Over 20 Global ADC Clinical Programs Terminated in 2023 Amid Efficacy and Safety Challenges

　　【Pharmaceutical Network Industry DynamicsRecently, Sanofi issued a statement announcing the termination of its global clinical development plan for Tusamitamab Ravtansine (SAR408701, IBI-126), a novel antibody-drug conjugate (ADC) targeting CEACAM5. This decision was primarily based on interim analysis data from the Phase III CARMEN-LC03 study, which evaluated the drug as a second-line treatment for CEACAM5-positive metastatic non-squamous non-small cell lung cancer (nsqNSCLC). The results showed that, compared to docetaxel, tusamitamab ravtansine as a monotherapy demonstrated an improved trend in overall survival (OS) but failed to meet the dual primary endpoint of progression-free survival (PFS).
 

Industry insiders pointed out that Sanofi was not the first pharmaceutical company to stumble in ADC development, and SAR408701 was not the first late-stage clinical ADC to be declared a failure. Data shows that from 2000 to April 2023, a total of 97 ADC projects entered clinical stages but were terminated, including four projects halted in Phase III clinical trials and twelve projects halted in Phase II clinical trials.
 

In addition, relevant reports on the termination of global ADC projects in 2023 with data statistics show that, conservatively, more than 20 ADC clinical pipelines globally were terminated in 2023.
 

Pfizer's CMB-401 is an ADC targeting MUC1. It was terminated in Phase II clinical trials for NSCLC due to poor efficacy, which was considered to be caused by the use of an unstable amd linker leading to premature release of the calicheamicin payload, resulting in less payload reaching the tumor.
 

Novartis' PCA062 is a P-cadherin-targeted antibody-drug conjugate that has demonstrated potent antitumor activity against malignancies expressing P-cadherin. It entered Phase I clinical trials in 2015, with a total of 47 patients participating. However, in the Phase II clinical trial, all patients experienced at least Grade 1 adverse events (AEs), and 32 patients had AEs of Grade ≥3. Among them, 37 patients reported AEs suspected to be related to the study drug PCA062. Ultimately, Novartis announced the termination of PCA062's clinical development due to limited antitumor activity at the maximum tolerated dose (MTD) level.
 

AbbVie's journey in the ADC field has not been smooth, with seven of its ADCs having been terminated. In 2023, AbbVie continued to scale back its ADC pipeline, cutting ABBV-154, ABBV-011, and ABBV-647. Among them, ABBV-154 is a new ADC that was upgraded from ABBV-3373, mainly optimizing linker technology, showing higher therapeutic potential compared to its predecessor. Although it successfully advanced to Phase II clinical trials, it was terminated due to observed changes in biomarkers and high-dose systemic glucocorticoid exposure, which resulted in an insufficient risk-benefit ratio and an inability to differentiate from other therapies.
 

In the Chinese market, Tot Biopharm also announced in March 2023 that, regarding the HER2-targeted antibody-drug conjugate TAA013 independently developed by the group, a comprehensive and cautious analysis and evaluation of the drug's future commercial value and market sales performance had been conducted. In alignment with the company’s strategic planning, the decision was made to terminate the Phase III clinical trial and development of TAA013 in China.
 

Analysts said that although ADC drugs have entered the mature stage after decades of development, and 15 ADCs have been approved globally, bringing significant clinical benefits to cancer patients, the R&D of ADC drugs has not been smooth sailing. To date, nearly 100 ADC clinical pipelines have been terminated, most of which were due to on-target/off-tumor toxicity and insufficient efficacy.
 

Facing the development of a new generation of ADCs in the future, analysts said that companies need to start from the components of ADCs, comprehensively consider antibodies, linkers, and payloads that match the characteristics of indications and targets, in order to build safer and more effective ADC drugs.
 

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