1. 7asdf Omapatrilat in the Treatment of Hypertension Efficacy and Safety NDA 21-188 FDA Cardiovascular and Renal Drugs Advisory Committee Meeting July 19, 2002 Elliott Levy, M.D. Vice President, Clinical Design and Evaluation Pharmaceutical Research Institute

2. Efficacy

3. 7/19-3 Omapatrilat Target Population Patients with: A high risk of major cardiovascular events* A high risk of major cardiovascular events* –Cardiovascular disease (e.g., MI, CHF) –Target organ damage (e.g., LVH, proteinuria) –3 or more cardiovascular risk factors –Diabetes or renal disease and and Hypertension that is difficult to control with existing medications Hypertension that is difficult to control with existing medications *Based on WHO-ISH guidelines Use with special caution in black patients and current smokers

4. 7/19-4 Order of Presentation In 4 placebo-controlled trials (2369 patients), dose related reduction demonstrated in systolic and diastolic blood pressure In 4 placebo-controlled trials (2369 patients), dose related reduction demonstrated in systolic and diastolic blood pressure In 6 active-controlled trials (2742 patients), omapatrilat 80 mg shown to be more effective monotherapy than lisinopril 40 mg, amlodipine 10 mg, losartan 100 mg In 6 active-controlled trials (2742 patients), omapatrilat 80 mg shown to be more effective monotherapy than lisinopril 40 mg, amlodipine 10 mg, losartan 100 mg In OCTAVE (25,302 patients), omapatrilat-based regimen consistently more effective than enalapril-based regimen In OCTAVE (25,302 patients), omapatrilat-based regimen consistently more effective than enalapril-based regimen Greater BP reduction preserved in patients with comorbidity and difficult to control hypertension Greater BP reduction preserved in patients with comorbidity and difficult to control hypertension

5. 7/19-5 Dose-Related Mean Reduction from Baseline in Trough Blood Pressure Weeks 6-9 CV137-006, -022, -024 and -045 -20 -15 -10 -5 0 Pbo 10 mg 20 mg 40 mg 80 mg Pbo 10 mg 20 mg 40 mg 80 mg Pbo 10 mg 20 mg 40 mg 80 mg Pbo 10 mg 20 mg 40 mg 80 mg Change in BP (mmHg) Systolic -3.4 -11.4 -13.2 -17.0 -19.1 -4.4 -8.4 -10.2 -11.8 -14.1 Diastolic

6. 7/19-6 * p  0.05 vs. comparator ** p  0.001 vs. comparator Changes in Trough Systolic BP versus Active Comparators at Maximal Recommended Dose CV137-030 (n = 492) CV137-037 (n = 437) SBP Change (mmHg) CV137-077 (n = 203) -3.1* -5.2** -7.2** Week 10 oma 80 mg aml 10 mg oma 80 mg lis 40 mg oma 80 mg los 100 mg

7. 7/19-7 ** p  0.001 vs. comparator Changes in 24-Hour Average Ambulatory Systolic BP versus Active Comparators at Maximal Recommended Doses CV137-032 (n = 379) CV137-031 (n = 317) ASBP Change (mmHg) CV137-066 (n = 673) -5.9** -6.8** -5.4** Week 10 -8.9** oma 80 mg aml 10 mg oma 80 mg lis 40 mg oma 80 mg aml 10 mg los 100mg

8. 7/19-8 Effects of Omapatrilat and Amlodipine on Ambulatory Systolic Blood Pressure, by Hour ASBP (mmHg) Hour Post-Dose 246 8 1012141618202224 Difference in 24-hour Average ASBP = -5.9** CV137-032 ** p  0.001 vs. Amlodipine Omapatrilat (n = 192) Amlodipine (n = 187) Omapatrilat 80 mg Amlodipine 10 mg Baseline Week 10

