PII-180 - CLINICAL PHARMACOLOGY CONSIDERATIONS FOR FIRST-IN-HUMAN CLINICAL TRIALS FOR ENZYME REPLACEMENT THERAPY

S. Stern¹, J. Wang², R. Li³, R. Schuck³, M. Pacanowski³; ¹U.S. Food and Drug Administration, Silver Spring, MD, USA, ²U.S. Food and Drug Administration, Silver Spring, Maryland, , ³U.S. Food and Drug Administration.

Background: Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are diseases caused by deficiency or reduced activity of a single enzyme. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme. Clinical studies of ERT in healthy subjects are usually not recommended because of potential safety concerns resulting from cross-reactivity of anti-drug antibodies with endogenous enzyme. However, few patients may be available for enrollment in early phase clinical trials of ERTs. Therefore, designing an informative first-in-human (FIH) clinical trial is critical to streamlining drug development for ERT.

Methods: We reviewed FIH protocols, prescribing information, and FDA reviews for 17 Biologics License Applications (BLAs) for ERT approved by the U.S. Food and Drug Administration (FDA) from May 1994 to July 2023. The documents were surveyed to characterize the features of the FIH studies.

Results: Of the 17 FIH studies, 94% (n=16) studies were conducted in patients (i.e., not in healthy subjects) and 71% (n=12) studies used single or multiple ascending dose study design. Although the primary objective of FIH studies is usually evaluation of tolerability and safety, 71% (n=12) of the FIH studies included clinical endpoints and 94% (n=16) included biomarker assessments as secondary or exploratory objectives. Intravenous route of administration (ROA) was used in 88% (n=15) and weight-based dosing was used in 88% (n=15) of the FIH trials. All 17 FIH studies included immunogenicity assessment and 53% (n=9) provided a specified pretreatment of antihistamines with/without antipyretics prior to ERT administration. Likely because treatment withdrawal and retreatment may increase immunogenicity-related safety concerns for ERT, 47% (n=8) of FIH studies were followed by an open-label extension phase or allowed patients to enroll into a subsequent clinical trial.

Conclusion: Overall, patients with the approved indication were predominantly the target population in the FIH trial for ERT and frequently, the ROA and doses tested in the FIH trial included the ROA and doses in the approved label. Our review of the FIH studies for the approved ERTs demonstrates trends in the study design and may inform clinical pharmacology assessment for future clinical trials for ERT.