079: A Review of Immunogenicity & Its Effect on Efficacy & Safety of Biologics as Reported on the Prescribing Label to Support Strategic Thinking & Planning Labeling Communications

Statement of Purpose: US Food & Drug Administration (FDA) published a draft guidance (2022) incorporating immunogenicity information into a new section, 12.6. This section under the Clinical Pharmacology section of the drug product labeling will summarize immunogenicity (anti-drug antibody (ADA)) incidence and its effect on safety, pharmacokinetics (PK) and pharmacodynamics (PD). This review investigated currently available labeling information for biologics to summarize labeling recommendations by regulatory agencies regarding ADA impact on drug efficacy and safety and improve strategic thinking of immunogenicity of biologic drugs in labeling communications.

Description of Methods & Materials: Extensive labeling and literature searches were conducted to collect immunogenicity information of approved biologics drugs through FDALabel , Drugs@FDA and PubMed databases. A database was build-up via FDALabel searching and using the key words including “Biologics License Application (BLA) and New Drug Application (NDA)” for “human prescription drug”, “immunogenicity” for Section 6 of drug labeling, “subcutaneous (SQ) and intravenous (IV)” for administration routes. Subsequently, the database was delineated down to one latest approved BLA or NDA for each active pharmaceutical ingredient (API) via Drugs@FDA and PubMed validation as one API may be approved for multiple indications and with multiple formulations etc. Last but not the least, the immunogenicity responses for each API were summarized and categorized based on these results using BLA or NDA, incidence of immunogenicity and immunogenicity effect on drug safety and efficacy, etc.

Data & Results: There were 342 monoclonal antibodies or peptides identified that had immunogenicity from the FDALabel search, and 173 results (154 BLAs and 19 NDAs) were extracted for each API. Incidence cut off 20% was selected as a search criterion since drugs with ADA incidence < 20% seem to have fewer concerns (with some exceptions) regarding ADA impact on drug efficacy and/or safety. Out of 173 approved BLAs and NDAs, there were 17.9% (25 BLAs and 6 NDAs) with ADA incidence above 20%. Nine of 173 (5.2%) BLA/NDA among these 31 drugs reported ADA impact either on drug efficacy and/or safety. The nine drug APIs are risankizumab-rzaa, taliglucerase alfa, sebelipase alfa, elosulfase alfa, asfotase alfa, sargramostim, metreleptin, tirzepatide and lixisenatide. Among these nine drugs, monitoring hypersensitivity reaction (or anaphylaxis) were recommended, however, the effects of ADA on efficacy were stated but no dose adjustments were required.

Interpretation, Conclusion or Significance: With more requirements for reporting immunogenicity effect on biologic/peptide drugs efficacy and safety, the potential regulatory impact of the high ADA incidence on approvability and label is better understood. Even though ADA incidence or titres were not found to be predictive of effects on PD or efficacy, assays for ADA neutralization and for cross-reactivity with endogenous counterparts will likely be needed in NDA/BLA submission or as a post-market requirement. This analysis may support ADA-based risk mitigation for other biologics and peptide molecules, when the ADA incidence is high.

Disclosures: