Clevidipine Phase III Studies: Perioperative Hypertension

1. Clevidipine Phase III Studies: Perioperative Hypertension ESCAPE-1: Pre-operativeESCAPE-2: Post-operative Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

2. ESCAPE Protocol • Design: two double-blind, randomized, placebo-controlled trials in cardiac surgery • ESCAPE-1: preoperative patients with SBP ≥ 160 mm Hg • ESCAPE-2: postoperative patients with SBP ≥ 140 mm Hg • Primary endpoint: treatment failure • Premature and permanent discontinuation of study drug • Failure to decrease SBP by >15% from baseline within 30 minutes • Lack of efficacy • Insufficient efficacy • Safety • Secondary endpoints • Time to target BP • Change in MAP • Change in HR Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

3. ESCAPE Protocol • Inclusion Criteria • Age >18 yrs • Scheduled for cardiac surgery • On- or off-pump CABG • Minimally invasive CABG • And/or valve replacement or repair • SPB >140 (post-op) or >160 mm Hg (pre-op) • ESCAPE-1: Pre-existing hypertension requiring treatment or active hypertension on admission • ESCAPE-2: Hypertension within 4 hours of arrival to post-operative setting • Exclusion Criteria • CVA within 3 months • Pre-existing LBBB or permanent ventricular pacing • Known intolerance to calcium channel blockers • Allergy to soybean oil or egg lecithin Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

4. ESCAPE Protocol • Clevidipine dosing • 0.4 mcg/kg/min (approximately 2 mg/hr for an 80 kg. patient) • Dose doubled every 90 seconds until BP decreased by 15% or more • Once dose of 3.2 mcg/kg/min reached, could increase by 1.5 mcg/kg/min increments to maximum of 8 mcg/kg/min • Identical placebo • Drug continued for at least 30 minutes, up to 1 hour • D/C at induction of anesthesia for ESCAPE-1 • If target BP not reached at maximal dose, deemed treatment failure Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

5. ESCAPE: Perioperative Efficacy Trials ESCAPE-1 ESCAPE-2 Pre-operative Hypertension (SBP >160 mm Hg) Post-operative Hypertension (SBP >140 mm Hg) Placebo n=52 Clevidipine n=53 Clevidipine n=61 Placebo n=49 Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

6. ESCAPE Results: Demographics Levy JH et al. Anesth Analg. 2007;105:918-925 * p<0.05 Singla N et al. Anesth Analg. 2008;107:59-67

7. ESCAPE Results: Procedural Characteristics Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

8. ESCAPE Results: Treatment Success Rate p<0.0001 p<0.0001 92.5 91.8 100 80 Clevidipine 60 Placebo % Success 40 20.4 17.3 20 N=53 N=61 N=52 N=49 0 ESCAPE-1 ESCAPE-2 Treatment success = absence of treatment failure Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

9. ESCAPE Results: Clevidipine Onset and Time-to-Target Effect • Onset of BP-lowering effect: within 1-2 minutes of infusion • Time to target BP (15% reduction): ESCAPE-1 = 6 min; ESCAPE-2 = 5.3 min ESCAPE-1 ESCAPE-2 Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

10. ESCAPE Results: Safety Treatment emergent adverse reactions and the category on “any common adverse event” in ESCAPE-1 and ESCAPE-2 where the rate on Cleviprex exceeded the rate on Placebo by at least 5% (common adverse reactions) Clevidipine Product Information August 2008; The Medicines Company

11. ESCAPE Results: Safety • Clevidipine was well tolerated • AEs were similar between clevidipine- and placebo-treated patients • AEs were as expected for a cardiac surgery population • Three AEs considered related to clevidipine treatment: atrial fibrillation, thrombophlebitis, and insomnia (1 patient each) • No clinically relevant reflextachycardia Levy JH et al. Anesth Analg. 2007;105:918-925 Singla N et al. Anesth Analg. 2008;107:59-67

12. Blood Pressure Control with Clevidipine Compared with Nitroglycerin, Sodium Nitroprusside, or Nicardipine in the Treatment of Perioperative Hypertension: Results of the Three Randomized ECLIPSE Trials Aronson S et al. Anesth Analg 2008 (in press)

