1. Topic II: Heterogeneity of Commercial Alpha-1- Proteinase Inhibitor (Human) [A 1 PI ] Products – Implications for Longer-Term Safety and Efficacy? Introduction and Questions to the Committee Andrew Shrake, Ph.D., OBRR/CBER/FDA

2. The physiological target of alpha-1-proteinase inhibitor (  1 -PI) is neutrophil elastase. Individuals homozygous for mutant  1 -PI (Z mutant) have low circulating levels due to the tendency of Z mutant to form inclusion bodies within hepatocytes.  1 -PI deficient individuals have COPD and usually progressive ultimately fatal emphysema due to the action of uninhibited elastase in the lower lung, and some manifest chronic liver disease including hepatocellular carcinoma. Such deficient patients receive  1 -PI replacement therapy to slow the rate of progression of emphysema.

3. Currently, three plasma-derived A 1 PI products are approved for augmentation therapy of patients with severe hereditary  1 -PI deficiency: Prolastin (Talecris, Dec. 1987) Aralast (Baxter, Dec. 2002) Zemaira (Behring, July 2003) 60 mg of functional  1 -PI per kg of body mass is administered i.v. weekly to maintain antigenically measured plasma levels of  1 -PI at  11  M.

4. September 16, 2004: Dr. Brantly contacted our lab concerning an atypical isoelectric focusing (IEF) pattern found in sera of patients receiving Aralast. September 24, 2004: CBER initially contacted Baxter to request lots for IEF analysis both by CBER and Baxter. October 14, 2004: The Alpha One Foundation contacted the CBER Center Director’s Office reporting the same observation, but from a different laboratory. October 15, 2004: CBER contacted Baxter again and requested pharmaco-vigilance data, an inventory of samples (of product and serum), Baxter IEF results, and identification of root cause. Chronology

5. October 20, 2004: Baxter speculated the additional IEF band is a rare glycoform, highly enriched in Aralast, whereas CBER suggested an anodic shift by a whole negative charge of most of the major bands. CBER IEF results also demonstrated consistency of manufacture back to conformance lots. November 2004: CBER continued the investigation by comparing IEF properties of all three products with those of plasma and reported the results to CBER management on December 7, 2004. Shortly after, CBER confirmed consistency of atypical IEF properties of Aralast during the phase III clinical trial. January 11, 2005: The Alpha One Foundation sent a letter to patient users concerning the IEF pattern of Aralast. June 9, 2005: Baxter presented results of a biochemical analysis of Aralast.

6. A 1 PI Topics: Observations on Marketed A 1 PI Products (Ewa Marszal, CBER) Identification and Possible Implications of a Human Plasma Purified Anodal Variant of Alpha-1-Antitrypsin (Mark Brantly, University of Florida Medical School) Characterization of Aralast Compared to Other A1PI Preparations (Hans Peter Schwarz, Baxter Healthcare, Vienna Austria) Safety Reporting for A 1 PI Products (Tina Khoie, CBER) Post-Marketing Study Commitments for Licensed A 1 PH Products  Rationale (Ross Pierce, CBER) Licensed Therapeutic Protein Products with Known Structural Modifications (Andrew Chang and Kurt Brorson, CBER)

7. QUESTIONS FOR BPAC Based on the differences in primary structure of  1 -PI and the concentrations of polymers in A 1 PI products, does the Committee have any comments and/or recommendations regarding: a. The adequacy of the requested/planned post- marketing commitment studies to evaluate the longer-term safety and efficacy of A 1 PI products, as measured by specified clinically meaningful endpoints? b. The adequacy of the proposed safety monitoring programs? c. Any other suggested actions (e.g., additional communications through labeling or other venues)?