Hereditary angioedema is caused by abnormalities in C1 inhibitor levels or functionality. Past treatments for acute attacks included IV fluids and pain/nausea medications, while long-term prophylaxis included anabolic androgens or antifibrinolytics. Newly approved treatments in the US include plasma-derived C1INH concentrates like Berinert and Cinryze, which have been shown in clinical trials to significantly shorten time to relief of symptoms from acute attacks. Cinryze has also been approved for prophylaxis as it significantly reduced the rate of attacks compared to placebo in a clinical trial. Additionally, the plasma kallikrein inhibitor ecallantide was approved for

1. Treatment of hereditary angioedema Boonthorn 24 december 2010

2. Outline Introduction HAE treatment: past present and future 2010 International consensus

3. Introduction Hereditary angioedema autosomal-dominant disorder abnormality in levels or functionality of C1INH Mutations (> 200) located on chromosome 11 20- 25% of cases result from new spontaneous mutation Prevalence : 1 in 50,000 Type 1 HAE (80- 85%) reduced circulating C1INH concentrations ( levels ~ 5- 30% of expected values) mutations occur throughout the gene type 2 HAE (15- 20%) dysfunctional protein , single amino acid substitutions mutations J Allergy ClinImmunol2010;126:918-25.

4. Introduction Hereditary angioedema Type 3 HAE predominantly in female subjects not related to C1INH deficiency missense mutation in factor XII gene7 (subpopulation) Excessive bradykinin formation predisposing factor apart from estrogen or trauma Attacks in untreated patients can last 2-5 days history of recurrent attacks of peripheral angioedema (nonpruritic, nonpitting) and/or abdominal pain in absence of urticaria Swelling most commonly extremities, face, or genitalia J Allergy ClinImmunol2010;126:918-25.

5. Diagnostic features and laboratory findings J Allergy ClinImmunol2010;126:918-25.

6. Diagnostic features and laboratory findings J Allergy ClinImmunol2010;126:918-25

8. Reaction 2 : Cleavage of surface-bound factor XII by factor XIIa followed by feedback activation by kallikrein

9. Reaction 3: Plasmin activates factor XII similarly but may not contribute significantly unless plasma is deficient in C1INH

10. Factor XIIf activates complementJ Allergy ClinImmunol2010;126:918-25

11. Kallikrein-dependent reactions to produce bradykinin and augment fibrinolysis J Allergy ClinImmunol2010;126:918-25

13. reaction is facilitated when C1INH is absent.

14. Kallikrein thus formed (dotted lines) caninitiate factor XII-dependent activation at adjacent cellsJ Allergy ClinImmunol2010;126:918-25

15. Dysregulation of Complement, Coagulation, and Contact Cascades in Hereditary Angioedema C1 inhibitor controls activation in complement, coagulation, and contact cascades, and all three cascades are dysregulated in HAE N Engl J Med 363;6 Nejm.Org August 5, 2010

16. HAE treatment: The past Treatment of acute HAE attacks Until late 2008, no drug approved in US symptomatic control of swelling Aggressive IV replacement, control of pain and nausea with parenteralnarcotic and antiemetic drugs ( abdominal attack ) Intubate or emergency tracheotomy ( airway attack ) Not require treatment (angioedemaof extremities ) Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

17. HAE treatment: The past Long-term prophylaxis Goal : decrease frequency and/or severity of swelling attacks attack every 3 months location of attacks (airway attacks ) Accessibility to appropriate medical care Avoid ACEI, Birth control pills and HRT Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

18. HAE treatment: The past Long-term prophylaxis anabolic androgens increase C1INH plasma levels and decrease attacks of HAE Danazol and stanozolol (synthetic 17-a-alkylated androgens ) 2 mg stanozolol OD or AD or 200 mg danazol OD or AD precise mechanism be elucidated side effects (dose related) : hepatotoxicity , hepatic adenoma and virulization Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

19. HAE treatment: The past Long-term prophylaxis anti-fibrinolytics epsilon aminocaproicacid (EACA or Amicar) and tranexamicacid Less effective than anabolic hormone reserved for not tolerate anabolic androgens ( children and pregnant women ) Tranexamicacid not currently available in US EACA : 1 gm orally 3-4 times per day Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

