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Hereditary angioedema

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Hereditary angioedema

  1. 1. Treatment of hereditary angioedema<br />Boonthorn<br />24 december 2010<br />
  2. 2. Outline <br />Introduction<br />HAE treatment: past present and future<br />2010 International consensus<br />
  3. 3. Introduction<br />Hereditary angioedema<br />autosomal-dominant disorder<br />abnormality in levels or functionality of C1INH<br />Mutations (> 200) located on chromosome 11<br />20- 25% of cases result from new spontaneous mutation<br />Prevalence : 1 in 50,000<br />Type 1 HAE (80- 85%) reduced circulating C1INH concentrations ( levels ~ 5- 30% of expected values) mutations occur throughout the gene<br />type 2 HAE (15- 20%) dysfunctional protein , single amino acid substitutions mutations <br />J Allergy ClinImmunol2010;126:918-25.<br />
  4. 4. Introduction<br />Hereditary angioedema<br />Type 3 HAE<br />predominantly in female subjects<br />not related to C1INH deficiency<br />missense mutation in factor XII gene7 (subpopulation) <br />Excessive bradykinin formation <br />predisposing factor apart from estrogen or trauma<br /> Attacks in untreated patients can last 2-5 days<br />history of recurrent attacks of peripheral angioedema (nonpruritic, nonpitting) and/or abdominal pain in absence of urticaria<br />Swelling most commonly extremities, face, or genitalia<br />J Allergy ClinImmunol2010;126:918-25.<br />
  5. 5. Diagnostic features and laboratory findings<br />J Allergy ClinImmunol2010;126:918-25.<br />
  6. 6. Diagnostic features and laboratory findings<br />J Allergy ClinImmunol2010;126:918-25<br />
  7. 7. Factor XII-dependent reactions<br /><ul><li>Reaction 1 : Initiation begins with factor XII autoactivation
  8. 8. Reaction 2 : Cleavage of surface-bound factor XII by factor XIIa followed by feedback activation by kallikrein
  9. 9. Reaction 3: Plasmin activates factor XII similarly but may not contribute significantly unless plasma is deficient in C1INH
  10. 10. Factor XIIf activates complement</li></ul>J Allergy ClinImmunol2010;126:918-25<br />
  11. 11. Kallikrein-dependent reactions to produce bradykinin and augment fibrinolysis<br />J Allergy ClinImmunol2010;126:918-25<br />
  12. 12. Assembly and activation of the kinin-forming cascade on endothelial cells<br /><ul><li> Activated endothelial cells present HSP-90 or prolylcarboxypeptidase independent of any factor XII present to generate bradykininstoichiometrically.
  13. 13. reaction is facilitated when C1INH is absent.
  14. 14. Kallikrein thus formed (dotted lines) caninitiate factor XII-dependent activation at adjacent cells</li></ul>J Allergy ClinImmunol2010;126:918-25<br />
  15. 15. Dysregulation of Complement, Coagulation, and Contact Cascades in Hereditary Angioedema<br />C1 inhibitor controls activation in complement, coagulation, and contact cascades, and all three cascades are dysregulated in HAE<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  16. 16. HAE treatment: The past<br />Treatment of acute HAE attacks<br />Until late 2008, no drug approved in US<br />symptomatic control of swelling<br />Aggressive IV replacement, control of pain and nausea with parenteralnarcotic and antiemetic drugs ( abdominal attack )<br />Intubate or emergency tracheotomy ( airway attack )<br />Not require treatment (angioedemaof extremities )<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  17. 17. HAE treatment: The past<br />Long-term prophylaxis<br />Goal : decrease frequency and/or severity of swelling attacks<br />attack every 3 months <br />location of attacks (airway attacks )<br />Accessibility to appropriate medical care<br />Avoid ACEI, Birth control pills and HRT<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  18. 18. HAE treatment: The past<br />Long-term prophylaxis<br />anabolic androgens <br />increase C1INH plasma levels and decrease attacks of HAE<br />Danazol and stanozolol (synthetic 17-a-alkylated androgens )<br />2 mg stanozolol OD or AD or 200 mg danazol OD or AD<br />precise mechanism be elucidated<br />side effects (dose related) : hepatotoxicity , hepatic adenoma and virulization<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  19. 19. HAE treatment: The past<br />Long-term prophylaxis<br />anti-fibrinolytics<br />epsilon aminocaproicacid (EACA or Amicar) and tranexamicacid<br />Less effective than anabolic hormone<br />reserved for not tolerate anabolic androgens ( children and pregnant women )<br />Tranexamicacid not currently available in US<br />EACA : 1 gm orally 3-4 times per day<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  20. 20. HAE treatment: The past<br />Short-term prophylaxis<br />All HAE patients need for short-term prophylaxis<br />Prevent attacks before expected trauma eg. surgery or dental procedures<br />avoid potentially catastrophic swelling<br />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 <br />2 units of FFP several hours before procedure<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23 <br />
