C1 Esterase Inhibitor (Human) (Cinryze

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 todays
  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 (gt 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 gt 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

(N22)

(N22)

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
lt 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 gt75
• 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