United States: Cancer Drugs (Antibody Drug Conjugates): An FDA Perspective

Antibody Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds. ADCs are widely used in the treatment of hematologic malignancies and solid tumors.

In contrast to conventional chemotherapeutic drug-based therapies that are mainly associated with modest specificity and therapeutic benefit, ADCs are composed of three critical components: (1) a monoclonal antibody; (2) bound to a cytotoxic drug; and (3) a chemical linker moiety. They are a class of targeted drugs composed of a payload linked to an mAbs (antibody) that is designed to specifically release their payload at a tumor site. ADCs are capable of achieving clinical benefit in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tumor toxicity. ADCs are being increasingly used in combination with other agents, including as first-line cancer therapies.

The antibody moiety targets a specific cell surface antigen expressed by tumor cells and/or cells of the tumor microenvironment. The antibody acts as a carrier that delivers the cytotoxic payload within the tumor mass. Notwithstanding, the development of ADCs has challenges, including: (a) low tumor selectivity when the target antigens are not exclusively expressed by cancer cells; (b) premature release of the cytotoxic drug into the bloodstream as a consequence of linker instability; and (c) development of tumor resistance mechanisms to the payload. These factors may contribute to a decrease in efficacy and/or in no safety improvement compared to unconjugated cytotoxic agents.

ADCs are subject to all pertinent laws and regulations for biological products, including those governing product development under Investigation New Drug exemptions (INDs), testing, and approval as outlined in section 351 of the Public Health Service Act (42 U.S.C. 262). In March 2024, the U.S. Food and Drug Administration (FDA) issued a guidance on the Clinical Pharmacology Considerations for Antibody-Drug Conjugates. FDA's Guidance specifically outlines clinical pharmacology considerations of ADC development programs.

The FDA Guidance includes regulatory development considerations information in the following areas:

1. Key Considerations for ADC Dosing Strategies, including dosing strategies and external and intrinsic dosing considerations,
2. Clinical Pharmacology, including bioanalytical approaches, dose and exposure response, intrinsic factors for consideration, and pharmacogenomics,
3. Assessment of the product on the QTc interval, (a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart),
4. Immunogenicity, and
5. Drug-Drug Interactions.

As is clearly evident from the comprehensive nature of FDA's guidance as well as the approvals included in the table below, ADCs offer a novel approach to targeted cancer therapy. The diversification of antigenic targets as well as bioactive payloads rapidly broadens the scope of tumor indications for ADCs. Moreover, novel vector protein formats as well as mAbs targeting the tumor microenvironment can be expected to improve the intratumor distribution or activation of ADCs, and consequently their anticancer activity. As with many oncology agents, toxicity remains a key issue in the development of ADCs and better understanding and management of ADC-related toxicities will be essential for further optimization.

These ADCs represent a significant breakthrough in the treatment of cancer. It is important that companies carefully consider their development programs in order to expedite the FDA review and approval process. Both companies and patients benefit from these new treatment modalities. Foley's team of FDA regulatory and clinical trial experts can help companies navigate through product development and FDA's submission, review and approval process.

15 ADCs have been approved as of October 2023 for marketing by the FDA for use in clinical oncology as seen in the table below.

For additional resources on Antibody Drug Conjugates (ADCs) and how they will change the health care & life sciences and technology industries, click here to read the other articles in our series.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.