  21. 21. HAE treatment: The present<br />Over the past 18 months, 3 new medications for treatment of HAE approved in US<br />Plasma-derived C1INH concentrates<br />Pasteurized plasma-derived C1INH concentrate<br />Nanofiltered and pasteurized plasma-derived C1INH concentrate<br />Plasma kallikrein inhibitor: Ecallantide<br />
  22. 22. Pasteurized plasma-derived C1INH concentrate<br />Berinert (CSL Behring) : pasteurized lyophilized human plasma-derived C1 inhibitor concentrate<br />licensed in Europe over 20 years (acute, short term)<br />phase III study for acute attacks ( IMPACT1)<br />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<br />primary outcome : time from start of treatment to onset of symptom relief<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  23. 23. Pasteurized plasma-derived C1INH concentrate<br />J Allergy ClinImmunol 2009;124:801-8.<br />
  24. 24. Pasteurized plasma-derived C1INH concentrate<br />J Allergy ClinImmunol 2009;124:801-8<br />
  25. 25. Berinertreceived approval from FDA (2009) for use in treatment of acute angioedema attacks in adolescent and adult HAE patients<br />Pasteurized plasma-derived C1INH concentrate<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  26. 26. Nanofiltered and pasteurized plasma-derived C1INH concentrate<br />Cinryze (ViroPharmaIncorporated)<br />nanofiltered pasteurized lyophilized C1INH concentrate<br />Manufactured in Netherlands, using U.S. plasma<br />final nanofiltration step, provides additional protection against enveloped and non-enveloped viral particles and possibly prions<br />Two separate randomized double-blind placebo controlled studies of Cinryze performed in US<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  27. 27. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE<br />CHANGE part A<br />efficacy and safety of C1INHnf for treatment of moderate to severe acute attacks of facial, abdominal or genitourinary angioedemain HAE patients<br />infused with C1INH-nf 1,000 IU (35pt.) or placebo (33pt.) at time 0<br />If significant relief not reported within 60 minutes, given second dose of same study drug <br />All subjects eligible to receive open-label Cinryze after 4 hours<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  28. 28. Nanofiltered and pasteurized plasma-derived C1INH concentrate<br />primary end point : time to onset of unequivocal relief of symptom at defining sites<br />median time to onset of unequivocal relief from attack =2 hours ( C1 INHnf ) but > 4 hours in placebo (P = 0.02)<br />median time to complete resolution of symptoms was 12.3 hours (C1 inh group) and 25.0 hours ( placebo group) (P = 0.004)<br />
  29. 29. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE<br />Primary Outcome in the Trial of C1 Inhibitor<br />Therapy for Acute Attacks of Angioedema<br />Cumulative incidence estimates for time to onset of unequivocal relief (primary outcome) 35 subjects received C1 INHnfand 33 subjects received placebo<br />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<br />(60%)<br />(P=0.06)<br />(42%)<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  30. 30. Nanofiltered C1 Inhibitor Concentrate for prophylaxis of HAE<br />CHANGE part B<br />Longterm prophylaxis to prevent attacks of angioedema<br />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<br />primary end point : number of attacks of angioedema per period<br />During C1INH-nf treatment periods, showed highly significant decrease in HAE attacks (6.26 versus 12.73 attacks; p < 0.0001)<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  31. 31. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE<br />attack rates are shown for each of 22 subjects during 12-week period when either placebo or C1 INHnf<br />black horizontal lines indicate mean attack rates for two treatments, 6.3 and 12.7 for C1 inhibitor group and placebo group, respectively<br />Normalized Rate of Angioedema Attacks<br />During Prophylaxis Trial<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  32. 32. Nanofiltered C1 Inhibitor Concentrate for Treatment of acute HAE<br />Adverse events<br />In C1 INH group<br />Possibly : fever (1),lightheadedness (1)<br />Definitely : rash at injection site (1), pruritus and rash (1)<br />In placebo group<br />Possibly : carpopedal spasm (1), erythema (1)<br />Definitely : contact dermatitis (1), chest discomfort (1), cough (1)<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  33. 33. <ul><li>Cinryze received FDA (2008) approval for prophylactic treatment in adolescent and adult HAE patients
