruda (K drug) voluntarily withdrew after being approved for this indication
.

August 2018, total effective rate (ORR; 12%) and median efficiency (DOR; 17.
9 months), the FDA approved Opdivo for the treatment of small cell lung cancer patients
who had received platinum-based chemotherapy and at least one other therapy.
However, three months after Opdivo was approved for accelerated marketing, Opdivo's second-line checkMate-331 and CheckMate-451 phase III clinical trials for small cell lung cancer failed
one after another.

August 2018, total effective rate (ORR; 12%) and median efficiency (DOR; 17.
9 months), the FDA approved Opdivo for the treatment of small cell lung cancer patients
who had received platinum-based chemotherapy and at least one other therapy.
However, three months after Opdivo was approved for accelerated marketing, Opdivo's second-line checkMate-331 and CheckMate-451 phase III clinical trials for small cell lung cancer failed
one after another.

In June 2019, the FDA accelerated approval of Keytruda for marketing
based on tumor response rate and response persistence data from KEYNOTE-158 (Cohort G) and KEYNOTE-028 (Cohort C1).
Continued approval of this indication will depend on Keytruda's post-marketing requirements, i.
e.
its superiority
is determined by total survival (OS).
However, in January 2020, Merck announced that Keytruda's Phase III validating study for this indication (KEYNOTE-604) achieved one of the dual primary endpoints for progression-free survival, but failed to reach the other major endpoint
of OS.

In June 2019, the FDA accelerated approval of Keytruda for marketing
based on tumor response rate and response persistence data from KEYNOTE-158 (Cohort G) and KEYNOTE-028 (Cohort C1).
Continued approval of this indication will depend on Keytruda's post-marketing requirements, i.
e.
its superiority
is determined by total survival (OS).
However, in January 2020, Merck announced that Keytruda's Phase III validating study for this indication (KEYNOTE-604) achieved one of the dual primary endpoints for progression-free survival, but failed to reach the other major endpoint
of OS.

Due to the failure of previous clinical trials of PD-1 inhibitors for SCLC, many scholars have questions
about whether PD-1 inhibitors can solve sclc's treatment problems.
If industry insiders suggest, in theory, PD-L1 is mainly expressed on the surface of tumor cells, while PD-1 is mainly expressed
on T cells.
Based on available clinical data, PD-1 inhibitors perform better in NSCLC and are less than ideal
in SCLC.

Due to the failure of previous clinical trials of PD-1 inhibitors for SCLC, many scholars have questions
about whether PD-1 inhibitors can solve sclc's treatment problems.
If industry insiders suggest, in theory, PD-L1 is mainly expressed on the surface of tumor cells, while PD-1 is mainly expressed
on T cells.
Based on available clinical data, PD-1 inhibitors perform better in NSCLC and are less than ideal
in SCLC.

Until the emergence of ASTRUM-005, the international multicenter phase III clinical study of Henlius H, many patients showed good efficacy, and some patients even maintained treatment for nearly 2 years, which was undoubtedly encouraging
.
Moreover, the overall safety of the drug is also better
.

Until the emergence of ASTRUM-005, the international multicenter phase III clinical study of Henlius H, many patients showed good efficacy, and some patients even maintained treatment for nearly 2 years, which was undoubtedly encouraging
.
Moreover, the overall safety of the drug is also better
.

At present, there are many PD-1 inhibitors that have been listed at home and abroad, and if you want to stand out from similar products, you must have something special or innovative
.
From the perspective of pharmacological properties, a basic study of slulizumab shows that slullimonab has the characteristics
of stable structure, antibody-dependent cytotoxic effect (ADCC) and complement-dependent cytotoxic effect (CDC) effect, certain antibody-dependent cell phagocytosis (ADCP) effect, large binding epitope area, high affinity, slow dissociation, strong tumor suppressant activity, and low immunogenicity.

At present, there are many PD-1 inhibitors that have been listed at home and abroad, and if you want to stand out from similar products, you must have something special or innovative
.
From the perspective of pharmacological properties, a basic study of slulizumab shows that slullimonab has the characteristics
of stable structure, antibody-dependent cytotoxic effect (ADCC) and complement-dependent cytotoxic effect (CDC) effect, certain antibody-dependent cell phagocytosis (ADCP) effect, large binding epitope area, high affinity, slow dissociation, strong tumor suppressant activity, and low immunogenicity.

Specifically, slulizumab replaces the 228th position of serine of the wild-type IgG4 subclass antibody with proline (S228P), and the structural modification of S228P avoids the occurrence of "half-molecular exchange", so that the drug can stably exert its efficacy and avoid the unpredictability of clinical efficacy; Slulizumab is an IgG4 subtype antibody, ADCC, CDC, ADCP effect is weak, effectively avoiding target cells, that is, active T cells, by NK cells, macrophages, etc.
, thereby retaining the killing ability of T cells to tumor cells, so that Slulizumab can play a better anti-tumor effect
.