9. 7/19-9 OCTAVE: Rationale In 6 active controlled monotherapy trials, omapatrilat 80 mg reduced blood pressure to a greater extent than maximal doses of amlodipine, losartan and lisinopril In 6 active controlled monotherapy trials, omapatrilat 80 mg reduced blood pressure to a greater extent than maximal doses of amlodipine, losartan and lisinopril OCTAVE was designed to evaluate whether omapatrilat would be superior to another agent (enalapril) in clinical use conditions, where therapy is titrated electively and supplemented by other agents to reach BP target OCTAVE was designed to evaluate whether omapatrilat would be superior to another agent (enalapril) in clinical use conditions, where therapy is titrated electively and supplemented by other agents to reach BP target OCTAVE was large enough to characterize efficacy and safety in important subgroups OCTAVE was large enough to characterize efficacy and safety in important subgroups

10. 7/19-10 OCTAVE: Study Design 10 mg 10 mg 5 mg SBP  140 or or DBP  90 24681624 20 10 40 20 80 40 + Adjunctive Rx Week: Week: Omapatrilat Enalapril Titration to Target Adjunctive Rx to Target Target BP:  140/90 mmHg * *Forced Titration

11. 7/19-11 JNC VI Stage I-III Untreated JNC VI Stage I Despite Treatment Replacement (Group 2) Add-on (Group 3) Initial (Group 1) R n = 9,292 n = 11,224 n = 4,751 EnaOmaEnaOmaEnaOma OCTAVE: Study Groups RR JNC VI Stage II Despite Treatment Baseline BP (mmHg) 156 / 96150 / 91166 / 97

12. 7/19-12 OCTAVE: Study Endpoints Efficacy (Co-Primary) Change in systolic blood pressure from baseline to Week 8, by study group Change in systolic blood pressure from baseline to Week 8, by study group Use of new adjunctive antihypertensive therapy between Weeks 8 and 24, by study group Use of new adjunctive antihypertensive therapy between Weeks 8 and 24, by study groupSafety Incidence of adverse events Incidence of adverse events Incidence and severity of angioedema Incidence and severity of angioedema

13. 7/19-13 OCTAVE: Efficacy Results at Week 8 % of Patients Change in Systolic BP Titration to Top Dose (Oma 80 mg, Ena 40 mg) Omapatrilat Enalapril Initial Group 1 Replacement Group 2 Add-on Group 3 -3.2** -3.8** -3.6** Initial Group 1 Replacement Group 2 Add-on Group 3 SBP Change (mmHg) ** p  0.001 vs enalapril ** ** **

14. 7/19-14 OCTAVE: Efficacy Results at Week 24 Change in Systolic BP Use of New Adjunctive Therapy Initial Group 1 Replacement Group 2 Add-on Group 3 -3.1** -3.1** -2.8** Initial Group 1 Replacement Group 2 Add-on Group 3 SBP Change (mmHg) ** p  0.001 vs enalapril ** % of Patients Omapatrilat Enalapril

15. 7/19-15 Demographic Subgroups: Change in Systolic BP at Week 24 Adjusted SBP Change at Week 24 (mmHg) OmapatrilatEnalapril Difference (oma / ena) Age, n (%)  65 years (n = 17,569)  65 years (n = 6887)  75 years (n = 2026) -20.0 -19.0 -18.9 -16.9 -16.1 -15.7 -3.1 -2.9 -3.2 Gender, n (%) Male (n = 12,717) Female (n = 11,739) -19.1 -20.4 -16.2 -17.2 -2.9 -3.2 Race, n (%) White (n = 21,651) Black (n = 2420) -20.3 -14.5 -17.3 -10.9 -3.0 -3.6 OCTAVE (CV137-120)

