C1 Esterase Inhibitor (Human) (Cinryze�) Lev Pharmaceuticals, Inc by wFjZG2m

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									C1 Esterase Inhibitor (Human)
         (Cinryze™)

  Lev Pharmaceuticals, Inc.
         Basil Golding, MD
  Director, Division of Hematology
         OBRR/CBER/FDA
      Regulatory Chronology

• Orphan designation was granted for
  "treatment of angioedema."

• Fast Track designation granted under IND

• Priority Review granted under BLA
             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
            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.
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.
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
        Brief Synopsis of Study
      Procedures 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.
 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.
        Pharmacokinetics: Results

Table 1: Pharmacokinetic parameters of Cinryze (functional C1INH), mean + SD
Parameters                              Single Dose (n = 13)      Double Dose (n = 14)
Cbaseline (U/mL)                            0.31 ± 0.20               0.33 ± 0.20
Baseline corrected Cmax (U/mL)              0.37 ± 0.15               0.51 ± 0.19
Baseline corrected AUC(0-∞) (U*hr/mL)       24.5 ± 19.1               39.1 ± 19.9
CL (mL/min)                                 0.85 ± 1.07               1.17 ± 0.78
Half-life (hours)                             56 ± 36                   62 ± 38
Mean residence time (MRT) hrs                 84 ± 50                   91 ± 52
             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.
 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
       Prophylaxis: Results

                            Cinryze™   Placebo
                Statistic
                            (N=22)     (N=22)
    Number of
                 Mean        6.1        12.7
     attacks
                   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.
            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.
                                                                                                                                       0%
                                                                                                                                    10
                                                                                                                                 to
                                                                                                                     100




                                                                                                                              % 0%
                                                                                                                           91       9
                                                                                                                                to
                            Histogram of the Percent Reduction of HAE Attack Frequency while on




                                                                                                                              %        %
                                                                                                                           81       80
                                                                                                                                to
                                                                                                                              %        %
Distribution of Responses




                                                                                                                           71       70
                                                                                                                                to
                                                                                                                              %        %
                                                                                                                           61       60
                                                                                                                                to
                                                                                                                              %        %
                                                                                                                           51       50
                                                                                                                                to
                                                                                                                                            Percent Reduction in HAE Attack Frequency
                                                                                                                              %        %
                                                                                                                           41       40
                                                                                                                                to
                                                                                                                              %        %
       Prophylaxis:




                                                                                                                           31       30
                                                                                                                                to
                                                                                                                              %        %
                                                                                                                           21       20
                                                     C1INH Prophylaxis




                                                                                                                                to
                                                                                                                              %
                                                                                                                           11 10%
                                                                                                                               to
                                                                                                                           1% 0%
                                                                                                                                to
                                                                                                                             %         0%
                                                                                                                                     -1



                                                                                                                     0
                                                                                                                           -9
                                                                                                                                  to
                                                                                                                             9% -20%
                                                                                                                           -1
                                                                                                                                  to
                                                                                                                             9% -30%
                                                                                                                           -2
                                                                                                                                  to
                                                                                                                             9% -40%
                                                                                                                           -3
                                                                                                                                  to
                                                                                                                             9% -50%
                                                                                                                           -4
                                                                                                                                  to
                                                                                                                             9% -60%
                                                                                                                           -5
                                                                                                                                  to
                                                                                                                             9% -70%
                                                                                                                           -6
                                                                                                                                  to
                                                                                                                             9% -80%
                                                                                                                           -7
                                                                                                                                  to
                                                                                                                             9%
                                                                                                                           -8




                                                                                                                   0 100
                                                                                                                   -
                                                                                                   4
                                                                                                       3
                                                                                                           2
                                                                                                               1
                                                                                                  Number of Subjects
            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
 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
       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.
         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
   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.
        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
      Serious Adverse Events

• 4 SAEs attributed to HAE attacks and not
  related to study medication

• No deaths

• No signs of hypersensitivity drug reactions
           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.
             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.
  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
     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

								
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