At this stage, there is a "differentiation" in the domestic pharmaceutical field.
In various pharmaceutical market segments, monoclonal antibodies are still mainstream, but PD-1 monoclonal antibodies have been extremely involuted, and biosimilars of PD-1 monoclonal antibodies are expected to appear in the next few years.
At the same time, dual antibodies and ADCs are in a stage of rapid development, and their market share is expanding, and there is still great growth potential in the future.
Take biclonal antibodies as an example. Up to now, 12 bispecific antibody drugs have been approved for marketing worldwide (1 of which was delisted in 2017), and Akeso's PD-1/CTLA-4 bispecific antibody cardunilimab is the only domestic bispecific antibody drug.
Although the current market competition pattern is relatively relaxed, the two anti-rivers and lakes are not calm as water.
In particular, the clinical progress of domestic emerging innovative pharmaceutical companies such as Akeso, Corning Jerry Pharmaceutical, and Innovent Biologics is in the forefront of China, and the pipeline richness is more competitive than that of multinational pharmaceutical companies, which is setting off a wave of double resistance.
Clinical pattern of domestic biclonal antibody market (number of clinical items)
Source: CITIC Securities Research Department
1
Akeso
Won the first domestic dual antibody and reached a $5 billion BD deal
Akeso is undoubtedly the "leader" in the field of dual antibodies.
On June 29, 2022, Akeso's cardunilimab (AK104, kaitanil) was approved by the State Food and Drug Administration for the treatment of patients with recurrent or metastatic cervical cancer who had previously failed platinum-containing chemotherapy, becoming the first domestic bispecific antibody approved for marketing and the world's first PD-1/CTLA-4 bi-antibody.
The approval of Cardunigli not only fills the gap in immunotherapy for advanced cervical cancer in China, but also stimulates the enthusiasm of domestic pharmaceutical companies to develop bispecific antibody drugs with beautiful sales data.
Only half a year after its launch, Cardunigli achieved sales of 546 million yuan with monotherapy for the small indication of second/third-line cervical cancer. Moreover, sales in the first half of 2023 continued to rise, driving Akeso's performance to explode.
Previously, Akeso released a positive profit forecast, benefiting from the acceleration of clinical and commercialization of Evoxi (PD-1/VEGF dual antibody) and cardonilimab, and is expected to record a profit of about 2.3 billion yuan in the first half of 2023, achieving its first profit.
At present, cardunilimab is also efficiently advancing the registrational/phase III clinical study of first-line treatment of cervical cancer, first-line gastric cancer, liver cancer and other large indications, with a huge potential patient population and great explosive potential, among which 1L cervical cancer and gastric cancer clinical trials have been completed.
Clinical trials of kadunilimab
Source: West China Securities
Single antibody to see the target, double antibody to see the platform. The achievement of kadunilimab is due to the support of Akeso's self-developed integrated development platform (ACE platform) and proprietary technology (Tetrabody technology).
At present, Akeso has successfully developed 6 bispecific antibody drugs based on proprietary technology, including cardunilib, evoximab (AK112), and AK130, the world's first and only TIGIT/TGF-β dual-target antibody fusion protein new drug under development.
Evoximab is undoubtedly the next killer of Akeso, but it takes the license-out route.
In 2022, Akeso awarded the overseas rights of Ivisi to Summit Therapeutics of the United States for a total transaction amount of up to US$5 billion, setting a new record for domestic innovative drugs going overseas.
Biotech, which dares to conduct head-to-head trials, is not good. Akeso has also initiated three projects, including cardunilimab plus chemotherapy head-to-head tislelizumab plus chemotherapy for PD-L1-negative NSCLC, while AK112 is conducting two PD-1 head-to-head clinical trials in China for BeiGene's tislelizumab and K drug, respectively.
To sum up, it can be seen that Akeso is indeed very capable of fighting in the field of double antibodies.
2
Corning Jerry Pharmaceuticals
The road of double resistance is full of thorns, but it has not broken
In the field of dual antibodies, the relationship between Corning Jerey Pharmaceutical and Akeso may be like Gree and Midea in the air conditioning industry.
