1. C1 ESTERASE INHIBITOR (HUMAN) For the prevention and treatment of acute attacks of Hereditary Angioedema Reid Nakagawa November 31, 2013

2. OUTLINE  Hereditary Angioedema  Definition  Epidemiology  Pathophysiology  C1 esterase inhibitor (human)  Indications & Usage  Dosing & Administration  Mechanism of Action  Pharmacokinetics  Drug Interactions  Clinical Manifestations  Treatment  Adverse Effects  Precautions  Pregnancy & Lactation  Reconstitution  Place in Practice

3. ANGIOEDEMA  Angioedema is the result of localized blood vessel dilation and increased permeability that causes rapid swelling of the subcutaneous, mucosal, and submucosal tissues.  Hereditary Angioedema Triggers:  Dental work, trauma, anxiety, stress, etc.  Attacks can occur spontaneously in the absence of triggers

4. EPIDEMIOLOGY  Affects approximately 1 in 50,000 individuals (1:10,000 – 1:150,000)  Males and females are affected equally  The prevalence of HAE is highest in Europe and North America  Mean age of onset is 8 to 12 years  75% experience first attack by the age of 15 years

5. PATHOPHYSIOLOGY  Hereditary Angioedema (HAE) is an autosomal dominant disorder where there is a deficiency or dysfunction in endogenous C1 esterase inhibitor (C1-INH)  Type 1: deficiency in C1-INH (~85%)  Type II HAE: dysfunctional CI-INH (~15%)  HAE with normal C1-INH: mutations in Factor XII?  Acquired C1-INH deficiency: associated with autoimmune disorders  C1 esterase inhibitor (C1-INH) is a member of the serine protease inhibitors “serpin” superfamily. It is an inhibitor of the kinin-generating, coagulation, and fibrinolytic pathways.

7. CLINICAL MANIFESTATIONS  Prodromal symptoms: fatigue, irritability, nausea, myalgias, flu-like symptoms, erythema marginatum  Affected areas: Skin, GI tract, GU tract, and upper airway  Edema involves the subcutaneous, mucosal, and submucosal tissues  Urticaria and pruritis are absent,  Severity: inconvenient cutaneous edema - life-threatening laryngeal edema  Duration of attacks: 48-96 hours

10. TREATMENT  Patients with HAE tend not to respond to epinephrine, antihistamines, or glucocorticoids  Plasma kalikrein inhibitor  Ecallantide (Kalbitor)  Bradykinin receptor antagonist  Icatibant acetate (Firazyr)  C1 esterase inhibitor  C1 esterase inhibitor, human (Cinryze, Berinert)

11. C1 ESTERASE INHIBITOR

12.  INDICATIONS & USAGE:  For routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (Cinryze).  For the treatment of acute abdominal, facial, or laryngeal attacks of Hereditary Angioedema in adult and adolescent patients (Berinert).

13. MECHANISM OF ACTION

14. PHARMACOKINETICS / DYNAMICS Single DoseDouble Dose C baseline (units/mL)0.31 +/- 0.200.33 +/- 0.20 C max (units/mL)0.68 +/- 0.080.85 +/- 0.12 T max (hours)3.9 +/- 7.32.7 +/- 1.9 T 1/2 (hours)56 +/- 3662 +/- 38  Onset of action: 1 hour or less  Vd: 0.43 dL/kg  No known drug-drug interactions

15. PRECAUTIONS  Severe hypersensitivity reactions may occur.  CONTRAINDICATION  Thrombotic Events  Thrombotic events have been reported following the administration of high doses of CI-INH  Transmissible Infectious Agents  C1-INH has the risk of transmitting infectious agents, e.g. HIV, HepC, CJD, etc.

