1. Postmarketing Clinical Studies of A 1 PI Products L. Ross Pierce, M.D. Medical Officer, Clinical Review Branch, Div. of Hematology, FDA

2. QUESTIONS FOR THE COMMITTEE: Based on the differences in primary structure of A 1 PI…, does the Committee have comments/ recommendations re: –Adequacy of requested/planned post- marketing commitment studies to evaluate the longer-term safety & efficacy of A 1 PI products, as measured by specified clinically meaningful endpoints? –Adequacy of proposed safety monitoring programs ?

3. Pre-marketing Clinical Studies of Intravenous A 1 PI Products Pivotal trials (14 - 30 subjects) based on the biochemical surrogate endpoints, antigenic A 1 PI and neutrophil elastase inhibitory capacity: –Maintenance of trough steady state serum levels greater than arbitrary threshold and not inferior to that of Prolastin –Levels in bronchopulmonary lavage (BAL) fluid significantly greater than pre-treatment –6 month safety data including anti- A 1 PI antibodies.

4. Sponsors of all 3 US-licensed A1PI products to conduct postmarketing studies to help evaluate efficacy in terms of clinically meaningful endpoints directly relating to emphysema. –Prolastin: Epidemiology study completed –Zemaira: Placebo-control RCT approved –Aralast: RCT requested, final protocol pending

5. Prolastin Postmarketing Study Completed “NIH Registry [Epidemiology] Study” –At the time, a RCT thought unfeasible –Non-Randomized Design incapable of validating PK surrogate –No testing of A 1 PI blood levels –Large numerical imbalances –Am. J. Respir Crit Care Med 1998;158:49-59

6. NHLBI Registry Study Outcomes Decreased mortality among those who received A 1 -PI (Prolastin, RR 0.64, 95% CI 0.43-0.94 (p = 0.02) No difference in rate of FEV 1 decline, except in post-hoc moderate subgroup

7. Several experts have recommended RCTs to establish efficacy of A 1 PI augmentation “Definitive conclusion will require a randomized controlled trial.” – NHLBI Registry Study Group Am. J. Respir Crit Care Med 1998;158:49-59 The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000;161:796-801. “Urgent need” M. Luisetti. Eur Respir Rev 2002;12:309 “Augmentation therapy …costly and inconvenient…” J.K. Stoller. Eur Respir Rev 2002;12:86/87:311-315

8. One RCT Evaluating French A 1 PI Effects on Lung Function and CT Density Completed Dirksen et al. Am J Respir Crit Care Med 1999;160:1468 –N = 56; NS trend A 1 PI worse than Placebo by FEV 1 (p =0.20); A 1 PI better than Placebo by CT (p 0.07) –Retrospective power suggests n = 130 needed for CT endpoint RCT

9. Postmarketing Studies of Newer Intravenous A 1 PI Products 2-Stage Investigations of 1 or more Clinically meaningful efficacy endpoints: –Serial Lung Density Changes by CT –Pulmonary Exacerbations of COPD –Serial Pulmonary Function Testing –(Mortality)

10. Postmarketing Studies of Newer Intravenous A 1 PI Products Stage I PMC RCT Objective: –Estimate magnitude treatment effect –Assist sample size determination for adequately-powered Stage 2 f/u study Stage 2 PMC RCT Objective: –Substantial evidence of efficacy? –Additional longer-term safety data.

11. Stage I Postmarketing Studies of Newer IV A 1 PI Products Randomized, controlled, parallel, masked design. Minimum 60 subjects (30 per group) Control: –Dose-controlled (i.e., 120 mg/kg/week or 240 mg/kg/2 weeks vs. labeled 60 mg/kg/week) or –Placebo-controlled. Minimum 1-year duration to avoid seasonal bias in pulmonary exacerbations. Baseline & steady state antigenic and functional  1 PI blood levels. +/- longer post-trial follow-up.

12. Stage 2 Postmarketing Studies of Newer IV A 1 PI Products Conduct of Adequately Powered Stage 2 Study may be contingent on: –Outcome of Stage I Study –Strongly positive outcome in Stage I study may obviate need for Stage 2 study. –Amount of Product(s) available –Availability of Subjects –Number of Subject-Years of f/u needed –Participation of other A 1 PI manufacturer(s) (possible factorial design)

13. Baxter Postmarketing Studies Stage I Efficacy RCT – investigational version A 1 PI Stage II Efficacy RCT – investigational version A 1 PI Repeat BAL RCT –investigational version A 1 PI Uncontrolled Safety Study - current version A 1 PI in 60 subjects x 2 years for anti-A 1 PI antibodies, hepatic and renal function, AEs, and quality of life measures.

14. ZLB Behring Postmarketing Studies 2 year, 100 subject Placebo-controlled multinational, parallel group Stage I RCT –Primary objective: Effect of Zemaira on progression of emphysema, assessed by decline in lung density, measured by CT (detect trend with P < 0.20) –Secondary objectives: Assess effect of treatment of A1-I on the number and duration of pulmonary exacerbations FEV 1, DL CO, A 1 PI levels, exercise capacity, mortality, BMI, safety, QOL, anti- A 1 PI antibodies

15. Postmarketing Studies Conclusion –Definitive efficacy data lacking for A 1 PI products –Newer data suggest Efficacy studies now feasible –Sponsors of all newer intravenous A 1 PI products are asked to conduct 2-stage postmarketing investigations of 1 or more clinically meaningful endpoints. –Longer term (2 year) safety data are being collected for Aralast and Zemaira in 50-60 subjects to include anti- A 1 PI antibodies.

16. QUESTIONS FOR THE COMMITTEE: Based on the differences in primary structure of A 1 PI…, does the Committee have comments/ recommendations re: –Adequacy of requested/planned post- marketing commitment studies to evaluate the longer-term safety & efficacy of A 1 PI products, as measured by specified clinically meaningful endpoints? –Adequacy of proposed safety monitoring programs?

17. Need and Feasibility of RCTs in Evaluating A 1 PI Effects on Lung “In the context that i.v. augmentation therapy remains costly and inconvenient but that definitive, supportive data from a randomized, controlled clinical trial remain unavailable, definitive studies to resolve this ongoing controversy are clearly desirable.” - J.K. Stoller. Eur Respir Rev 2002;12:86/87:311-315.

18. NIH (NHLBI) Registry Study “…Finding that recipients of augmentation therapy have better survival…and the rate in decline in FEV 1 values of 35 to 49% predicted suggest clinical efficacy…, although these differences may have been due to factors for which we could not control.” “A definitive conclusion will require a randomized controlled trial.”

19. Need and Feasibility of RCTs in Evaluating A 1 PI Effects on Lung “Unambiguous evidence of [augmentation therapy with A1PI]…efficacy on progression of emphysema is still lacking.” “There is urgent need of clinical trials to optimise the medical management of inherited  1-antitrypsin deficiency.” –-M. Luisetti. Eur Respir Rev 2002;12:309

20. Need and Feasibility of RCTs in Evaluating A 1 PI Effects on Lung “Although significant obstacles to conducting a placebo-controlled clinical trial still exist, like others, we recommend a randomized, placebo- controlled clinical trial as the best method to definitively evaluate the efficacy of IV augmentation therapy…” The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000;161:796-801.

21. Need and Feasibility of RCTs in Evaluating A 1 PI Effects on Lung The Alpha 1-Antitrypsin Deficiency Registry Study Group: “…Our calculation of required sample sizes for a placebo-controlled [RCT]…using estimates derived from the large NHLBI-sponsored Registry suggests that fewer subjects would be needed than were originally projected…”