Roche's Kadcyla Nears Approval in China, Set to Fill Domestic ADC Drug Gap

Text | Zhang Hongli

Recently, the National Medical Products Administration updated Roche’s HER2-ADC drug, ado-trastuzumab emtansine for injection (brand name: Kadcyla^®) processing status has changed to "Under Review," and it is expected to be approved for marketing in the near future.

On March 27, 2019, the marketing application for Kadcyla in China was accepted by the Center for Drug Evaluation (CDE), with acceptance numbers JXSS1900012/13, and it entered the priority review pathway in June 2019. If approved smoothly, trastuzumab emtansine will become the first antibody-drug conjugate (ADC) drug to be marketed in China.

Kadcyla is composed of trastuzumab (the active pharmaceutical ingredient in Herceptin) linked to ImmunoGen’s cytotoxic agent DM1 via a stable linker, forming a conjugate that delivers DM1 to HER2-positive breast cancer cells. Approved for marketing in 2013, Kadcyla is the first and only antibody-drug conjugate approved as a single agent for the treatment of patients with HER2-positive metastatic breast cancer who have previously received Herceptin and taxane chemotherapy, either separately or in combination.

Antibody-Drug Conjugates (ADCs) are a novel class of targeted anti-tumor agents that utilize monoclonal antibodies to deliver conjugated cytotoxic drugs specifically to tumor cells, thereby enhancing the therapeutic efficacy of the antibody, improving the targeted cytotoxicity against tumor cells, and reducing adverse effects on normal tissues.

In 2000, Mylotarg, the world’s first antibody-drug conjugate (ADC), received FDA approval for the treatment of acute myeloid leukemia. However, due to limitations in conjugation technology, targeting specificity, and efficacy, the intact ADC exhibited instability in the bloodstream, leading to fatal toxicities and resulting in its voluntary withdrawal from the market in 2010. In September 2017, Mylotarg was re-approved by the FDA.

Although antibody-drug conjugates (ADCs) have complex structures, they offer advantages such as high specificity, strong selectivity, and reduced systemic cytotoxicity. As the technology continues to mature, ADCs have become a focal point and key direction in the research and development of targeted cancer therapies. In recent years, seven ADC drugs have received FDA approval for market launch, and dozens of additional ADC candidates worldwide have entered clinical trials.

Table 1 FDA-Approved ADC Drugs on the Market

Note: * indicates the date of re-approval after market withdrawal.

Among the marketed ADC drugs, Kadcyla demonstrated the best market performance. According to Roche’s annual report, the drug’s global sales in 2018 amounted to CHF 979 million (approximately USD 1.001 billion).

Currently, no antibody-drug conjugate (ADC) drugs have been approved for marketing in China. Among the ADC drugs under development domestically, those targeting HER2 are the most numerous. HER2 is a member of the human epidermal growth factor receptor (EGFR) family of proteins. HER2-positive breast cancer accounts for approximately 20% to 25% of all breast cancers; this subtype is highly aggressive and associated with a poor prognosis. According to a report by Frost & Sullivan, the number of patients with advanced HER2-positive breast cancer in China increased from 15,700 in 2014 to 16,900 in 2018, representing a compound annual growth rate (CAGR) of 1.8%. The number of such patients in China is projected to reach 18,200 by 2023, and then continue to grow at a CAGR of 1.0%, reaching 19,600 by 2030.

In addition to Roche, several domestic companies have also begun to layout the ADC drug market, including Bio-Thera Solutions, RemeGen, Hengrui Medicine, Zhejiang Medicine, CSPC Pharmaceutical Group, Fosun Pharma, and Shanghai Jiaolian. Among them, the ones with faster progress are BAT8001 (Phase III) from Bio-Thera Solutions and RC48 (Phase II) from RemeGen, while others are all in Phase I clinical trials.

Table 2 Anti-HER2 Monoclonal Antibody ADC Drugs in China That Have Entered Phase II Clinical Trials or Beyond