16. 7/19-16 Subgroups at Increased CV Risk: Change in Systolic BP at Week 24 Adjusted SBP Change at Week 24 (mmHg) Omapatrilat Enalapril Difference (oma / ena) -18.7 -36.6 Severe Hypertension (n = 7197) Group 1 (n = 983) -2.7 -4.6 -17.6Diabetes Mellitus (n = 3275)-4.2 -20.7Atherosclerotic Disease* (n = 2283)-2.7 -22.2ISH (n = 1332)-4.5 -17.0Renal Disease (n = 582)-3.6 -20.9Heart Failure (n = 233)-4.5 -15.9 -32.0 -13.4 -18.0 -17.7 -13.4 -16.4 *Includes chronic stable angina, unstable angina, myocardial infarction, and stroke / TIA OCTAVE (CV137-120)

17. 7/19-17 OCTAVE Conclusion Greater BP reduction with omapatrilat-based regimen, despite more frequent use of maximal doses and adjunctive therapy with enalapril Greater BP reduction with omapatrilat-based regimen, despite more frequent use of maximal doses and adjunctive therapy with enalapril Highly consistent results regardless of patient subgroup or manner of use of study drug Highly consistent results regardless of patient subgroup or manner of use of study drug Greater BP reduction observed at week 8 and preserved over 24 weeks, despite use of adjunctive therapy Greater BP reduction observed at week 8 and preserved over 24 weeks, despite use of adjunctive therapy

18. 7/19-18 Role of Omapatrilat in Difficult to Control Hypertension In many patients, hypertension can be readily controlled with existing therapy In many patients, hypertension can be readily controlled with existing therapy OCTAVE and other large clinical trials demonstrate that hypertension is difficult to control in many patients OCTAVE and other large clinical trials demonstrate that hypertension is difficult to control in many patients In patients not readily controlled with existing therapies, an omapatrilat-based regimen provides lasting efficacy advantage In patients not readily controlled with existing therapies, an omapatrilat-based regimen provides lasting efficacy advantage

19. 7/19-19 Efficacy at Week 24 in Subgroups Defined by Baseline JNC-VI Stage Omapatrilat Enalapril SBP Change (mmHg) -2.6** -3.0** -4.6** Stage I (n = 4160) 147 Stage II (n = 3864) 160 Stage III (n = 983) 178 % of Patients Stage I Stage II Stage III Use of New Adjunctive Antihypertensive Therapy JNC-VI Change in Systolic BP – JNC-VI Baseline SBP (mmHg) ** p  0.001 vs enalapril OCTAVE (CV137-120) Group 1 **

20. 7/19-20 Control of BP (  140/90 mmHg) in Multi-Drug Resistant Patients in Group 3 at Week 24 % Controlled Omapatrilat Enalapril 2 or More Baseline Meds (n = 2309) OCTAVE (CV137-120) 3 or More Baseline Meds (n = 703)

21. 7/19-21 Difficult to Control Hypertension: Patients Uncontrolled with ACE-Inhibitor Regimen Maximal ACE-I (alone or as part of regimen) SBP  140 or DBP  90 Titration 2-4 Weeks Maintenance 4 Weeks Enrollment / Lead-In 2+ weeks Randomization D/C ACE-I Continue other antihypertensives (if any) at established dose CV137-073 Omapatrilat 20 40 80 Lisinopril 20 20 40

22. 7/19-22 ASBP (mmHg) Hour Post-Dose Changes in Ambulatory Systolic BP in Subjects Uncontrolled with ACE-Inhibitor Regimen Week 4 Maintenance * *p  0.001 vs. lisinopril Average ambulatory difference from Lisinopril = -8.8** Trough difference from Lisinopril = -7.0** Omapatrilat 80 mg (n = 124) Lisinopril 40 mg (n = 122) CV137-073

23. 7/19-23 CV137-073 ASBP Change (mmHg) ACE-I Monotherapy (n = 171) ACE-I Combination (n = 75) Change in 24-Hour Average Ambulatory Systolic BP in Patients Uncontrolled with ACE-Inhibitor Regimens at Baseline Omapatrilat 80 mgLisinopril 40 mg -7.6** -11.5** Week 4 Maintenance * *p  0.001 vs. lisinopril

