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

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  1. NDA 21-188 Omapatrilat in the Treatmentof HypertensionEfficacy and Safety Elliott Levy, M.D.Vice President, Clinical Design and EvaluationPharmaceutical Research Institute 7asdf • FDA Cardiovascular and Renal DrugsAdvisory Committee Meeting • July 19, 2002

  2. Efficacy

  3. Omapatrilat Target Population • Patients with: • 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 • Hypertension that is difficult to controlwith existing medications Use with special caution in black patientsand current smokers *Based on WHO-ISH guidelines

  4. Order of Presentation • In 4 placebo-controlled trials (2369 patients), doserelated reduction demonstrated in systolic and diastolic blood pressure • In 6 active-controlled trials (2742 patients), omapatrilat80 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 • Greater BP reduction preserved in patients with comorbidity and difficult to control hypertension

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

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

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

  8. 2 4 6 10 12 14 16 18 20 22 24 8 Hour Post-Dose Effects of Omapatrilat and Amlodipine on Ambulatory Systolic Blood Pressure, by Hour Difference in 24-hourAverage ASBP = -5.9** ASBP (mmHg) Week 10 Baseline Omapatrilat (n = 192) Amlodipine (n = 187) Omapatrilat 80 mg Amlodipine 10 mg CV137-032 **p £ 0.001 vs. Amlodipine

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

  10. OCTAVE: Study Design + Adjunctive Rx 10 mg 20 40 80 Omapatrilat SBP  140 or DBP  90 Target BP: < 140/90 mmHg Enalapril 20 40 10 5 mg + Adjunctive Rx Titration to Target Adjunctive Rx to Target * Week: 2 4 6 8 16 24 *Forced Titration

  11. R R R OCTAVE: Study Groups JNC VI Stage I-IIIUntreated JNC VI Stage IDespite Treatment JNC VI Stage IIDespite Treatment Initial (Group 1) Replacement (Group 2) Add-on (Group 3) Oma Ena Oma Ena Oma Ena n = 9,292 n = 11,224 n = 4,751 Baseline BP(mmHg) 156 / 96 150 / 91 166 / 97

  12. OCTAVE: Study Endpoints • Efficacy (Co-Primary) • 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 • Safety • Incidence of adverse events • Incidence and severity of angioedema

  13. Omapatrilat Enalapril OCTAVE: Efficacy Results at Week 8 Change in Systolic BP Titration to Top Dose(Oma 80 mg, Ena 40 mg) InitialGroup 1 ReplacementGroup 2 Add-onGroup 3 ** ** % of Patients SBP Change (mmHg) -3.8** ** -3.2** -3.6** InitialGroup 1 ReplacementGroup 2 Add-onGroup 3 ** p< 0.001 vs enalapril

  14. Omapatrilat Enalapril OCTAVE: Efficacy Results at Week 24 Change in Systolic BP Use of NewAdjunctive Therapy InitialGroup 1 ReplacementGroup 2 Add-onGroup 3 % of Patients SBP Change (mmHg) ** -3.1** ** ** -3.1** -2.8** InitialGroup 1 ReplacementGroup 2 Add-onGroup 3 ** p< 0.001 vs enalapril

  15. Adjusted SBP Changeat Week 24 (mmHg) Difference(oma / ena) Omapatrilat Enalapril Age, n (%) -20.0 -16.9 -3.1 < 65 years (n = 17,569) -19.0 -16.1 -2.9 ³ 65 years (n = 6887) -18.9 -15.7 -3.2 ³ 75 years (n = 2026) Gender, n (%) Male (n = 12,717) -19.1 -16.2 -2.9 Female (n = 11,739) -20.4 -17.2 -3.2 Race, n (%) White (n = 21,651) -20.3 -17.3 -3.0 Black (n = 2420) -14.5 -10.9 -3.6 Demographic Subgroups:Change in Systolic BP at Week 24 OCTAVE (CV137-120)

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

  17. OCTAVE Conclusion • 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 • Greater BP reduction observed at week 8and preserved over 24 weeks, despite useof adjunctive therapy

  18. Role of Omapatrilat in Difficult to Control Hypertension • 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 • In patients not readily controlled with existing therapies, an omapatrilat-based regimen provides lasting efficacy advantage