  34. 34. The application for use of Cinryze to treat acute attacks of angioedemais still pending</li></ul>Nanofiltered and pasteurized plasma-derived C1INH concentrate<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  35. 35. Plasma kallikrein inhibitor: Ecallantide( Kalbitor )<br />novel, potent and specific plasma kallikreininhibitor<br />recombinant, 60-amino acid protein produced in Pichiapastoris yeast<br />recommended dose to treat angioedemaattack is 30 mg, administered as three 1 ml sc injections<br />Maximum ecallantidelevels reached 2-3 hours following subcutaneous injection, HL~ 2 hours<br />2 separate RDBPC phase III studies of ecallantide for Rx of acute attacks of HAE performed in US<br />EDEMA 3<br />EDEMA 4<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  36. 36. Ecallantide for the Treatment of Acute Attacks in HAE (EDEMA3)<br />RDBPC trial, acute attack , 1:1 ratio, to receive sc ecallantide (30 mg) or placebo<br />72 patients <br />Primary endpoint : treatment outcome score (TOS) at 4 hours<br />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<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  37. 37. Ecallantide for the Treatment of Acute Attacks in HAE<br />Efficacy Analyses with Respect to Primary and Secondary End Points, According to Study Group.<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  38. 38. Ecallantide for the Treatment of Acute Attacks in HAE<br />Efficacy Analyses with Respect to Primary and Secondary End Points, According to Study Group.<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  39. 39. Ecallantide for the Treatment of Acute Attacks in HAE<br />Kaplan–Meier Analysis of Time to Significant Improvement in Overall Response in the Intention-to-Treat Population.<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  40. 40. Ecallantide for the Treatment of Acute Attacks in HAE<br />Adverse Events in the Safety Population, According to Study Group<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  41. 41. Ecallantide for the Treatment of Acute Attacks in HAE (EDEMA4)<br />96 patients<br />primary endpoint : mean symptom complex severity (MSCS) at 4 hours<br />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<br />Mean decrease in symptom score at 4 hours of 0.81 (Ecallantide ) compared to 0.37 in placebo (p = 0.01)<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  42. 42. Plasma kallikrein inhibitor: Ecallantide<br />Prolongation of aPTT (common), without any enhanced risk of bleeding<br />Anaphylactic-like reactions in 10/255 (3.9%) subjects following exposure to ecallantide<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  43. 43. <ul><li>Based on data from both Phase III studies , approval for use of ecallantide to treat acute HAE attacks in patients aged >16 was granted on December 2 2009
  44. 44. black box warning on anaphylactic potential and requiring that the drug be administered by health care provider</li></ul>Plasma kallikrein inhibitor: Ecallantide<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  45. 45. HAE treatment: The future<br />Recombinant human C1INH<br />Icatibant<br />Other future directions<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  46. 46. Recombinant human C1INH<br />J Allergy ClinImmunol 2010;126:821-7.<br />Rhucin (Pharming NV) <br />recombinant human C1 inhibitor (rhC1INH) concentrate for iv infusion isolated from milk of transgenic rabbits<br />identical to human plasma derived C1INH at amino acid level<br />2separate phase III studies ,for rhC1INH in treatment of acute attacks of angioedemain HAE patients<br />
  47. 47. Recombinant human C1INH<br />European RDBPC rhC1INH (100 U/kg) in 32 HAE<br />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)<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  48. 48. Recombinant human C1INH<br />In US and Canada <br />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)<br />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)<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  49. 49. Recombinant human C1-inhibitor for treatment of acute angioedema attacks<br />Primary and secondary efficacy outcome in 3 treatment groups<br />J Allergy ClinImmunol 2010;126:821-7.<br />