24. 7/19-24 ACE-I Monotherapy (n = 2278) ACE-I + 1 Antihypertensive Med (n = 1368) SBP Change (mmHg) Omapatrilat Enalapril Efficacy at Week 24: OCTAVE Patients Not at Target with ACE-Inhibitor Regimens at Baseline ACE-I + 2 or More Antihypertensive Meds (n = 546) -3.5** -3.0** -5.9** Group 2 ** p  0.001 vs. enalapril

25. 7/19-25 ACE-I Monotherapy (n = 466) ACE-I + 1 Antihypertensive Med (n = 322) SBP Change (mmHg) ACE-I + 2 or More Antihypertensive Meds (n = 169) Efficacy at Week 24: OCTAVE Patients with Diabetes Not at Target with ACE-Inhibitor Regimens at Baseline -4.8** -6.9** -8.5* Omapatrilat Enalapril * p  0.05 ** p  0.001 vs. enalapril Group 2

26. 7/19-26 Efficacy Conclusions Greater antihypertensive efficacy with regimen based on omapatrilat Greater antihypertensive efficacy with regimen based on omapatrilat Greater efficacy apparent across patient subgroups and continued over time Greater efficacy apparent across patient subgroups and continued over time Greater efficacy maintained even when physicians encouraged to add adjunct to achieve BP goal Greater efficacy maintained even when physicians encouraged to add adjunct to achieve BP goal In patients with difficult to control hypertension, omapatrilat provides antihypertensive effect not achieved with current drugs In patients with difficult to control hypertension, omapatrilat provides antihypertensive effect not achieved with current drugs

27. Safety

28. 7/19-28 Omapatrilat Safety Database Overall: Overall: –34,780 hypertensive patients –18,723 exposed to omapatrilat Patients exposed by omapatrilat dose: Patients exposed by omapatrilat dose: 10 mg = 15,058 20 mg = 16,655 Patients exposed to omapatrilat by duration: Patients exposed to omapatrilat by duration:  3 months = 12,995  3 months = 12,995  1 year = 1,478  1 year = 1,478 Heart Failure (OVERTURE) Heart Failure (OVERTURE) 40 mg = 11,317 80 mg = 6,922

29. 7/19-29 Safety Summary Safety well-characterized through extensive program Safety well-characterized through extensive program Overall incidence of AE, SAE, D/C due to AE comparable for omapatrilat and ACE-I Overall incidence of AE, SAE, D/C due to AE comparable for omapatrilat and ACE-I Angioedema 3 times more common with omapatrilat Angioedema 3 times more common with omapatrilat

30. Angioedema: Clinical Overview FDA Cardiovascular and Renal Drugs Advisory Committee Meeting July 19, 2002 Allen Kaplan, M.D. Medical University of South Carolina Charleston, SC

31. 7/19-31 Localized edema in a variety of anatomical sites Localized edema in a variety of anatomical sites –Superficial (e.g., eyelids, lips, face) –Oropharyngeal (e.g., tongue, pharynx) –Lower airway (e.g., larynx) –Other (e.g., hands) Most common etiologies are inherited and drug-induced Most common etiologies are inherited and drug-induced Bradykinin is the mediator of inherited and ACE-I induced angioedema Bradykinin is the mediator of inherited and ACE-I induced angioedema ACE-I are the most common cause of drug-induced angioedema ACE-I are the most common cause of drug-induced angioedema Anaphylaxis and angioedema are different clinical syndromes Anaphylaxis and angioedema are different clinical syndromes Angioedema: Background Information