Specifically, slulizumab replaces the 228th position of serine of the wild-type IgG4 subclass antibody with proline (S228P), and the structural modification of S228P avoids the occurrence of "half-molecular exchange", so that the drug can stably exert its efficacy and avoid the unpredictability of clinical efficacy; Slulizumab is an IgG4 subtype antibody, ADCC, CDC, ADCP effect is weak, effectively avoiding target cells, that is, active T cells, by NK cells, macrophages, etc.
, thereby retaining the killing ability of T cells to tumor cells, so that Slulizumab can play a better anti-tumor effect
.

With good and excellent clinical trial performance, the application for listing registration (NDA) of H drug for ES-SCLC was accepted by the State Food and Drug Administration in April, and is expected to become the world's first-line treatment of SCLC anti-PD-1 monoclonal antibody
.

With good and excellent clinical trial performance, the application for listing registration (NDA) of H drug for ES-SCLC was accepted by the State Food and Drug Administration in April, and is expected to become the world's first-line treatment of SCLC anti-PD-1 monoclonal antibody
.

H-drug combination chemotherapy has recently been recommended as a first-line therapy for ES-SCLC in the 2022 CSCO Small Cell Lung Cancer Diagnosis and Treatment Guidelines, and has been authoritatively recognized
.

H-drug combination chemotherapy has recently been recommended as a first-line therapy for ES-SCLC in the 2022 CSCO Small Cell Lung Cancer Diagnosis and Treatment Guidelines, and has been authoritatively recognized
.

At present, the first MSI-H solid tumor indications for H drugs have been approved first, and the marketing applications of ES-SCLC and sqNSCLC have been accepted
by the China Food and Drug Administration.
In addition, the treatment of H drug for SCLC has also been granted orphan drug qualification by the US FDA, and Henlius plans to submit an application for
marketing registration of H drug for ES-SCLC indications in the European Union in 2022.

At present, the first MSI-H solid tumor indications for H drugs have been approved first, and the marketing applications of ES-SCLC and sqNSCLC have been accepted
by the China Food and Drug Administration.
In addition, the treatment of H drug for SCLC has also been granted orphan drug qualification by the US FDA, and Henlius plans to submit an application for
marketing registration of H drug for ES-SCLC indications in the European Union in 2022.

As a broad-spectrum anticancer drug, H drug is also continuing to deepen the unmet clinical needs, in the field of localized small cell lung cancer (LS-SCLC) segmentation, the international multicenter phase 3 clinical study of slullimonab combined with chemotherapy and simultaneous radiotherapy is also underway; On the mCRC, slullimonaumab combined with HLX04 (recombinant anti-VEGF humanized monoclonal antibody) combined with chemotherapy (XELOX), first-line treatment of patients with metastatic colorectal cancer (mCRC) randomized, double-blind, multicenter, phase II/III clinical studies are also underway.
.
.

As a broad-spectrum anticancer drug, H drug is also continuing to deepen the unmet clinical needs, in the field of localized small cell lung cancer (LS-SCLC) segmentation, the international multicenter phase 3 clinical study of slullimonab combined with chemotherapy and simultaneous radiotherapy is also underway; On the mCRC, slullimonaumab combined with HLX04 (recombinant anti-VEGF humanized monoclonal antibody) combined with chemotherapy (XELOX), first-line treatment of patients with metastatic colorectal cancer (mCRC) randomized, double-blind, multicenter, phase II/III clinical studies are also underway.
.
.

Globally, slullizumab is simultaneously conducting a number of clinical trials of combination immunotherapy, covering a wide range of high-incidence large tumors
such as lung cancer, esophageal cancer, head and neck cancer, stomach cancer and liver cancer.

Globally, slullizumab is simultaneously conducting a number of clinical trials of combination immunotherapy, covering a wide range of high-incidence large tumors
such as lung cancer, esophageal cancer, head and neck cancer, stomach cancer and liver cancer.

"New drug research and development should start from a global perspective"

"New drug research and development, to start from a global perspective" "new drug research and development, to start from a global perspective"

In recent years, more and more international multi-center clinical trials led by Chinese researchers such as ASTRUM-005 have appeared in front of everyone, which means that Chinese researchers are capable of doing international multi-center clinical trials, and the degree of research in lung cancer and other fields is not inferior to other countries
.

In recent years, more and more international multi-center clinical trials led by Chinese researchers such as ASTRUM-005 have appeared in front of everyone, which means that Chinese researchers are capable of doing international multi-center clinical trials, and the degree of research in lung cancer and other fields is not inferior to other countries
.

Zhu Jun pointed out that for China's Biotech and Biopharma, if they only do Chinese clinical, they will only narrow
their own path.
The development of innovative drugs, especially biological drugs, must be developed from a global perspective to develop clinical development strategies, so as to make drugs that can truly solve clinical pain points, and can also have a certain impact on the industry and promote pharmaceutical progress
.

Zhu Jun pointed out that for China's Biotech and Biopharma, if they only do Chinese clinical, they will only narrow
their own path.
The development of innovative drugs, especially biological drugs, must be developed from a global perspective to develop clinical development strategies, so as to make drugs that can truly solve clinical pain points, and can also have a certain impact on the industry and promote pharmaceutical progress
.