16. ADVERSE EFFECTS  Common  Headache  Nausea  Rash  Sinusitis  URI  Serious  Hypersensitivity  DVT  PE 7.0% - 28% 1.8% - 18% 3.5% - 10% 5% or greater 1.8% or greater  MI  CVA

17. PREGNANCY & BREASTFEEDING  Pregnancy Category: C (All Trimesters)  No animal data are available  No adequate and well-controlled studies were conducted in pregnant women  C1-INH should be given to pregnant women only if clearly needed  Breastfeeding:  It is not known whether C1-INH is excreted in breast milk  Caution should be exercised when C1-INH is administered to a nursing mother

18. STORAGE AND HANDLING  Storage: 2 O C – 22 O C (36 O F – 77 O F)  Do not freeze  Store the vial in the original container to protect it from light

19. RECONSTITUTION

20. DOSING & ADMINISTRATION  For intravenous use only.  Can be given as either an IV push over 10 minutes or as an IV drip over 10 minutes  Administer within 3 hours of reconstitution  HAE, Prophylaxis (Cinryze):  1,000 Units IV push/infusion over 10 minutes Q3 - 4 days  HAE, abdominal, facial, or laryngeal attacks (Berinert):  20 International Units/kg IV infusion at a rate of approximately 4 mL/min

21. TRADITIONAL PLACE IN PRACTICE  Prophylaxis  The use of C1-INH for prophylaxis against Hereditary Angioedema attacks has been established  C1-INH can either be administered by a healthcare provider in clinic or self-administered by the patient at home  Treatment  For acute attacks of HAE in patients presenting to the Emergency Department  Cinryze is FDA approved for treatment of HAE, but has been studied  Dosing: 1,000 units IV over 10 minutes; 2 nd dose may be administered 60 minutes after first dose if no improvement in symptoms is seen - or -  20 units/kg IV; rate not to exceend 4 mL/min

22. EFFICACY

24. TREATMENT TRIAL  37 sites, N = 68 patients  Study drug : 35 patients  1,000 units (10 mL) IV over 10 minutes; repeat x 1 if no symptomatic relief after 60 minutes  Placebo: 33 patients  10 mL NS over 10 minutes  Primary Endpoint  Time from administration of the study drug to unequivocal relief of symptoms at the defining site  Secondary Endpoints  Percentage of subjects who had an onset of unequivocal relief of symptoms w/in 4 hours after receiving treatment  Time to complete resolution of the attack

25. TREATMENT TRIAL Median time to symptom relief  2 hours VS 4 hours (CI: 1.17 – 4.95) P =0.02 Percentage of subjects with onset of relief within 4 hours  60% VS 42%; P =0.06 Time to complete resolution of attack  12.3 hours VS 25.0 hours; P =0.004

26. PROPHYLAXIS TRIAL  N = 22 patients  24 week crossover  Primary Endpoint  Number of attacks of angioedema during each treatment period  Average severity of attacks (on a scale of 1-3)  1-mild 2-moderate3-severe  Average duration of attacks  Number of open label injections of C1-INH  Total number of days of swelling

27. PROPHYLAXIS TRIAL Number of angioedema attacks  6.26 VS 12.73 (CI: 4.21 – 8.73) P<0.001 Average severity of attacks  1.3 +/- 0.85 VS 1.9 +/- 0.36 P<0.001 Average duration of attacks  2.1 +/- 1.13 d VS 3.4 +/- 1.39 d P=0.002 Number of open-label injections  4.7 +/- 8.66 VS 15.4 +/- 8.41 P<0.001 Total number of days of swelling  10.22 +/- 10.73 d VS 29.6 +/- 16.9 d P<0.001

28. NEXT FRONTIER  C1-INH in patients with HAE with normal C1-INH levels  Patients are usually refractory to epinephrine, antihistamines, and glucocorticoids  C1-INH has been used in these patients to presumably raise the set point for activation of kallikrein and generation of bradykinin.  Further research is needed to validate its use in this patient population  C1-INH in patients with Idiopathic Angioedema  2 main types  Histaminergic angioedema  Bradykinergic angioedema  Most patients do not respond to epinephrine, antihistamines, and glucocorticoids  The use of C1-INH in this patient population is currently being discussed by experts

29. QUESTIONS

30. REFERENCES  Berinert [package insert]. Kankakee, IL: CSL Behring LLC; 2012  Cinryze [package insert]. Exton, PA: ViroPharm Biologics, Inc.; 2010- 2013.  Lang DM, Aberer W, Bernstein JA, et al. International Consensus on Hereditary and Acuired Angioedema. Ann Allergy Asthma Immunol 2012;109:395-402.  Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. N Engl J Med 2010;363: 513-22.