32. 7/19-32 Angioedema: Clinical Information Generally develops over several hours but may progress over 1-2 hours in severe cases Generally develops over several hours but may progress over 1-2 hours in severe cases Patients are aware of the swelling of angioedema Patients are aware of the swelling of angioedema In contrast to antihistamines, treatment with epinephrine can halt further progression of episode In contrast to antihistamines, treatment with epinephrine can halt further progression of episode Laryngeal edema without other symptoms is very rare Laryngeal edema without other symptoms is very rare

33. 7/19-33 Anaphylaxis Compared with Angioedema Time Course Symptoms Mediators Treatment Rapid evolution; typically occurs over several minutes after antigen exposure Mucocutaneous - swelling, erythema, urticaria Cardiovascular - hypotension, shock Respiratory - laryngeal edema, bronchial constriction Multiple inflammatory mediators including histamine Epinephrine, steroids, anti-histamine Evolves over hours Mucocutaneous - localized edema of face, oropharynx Cardiovascular - none Respiratory - laryngeal edema Bradykinin Epinephrine; observation Drug-Induced or Inherited Angioedema Anaphylaxis

34. Safety of Omapatrilat

35. 7/19-35 Angioedema reported as adverse event Angioedema reported as adverse event Precise incidence of angioedema difficult to determine Precise incidence of angioedema difficult to determine –ICD-9 based coding system assigned potential angioedema events to several terms (angioedema, head/neck edema) –AE reports generally did not provide sufficient detail to further assess cases Angioedema with Omapatrilat: Findings Prior to OCTAVE

36. 7/19-36 Adverse Event Frequency of Angioedema and Head and Neck Edema with Omapatrilat (Prior to OCTAVE*) Head and Neck Edema, n (%) Airway Compromise, n (%) Angioedema, n (%)  20 mg (N = 1544)  20 mg (N = 2740) 11 (0.71)29 (1.06) 0 (0) 4 (0.15) 7 (0.45)37 (1.35) Total (N = 4284) 40 (0.93) 4 (0.09) 44 (1.03) *Randomized controlled HTN studies

37. 7/19-37 Description of Airway Compromise Cases (Prior to OCTAVE) 4 patients required airway protection in previous NDA submission Patient 1 (CV137-024;020-001) Patient 2 (CV137-037;034-029) Patient 3 (CV137-037;089-017) RaceWhiteBlack Clinical Presentation Initial dose (20 mg) 2 hours post dose experienced flushing, swelling of face, tongue and lips. Presented to ER and following many interventions, developed stridor and desatrurated. 11 days since randomization (20 mg) 2-3 hours post dose experienced facial and glosso- pharyngeal edema and difficulty breathing Within 1 hour of first dose (20 mg) experienced swelling of lips, throat, and dyspnea. Evaluated in ER, treated and released. Presented to ER 3 hr later with difficulty breathing. Treatment Epi, steroids, diphenhydramine, lidocaine, tracheostomy Epi, steroids, diphenhydramine, diltiazem, intubation Epi, steroids, diphenhydramine, albuterol nebulizer tx, intubated Current Smoker YesNoYes Patient 4 (CV137-042;094-009) White 6 days since randomization (20 mg) hospitalized for LOC with head injury. While under observation developed subsequent glottis and laryngeal edema, tongue swelling and difficulty speaking. Steroids, Amoxicillin cricothyrotomy with subsequent tracheostomy No

38. 7/19-38 OCTAVE: Assessment of Angioedema Compare incidence of angioedema with omapatrilat (10-80 mg) and enalapril (5-40 mg) Compare incidence of angioedema with omapatrilat (10-80 mg) and enalapril (5-40 mg) Incidence of angioedema with a starting dose of 10 mg vs. 20 mg omapatrilat was not tested Incidence of angioedema with a starting dose of 10 mg vs. 20 mg omapatrilat was not tested Special process created for evaluation of angioedema Special process created for evaluation of angioedema –Active collection of all potential events –Detailed follow-up information collected on structured questionnaire –Potential angioedema cases adjudicated by expert committee without knowledge of treatment assignment