But the difference is that Corning Jerry's "luck" seems to be a little worse, so far no bispecific antibody products have been approved for marketing, and the road to research and development is full of bumps.
Envolimab (KN035, Envida ®) is Corning Jerry's first and currently only commercial product, the world's first subcutaneous injection of PD-L1 antibody drug, with differentiation and first-mover advantages, and the sales strategy adopts an external cooperation approach.
According to the 2023 interim report, Corning Jereh achieved revenue of about 136 million yuan, a year-on-year increase of 154.75%, and a loss of 39.862 million yuan during the period, a year-on-year decrease of 72.94%, of which the income from the sale of KN035 products to Sichuan Sichuan Idea Kangrui Pharmaceutical was 71.5 million yuan, compared with 27.2 million yuan in the same period in 2022; Royalty income was $45.5 million, compared to $25.4 million for the same period in 2022.
From the perspective of research and development progress, Corning Jerry has two bispecific antibody drugs that are about to enter the commercialization stage, including PD-L1/CTLA-4 bispecific antibody KN046 and HER2 bispecific antibody KN026.
Corning Jereh Pharmaceuticals R&D pipeline
Source: 2023 Half-Year Report
However, the development of the KN046 did not go well.
In May this year, due to the failure to achieve a statistically significant difference in OS (overall survival), the phase III clinical trial of KN046-301 for advanced squamous non-small cell lung cancer was unsuccessfully unblinded, which meant that the new drug application may be delayed, causing Corning Jerry's stock price to fall by 40% in 5 days.
In addition, according to the announcement, considering the difficulties in recruiting qualified patients for clinical trials, Corning Jerry has suspended further clinical development of the KN046 thymic carcinoma indication, which has relatively limited cases.
Based on this, the market's expectations for KN046 fell on pancreatic cancer indications. This is also the core of whether the company's future development and market value can be improved, and there is no room for mistakes.
Pancreatic cancer is recognized as the "king of cancer" in the medical community, of which about 90% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), with a high fatality rate and a lack of effective clinical treatment. At present, other clinical trials of PD-1/L1 monoclonal antibody for the treatment of pancreatic cancer have basically failed, and domestic PD-1/L1 monoclonal antibody or dual antibody has not been deployed for pancreatic cancer, and there is a huge medical gap and market prospects.
KN046 is one of the few IO products that is advancing the first-line phase III clinical trial of pancreatic cancer, and once clinically successful, it is expected to be verified as a BIC product, and even impact pancreatic cancer FIC. According to the results of the phase II KN046-IST-04 study, the ORR of 31 treatment-naïve patients was 45.2%, and the disease control rate (DCR) was 93.5%.
Source: Corning Jerry website
KN026 is a HER2 bispecific antibody developed by Corning Jereh using Fc heterodimer platform technology (CRIB), which exhibits high efficiency and low toxicity, and is currently undergoing clinical trials for indications including breast and gastric cancer.
According to the phase II clinical study of KN026 in combination with docetaxel in the treatment of HER2-positive relapsed/metastatic breast cancer (a total of 57 female patients), the confirmed ORR was 76.4%, the median DoR was 24.0 months, and the DCR was 100%. The median progression-free survival was followed up at 16.6 months, and the median PFS was 25.4 months and immature.
In addition, according to the results of clinical research, KN026 gastric cancer monotherapy efficacy is better than the previous generation HER2 ADC and the safety is better than Enhertu, and the second-line phase III clinical trial of gastric cancer is being advanced.
Comparison of efficacy of KN026 gastric cancer
Source: Corning Jerry website
At least from the current stage, Corning Jerry has not yet broken in the field of dual antibodies, but in order to prove its research and development strength and break through the ceiling of the company's revenue, it really has to work hard.
3
Innovent Biologics
Layout differentiation "global new" dual antibody
Innovent Biologics is one of the first batch of enterprises in China to successfully transform from Biotech to Biopharma, and it is also one of the enterprises at the forefront of the domestic bi-antibody field.