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

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

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

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

  23. Change in 24-Hour Average AmbulatorySystolic BP in Patients Uncontrolledwith ACE-Inhibitor Regimens at Baseline ACE-I Monotherapy(n = 171) ACE-ICombination(n = 75) ASBP Change (mmHg) -11.5** -7.6** Week 4 Maintenance * *p < 0.001 vs. lisinopril Omapatrilat 80 mg Lisinopril 40 mg CV137-073

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

  25. Omapatrilat Enalapril Efficacy at Week 24: OCTAVE Patients withDiabetes Not at Target with ACE-InhibitorRegimens at Baseline ACE-I + 1 Antihypertensive Med (n = 322) ACE-I + 2 or More AntihypertensiveMeds (n = 169) ACE-IMonotherapy (n = 466) -8.5* SBP Change (mmHg) -6.9** -4.8** Group 2 * p < 0.05 ** p < 0.001 vs. enalapril

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

  27. Safety

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

  29. Safety Summary • Safety well-characterized through extensiveprogram • Overall incidence of AE, SAE, D/C due to AE comparable for omapatrilat and ACE-I • Angioedema 3 times more common withomapatrilat

  30. Angioedema: Clinical Overview Allen Kaplan, M.D.Medical University of South CarolinaCharleston, SC • FDA Cardiovascular and Renal DrugsAdvisory Committee Meeting • July 19, 2002

  31. Angioedema: Background Information • 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 • Bradykinin is the mediator of inherited and ACE-Iinduced angioedema • ACE-I are the most common cause of drug-inducedangioedema • Anaphylaxis and angioedema are differentclinical syndromes

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

  33. Time Course Symptoms MediatorsTreatment Anaphylaxis Compared with Angioedema Drug-Induced or Inherited Angioedema Anaphylaxis Rapid evolution; typically occursover several minutes afterantigen 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 BradykininEpinephrine; observation

  34. Safety of Omapatrilat

  35. Angioedema with Omapatrilat:Findings Prior to OCTAVE • Angioedema reported as adverse event • Precise incidence of angioedema difficultto determine • ICD-9 based coding system assignedpotential angioedema events to severalterms (angioedema, head/neck edema) • AE reports generally did not providesufficient detail to further assess cases

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

  37. Patient 1 Patient 2 Patient 3 (CV137-024;020-001) (CV137-037;034-029) (CV137-037;089-017) Description of Airway Compromise Cases (Prior to OCTAVE) Patient 4 (CV137-042;094-009) Race White Black Black White Current Smoker Yes No Yes No ClinicalPresentation Initial dose (20 mg)2 hours post doseexperienced flushing, swelling of face, tongue and lips. Presented to ER and following many interventions, developed stridor and desatrurated. 11 days sincerandomization(20 mg) 2-3 hourspost doseexperienced facialand glosso-pharyngeal edemaand difficultybreathing 6 days sincerandomization(20 mg) hospitalizedfor LOC with head injury. While underobservation developed subsequent glottis and laryngeal edema,tongue swelling anddifficulty speaking. Within 1 hour offirst dose (20 mg) experiencedswelling 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 Steroids, Amoxicillincricothyrotomy withsubsequenttracheostomy 4 patients required airway protection in previous NDA submission

  38. OCTAVE: Assessment of Angioedema • Compare incidence of angioedema withomapatrilat (10-80 mg) and enalapril (5-40 mg) • Incidence of angioedema with a starting doseof 10 mg vs. 20 mg omapatrilat was not tested • Special process created for evaluationof angioedema • Active collection of all potential events • Detailed follow-up information collectedon structured questionnaire • Potential angioedema cases adjudicatedby expert committee without knowledgeof treatment assignment

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

  40. OCTAVE: Pre-specified Severity Scale Severity I No treatment administered or antihistaminesonly II Treated with catecholamines or steroids III Hospitalized but no mechanical airwayprotection IIIa No airway compromise IIIb With airway compromise IV Mechanical airway protection or death fromairway compromise*

