019: Clinical Pharmacology Insights into Dosing Strategies of Approved Antibody-Drug Conjugates

Statement of Purpose, Innovation or Hypothesis: Over the past decade, Antibody Drug Conjugates (ADCs) have quickly emerged, capitalizing upon the success of specificity of antibodies and to minimize drug toxicity of potent payloads/warheads without compromising efficacy. Currently there are 11 ADCs approved by US FDA of which 8 were approved between 2017 through 2023, reflecting upon the steady growth observed in this field. With continued interest in this modality, it is important to understand how the knowledge of current ADCs could be used to conduct dose selection of the future ADCs. Given the similarities across payloads and/or mechanism of actions, learnings from approved ADCs were extrapolated towards drug development of future ADCs.

Description of Methods & Materials: A dataset comprising all approved Antibody-Drug Conjugates (ADCs) was compiled using US FDA labels, on doses evaluated in First-in-Human (FIH) dose escalation and selection, Pharmacokinetic (PK) characteristics, Population PK analysis, Drug-Drug interactions, Exposure-Response analysis, Adverse Event, Immunogenicity, Post marketing requirement and Post marketing commitments. The primary source of data for doses evaluated was the “Clinical Pharmacology Biopharmaceutics Review(s)” or “Multi-Discipline Reviews”. However, in instances where accelerated approval was granted, with data from preliminary clinical trial data from smaller cohorts the clinical pharmacology updates available online, including published articles, abstracts, and relevant sources were also utilized.

Data & Results: Starting dose for First-in-human studies, ranged from 1/6th to 1/37th of the highest non-severely toxic dose in non-human primates. Except for Trodelvy, the starting doses of all ADCs ranged from 0.015 -0.8 mg/kg, IV, Q3W; while it was 8 mg/kg, IV for Trodelvy. Dose escalation progressed through up to 6 dose levels where increments of 25-265% were pursued at the first 2 dose levels followed by increments of 33% for remaining dose levels (only 4 dose levels were tested for Trodelvy). For almost 70% of the ADCs, MTD was achieved and for 40% of them the RP2D and the P3D were equivalent to the MTD; approved doses ranged from 1.25-fold to 40-fold higher than FIH starting dose levels. Most ADCs exhibited dose-proportional pharmacokinetics based on analyte ADC or total ADC; exposure-response analyses for efficacy/safety demonstrated meaningful correlations between ADC or payload exposures vs efficacy/safety. While DDI potential appears to be low, MMAEs and Maytansinoid class of payloads may have the potential to interact with CYP3A inhibitors and carries a label warning for monitoring purposes; similarly, camptothecin containing payloads are contraindicated with UGT1A1 inhibitors. At approved doses, immunogenicity assessments indicated varying incidence rates of antidrug antibodies across different ADCs, with limited impact on pharmacokinetics, safety, or efficacy observed in most cases.

Interpretation, Conclusion or Significance: This work summarizes approved ADCs and dosing strategies from end-to-end clinical development based on their clinical pharmacology characteristics. By conducting an analysis of US FDA labels of all approved ADCs w.r.t first-in-human, dose escalation, exposure-response relationships (efficacy and safety), and immunogenicity the review provides invaluable insights into dosing of ADCs during clinical development. Through synthesizing existing knowledge this work informs the key challenges and opportunities of ADC therapeutics.

Disclosures: This work has been done as a part of my 2023 Summer Internship at AstraZeneca.

Additional Information/Authors: Acknowledgements: Dr. Bernd Meibohm (The University of Tennessee Health science Center), Dr. Shankar Lanke (AstraZeneca)