Rapid Global Expansion of Chinese PD-1/PD-L1 Key Players

Immune checkpoint inhibitors (ICIs) are currently among the most widely used treatments for cancer. Chinese pharmaceutical companies have been making significant strides in developing PD-1 and PD-L1 inhibitors, used to treat various cancers. Several of these companies are now entering or planning to enter the US and European markets. Beigene, Hengrui Medicine, Junshi Biosciences, and Innovent Biologics are at the forefront of PD-1/PD-L1 development in China, with several approved and under-development assets.

One of the key motivators for Chinese PD-1 drug developers to expand internationally is the pricing pressure they face in their domestic market. Due to significant price cuts to be included in the national drug reimbursement list, the larger sales potential may lie outside of China. The primary competitive edge of Chinese PD-1/PD-L1 drugs is their lower cost.

LOQTORZI Triumphs: First Chinese PD-1 Inhibitor Approved in the US

Securing Food and Drug Administration (FDA) approval has always been challenging for China-made PD-1 inhibitors in the US. This process involves navigating rigorous regulatory standards, extensive clinical trials, and overcoming potential biases against foreign pharmaceuticals. Despite these hurdles, some Chinese companies have successfully demonstrated the safety and efficacy of their experimental therapies, gradually earning the FDA’s trust and paving the way for future approvals. Earlier, the FDA rejected the applications for sintilimab and sugemalimab for NSCLC, a major indication due to reliance on China-only data.

LOQTORZI, which has been available in China since 2018 and authorized for six indications, was granted FDA clearance in the United States in October 2023 for nasopharyngeal carcinoma. 

Nasopharyngeal carcinoma, a rare type of head and neck cancer in the United States, predominantly impacts Asian populations. According to DelveInsight, LOQTORZI has the potential to achieve peak sales of USD 200 million in this specialized market. To boost revenue, Coherus is also aiming to treat esophageal squamous cell carcinoma alongside nasopharyngeal carcinoma in EU4 and the UK.

Coherus set LOQTORZI’s list price 20% lower than KEYTRUDA’s tri weekly price of USD 1,115, which is still higher than the 40% discount Eli Lilly once promised for another China-made PD-1 inhibitor, TYVYT (sintilimab), compared to existing PD-1s. That pricing strategy never materialized after the FDA rejected TYVYT’s approval as a treatment for non-small cell lung cancer, leading Lilly to return the drug to Innovent subsequently.

This approval of LOQTORZI signifies the re-opening of a regulatory pathway previously hindered by COVID-related travel restrictions from China. This development is promising for the pending approvals of penpulimab and camrelizumab.

FDA’s Green Light to another Chinese PD-1: Tislelizumab Shines, Camrelizumab Left in the Dark

After a year delay, BeiGene’s PD-1, TEVIMBRA (tislelizumab), has finally received FDA approval for advanced esophageal squamous cell carcinoma following prior chemotherapy, excluding patients previously treated with a PD-1/L1 inhibitor. The delay stemmed from COVID-related travel restrictions preventing inspections in China. TEVIMBRA, first approved in China in December 2019 for classical Hodgkin lymphoma, now competes with Merck’s KEYTRUDA and Bristol Myers Squibb’s OPDIVO in the US. The FDA is reviewing another TEVIMBRA application in first-line esophageal cancer, with a PDUFA date of December 2024.

While BeiGene’s TEVIMBRA sailed through the tough regulatory pathway of the US, Jiangsu HengRui’s Camrelizumab was left in the middle. In May 2024, the FDA issued a complete response letter for frontline camrelizumab plus rivoceranib for treating unresectable or metastatic hepatocellular carcinoma (HCC). However, the good news is that the FDA rejected the first US filing for camrelizumab not due to insufficient clinical data but because of manufacturing site defects and the inability to inspect some sites in Russia and Ukraine.