  41. OCTAVE: Pre-specified Severity Scale Number (%) of Patients Severity Omapatrilat Enalapril (N = 12,609) (N = 12,557) I No treatment administered or antihistaminesonly 161 (1.28%) 65 (0.52%) II Treated with catecholamines or steroids 94 (0.75%) 19 (0.15%) III Hospitalized but no mechanical airwayprotection 18 (0.14%) 2 (0.02%) IIIa No airway compromise 17 2 IIIb With airway compromise 1 0 IV Mechanical airway protection or death fromairway compromise* 1 (0.01%) 0 (0.00%) Total 274 (2.17%) 86 (0.68%) * No deaths occurred from angioedema

  42. Risk of Angioedema withAirway Compromise Treatment N Rate of Angioedema Events with Airway Compromise per 10,000 treated (95% CI) Duration (weeks) Number ofevents (%) OCTAVE 24 Enalapril 12,557 0 0 (0.0, 2.9) OCTAVE 24 Omapatrilat 12,609 2 1.6 (0.2, 5.7) Combined OCTAVE/Pre-OCTAVE Studies 8 - 24 Omapatrilat 18,723 6 3.2 (1.2, 7.0)

  43. OCTAVE: Angioedema with Airway Compromise Did Not Require Airway Protection (n = 1) Required Airway Protection (n = 1) Race White Black Current Smoker Yes No ClinicalPresentation • Edema of the • Eyelid(s) • Lip(s) • Neck • Difficulty speaking • Difficulty swallowing • Dyspnea • Hoarseness • Hypotensive • Cyanotic • Edema of the • Eyelid(s) • Face • Lip(s) • Mucous Membranes • Neck • Pharynx • Tongue • Difficulty speaking • Difficulty swallowing Treatment Epinephrine Epinephrine, Steroids, Tracheostomy

  44. Angioedema Hospitalizations withoutAirway Compromise Omapatrilat (n = 17) Enalapril (n = 2) Airway compromise None None Signs/Symptoms 8 tongue swelling 1 tongue swelling 9 lip swelling 2 lip swelling Other Indicationsfor observation 7 late hour 1 comorbid conditions 3 social factors 2 comorbid conditions Progression inHospital None None Treatment Epi (5) / steroids (16) Epi (1) / steroids (2) Time to Discharge 14 next day 1 next day 3 after 2 days 1 after 6 days

  45. Patient Response to Symptomsof Angioedema OCTAVE: Class II-IV Patients • Most (80.5%) angioedema events occurred outside the physician’s office • Most (63.7%) patients with angioedema occurring outside of physician’s officepresented 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

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

  47. Omapatrilat Enalapril Time Period (N = 12,609) (N = 12,557) Day 1 88 (0.70 %) 3 (0.02%) Day 2 – Week 4 83 (0.66 %) 43 (0.34%) Week 5 – Week 8 44 (0.38%) 22 (0.19%) Week 9 – Week 12 25 (0.23%) 3 (0.03%) Week 13 – Week 16 14 (0.13%) 7 (0.06%) Week 17 – Week 20 10 (0.09%) 4 (0.04%) Week 21 – Week 24 10 (0.10%) 4 (0.04%) Total 274 (2.17%) 86 (0.68%) OCTAVE: Incidence of Angioedema by Time Period OCTAVE (CV137-120)

  48. 2.96 1.51 1.17 1.91 0.58 0.55 0.97 1.55 2.58 1.48 0.5 1.0 2.0 4.0 OCTAVE: Summary of Angioedema Riskwith Omapatrilat in Subgroups* Subgroup Incidence Relative Risk Black race Current smoker** Renal disease Seasonal allergies Female gender Former smoker** Age  65 years ACE-I use Diabetes Atherosclerotic disease 72 (5.5%) 89 (3.9%) 11 (3.6%) 55 (3.3%) 153 (2.5%) 78 (2.1%) 70 (2.0%) 90 (2.0%) 23 (1.3%) 14 (1.2%) Decreased Risk Increased Risk (vs. those without characteristics) * Multivariate logistic regression model with angioedema as the dependent variable and all other listed variables as independent variables. ** vs those who never smoked.

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

  50. Risk Management • Angioedema has clinical features which facilitateits management through patient education: • Symptomatic, recognizable clinical presentation • Rapid but not fulminant progression • Effective therapy exists which can preventpoor outcomes

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