20. HAE treatment: The past Short-term prophylaxis All HAE patients need for short-term prophylaxis Prevent attacks before expected trauma eg. surgery or dental procedures avoid potentially catastrophic swelling High-dose anabolic androgen therapy (stanozolol 2 mg three times daily or danazol 200 mg three times daily) begun 5 to 7 days before procedure 2 units of FFP several hours before procedure Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

21. HAE treatment: The present Over the past 18 months, 3 new medications for treatment of HAE approved in US Plasma-derived C1INH concentrates Pasteurized plasma-derived C1INH concentrate Nanofiltered and pasteurized plasma-derived C1INH concentrate Plasma kallikrein inhibitor: Ecallantide

22. Pasteurized plasma-derived C1INH concentrate Berinert (CSL Behring) : pasteurized lyophilized human plasma-derived C1 inhibitor concentrate licensed in Europe over 20 years (acute, short term) phase III study for acute attacks ( IMPACT1) Compared efficacy (shortening onset of relief of symptoms) Berinert (10 U/kg and 20 U/kg) to placebo in 125 HAE patients with moderate to severe abdominal or facial angioedema attacks primary outcome : time from start of treatment to onset of symptom relief Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

23. Pasteurized plasma-derived C1INH concentrate J Allergy ClinImmunol 2009;124:801-8.

24. Pasteurized plasma-derived C1INH concentrate J Allergy ClinImmunol 2009;124:801-8

25. Berinertreceived approval from FDA (2009) for use in treatment of acute angioedema attacks in adolescent and adult HAE patients Pasteurized plasma-derived C1INH concentrate Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

26. Nanofiltered and pasteurized plasma-derived C1INH concentrate Cinryze (ViroPharmaIncorporated) nanofiltered pasteurized lyophilized C1INH concentrate Manufactured in Netherlands, using U.S. plasma final nanofiltration step, provides additional protection against enveloped and non-enveloped viral particles and possibly prions Two separate randomized double-blind placebo controlled studies of Cinryze performed in US Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

27. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE CHANGE part A efficacy and safety of C1INHnf for treatment of moderate to severe acute attacks of facial, abdominal or genitourinary angioedemain HAE patients infused with C1INH-nf 1,000 IU (35pt.) or placebo (33pt.) at time 0 If significant relief not reported within 60 minutes, given second dose of same study drug All subjects eligible to receive open-label Cinryze after 4 hours N Engl J Med 363;6 Nejm.Org August 5, 2010

28. Nanofiltered and pasteurized plasma-derived C1INH concentrate primary end point : time to onset of unequivocal relief of symptom at defining sites median time to onset of unequivocal relief from attack =2 hours ( C1 INHnf ) but > 4 hours in placebo (P = 0.02) median time to complete resolution of symptoms was 12.3 hours (C1 inh group) and 25.0 hours ( placebo group) (P = 0.004)

29. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE Primary Outcome in the Trial of C1 Inhibitor Therapy for Acute Attacks of Angioedema Cumulative incidence estimates for time to onset of unequivocal relief (primary outcome) 35 subjects received C1 INHnfand 33 subjects received placebo circles represent subjects who received rescue therapy before 4 hours ( 2 subjects in placebo group received narcotic rescue at 15 and 146 minutes, respectively, and 1 subject in C1 INH group received open-label C1 INH rescue at 110 minutes) or those who not have onset of unequivocal relief before 4 hours (60%) (P=0.06) (42%) N Engl J Med 363;6 Nejm.Org August 5, 2010

30. Nanofiltered C1 Inhibitor Concentrate for prophylaxis of HAE CHANGE part B Longterm prophylaxis to prevent attacks of angioedema RDBPC crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of C1 INHnf (1000 units) with placebo during two 12-week periods primary end point : number of attacks of angioedema per period During C1INH-nf treatment periods, showed highly significant decrease in HAE attacks (6.26 versus 12.73 attacks; p < 0.0001) N Engl J Med 363;6 Nejm.Org August 5, 2010

31. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE attack rates are shown for each of 22 subjects during 12-week period when either placebo or C1 INHnf black horizontal lines indicate mean attack rates for two treatments, 6.3 and 12.7 for C1 inhibitor group and placebo group, respectively Normalized Rate of Angioedema Attacks During Prophylaxis Trial N Engl J Med 363;6 Nejm.Org August 5, 2010

32. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE Adverse events In C1 INH group Possibly : fever (1),lightheadedness (1) Definitely : rash at injection site (1), pruritus and rash (1) In placebo group Possibly : carpopedal spasm (1), erythema (1) Definitely : contact dermatitis (1), chest discomfort (1), cough (1) N Engl J Med 363;6 Nejm.Org August 5, 2010

34. The application for use of Cinryze to treat acute attacks of angioedemais still pendingNanofiltered and pasteurized plasma-derived C1INH concentrate Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

35. Plasma kallikrein inhibitor: Ecallantide( Kalbitor ) novel, potent and specific plasma kallikreininhibitor recombinant, 60-amino acid protein produced in Pichiapastoris yeast recommended dose to treat angioedemaattack is 30 mg, administered as three 1 ml sc injections Maximum ecallantidelevels reached 2-3 hours following subcutaneous injection, HL~ 2 hours 2 separate RDBPC phase III studies of ecallantide for Rx of acute attacks of HAE performed in US EDEMA 3 EDEMA 4 N Engl J Med 363;6 Nejm.Org August 5, 2010

36. Ecallantide for the Treatment of Acute Attacks in HAE (EDEMA3) RDBPC trial, acute attack , 1:1 ratio, to receive sc ecallantide (30 mg) or placebo 72 patients Primary endpoint : treatment outcome score (TOS) at 4 hours TOS : patient-reported measure of response to therapy using categorical scale from 100 (significant improvement) to -100 (significant worsening) for each symptom complex, weighted according to its baseline severity N Engl J Med 363;6 Nejm.Org August 5, 2010

37. Ecallantide for the Treatment of Acute Attacks in HAE Efficacy Analyses with Respect to Primary and Secondary End Points, According to Study Group. N Engl J Med 363;6 Nejm.Org August 5, 2010

38. Ecallantide for the Treatment of Acute Attacks in HAE Efficacy Analyses with Respect to Primary and Secondary End Points, According to Study Group. N Engl J Med 363;6 Nejm.Org August 5, 2010

39. Ecallantide for the Treatment of Acute Attacks in HAE Kaplan–Meier Analysis of Time to Significant Improvement in Overall Response in the Intention-to-Treat Population. N Engl J Med 363;6 Nejm.Org August 5, 2010

40. Ecallantide for the Treatment of Acute Attacks in HAE Adverse Events in the Safety Population, According to Study Group N Engl J Med 363;6 Nejm.Org August 5, 2010

41. Ecallantide for the Treatment of Acute Attacks in HAE (EDEMA4) 96 patients primary endpoint : mean symptom complex severity (MSCS) at 4 hours MSCS score : patient-reported point-in-time measure of symptom severity based on symptom rating of 0 (none) to 3 (severe) for each potential symptom complex Mean decrease in symptom score at 4 hours of 0.81 (Ecallantide ) compared to 0.37 in placebo (p = 0.01) Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

42. Plasma kallikrein inhibitor: Ecallantide Prolongation of aPTT (common), without any enhanced risk of bleeding Anaphylactic-like reactions in 10/255 (3.9%) subjects following exposure to ecallantide Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

44. black box warning on anaphylactic potential and requiring that the drug be administered by health care providerPlasma kallikrein inhibitor: Ecallantide Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

45. HAE treatment: The future Recombinant human C1INH Icatibant Other future directions Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

46. Recombinant human C1INH J Allergy ClinImmunol 2010;126:821-7. Rhucin (Pharming NV) recombinant human C1 inhibitor (rhC1INH) concentrate for iv infusion isolated from milk of transgenic rabbits identical to human plasma derived C1INH at amino acid level 2separate phase III studies ,for rhC1INH in treatment of acute attacks of angioedemain HAE patients

47. Recombinant human C1INH European RDBPC rhC1INH (100 U/kg) in 32 HAE patients was stopped on ethical grounds because of strong and highly significant positive advantage for rhC1INH versus placebo in median time to beginning of relief (62 versus 508 minutes, p = 0.0009) as well as time to minimal symptoms (480 versus 1480 minutes, p = 0.0038) Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

48. Recombinant human C1INH In US and Canada 39 subjects showed significant benefit for rhC1INH versus placebo in median time to beginning of relief (68 minutes for rhC1INH 100 U/kg, 122 minutes for rhC1INH 50 U/kg, and 258 minutes for placebo) Time to minimal symptoms significantly shortened after treatment with rhC1INH (245 minutes at 100 U/kg and 247 minutes at 50 U/kg) compared to placebo (1101 minutes) (P<0.01) Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

49. Recombinant human C1-inhibitor for treatment of acute angioedema attacks Primary and secondary efficacy outcome in 3 treatment groups J Allergy ClinImmunol 2010;126:821-7.

