Challenges and best practices for developing Antibody-Drug Conjugates (ADCs)

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Since the first treatment Mylotarg® was approved nearly 25 years ago, many ADCs have been authorized worldwide, with almost 100 new products currently undergoing clinical studies. ADCs are gradually revolutionizing cancer treatment through their potential to deliver highly potent payloads to the specific site of action compared to the off-target toxicity observed with conventional systemic chemotherapy agents. 

In a webinar moderated by Mathias Ditzen, regulatory strategy experts and former regulators, including Michael Craig, VP Technical (ex-MHRA), Sinan B. Sarac, Senior VP and Head of Regulatory Strategy Europe (ex-EMA), Pengfei Song, VP Technical (ex-FDA) and Belén Gracia, VP Technical (ex-AEMPS), provided a comprehensive assessment of ADC development, including, CMC, non-clinical and clinical perspectives. 

Here, we discuss an overview of the challenges and best practices. For more details on the multidimensional aspects of ADCs and their potential to revolutionize cancer treatment, the full 90-minute session is now available to watch on demand.

>>>Watch the ADC webinar now<<<

CMC complexities 

In short, the treatment consists of a monoclonal antibody, which contributes specificity and a long circulation time; the drug, known as the “payload,” which delivers a cytostatic treatment to the site of action; and the drug linker. 

Given the mixed modality, this complex composition creates challenges in CMC management and regulatory approval. These include:

1. Two different intermediates, which require more points of control and therefore more testing.
2. Intensified characterization of the small molecule, the monoclonal antibody, and the conjugated drug substance. 
3. Overall CMC complexity increases the volume of content in the CTD Module 3 section of the investigational and marketing application dossiers, which requires systematic and clear data presentation. While ICH guidelines exist regarding CMC considerations for small and large molecules, there are no ADC-specific CMC guidelines from EMA or FDA, leading to ambiguity in regulatory requirements for intermediates. However, the EFPIA’s draft white paper¹ provides recommendations for reducing risk in comparability studies, control strategies, and data presentation in Module 3. 

Given the complexity of ADC products and regulatory ambiguities in CMC requirements, we recommend frequent communication with regulators, as well as utilization of consultants with strong process and product knowledge (for example, to perform a critical assessment of existing CMC data at key development stages, to identify important gaps and identify solutions). 

The non-clinical strategy 

For ADCs, the non-clinical approach focuses on pharmacodynamics, pharmacokinetics, and toxicology of the product, aiming to identify target organs for toxicity and off-target effects to guide dose selection in clinical trials. Challenges here include selecting relevant animal models, addressing manufacturing process variations, determining the optimal drug-to-antibody ratio, and assessing potential immunogenicity and off-target toxicity. 

However, with adequate pharmacological and toxicological rationale, the non-clinical program and data package to support a marketing application for an ADC product could potentially be simplified. We recommend consultation with nonclinical experts experienced in ADC development to define the most streamlined non-clinical development strategy, and early and regular interactions with regulators for scientific advice to seek ongoing concurrence.

Focus on clinical development

With improved benefit/risk balance, better drug linker technology, and advances in biomarker technology, there is an increasing number of Phase I and II studies of new ADCs, with many expected to progress to Phase III. Successful ADC drug development should also demonstrate favorable clinical benefits/risk profiles to regulators, focusing on three core deliverables: target validation, disease selection, and dose optimization.

Target validation and disease selection

Early incorporation of biomarker development and comprehensive biomarker analysis is crucial for identifying suitable patient populations and meeting regulatory expectations.

We can now better identify the optimal targets that are highly expressed on tumors but minimally expressed on normal tissue cells, through biomarker technology improvements and advances in genomics, proteomics, and screening techniques, with a focus on developing ADCs against multiple epitopes and considering targets in specific metabolic pathways. Combination therapies and companion diagnostics are also being explored to address target heterogeneity and improve patient selection, with seamless and adaptive trial designs providing flexibility in development. 

Dose optimization 

Project Optimus², an FDA initiative, emphasizes the importance of dose optimization before initiating registrational trials in oncology drug development.

ADC dose optimization³ is particularly challenging due to steep dose/exposure-response relationships and structural complexity, necessitating thoughtful considerations and proactive planning. A seamless clinical study design approach, including randomized dose-finding studies and backfilling strategies, can help develop ADC drugs efficiently while meeting regulatory requirements. Key tips for success include presenting a compelling story to a regulatory agency, demonstrating continuous efforts to establish dose optimization, and ensuring the clinical development program reflects consideration of the agency's expectations for addressing target validation, disease selection, and dose optimization simultaneously through randomized dose-finding studies.

Ongoing benefit-risk assessment

Post-marketing surveillance, including extended follow-up periods and patient registries, is also essential to support clinical trial safety findings and risk minimization strategies and provide data to demonstrate the sustained clinical manageability of ADCs' safety profiles.  Post-marketing data enable ADC developers to adapt their programs in response to emerging patient experience information, changes in the treatment landscape, and evolving regulatory requirements.

By considering a multi-perspective approach, and staying informed about regulatory changes, developers can navigate the complexities of ADC development more effectively, potentially bringing these promising cancer treatments to patients faster. 
For more detailed ADCs guidance, please review the listed blogs: 

• Best practices for manufacturing Antibody Drug Conjugates (ADCs)
• Non-Clinical Considerations for Antibody Drug Conjugates (ADCs)
• Regulatory strategies for ADCs
• Identifying Optimal Targets for Antibody Drug Conjugates (ADCs)

Our team of commercial strategists, clinicians, former regulators, and market access experts can partner with you to de-risk your drug development and illuminate the path to commercial success. It is an exciting time for the industry, and we look forward to joining you in the journey to bring important innovations to patients. 

Parexel Biotech offers the personal, responsive, and committed approach of a small CRO, with all the benefits of a large CRO, to help you develop life-changing treatments for patients. Connect with us today. 
 

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References

1. Bechtold-Peters, K et al. CMC Regulatory Considerations for Antibody-Drug Conjugates. 2023. Journal of Pharmaceutical Sciences.
2. Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
3. Guidance for Industry: Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases https://www.fda.gov/media/164555/download

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