Meeting Highlights: DIA China 2021

Preparing for Unknown Risks in Exploratory Clinical Trials: Guideline from China CDE
Yuan Yao
Takeda Development Center Asia

ew treatment areas including gene therapy, cell therapy, oncolytic virus, and proteolysis targeting chimera (PROTAC) products are growing into hotspots for early drug development in China. The recently issued Center for Drug Evaluation (CDE) Technical Guideline for the clinical trials of the oncolytic virus products emphasized methods of risk control in exploratory clinical trials for these products.

Biotechnology researchers in China are building sophisticated platforms to address early development risks and favor PROTAC as a potent technique to target previously undruggable proteins. However, with these opportunities come greater risk in first-in-human (FIH) starting dose selection. Minimum anticipated biological effect level (MABEL) has been widely used to lower this risk.

Oncolytic Virus Products

In February 2021, CDE issued this Technical Guideline to meet the growing number of clinical trial applications (10 approved in the past four years) and standardize communication about these trials with CDE. It emphasizes considering risk in exploratory clinical trials. For example, clinical trials should first be conducted in patients who failed standard treatment; sponsors should focus on pre-existing immunity data in the population; intratumor injection is recommended in solid tumor exploratory studies; and conducting extremely cautious dose escalation is recommended. In addition, risk of the transmission of viruses to untreated individuals should be assessed and shedding data should be collected. Clinical trial applications should be submitted with a separate risk-management plan.

Lacking biomarkers for accurate diagnosis has always been a challenge for oncolytic virus products, which could lead to the arduous and risky trial-and-error process of finding the right target patients. For example, a search of biomarkers for M1 virus recently discovered that the strong oncolytic effect of M1 virus was determined both by the high expression of cell adhesion molecule MXRA8 and the low expression of intracellular biomarker ZAP. This type of dual biomarker will drive a basket trial in multiple malignancies.

Proteolysis Targeting Chimera (PROTAC)

PROTAC is another hot topic. The advantages of PROTAC include targeting previously undruggable proteins; not being limited to a single site target; reduction of dose due to catalytic mechanism; and E3-based tissue-selective targeting. These features could lower the risk of failure in drug development, decreasing the burden of early investment. Twenty years of patent rights to the chemical structure have created even more motivation for the biotechnology industry in China to pursue these therapies.

A successful PROTAC development platform selects the correct cancer target, avoids toxicity while achieving desired tissue distribution, and chooses the proper linking mechanism to optimize oral absorption and other druglike properties. Recent success in using PROTAC to target c-Myc for the treatment of hematologic malignancies demonstrates the power of this technique on previously undruggable targets.

Selecting First-in-Human (FIH) Starting Dose

As novel treatment areas continue to advance, minimum anticipated biological effect level (MABEL) is frequently employed as a method of lowering the potential risk in FIH trials. In 2016, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) convened a Working Group to investigate how MABEL is used to select the FIH starting dose. This group studied 88 molecules across multiple therapeutic areas from 16 companies; about 70% were protein products and 20% were small molecules. Results and the learnings from this survey illustrate that most companies use MABEL, and the most frequently cited reasons include work with molecules with high or unknown risk, first-in-class molecules, and the lack of relevant toxicology species. However, the desired dose was >100-fold higher than the starting dose in about one-third of these projects, which potentially presents unnecessary exposure to healthy volunteers or potential ethical concerns for patients struggling with severe or life-threatening disease.

This Working Group has proposed using a risk-based dose-selection decision tree to choose MABEL or non-MABEL methods to lower the potential risk in FIH trials. This decision should account for safety risks, the availability of relevant in vitro human assays and/or in vivo animal assays for toxicity testing, and the availability of in vitro or in vivo toxicity profiles including high safety risk for FIH subjects. Other recommendations for MABEL determination include using the most relevant (instead of the most sensitive) assay that reflects in vivo efficacy and safety endpoints and employing PK/PD modeling-based approaches to integrating data.