50. Recombinant human C1-inhibitor for treatment of acute angioedema attacks Course of mean VAS scores in time in rhC1INH and saline groups Data indicate mean VAS scores and 95% CIs. J Allergy ClinImmunol 2010;126:821-7.

51. Recombinant human C1-inhibitor for treatment of acute angioedema attacks Adverse events In C1 INH Headache, vertigo colitis In placebo Headache, injection site swelling, epistaxis, hypotension J Allergy ClinImmunol 2010;126:821-7.

52. Icatibant, New Bradykinin-Receptor Antagonist, in HAE Icatibant (Firazyr, Shire) synthetic selective decapeptidebradykinin B2 receptor competitive antagonist contains 5 non-natural amino acids to enhance resistance to peptidases Icatibant administered sc injection as single 30 mg peak concentration within 30 minutes, and HL~ 1-2 hours 2 RDBPC phase III study : FAST-1(US) ,FAST-2 (Europe) N Engl J Med 363;6 Nejm.Org August 5, 2010

53. Icatibant, New Bradykinin-Receptor Antagonist, in HAE 56 subjects (FAST-1) 72 subjects (FAST-2) moderate to severe abdominal or cutaneousangioedemaattack Primary endpoint time to onset of symptom relief assessed by subject recorded visual analog scale (VAS) Secondary endpoints time to almost complete symptom relief and response rate at 4 hours Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23

54. Icatibant, New Bradykinin-Receptor Antagonist, in HAE N Engl J Med 363;6 Nejm.Org August 5, 2010

55. Icatibant, New Bradykinin-Receptor Antagonist, in HAE Adverse Events in the Safety Populations of the FAST-1 and FAST-2 Trials. N Engl J Med 363;6 Nejm.Org August 5, 2010

57. The FDA disapproved the application for licensure,And new RDBPC phase III trial (FAST3) is ongoingIcatibant, New Bradykinin-Receptor Antagonist, in HAE N Engl J Med 363;6 Nejm.Org August 5, 2010

58. Other future directions administering C1INH concentrate by sub-cutaneous infusion steady plasma levels of C1INH during longterm prophylaxis inhibition of factor XII activity might prevent bradykiningeneration Like strategies targeting plasma kallikrein orally available bradykininreceptor antagonists combined bradykinin B2 and B1 receptor antagonism recent demonstration that B1 receptor may play role in swelling of HAE patients gene repair or intracellular trafficking for molecular correction of defects in HAE N Engl J Med 363;6 Nejm.Org August 5, 2010

59. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

60. HAE Diagnosis Algorithm Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

61. HAE Diagnosis Algorithm ( cont. ) Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

62. Short-Term Prophylaxis Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

63. Long-Term Prophylaxis Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

64. Treatment of Acute HAE - Attacks Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24

65. Take home message Treament of HAE Past Prophylaxis : androgen, antifibrinolytic Present Pasturized C1 INH concentrate (acute attack) NanofilteredPasturizedC1 INH concentrate (prophylaxis) Ecallantide (acute attack) Future Recombinant human C1INH Icatibant

66. Efficacy results from key clinical studies of C1-INH replacement products Allergy Asthma Proc 31 :398-406,2010.

67. Efficacy results from key clinical studies of C1-INH replacement products Allergy Asthma Proc 31 :398-406,2010.

68. Efficacy results from key clinical studies of ecallantide Allergy Asthma Proc 31 :398-406,2010.

69. Efficacy results from key clinical studies of C1-INH replacement products Allergy Asthma Proc 31 :398-406,2010.

70. Efficacy results from key clinical studies of icatibant Allergy Asthma Proc 31 :398-406,2010.