39. 7/19-39 OCTAVE: Incidence of Angioedema Omapatrilat (N = 12,609) Enalapril (N = 12,557) Patients with Angioedema, n (%) 274 (2.17%)86 (0.68%) Risk Ratio (95% CI)3.17 (2.52, 4.12)

40. 7/19-40 OCTAVE: Pre-specified Severity Scale Severity INo treatment administered or antihistamines only Treated with catecholamines or steroids Hospitalized but no mechanical airway protection IIIa No airway compromise IIIb With airway compromise IVMechanical airway protection or death from airway compromise* III II

41. 7/19-41 OCTAVE: Pre-specified Severity Scale Number (%) of Patients Severity Omapatrilat (N = 12,609) Enalapril (N = 12,557) INo treatment administered or antihistamines only Treated with catecholamines or steroids Hospitalized but no mechanical airway protection IIIa No airway compromise IIIb With airway compromise IVMechanical airway protection or death from airway compromise* 161 (1.28%) 94 (0.75%) 18 (0.14%) 17 1 1 (0.01%) 65 (0.52%) 19 (0.15%) 2 (0.02%) 2 0 0 (0.00%) 274 (2.17%) * No deaths occurred from angioedema Total86 (0.68%) III II

42. 7/19-42 Risk of Angioedema with Airway Compromise N Number of events (%) Rate of Angioedema Events with Airway Compromise per 10,000 treated (95% CI)Treatment 12,557 OCTAVE 0 0 (0.0, 2.9)Enalapril 12,609 OCTAVE 21.6 (0.2, 5.7)Omapatrilat Duration (weeks) 24 18,723 Combined OCTAVE/ Pre-OCTAVE Studies 63.2 (1.2, 7.0) Omapatrilat 8 - 24

43. 7/19-43 OCTAVE: Angioedema with Airway Compromise Did Not Require Airway Protection (n = 1) Race Clinical Presentation Treatment WhiteBlack Required Airway Protection (n = 1) Current SmokerYesNo Edema of the –Eyelid(s) –Lip(s) –Neck Difficulty speaking Difficulty swallowing Dyspnea Hoarseness Hypotensive Cyanotic Epinephrine Edema of the –Eyelid(s) –Face –Lip(s) –Mucous Membranes –Neck –Pharynx –Tongue Difficulty speaking Difficulty swallowing Epinephrine, Steroids, Tracheostomy

44. 7/19-44 Omapatrilat (n = 17) Enalapril (n = 2) Airway compromiseNone Signs/Symptoms8 tongue swelling 9 lip swelling 1 tongue swelling 2 lip swelling Other Indications for observation 7 late hour 3 social factors 2 comorbid conditions 1 comorbid conditions Progression in Hospital None TreatmentEpi (5) / steroids (16)Epi (1) / steroids (2) Time to Discharge14 next day 3 after 2 days 1 next day 1 after 6 days Angioedema Hospitalizations without Airway Compromise

45. 7/19-45 Patient Response to Symptoms of Angioedema Most (80.5%) angioedema events occurred outside the physician’s office Most (80.5%) angioedema events occurred outside the physician’s office –Most (63.7%) patients with angioedema occurring outside of physician’s office presented to medical facilities more than one hour after onset of symptoms –Many (28.6%) patients presented to medical facilities more than 6 hours after onset of symptoms OCTAVE: Class II-IV Patients

46. 7/19-46 Patient’s Ability to Recognize Angioedema Patients with airway compromise were highly symptomatic with a constellation of symptoms Patients with airway compromise were highly symptomatic with a constellation of symptoms Patients without airway compromise also had clinically overt presentation with visible swelling +/- functional complaints Patients without airway compromise also had clinically overt presentation with visible swelling +/- functional complaints No patients with angioedema had non-specific lower airway complaints (stridor, dyspnea, hoarseness) alone No patients with angioedema had non-specific lower airway complaints (stridor, dyspnea, hoarseness) alone