  50. 50. Recombinant human C1-inhibitor for treatment of acute angioedema attacks<br />Course of mean VAS scores in time in rhC1INH and saline groups <br />Data indicate mean VAS scores and 95% CIs.<br />J Allergy ClinImmunol 2010;126:821-7.<br />
  51. 51. Recombinant human C1-inhibitor for treatment of acute angioedema attacks<br />Adverse events<br />In C1 INH<br />Headache, vertigo<br />colitis<br />In placebo<br />Headache, injection site swelling, epistaxis, hypotension<br />J Allergy ClinImmunol 2010;126:821-7.<br />
  52. 52. Icatibant, New Bradykinin-Receptor Antagonist, in HAE<br />Icatibant (Firazyr, Shire) <br />synthetic selective decapeptidebradykinin B2 receptor competitive antagonist<br />contains 5 non-natural amino acids to enhance resistance to peptidases <br />Icatibant administered sc injection as single 30 mg <br />peak concentration within 30 minutes, and HL~ 1-2 hours<br />2 RDBPC phase III study : FAST-1(US) ,FAST-2 (Europe)<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  53. 53. Icatibant, New Bradykinin-Receptor Antagonist, in HAE<br />56 subjects (FAST-1)<br />72 subjects (FAST-2) <br />moderate to severe abdominal or cutaneousangioedemaattack<br />Primary endpoint <br />time to onset of symptom relief assessed by subject recorded visual analog scale (VAS)<br />Secondary endpoints <br />time to almost complete symptom relief and response rate at 4 hours<br />Zuraw Allergy, Asthma & Clinical Immunology 2010, 6:23<br />
  54. 54. Icatibant, New Bradykinin-Receptor Antagonist, in HAE<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  55. 55. Icatibant, New Bradykinin-Receptor Antagonist, in HAE<br />Adverse Events in the Safety Populations of the FAST-1 and FAST-2 Trials.<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  56. 56. <ul><li>Approved for use for acute attacks in the European Union
  57. 57. The FDA disapproved the application for licensure,And new RDBPC phase III trial (FAST3) is ongoing</li></ul>Icatibant, New Bradykinin-Receptor Antagonist, in HAE<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  58. 58. Other future directions<br />administering C1INH concentrate by sub-cutaneous infusion <br />steady plasma levels of C1INH during longterm prophylaxis<br />inhibition of factor XII activity might prevent bradykiningeneration<br />Like strategies targeting plasma kallikrein<br />orally available bradykininreceptor antagonists <br />combined bradykinin B2 and B1 receptor antagonism<br />recent demonstration that B1 receptor may play role in swelling of HAE patients <br />gene repair or intracellular trafficking for molecular correction of defects in HAE<br />N Engl J Med 363;6 Nejm.Org August 5, 2010<br />
  59. 59. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  60. 60. HAE Diagnosis Algorithm<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  61. 61. HAE Diagnosis Algorithm ( cont. )<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  62. 62. Short-Term Prophylaxis<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  63. 63. Long-Term Prophylaxis<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  64. 64. Treatment of Acute HAE - Attacks<br />Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24<br />
  65. 65. Take home message<br />Treament of HAE<br />Past<br />Prophylaxis : androgen, antifibrinolytic<br />Present<br />Pasturized C1 INH concentrate (acute attack)<br />NanofilteredPasturizedC1 INH concentrate (prophylaxis)<br />Ecallantide (acute attack)<br />Future<br />Recombinant human C1INH<br />Icatibant<br />
  66. 66. Efficacy results from key clinical studies of C1-INH replacement products<br />Allergy Asthma Proc 31 :398-406,2010.<br />
  67. 67. Efficacy results from key clinical studies of C1-INH replacement products<br />Allergy Asthma Proc 31 :398-406,2010.<br />
  68. 68. Efficacy results from key clinical studies of ecallantide<br />Allergy Asthma Proc 31 :398-406,2010.<br />
  69. 69. Efficacy results from key clinical studies of C1-INH replacement products<br />Allergy Asthma Proc 31 :398-406,2010.<br />
  70. 70. Efficacy results from key clinical studies of icatibant<br />Allergy Asthma Proc 31 :398-406,2010.<br />

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