Clarion Blog

By: Dennis Chang, Ph.D., managing director and Letao Fan, Ph.D., senior associate

In 2022, China was at the center of a significant amount of international news coverage, most of which focused on the ongoing COVID-19 pandemic, including widespread lockdowns. These reports painted a picture of disruption to society and the economy. However, China’s oncology pipeline seems more robust than ever. The 25^th Annual Meeting of Chinese Society of Clinical Oncology (CSCO) showcased signs of growth and acceleration in the oncology pipeline.

Impressive numbers of oncology programs

At CSCO’s opening session, officials from China’s Center for Drug Evaluation (CDE), part of the National Medical Products Administration (NMPA; formerly the China FDA), provided a review of the year’s clinical and regulatory activities in oncology (Jan through Oct 2022) and the numbers are startling.

• New clinical trials: CDE reported 1378 new oncology clinical trials initiated, almost a quarter (23.9%) of all oncology clinical trials initiated worldwide during the first 10-months of 2022 [1]. An analysis of ClinicalTrials.gov found 1574 interventional trials in U.S. sites within the same time frame [2].
• Investigational New Drug applications (INDs): CDE reported 871 oncology INDs, almost half of the 1941 INDs registered across all therapeutic areas in the 10-month period [1]. By comparison, for the 12-month period from Oct 2020 through Sep 2021, FDA reported only 777 IND applications received across all therapeutic areas [3].
• New Drug Applications (NDAs): CDE reported 63 oncology NDAs registered out of total of 268 NDAs in the 10-month period, and 55 NDA approvals [1]. By comparison, the FDA announced 30 oncology approvals in that same time period [3].

Thus, China is closing in on the U.S. in terms of the number of oncology clinical trials—and exceeding the U.S. in oncology INDs and NDAs. This is the culmination of steady growth in oncology clinical development since China enacted a major regulatory reform, the 2017 Opinion Regarding the Stimulation of Pharmaceutical Innovation and Implication of Priority Review and Approval (the “2017 Opinion,” 《关于鼓励药品创新实行优先审评审批的意见) [4]. This growth has continued even after the Priority Review pathway established in the 2017 Opinion was narrowed substantially in 2020 with the New Administrative Measures for Drug Registration (the “2020 New Measures,” 新《药品注册管理办法》) [5], though the pace of growth is expected to slow moving forward [1].

Figure 1. (A) Numbers of IND registrations in China from 2018 to October in 2022. The total number of IND registrations in that year is shown in blue, the number of oncology INDs is shown in orange. (B) Numbers of NDA registrations in China since 2018 to October in 2022. The total number of NDA registrations in that year is shown in blue, the number of oncology NDAs is shown in orange [1].

…but how new are China’s new products?

The impressive number of clinical programs are tempered by the relatively limited extent of new product innovation. As of October 31, 2022, out of 55 oncology approvals in China, there were only four new therapeutics approved for their first indication that also originated in China:

• Ripertamab (瑞帕妥单抗注射液), a recombinant human-mouse chimeric anti-CD20 IgG1 mAb developed by SinoCellTech
• Serplulimab (斯鲁力单抗注射液), a recombinant humanized anti-PD-1 mAb, developed by Shanghai Henlius Biotech
• Rezvilutamide (瑞维鲁胺片), a small-molecule androgen receptor (AR) antagonist, developed by Jiangsu Hengrui Pharmaceuticals
• Cadonilimab (卡杜尼利单抗注射液，双抗), an anti-PD1 × CTLA4 bispecific mAb, developed by Akeso Bio

Among these four homegrown new products, only one constitutes as a first-in-class approval; cadonilimab is the first anti-PD1 × CTLA4 bispecific to be approved worldwide. The remaining products fall into well-established drug classes. Similarly, many new data presentations at CSCO 2022 were for new Chinese products with mechanisms of action proven by others. Examples include Dizal’s sunvozertinib, an EGFR exon 20 small-molecule inhibitor similar to Takeda’s mobocertinib, or Zentera’s ZN-c3, a WEE1 inhibitor similar to AstraZeneca’s adavosertib (AZD1175).

While China continues to generate only a small number of first-in-class new drugs, the fact remains that China has demonstrated the ability to do so. Furthermore, the “me-too” products that China develops are competitive with their Western counterparts. For example, ripertamab demonstrated non-inferiority to rituximab in a head-to-head phase 3 trial, with numerically lower rates of anti-drug antibodies [6], and serplulimab improved OS in a phase 3 trial for first-line treatment for extensive-stage small-cell lung cancer (1L ES-SCLC) [7], an indication where pembrolizumab failed to do the same [8].