47. 7/19-47 OCTAVE: Incidence of Angioedema by Time Period OCTAVE (CV137-120) Time Period OmapatrilatEnalapril Day 188 (0.70 %)3 (0.02%) Day 2 – Week 483 (0.66 %)43 (0.34%) Week 5 – Week 844 (0.38%)22 (0.19%) Week 9 – Week 1225 (0.23%)3 (0.03%) Week 13 – Week 1614 (0.13%)7 (0.06%) Week 17 – Week 2010 (0.09%)4 (0.04%) Week 21 – Week 2410 (0.10%)4 (0.04%) (N = 12,609)(N = 12,557) Total274 (2.17%)86 (0.68%)

48. 7/19-48 OCTAVE: Summary of Angioedema Risk with Omapatrilat in Subgroups* 2.96 1.51 1.17 Relative Risk 2.58 Black race Current smoker** Renal disease Seasonal allergies Female gender Former smoker** Age  65 years ACE-I use Diabetes Atherosclerotic disease 0.58 0.55 1.55 0.97 1.48 Decreased Risk Increased Risk * Multivariate logistic regression model with angioedema as the dependent variable and all other listed variables as independent variables. ** vs those who never smoked. 72 (5.5%) 72 (5.5%) 89 (3.9%) 89 (3.9%) 11 (3.6%) 11 (3.6%) 55 (3.3%) 55 (3.3%) 153 (2.5%) 78 (2.1%) 78 (2.1%) 70 (2.0%) 70 (2.0%) 90 (2.0%) 90 (2.0%) 23 (1.3%) 23 (1.3%) 14 (1.2%) 14 (1.2%) Incidence (vs. those without characteristics) Subgroup1.91 0.51.02.04.0

49. 7/19-49 Angioedema Safety Summary Incremental risk of angioedema relative to ACE-I treatment Incremental risk of angioedema relative to ACE-I treatment Angioedema has wide spectrum of severity Angioedema has wide spectrum of severity Current smokers and black patients have a higher incidence of angioedema Current smokers and black patients have a higher incidence of angioedema Life-threatening in 1.6/10,000 (95% CI 0.2-5.7) Life-threatening in 1.6/10,000 (95% CI 0.2-5.7) Symptomatic event with characteristic presentation Symptomatic event with characteristic presentation Onset rapid but not fulminant Onset rapid but not fulminant Effective treatment exists for angioedema Effective treatment exists for angioedema

50. 7/19-50 Risk Management Angioedema has clinical features which facilitate its management through patient education: Symptomatic, recognizable clinical presentation Symptomatic, recognizable clinical presentation Rapid but not fulminant progression Rapid but not fulminant progression Effective therapy exists which can prevent poor outcomes Effective therapy exists which can prevent poor outcomes

51. 7/19-51 Risk Management Labeling and packaging Indication, warning, risk factors, etc. Indication, warning, risk factors, etc. Unit of use packaging Unit of use packaging Comprehensive educational program Includes mandatory patient counseling Includes mandatory patient counseling Multiple points of contact (physicians, patients, pharmacists) Multiple points of contact (physicians, patients, pharmacists) Post-marketing surveillance Includes prospective observational cohort study Includes prospective observational cohort study Ongoing assessment of program effectiveness Expert panel Expert panel

52. 7/19-52 Projected Reduction in CV Events Per annum per 10,000 Treated CV Risk Category Projected Reduction in CV Events BP Reduction 3/2 mmHg BP Reduction 5/3 mmHg Projected CV Events Low (1.5% per annum)  15  23  150 Medium (1.5-2% per annum)15 - 2023 - 30150 - 200 High (2-3% per annum)20 - 3030 - 45200 - 300 Very High (  3% per annum)  30  45  300 Observed incidence of angioedema with airway compromise over 24 weeks in OCTAVE: 1.6 (95% CI 0.2 -- 5.7) per 10,000