Yervoy Priced at RMB 28,000 per Vial in China; Domestic Players Including Innovent, Fosun, and Alphamab Accelerate CTLA-4 Pipeline Development

Recently (October 12), Bristol-Myers Squibb announced that Yervoy (ipilimumab injection), the world's first CTLA-4 inhibitor, has officially been launched in China. Meanwhile, the sales price of ipilimumab injection (ipilimumab, Yervoy) in China has been disclosed (specification: 50 mg/10 mL; price: RMB 28,000), sparking significant attention and discussion within the industry.

According to publicly available information, ipilimumab has currently been approved for four indications globally. The dosing regimens, treatment durations, and pricing vary across different indications. The specific prices are shown in the table below:

Note: The price unit is "Yuan".

Upon the announcement of this price, some netizens commented that the pricing of ipilimumab injection is excessively high, indicating that BMS completely disregards the Chinese market; compared to the currently popular "miracle anti-cancer drug" PD-1, the price gap is even more staggering.

Currently, the annual treatment cost for PD-1 inhibitors in China is approximately RMB 40,000 to 50,000 (all four major domestically produced PD-1 inhibitors have been included in the national medical insurance). The annual cost for ipilimumab reaches a maximum of RMB 1.34 million, which is 33 times that of PD-1, and a minimum of RMB 500,000, which is 13 times higher. Given such pricing, the absence of medical insurance reimbursement would inevitably deter Chinese patients. However, some netizens have pointed out that this is intended to maintain global pricing consistency; others have noted that a high price is acceptable as long as it aligns with clinical efficacy. This pricing strategy may also be a preparatory step for upcoming medical insurance negotiations, given that anti-cancer drugs consistently face substantial price reductions during the annual reimbursement talks.

What exactly sets ipilimumab injection apart? Why is it widely regarded as so expensive? What are its future prospects? How are pharmaceutical companies in China strategically positioning themselves?

Ipilimumab

The World's Only Approved CTLA-4 Inhibitor

Ipilimumab injection is a recombinant humanized monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a member of the immunoglobulin superfamily expressed on the surface of activated T cells. By binding to receptors on antigen-presenting cells, it downregulates immune responses and terminates immune reactions. In other words, CTLA-4 participates in negative immune regulation. Consequently, CTLA-4 inhibitors block the interaction between CTLA-4 molecules and their ligands CD80/CD86, thereby enhancing T-cell activation and proliferation to attack tumor cells.

Ipilimumab, a representative CTLA-4 inhibitor, was approved by the FDA on March 25, 2011, as monotherapy for patients with unresectable or metastatic melanoma, and remains the only approved CTLA-4 inhibitor globally to date. As the first and currently only CTLA-4 inhibitor approved in China, Yervoy will be used in combination with the PD-1 inhibitor Opdivo (nivolumab injection) for the treatment of adult patients with unresectable, treatment-naive, non-epithelioid malignant pleural mesothelioma.

1+1＞2

Pioneering the Era of Immunotherapy Innovation

It is worth noting that CTLA-4 and PD-1/PD-L1 inhibitors are both immune checkpoint inhibitors with similar yet distinct mechanisms of action. CTLA-4 inhibitors primarily act during the early activation phase of T cells, whereas PD-1 inhibitors mainly function during the effector phase following T-cell maturation. Together, they systemically modulate multiple stages and dimensions of antitumor immunity. PD-1/PD-L1 inhibitors serve to normalize the host immune response, while CTLA-4 inhibitors act as immune potentiators that enhance systemic immune cytotoxicity. Simply put, one agent activates T cells, while the other harnesses these activated T cells to eradicate tumor cells.

Image Source: Drug Finder Guide

In fact, research on CTLA-4 inhibitors preceded that on PD-1/PD-L1 inhibitors; however, due to the low monotherapy efficacy and higher toxicity of CTLA-4 inhibitors, they were ultimately "overtaken from behind" by PD-1/PD-L1 inhibitors.

