How is the progress of China’s domestically produced PD-(L)1 “going global”?

Recently, Coherus BioSciences announced that the FDA has approved the launch of PD-1 antibody toripalimab (marketed jointly by Junshi Biosciences and Coherus) for use in combination with gemcitabine/cisplatin as a first-line treatment for advanced recurrent or metastatic nasopharyngeal carcinoma (NPC). The monotherapy has also been approved for second-line and subsequent treatments after platinum-containing therapy for recurrent or metastatic NPC.

Toripalimab (commercially known as Tu Yi) is a PD-1-targeted monoclonal antibody independently developed by Junshi Biosciences. The application for its market approval is based on the results of the JUPITER-02 study (a randomized, double-blind, placebo-controlled, international multicenter phase III clinical trial) and the POLARIS-02 study (a multicenter, open-label, phase II pivotal registration clinical trial).

In the JUPITER-02 study, the results showed that compared to the chemotherapy alone group, the combination of toripalimab and chemotherapy significantly improved the overall survival (OS) of patients with recurrent or metastatic NPC in the first-line treatment. The 3-year OS rate reached 64.5%, and the risk of death decreased by 37% (median not reached vs 33.7 months, HR=0.63, P=0.0083), setting a new record for OS benefit in advanced NPC patients.

In the POLARIS-02 study, 190 patients with recurrent or metastatic nasopharyngeal carcinoma who had previously failed second-line or subsequent systemic therapy received toripalimab monotherapy. In the overall population, 5 cases achieved complete response (CR), 34 cases achieved partial response (PR), and 40 cases achieved stable disease (SD), resulting in an objective response rate (ORR) of 20.5%, meeting the primary endpoint of the study. The results of POLARIS-02 showed that toripalimab demonstrated durable anti-tumor activity and survival benefit, with controllable safety, and benefited patients regardless of PD-L1 expression.

Currently, the majority of NPC patients are diagnosed at an advanced stage, with approximately 10% of patients having distant metastasis. Although the 5-year survival rate for early-stage NPC reaches around 90% after treatment, the survival rate for advanced-stage patients remains low. Therefore, advanced NPC has become one of the important diseases seriously affecting human health.

Traditional treatment modalities for NPC include surgery, radiotherapy, and chemotherapy, with radiotherapy being the preferred curative treatment. However, some advanced NPC patients may still experience recurrence or distant metastasis despite receiving radiotherapy. Therefore, there is an urgent need for clinical exploration of new treatment strategies to improve the prognosis of advanced NPC patients.

After the approval of toripalimab, it became the first FDA-approved drug for the treatment of nasopharyngeal carcinoma. However, the road to approval for toripalimab has been quite challenging.

In March 2021, Junshi Biosciences and Coherus submitted a rolling Biologics License Application (BLA) to the FDA for toripalimab for the treatment of recurrent or metastatic nasopharyngeal carcinoma and received FDA’s rolling review. In May 2022, Junshi Biosciences announced that due to “travel restrictions caused by the pandemic,” the FDA was unable to complete the on-site inspection of the drug’s manufacturing facilities. In July 2022, the FDA requested Junshi to make an easily manageable process change for quality control, and subsequently re-submitted the application to the FDA. Due to the impact of the pandemic, the FDA was unable to conduct the on-site inspection within the current review cycle, resulting in another delay in the approval process.

In July of this year, Junshi Biosciences stated that they successfully completed the on-site inspection of the domestic manufacturing base for toripalimab by the FDA at the end of May. Their partner, Coherus, is preparing for the commercialization of toripalimab in the United States.

On October 28th of this year, Junshi Biosciences/Coherus announced that the FDA had approved toripalimab in combination with gemcitabine/cisplatin as a first-line treatment for advanced recurrent or metastatic nasopharyngeal carcinoma patients, and also as a monotherapy for second-line and above treatment for recurrent or metastatic nasopharyngeal carcinoma after platinum-based chemotherapy.

Toripalimab becomes the first approved immune therapy for the treatment of nasopharyngeal carcinoma by the FDA and the first market approval of a domestically produced PD-1 inhibitor in the United States, which is a significant milestone. Additionally, the combination of toripalimab with chemotherapy is expected to become a new standard of care for first-line treatment of nasopharyngeal carcinoma. The market size is expected to reach $200 million by 2027.

Domestic PD-1 goes global, showing remarkable capabilities

Apart from Junshi Biosciences, there are also domestic companies such as Hengrui Medicine and BeiGene waiting for their PD-1 products to be approved by the FDA.

On May 17th this year, Hengrui Medicine's partner Elevar announced that they had submitted a new drug application to the FDA for the combination of PD-1 inhibitor camrelizumab (Ai Rika) and small molecule anti-angiogenic drug rivoceranib (Ai Tan), as a first-line treatment for unresectable hepatocellular carcinoma. Compared to sorafenib, the combination of camrelizumab and rivoceranib significantly prolongs the progression-free survival (PFS) and overall survival (OS) of patients with advanced liver cancer.

BeiGene's PD-1 inhibitor tislelizumab (Bai Ze An) has been approved for 11 indications and included in 9 medical insurance lists since its launch in China. In the first half of 2023, it ranked first in terms of PD-(L)1 sales in the Chinese market, with sales reaching 1.836 billion yuan. In September of this year, tislelizumab was granted approval by the European Commission as a monotherapy for the treatment of adult patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who have received prior platinum-based chemotherapy.

The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based on the RATIONALE 302 study. This is the first successful approval and market launch of a Chinese PD-1 product in the European Union.

Furthermore, the FDA has accepted another application for the market approval of tislelizumab, this time for the first-line treatment of unresectable locally advanced, recurrent, or metastatic ESCC patients (FDA is expected to make a decision on this application in the second half of 2024).

Currently, tislelizumab has been involved in 21 registered clinical trials in over 30 countries and regions. Applications for different indications of tislelizumab have been accepted in the United States, Europe, the United Kingdom, and other countries. The indication for ESCC is just the beginning.

It is worth mentioning that Junshi Biosciences has also expanded into the Southeast Asian and Latin American markets. In March of this year, Junshi Biosciences partnered with Consino BioMed to establish a joint venture company in 9 Southeast Asian countries, for the collaborative development and commercialization of toripalimab. In May, Junshi Biosciences reached a cooperation agreement with Dr. Reddy's Laboratories to grant them the rights for the development and commercialization of toripalimab in Brazil, Mexico, Colombia, Argentina, South Africa, and other regions.

Whether it is Junshi Biosciences, which crossed the finish line first, or BeiGene and others still awaiting news, they have all accumulated rich experience in taking Chinese innovative drugs global. The FDA's approval of toripalimab is not only a recognition of Junshi Biosciences but also a response to the efforts of Chinese pharmaceutical companies in the field of innovative drug research and development. The internationalization journey of Chinese innovative pharmaceutical companies has just begun, and the future is both challenging and promising.