China is planning a surge of investment in antibody-drug conjugates (ADCs)

Serplulimab is the most recent of nine China-originated PD1/PD-L1 inhibitors approved to date; there are dozens of others in the clinical pipeline including, bispecifics like cadonilimab and other variant molecules. This profusion of therapeutics targeting the PD1/PD-L1 axis are the fruits from a surge of investment made by the Chinese biopharma industry in immune checkpoint blockade after seeing the success in the West of nivolumab, pembrolizumab, and others. Although immunotherapy investment continues, China has declared a new focus area for investment and innovation: ADCs [9].

In June and September 2022, China’s CDE issued two guidelines to foster ADC research and development: the ADC Non-Clinical Research Principle Guideline (the “Non-Clinical Guideline,” 《抗体偶联药物非临床研究技术指导原则》) and Oncology ADC Clinical Research Principle Guideline (the “Clinical Guideline,” 《抗肿瘤抗体偶联药物临床研发技术指导原则》). The Non-Clinical Guideline advises pharmacology, pharmacokinetics, and toxicity research to support clinical development, while the Clinical Guideline highlighted considerations in the development of ADCs targeting the same antigen using different payloads, targeting tumors with different expression level of antigens, optimization of administration and dosing strategy in clinical studies, concerns for off-target risks, and applications in combination therapies. The CDE official called out the U.S.’ focus on ADCs as well, and benchmarked China’s ADC research guidelines to U.S.’ Clinical Pharmacology Considerations for ADC Guidance for Industry that FDA issued in February this year.

To date, the development of ADCs in China includes 24 targets (Figure 2) [9]. In line with China’s historical proclivity for copying successes made in other countries, there is a heavy emphasis on targets established by ADCs already, such as HER2, Trop2, and Nectin-4. However, there are also examples of innovation and leadership; China is leading the world on the development of Claudin18.2-targeted ADCs, and is also racing against Western countries to be the first to launch ADCs against known oncoproteins such as c-Met and EGFR.

Figure 2. Oncology ADC targets at clinical stage in China. Numbers of preclinical products are shown in grey, phase I in light blue, phase II in blue, phase III in yellow, NDA/marketed products shown in red [9].

Takeaways for the West

China’s biopharma industry should not be underestimated. Although the majority of China’s home-grown pipeline consists mainly of “me-too” therapies, the pipeline has grown vast and includes examples of first-in-class and potentially best-in-class products as well. When China invested full-throttle into immunotherapy, the generation of Chinese anti-PD1/PD-L1 products eventually exceeded that of all other countries combined, and included the world’s first approved anti-PD1 × CTLA4 bispecific. China is poised to do the same for ADCs and continues to develop prolific numbers of other therapeutics as well.

So, what should top global biopharma companies do?

• Up your game. Although the U.S. FDA has soundly rejected applications based only on Chinese clinical data [10], and thus China-developed products will not imminently flood the U.S. market, that is not a reason to become complacent. For every blockbuster that global companies develop, Chinese biopharma companies will generate multiple products with clinical profiles at least as good. Maintaining leadership will mean relentless improvement and innovation in an increasingly competitive global field.
• Make deals. The rise of good drugs from China may pose a competitive threat but also a tremendous BD&L opportunity. Many have adopted this strategy already including Janssen who licensed CAR-T cell therapy cilta-cel (Carvykti, FDA-approved in Feb 2022) from Legend Biotech based in Nanjing [3], and a variety of companies, large and small, that have in-licensed investigational programs [11].

If we rise to the challenge in these ways, then the resulting increase in productivity and innovation in oncology therapeutics will be a boon to cancer patients and their families.

Clarion, a Lumanity business, is committed to partnering with biopharma clients to anticipate evolving market dynamics and navigate their toughest challenges. Please contact us if you would like to learn more. For more information, visit www.clarionhealthcare.com and follow us on Instagram and LinkedIn.

Sources

[1] Zhiming Yang, 2022 Report on Evaluation of New Drugs in Oncology in China, CSCO 2022.

[2] Clinicaltrials.gov

[3] FDA.gov

[4] NMPA website: Policy illustration – Opinion Regarding the Stimulation of Pharmaceutical Innovation and Implications of Priority Review and Approval (Suspended) https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/zhcjd/tjzhc/tjzhcyp/20180112093701550.html

[5] NMPA website: Administrative Measures for Drug Registration https://gkml.samr.gov.cn/nsjg/fgs/202003/t20200330_313670.html

[6] Shi 2022 Hematol Oncol 40:930.

[7] Cheng 2022 JAMA 328:1223.

[8] Rudin 2020 J Clin Oncol 38:2369.

[9] Lin Xia, Oncology ADC Clinical Development and Review Considerations, CSCO 2022.

[10] Plieth, U-turn confirms that the US cut-price oncology model is dead. Evaluate Vantage, Nov 10, 2022.

[11] DealForma