1 / 17

Blood Products Advisory Committee November 4, 2005 Post-Licensure Commitment Study for Zemaira ® , Alpha 1 -proteinase

Blood Products Advisory Committee November 4, 2005 Post-Licensure Commitment Study for Zemaira ® , Alpha 1 -proteinase inhibitor (Human). Dr. Otto-Erich Girgsdies, ZLB Behring, Clinical Research Department, Marburg, Germany. Approval of Zemaira ® BLA.

rumer
Download Presentation

Blood Products Advisory Committee November 4, 2005 Post-Licensure Commitment Study for Zemaira ® , Alpha 1 -proteinase

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Blood Products Advisory CommitteeNovember 4, 2005Post-Licensure Commitment Study forZemaira®, Alpha1-proteinase inhibitor (Human) Dr. Otto-Erich Girgsdies, ZLB Behring, Clinical Research Department, Marburg, Germany

  2. Approval of Zemaira® BLA The biochemical efficacy and safety was assessed in 4 clinical studies involving 90 Zemaira®-treated subjects with A1-PI deficiency. This clinical program demonstrated that: • Zemaira® augments and maintains serum levels of A1-PI above the historic target threshold of 11 µM and raises A1-PI levels in the ELF of the lower lung. • Zemaira® has a similar PK profile and similar mean steady-state serum trough antigenic levels compared to another commercially available A1-PI augmentation therapy.

  3. Post-Licensure Commitment Study A Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase III/IV Study to compare the Efficacy and Safety of 60 mg/kg body weight of Zemaira® weekly i.v. administration with Placebo weekly i.v. administration in Chronic Augmentation and Maintenance Therapy in Subjects with Emphysema due to Alpha1-Proteinase Inhibitor Deficiency

  4. Design • Multicenter, randomized, placebo-controlled, double-blind • Weekly dosing, 60 mg/kg body weight • Two years observation period

  5. Inclusion Criteria • 18 – 60 years of age • Diagnosis of Alpha1 deficiency • Emphysema and FEV1>35 and <70% predicted

  6. Primary Endpoint • Lung density, measured by Computed Tomography (CT) scan • (0, 3, 12, 21, and 24 Months)

  7. Secondary Endpoints • Exacerbations • Lung function (FEV1 and DLco) • Exercise capacity • Body mass index • Tolerability • Mortality • Quality of life

  8. PulmonaryEmphysema • Loss of lung tissue • Decreased pulmonary blood flow • Increased areas of air trapping • Decrease in X-ray attenuation

  9. Histogram Emphysema Frequency Distribution Normal 0 -1000 -380 15th Percentile Points Shift in Lung Density Distribution due to Emphysema Density (Hounsfield Units)

  10. CT Acquisition Protocol • Optimized for density resolution • spatial resolution of minor importance • thick slices (5mm) and low energy (140kV, 40mAs) • radiation exposure down to 1.0 - 0.7 mSv effective dose • validated protocol available for multi-slice CTs • same scanner must be used throughout the study • all scans must be acquired according to the final acquisition protocol Stoel BC et al. Invest Radiol 2004;39:1:1-7

  11. Control of Inspiration Level • Duplicate CT reduces error in lung density estimation • at full inspiration level • at functional residual capacity reduces sample size requirement by a factor of up to 3.8 irrespective of effect size and power publication prepared by Stoel BC et al. abstract at European Respiratory Society, Copenhagen, 17-21 Sep 2005

  12. Software, Core Lab, Phantom • Software program: PULMO_CMS • Designed by the Division of Image Processing of the Department of Radiology, Leiden University Medical Center • Bio-Imaging Technologies, Inc. CT Image Core Lab Services

  13. Structural Differences between Zemaira, Prolastin, and Aralast Val Romberg, ZLB Behring, US Technical Operations, Kankakee, IL

  14. A1-PI A1-PI A1-PI Cys-S-S-Glutathione Cys-SH Cys-S-S-Cys The Cysteine Amino Acid Residue in A1-PI • In vivo, the cysteine residue exists in both the reduced and oxidized state. Free/Reduced Mixed Disulfide/Oxidized • Laurell, C.-B in The Chemistry and Physiology of the Human Plasma Proteins: Proceedings of Conference (Bing, D.M., ed) pp. 329-341, Pergamon Press, New York (1979) • Tyagi, S. C. and Simon, S. R., Biochemistry, 31, pp. 10584-10590 (1992)

  15. The Cysteine Amino Acid Residue in A1-PI • Mass Spectrometry analysis was performed on Zemaira, Prolastin, and Aralast • In Zemaira the cysteine is predominately free/reduced • In Prolastin and Aralast, the cysteines are predominantly bound to cysteine • Upon infusion, all products equilibrate to the natural state.

  16. The Terminal Lysine in A1-PI(H) • Mass Spectrometry analysis was performed on Zemaira, Prolastin, and Aralast • In Zemaira and Prolastin the terminal lysine is predominantly present • In Aralast, the terminal lysine is predominantly absent

  17. Thank you!

More Related