C1 Esterase Inhibitor (Human) (Cinryze™) Lev Pharmaceuticals, Inc.

1. C1 Esterase Inhibitor (Human) (Cinryze™)Lev Pharmaceuticals, Inc. Basil Golding, MDDirector, Division of HematologyOBRR/CBER/FDA

2. Regulatory Chronology • Orphan designation was granted for "treatment of angioedema." • Fast Track designation granted under IND • Priority Review granted under BLA

3. Clinical Studies The applicant conducted: • Phase 3 randomized double blinded studies: 1) Part A for treatment of HAE attacks in 71 subjects with hereditary angioedema 2) Part B for prophylaxis of HAE attacks in 22 subjects • A randomized, parallel group, open-label pharmacokinetics study

4. Clinical Studies(contd.) • Part A (treatment of HAE attacks) is still under FDA review, and will not be discussed before this Advisory Committee. • Part B (prophylaxis of HAE attacks) demonstrated safety and efficacy for the prophylaxis indication, and is the subject for today’s discussion.

5. Prophylaxis: Study Objectives and Endpoints Objective To investigate efficacy and safety of CinryzeTM as a prophylactic treatment to prevent HAE attacks. Primary endpoint: The number of attacks of HAE during active and placebo treatment phases of 12 weeks (normalized for the number of days the subject participated in this phase), using each subject as her/his own control.

6. Prophylaxis: Study Objectives and Endpoints (contd.) Secondary efficacy endpoints: • number of subjects dropping out at each treatment period • average severity of attacks • average duration of attacks • number of open-label C1INH infusions • change from baseline in C1INH antigenic and functional levels

7. Brief Synopsis of StudyProcedures for Prophylaxis • Subjects who had completed treatment of acute attacks and who had demonstrated a high frequency of HAE attacks (> 2 per month) were enrolled into Part B (24 enrolled, but 2 dropped out). • Subjects were randomized to 12 weeks prophylaxis with either 1000 U C1INH or placebo (infused twice weekly at the study site), followed by a crossover to 12 weeks prophylaxis with the other study agent. • HAE attacks of any severity were recorded. • Subjects in either arm could receive open-label C1INH 1000 U during acute attacks while on the prophylaxis part of the study.

8. Safety Monitoring for Prophylaxis Study • Adverse event information was collected at each visit. • Diary cards and weekly telephone calls also collected information on HAE attacks and adverse events. • Viral safety was monitored at a 3-month follow-up visit after the final prophylaxis treatment.

9. Pharmacokinetics: Results

10. PK: Conclusions • The PK of Cinryze™ in subjects with HAE indicates that the drug has a long half-life and slow clearance. • The long half life indicates that a dose schedule of 2 administrations per week is reasonable and would likely result in C1INH levels > 40% of normal which are generally regarded as levels sufficient to avoid attacks.

11. Demographics: Prophylaxis Study • 22 subjects • Age: • median 38.5 yrs; range 9 to 73 yrs. • Gender: • 2 males; 20 females • Ethnicity: • 21 Caucasian, 1 African American

12. Prophylaxis: Results Cinryze™ Placebo Statistic (N=22) (N=22) Number of attacks Mean 6.1 12.7 SD 5.43 4.80 Median 6.0 13.5 Min 0 6 Max 17 22 These descriptive attack frequency data were obtained by pooling data during active or placebo treatment phases.

13. Prophylaxis: Results Generalized Estimating Equation (GEE) Analysis Results P values Treatment Effect < 0.0001 Sequence Effect 0.3347 Period Effect 0.3494 • This table shows the pre-specified ANOVA using each individual as his/her control in the crossover study. • The treatment effect is highly significant and is not confounded by sequence and period effects. • FDA has verified these calculations showing a highly significant treatment effect.

14. Prophylaxis: Distribution of Responses - 100 100 0

15. Prophylaxis: Distribution of Responses Treatment with CinryzeTM resulted in varying reductions in HAE attack frequency: • 45 % (10/22) of individuals had a reduced attack frequency of >75% • 32% (7/22) had intermediate reductions (25-75) • 18% (4/22) had modest reductions (1-25%) in attack frequency • Two individuals (9%) had more attacks with Cinryze™ than with placebo

16. Prophylaxis: Secondary Endpoints • FDA evaluated events independent of primary endpoint: • Attack severity (p = 0.0056) • Duration (p = 0.0023) • FDA found both severity and duration of attacks to be reduced at a statistically significant level comparing CinryzeTM to placebo

17. Efficacy: Conclusions • The prophylaxis trial met its primary and secondary endpoints for efficacy. • Patients did not respond uniformly suggesting that dosing may not be optimal for some patients. • Phase 2 dosing studies might have helped find a more uniformly effective dose.

18. Gender Imbalance • There were 20 females and 2 males • The uneven gender distribution in this study for an autosomal dominant disease may be due to: • Estrogens predisposing females to more frequent attacks • Female aversion to preventive therapy with attenuated androgens

19. FDA Efficacy Conclusion Overall, FDA concludes that Cinryze™ has been demonstrated to be effective for prevention of HAE attacks when used for prophylaxis in persons with hereditary angioedema.

20. Safety: Prophylaxis Adverse event rates: • C1INH: 81 total events in 20 patients • Placebo: 36 total events in 13 patients Open-label use of C1INH for acute attacks increased the number of total infusions compared to placebo (1190 vs. 526). Thus the events per infusion were: 81/1190 = 0.068 for C1INH 36/526 = 0.068 for placebo

21. Serious Adverse Events • 4 SAEs attributed to HAE attacks and not related to study medication • No deaths • No signs of hypersensitivity drug reactions

22. Safety: Conclusions • The adverse events appear to be related to intercurrent illnesses and the underlying disease rather than being due to treatment with CinryzeTM. • CinryzeTM appears to have an acceptable safety profile for prophylaxis of HAE attacks when administered according to the proposed labeled dose schedule. • Since prophylaxis involves repeated and long-term treatment, post marketing safety monitoring may be required.

23. Immunogenicity Immunogenicity was evaluated in Part A (treatment of HAE attacks) and in Part B (prophylaxis of HAE attacks). • Lab 1: 93/329 subjects – 28% Ab positive (screening or pre-infusion); retesting samples → inconsistent results • Subset of 119 subjects tested at 2nd lab: • Lab 1: 58/119 (49%) pos. • Lab 2: 2/119 (0.8%) pos. • Another subset of 11 samples was sent to a third lab for retesting: • Lab 1: 5/11 (45%) pos. • Lab 3: 0/11 (0%) pos.

24. Immunogenicity: Conclusions • The results from Lab 1 were not confirmed in two other Labs • Since these are binding assays, not functional assays, it is not known whether these putative antibodies have neutralizing activity • There was no evidence that the putative antibody levels correlated with adverse events or treatment effects of CinryzeTM • However, post-marketing studies may be needed to resolve this issue

25. Questions to the Committee Question #1 Is the safety and efficacy evidence sufficient for approval of CinryzeTM for prophylactic treatment of HAE? Question #2 If the answer to Question #1 is yes, should post-marketing studies be performed to further evaluate the following: • the optimal dose for prophylaxis in males and females • immunogenicity • long-term safety