On August 23, Innovent announced its results for the first half of 2023: total revenue of 2.702 billion yuan, a year-on-year increase of 20.6%, and a loss of 139 million yuan during the period, a significant decrease of about 85.4% year-on-year; Product revenue was 2.458 billion yuan, a year-on-year increase of 20.4%, and the growth accelerated in the second quarter, with product revenue increasing by more than 35% year-on-year.
In terms of R&D, the R&D investment in the first half of the year reached 826 million yuan, and it currently has 8 pipelines in marketing application (NDA) or key clinical trials, and about 20 pipelines entering clinical research.
As far as dual antibodies are concerned, Innovence's strategy is to differentiate "global new" dual antibodies, and five bispecific antibodies have entered the clinical stage in the field of oncology, namely IBI323 (LAG3/PD-L1), IBI322 (PD-L1/CD47), IBI363 (PD-1/IL-2), IBI389 (CLDN18.2/CD3), IBI334 (EGFR/B7H3).
Innovent Biologics part of the R&D pipeline (yellow marked as bispecific antibody product under development)
Source: 2023 Half-Year Report
Specifically, IBI363, a potential first-in-class PD-1/IL-2 bi-antibody fusion protein, is currently undergoing phase I MRCT in Australia and China for the treatment of patients with advanced solid tumors, and has observed preliminary efficacy and safety; IBI334 is scheduled to enter the first human clinical study in the second half of 2023; IBI323 is already in Phase Ib clinical studies.
Among them, IBI363 has a stronger binding ability to PD-1, but at the same time retains CD25 activity to maximize efficacy. While IBI363 heats tumors, PD-1 antibodies enhance T cell function, which can improve IO treatment effects by mechanism, including PD-1/PD-L1 resistance and "cold tumors".
IBI323 is a 2+2 symmetric biantibody that targets PD-L1 and LAG-3 at the same time, which has two advantages: on the one hand, it can simultaneously inhibit the two inhibitory signaling pathways mediated by LAG-3 and PD-L1, which has a stronger and more durable T cell activation potential than a single target; On the other hand, through the bridging of dual antibodies, PD-L1-expressing tumor cells can be brought closer to LAG-3-expressing T cells, thereby forming stable TCR:MHC immune synapses and further activating T cells.
Therefore, compared with combination drugs, IBI323 provides patients with a more convenient and lower cost treatment regimen, and also has a dual advantage in terms of mechanism of action.
In addition, IBI389 is undergoing a Phase 1 clinical study for the treatment of patients with CLDN18.2-positive solid tumors; IBI-334, a potentially first-in-class EGFR/B7H3 dual antibody, has submitted an IND application in July 2023, and plans to conduct a Phase 1 clinical study in patients with advanced solid tumors in Australia and China.
It is not difficult to see that Innovent Biologics' dual antibody layout strategy takes a differentiated route. The advantage of this approach is that it avoids direct competition with competitors and reduces market risk and competitive pressure.
However, at present, the above-mentioned bispecific antibody under research is still in the early stage of clinical practice, and whether the final drug can be finalized remains to be read out in the later stage.
4
epilogue
Of course, in addition to Akeso, Corning Jerry and Innovent Biologics, there are many emerging innovative drug companies in China to deploy dual antibody pipelines, including BeiGene, Remegen, and Conoya.
In addition, Shuanganti Jianghu also brings together Hengrui Pharmaceutical, China Biopharmaceutical, CSPC and other powerful traditional pharmaceutical companies seeking innovation and transformation.
It is foreseeable that a fierce double resistance race is beginning.
Resources
1. Financial reports and announcements of each company
2. "Akeso-9926. HK-Leading Pharmaceutical Company with Double Antibody, Ushering in the Harvest Period of Commercialization", West China Securities
3. "Corning Jereh Pharmaceutical_B-9966.HK-Tracking Analysis Report: Innovative Differentiation Molding, KN046 is Expected to Impact Pancreatic Cancer FIC", Huachuang Securities
Article source: [Yaodu Daily] public number/Zongge 2025 original