On the other hand, the current development status of domestic innovative drugs - repeated targets, homogenization, serious internal volume, resulting in a lot of waste of resources, to avoid these, domestic innovative pharmaceutical companies must also be based on the global market, take the international, differentiated route
.

On the other hand, the current development status of domestic innovative drugs - repeated targets, homogenization, serious internal volume, resulting in a lot of waste of resources, to avoid these, domestic innovative pharmaceutical companies must also be based on the global market, take the international, differentiated route
.

This has to face the development
of a clinical development strategy that can be "handy", and differentiate international multi-center clinical trials, such as the country where the trial is carried out, the clinical trial center and the enrollment population.

This has to face the development
of a clinical development strategy that can be "handy", and differentiate international multi-center clinical trials, such as the country where the trial is carried out, the clinical trial center and the enrollment population.

In this regard, Zhu Jun shared that first of all, if you only use the experience and ideas of Chinese clinical trials to apply for international multi-center clinical trials (MRCT) may not be a good way
。 To assess whether an R&D project has prospects, a very important performance is to see if it can record patients in mature markets; Second, pharmaceutical companies must carry out clinical trials of new drugs simultaneously in the United States, Europe and other places, and the products themselves should have international market competitiveness; Third, to be familiar with the common standards of review and approval of various regulatory agencies, the requirements for research boundaries and clinical protocols are not the same
between China's NMPA, the US FDA, the EU EMA, etc.

In this regard, Zhu Jun shared that first of all, if you only use the experience and ideas of Chinese clinical trials to apply for international multi-center clinical trials (MRCT) may not be a good way
。 To assess whether an R&D project has prospects, a very important performance is to see if it can record patients in mature markets; Second, pharmaceutical companies must carry out clinical trials of new drugs simultaneously in the United States, Europe and other places, and the products themselves should have international market competitiveness; Third, to be familiar with the common standards of review and approval of various regulatory agencies, the requirements for research boundaries and clinical protocols are not the same
between China's NMPA, the US FDA, the EU EMA, etc.

International multi-center clinical trials are an important source of new drug registration data, and whether innovative drugs can be successfully marketed globally is closely
related to it.
In the vast international team, recently domestic pharmaceutical companies such as Cinda, Hehuang Pharmaceutical and other new drugs have encountered some setbacks in the listing of the United States, FDA approval tightened, pharmaceutical companies are not easy to
go to sea.
Behind the frequent setbacks in the "breakthrough" of domestic innovative drugs, it further reflects the importance of making excellent and differentiated international multi-center clinical trials, which must involve clinical research, multi-center data, and reviews of multi-racial patients
.

International multi-center clinical trials are an important source of new drug registration data, and whether innovative drugs can be successfully marketed globally is closely
related to it.
In the vast international team, recently domestic pharmaceutical companies such as Cinda, Hehuang Pharmaceutical and other new drugs have encountered some setbacks in the listing of the United States, FDA approval tightened, pharmaceutical companies are not easy to
go to sea.
Behind the frequent setbacks in the "breakthrough" of domestic innovative drugs, it further reflects the importance of making excellent and differentiated international multi-center clinical trials, which must involve clinical research, multi-center data, and reviews of multi-racial patients
.

In addition, for companies currently going to sea, CMC (Chemical Manufacturing and Control) is one of the elements that cannot be ignored
.
On May 9 of this year, the FDA released a new draft guidance detailing how to assess quality risks, sources of uncertainty, and possible mitigation strategies, including product quality assessments that need to determine the applicant's CMC strategy to consistently produce a finished drug or biological product
of acceptable quality when manufactured at the facility specified in the application.
Therefore, businesses need to have a program
that can be trusted with CMC quality.

In addition, for companies currently going to sea, CMC (Chemical Manufacturing and Control) is one of the elements that cannot be ignored
.
On May 9 of this year, the FDA released a new draft guidance detailing how to assess quality risks, sources of uncertainty, and possible mitigation strategies, including product quality assessments that need to determine the applicant's CMC strategy to consistently produce a finished drug or biological product
of acceptable quality when manufactured at the facility specified in the application.
Therefore, businesses need to have a program
that can be trusted with CMC quality.

New drug research and development is nine deaths, the probability of success is low, it can be said that it is a gamble
based on science.
Therefore, in terms of operation management, Zhu Jun suggested that pharmaceutical companies need to have the most perfect role mechanism, discussion mechanism, incentive mechanism, mature management module, etc.
is the key to the company's victory, in the process of resisting high-risk innovative drug research and development, it is not relying on the strength of one person, but the team to achieve collective collaboration in all aspects, so that the probability of success of new drug research and development is higher and higher
.

New drug research and development is nine deaths, the probability of success is low, it can be said that it is a gamble
based on science.
Therefore, in terms of operation management, Zhu Jun suggested that pharmaceutical companies need to have the most perfect role mechanism, discussion mechanism, incentive mechanism, mature management module, etc.
is the key to the company's victory, in the process of resisting high-risk innovative drug research and development, it is not relying on the strength of one person, but the team to achieve collective collaboration in all aspects, so that the probability of success of new drug research and development is higher and higher
.