HANSIZHUANG (Serplulimab)/HLX10 by Shanghai Henlius Biotech is another potential PD-1 that is expected to be launched by 2025 for extensive-stage small-cell lung cancer. Based on the positive feedback of the FDA, Henlius has initiated a bridging head-to-head trial in US patients with ES-SCLC to evaluate the efficacy of HANSIZHUANG, which propels the product toward US market approval further.

While other PD-(L)1 inhibitors are targeting well-occupied or crowded markets like NSCLC, Envafolimab by Alphamab Oncology is the only Chinese PD-L1 inhibitor targeting undifferentiated pleomorphic sarcoma or myxofibrosarcoma. The company anticipates submitting a BLA to the FDA for accelerated approval in 2024.

BeiGene Becomes the First Company to Secure First Ex-China PD-1 Approval in the European Union

BeiGene waited nearly 2 years to obtain approval for TEVIMBRA (tislelizumab) in the US due to delays in regulatory decisions caused by COVID-related travel restrictions. Similarly, in Europe, BeiGene waited 17 months to receive its first approval for esophageal cancer, as the marketing authorization application (MAA) was accepted in April 2022.

Finally, TEVIMBRA received its first approval in September 2023 for a second-line esophageal cancer indication. However, the company opted not to launch it immediately, instead waiting for the final European Commission approval for three NSCLC indications. It is important to note that both trials underpinning the first-line NSCLC approvals in the EU were conducted in China. However, the FDA has clearly indicated that this approach will not be acceptable for approvals in the US, except for niche indications.

In April 2024, BeiGene obtained a second approval for TEVIMBRA in treating NSCLC, thereby setting the stage for the initial European launches of the Chinese PD-1 inhibitor. As of now, BeiGene is all set to launch TEVIMBRA in the European market, few more approvals in indications, like first-line gastric cancer, ESCC, nasopharyngeal carcinoma, and SCLC, are anticipated in 2025.

BeiGene is not alone in experiencing extended wait times for approval in Europe. Junshi Biosciences also faces delays, with its marketing authorization application for Toripalimab (LOQTORZI) in nasopharyngeal carcinoma and esophageal squamous cell carcinoma, accepted in December 2022 and February 2023 respectively, still awaiting a response from the European Commission.

Another contender in the race to introduce a Chinese PD-1 inhibitor into the European market is Sugemalimab (EQRx and CStone Pharmaceuticals). Currently, two marketing authorization applications for sugemalimab in the UK and EU are actively under review for the treatment of NSCLC. CStone has successfully undergone Good Clinical Practice (GCP) inspection by the European Medicines Agency (EMA) and anticipates approvals for both applications in 2024.

HLX10 (Shanghai Henlius Biotech) and Envafolimab (Alphamab Oncology) are also expected to join other Chinese PD-(L)1 inhibitors in the European market for NSCLC, SCLC and soft tissue sarcoma.

Conclusion

The PD-(L)1 segment in China has been growing rapidly, and several businesses are attempting to market their products in developed nations and other foreign markets. Challenges, including regulatory obstacles, rivalry from well-established pharmaceutical businesses, and disparities in healthcare systems might arise when venturing into well-established markets. However, it also offers significant opportunities for growth and access to a larger patient population.

In the crowded PD-1/PD-L1 inhibitors market, the level of access to TEVIMBRA in the US and EU at the bedside will be crucial for patients weighing increased treatment choices and positive financial impacts, given Coherus’ pricing of LOQTORZI at a 20% lower rate than KEYTRUDA. Given the significant medical demand, these events are sure to be closely monitored by the medical field, patients, and insurance providers.

Success in the competitive field of PD-1/PD-L1 hinges on standing out from the crowd. Companies must make an effort to be creative and target areas where current treatments could be better. Coming out on top in novel measures or addressing a gap can also differentiate businesses in this cutthroat climate. Other PD-1/PD-L1 inhibitors recently developed are spartalizumab (Novartis), sasanlimab (Pfizer), zimberelimab (Arcus Biosciences), INCB99280 (Incyte Corporation), balstilimab (Agenus), and more.