Heterogeneity of Alpha-1 Proteinase Inhibitor (Human) Products
The U.S. licensed Alpha-1 Proteinase Inhibitor (Human) (α1-PI) plasma derived products are somewhat heterogeneous in terms of protein composition and chemical structures.1 In addition to α1-PI, these commercial products contain different amounts of other plasma proteins and different levels of inactive protein species, e.g., aggregates formed during product manufacturing. They also contain chemical modifications which arise during manufacturing and occur at minor to substantial levels varying from product to product. These modifications may include deamidation, presence of free (reduced) cysteine, and truncation of the C-terminal lysine. The effects, if any, of these variations/alterations in chemical structure on safety and/or efficacy may be product-dependent and are evaluated in pre- and post-licensure clinical trials and postmarketing surveillance of adverse events.2
Currently, there is no evidence demonstrating that these structural variations or modifications affect the activity, efficacy, safety, and immunogenicity of α1-PI. Some of the modifications mentioned above affect protein charge and give rise to distinct isoelectric focusing (IEF) patterns. FDA's and manufacturers' review of IEF patterns of different product lots over time have demonstrated consistency in the IEF pattern starting with lots from pre-licensure clinical trials up to those currently manufactured. Additional post-marketing studies are being performed by each manufacturer to evaluate the longer-term safety and efficacy of α1-PI products, as measured by specified clinically meaningful endpoints.3
On May 4, 2007, the U.S. Food and Drug Administration (FDA) announced the approval of Aralast NP® (Baxter Healthcare), a new version of the α1-PI product Aralast®. Aralast NP® is a similar product to Aralast, containing the same active component and identical formulation. As stated above, all U.S. licensed α1-PI plasma derived products contain chemical modifications which arise during manufacturing and occur in varying levels from product to product. Aralast NP® contains approximately 2% α1-PI with truncated C-terminal lysine (removal of Lys394), whereas Aralast® contains approximately 67% α1-PI with the C-terminal lysine truncation. No known data suggest influence of these structural modifications on the functional activity and immunogenicity of α1-PI. Aralast NP® will join the already-licensed α1-PI products, Aralast® (Baxter Healthcare), Prolastin® (Talecris Biotherapeutics) and Zemaira® (ZLB Behring), indicated for individuals with Alpha-1-Antitrypsin Deficiency and evidence of lung emphysema.
1 Discussed by the Blood Products Advisory Committee, November 4, 2005, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4190B2_01_issue%20summary.pdf
2 In an effort to gather additional information about α1-PI products, the FDA urges health care providers and patients to report suspected adverse event information to FDA via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/how.htm, and/or to the product manufacturer.
3 http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4190M1_quick%20minutes.htm