Subsequent clinical studies have demonstrated that ipilimumab can be combined with PD-1 inhibitors to exert a "release the brake, step on the accelerator" effect. Through complementary mechanisms, they synergistically amplify therapeutic efficacy, thereby achieving a 1+1>2 outcome. This not only provides a new R&D direction to address the current bottleneck of severe redundancy and homogenization in PD-1 targeting, but also further bolsters confidence in the development of CTLA-4 inhibitors, simultaneously ushering in an innovative era of immunotherapy.

According to incomplete statistics, over 300 registered clinical trials evaluating ipilimumab-based combination therapies have been initiated to date, primarily focusing on PD-1 antibody-sensitive tumors. Additionally, data from Yaozhi indicate that the FDA has approved multiple ipilimumab and nivolumab combination regimens. Clinical evidence demonstrates that, compared to monotherapy with either agent, the combination therapy yields significantly improved response rates and survival outcomes.

Overview of Research on Ipilimumab and Nivolumab Combination Therapy

Note: The above data were manually searched and compiled. If there are any omissions, please feel free to add them.

Furthermore, combination therapy with ipilimumab enhances therapeutic efficacy and continues to expand its indications, particularly in the “O+Y” combination regimen, with ongoing research continuously exploring its applications from first-line to adjuvant treatment settings.

This time, the indication approved in China for ipilimumab injection is for the combination therapy of nivolumab and ipilimumab (O+Y). It is the first and currently the only CTLA-4 inhibitor approved in China. Furthermore, according to Yaozhi Data, over 10 pivotal registration clinical trials for the classic O+Y dual immunotherapy combination are currently underway in China, spanning multiple cancer types including lung, liver, gastric, and esophageal cancers.

Detailed Progress of the O+Y Dual Immunotherapy Clinical Registration Trial in China

Data Source: Yaozhi Data

Combination Therapy Sparks a "Gold Rush" Journey

Innovent, Fosun Pharma, Alphamab Oncology, and Others Have Already Entered the Field.

According to reports, from 2012 to 2020, the sales revenue of Yervoy increased from $706 million to $1.682 billion. Additionally, according to a Frost & Sullivan report, global sales revenue for anti-CTLA-4 drugs is expected to reach $8.3 billion by 2030. In China, the anti-CTLA-4 drug market is projected to reach $1.7 billion by 2030, with a compound annual growth rate (CAGR) of 30.6% from 2024 to 2030.

Drugs with such promising market potential have undoubtedly attracted numerous pharmaceutical companies to compete in this field. Among them, Innovent Biologics and Alphamab Oncology have progressed the fastest, both advancing to Phase III clinical trials. Additionally, HLX13, a recombinant anti-CTLA-4 fully human monoclonal antibody injection developed by Fosun Pharma, indicated for the treatment of unresectable or metastatic melanoma, advanced renal cell carcinoma, metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency, as well as adjuvant therapy for melanoma, received clinical trial approval last year and has entered Phase I trials.

Research Progress on Domestic Ipilimumab Biosimilars

Data Source: Yaozhi Data

Summary

Currently, CTLA-4 inhibitors are under continuous and active development. Particularly following the introduction of dual immunotherapy as a novel paradigm in cancer treatment, combination therapies applicable to a wider spectrum of tumor indications and for adjuvant/neoadjuvant settings are expected to gain even greater traction. However, regarding its current pricing in China, the annual cost for monotherapy alone exceeds RMB 400,000, which is already prohibitive for the average patient. Coupled with the additional cost of PD-1 inhibitors required for combination regimens, the financial burden becomes truly unbearable. It is hoped that the swift market entry of subsequent CTLA-4 inhibitors produced in China will exert competitive pressure on originator drugs, significantly drive down drug prices, and expand therapeutic options for patients.

Executive Editor: Sanqi

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