PII-001 - APPROVED THERAPEUTIC PROTEINS WITH CHALLENGES IN CLINICAL ENDPOINTS EVALUATION WHERE PHARMACODYNAMIC BIOMARKERS MAY IMPROVE EFFICIENCY OF BIOSIMILAR DEVELOPMENT

A. Le, Y. Wang, Q. Sun; U.S. Food and Drug Administration, Silver Spring, United States.

Background: Therapeutic proteins (TPs) are expensive, and the cost could be >$1,000,000 per patient per year for most expensive ones. More than 230 TPs have been approved, but only 11 ( < 5%) have biosimilars approved. Most biosimilar programs include a comparative clinical study (CCS) in patients, which is costly and could be challenging or infeasible for some TPs. Pharmacodynamic (PD) biomarkers are generally more sensitive than clinical endpoints and may eliminate the need for a CCS in biosimilar programs. We conducted this study to identify TPs with challenges in CCS, which are in urgent need of PD biomarkers.

Methods: We first defined challenging factors as: a) long duration for efficacy evaluation, b) challenging sample size (n≥1000) or (n≤100, very rare disease), and c) indicated for young pediatrics only (≤12 years). Using FDA’s purple book and labeling we identified TPs with challenges in CCS, then characterized those TPs and investigated potential roles of PD biomarkers to provide case examples for addressing each defined challenging factor. Additional considerations and challenges remained were also evaluated.

Results: For 235 TPs approved by 2022, 108 (46%) have challenging factor(s), while none of 11 TPs with approved biosimilars has any challenging factor. Of these 108 TPs, 65/39/4 TPs are associated with 1/2/3 of the three defined challenging factors, and 71/56/16/11 are associated with long evaluation duration/very rare disease/large sample size/young pediatrics only, respectively. TPs with challenging factors have increased over time, and mainly impact treatments for cancer (41% of 108 TPs), cardiometabolic and endocrine (17%), inflammation and immune (15%), inborn-errors of metabolism (14%) diseases. Use of PD biomarkers can reduce study duration and sample size (e.g., natalizumab), facilitate biosimilar development for a very rare disease (e.g., velmanase alfa), and may address challenges for TPs indicated for young pediatrics only (e.g., palivizumab).

Conclusion: Our research suggests more challenges exist in future biosimilar development for more diversified TPs. PD biomarker can help address challenges of CCS, although challenges remain for some TPs (e.g., TPs for young pediatrics only). Investigation of potential PD biomarkers is essential to facilitate biosimilar development, especially for TPs with challenges in CCS.