13. ECLIPSE: Trial Design Perioperative Perioperative Postoperative Clevidipine vs sodium nitroprusside Clevidipinevs nicardipine Clevidipinevs nitroglycerin 1:1 1:1 1:1 NicardipineN=193 ClevidipineN=268 NitroglycerinN=278 ClevidipineN=296 ClevidipineN=188 SodiumnitroprussideN=283 Aronson S et al. Anesth Analg 2008 (in press)

14. Endpoints • Primary*- Cumulative rate of clinical outcomes at 30 days: • Death • MI: symptomatic presentation, enzyme release, &/or new ECG changes • Stroke: Hemorrhagic or ischemic • Renal Dysfunction: Serum creatinine ≥ 2.0 mg/dL with an increase of ≥ 0.7 mg/dL from pre- to post-op • Secondary • SAEs through day 7 • BP control during the first 24 h * Blinded CEC adjudication of all primary measures Aronson S et al. Anesth Analg 2008 (in press)

15. Inclusion Criteria • Pre-randomization • ≥ 18 years of age • Planned CABG and/or valve repair/replacement surgery • Post-randomization • Require treatment for perioperative hypertension per investigator decision Aronson S et al. Anesth Analg 2008 (in press)

16. Exclusion Criteria • CVA ≤3 months of randomization • Intolerance to calcium channel blockers • Hypersensitivity to NTG, SNP or NIC • Allergy to the lipid vehicle • Permanent ventricular pacing • Any disease/condition that would put the patient at risk • Participation in another trial within 30 days • Women of child bearing potential Aronson S et al. Anesth Analg 2008 (in press)

17. Treatment Protocol • Clevidipine • Initiated at 0.4 mcg/kg/min in pre-op, intra-op, or post-op setting • Titrated every 90 seconds in doubling increments up to 3.2 mcg/kg/min; infusion rates above 3.2 mcg/kg/min guided by patient response and permitted in serial increments of 1.5 mcg/kg/min. • Infusion rates between 4.4-8.0 mcg/kg/min were administered for no longer than 2 hours • Titration to higher infusion rates up to the maximal infusion rate of 8.0 mcg/kg/min was required before switching to or adding alternative antihypertensive drugs. • May continue through discharge from ICU • Target blood pressure – as deemed appropriate by the study physician • Comparators – dosed as per institutional practice • Nitroglycerin • Sodium nitroprusside • Nicardipine (post-operative only) Aronson S et al. Anesth Analg 2008 (in press)

18. Methods • Descriptive analytical methods • Prespecified safety analysis by treatment received • Pooled data for clevidipine and all comparator arms • Prespecified analyses of clevidipine versus each comparator • BP Control assessed as the summation of integrated SBP vs time curve excursions • SBP plotted versus time from study drug initiation to arterial line removed or 24 hours, whichever came first • Pre-determined target SBP range • 65-135 mm Hg intra-operatively • 75-145 mm Hg pre- and post-operatively • AUC = magnitude (mm Hg) x duration (minutes) of SBP outside range • AUC normalized per hour and expressed as mm Hg x min/hr Aronson S et al. Anesth Analg 2008 (in press)

19. Patient Disposition a Two patients in the CLV/NIC group did not receive study medication and were excluded from the safety population. In addition, one patient in the same treatment was randomized to NIC but received CLV instead. This patient was excluded from the NIC safety population and included in the CLV safety population Aronson S et al. Anesth Analg 2008 (in press)

20. Baseline Characteristics (Safety Population) *p<0.05, CLV vs. NIC Aronson S et al. Anesth Analg 2008 (in press)

21. Results: Procedural Characteristics (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

22. ECLIPSE NTG: Drug Administration (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

23. ECLIPSE SNP: Drug Administration (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

24. ECLIPSE NIC: Drug Administration (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

25. 30-Day Events (%) n=719 n=729 n=700 n=707 n=700 n=705 n=712 n=710 Death MI Stroke Renal Dysfunction Results: Primary Endpoint (Safety Population) p=NS for all Aronson S et al. Anesth Analg 2008 (in press)

26. ECLIPSE NTG: Primary Endpoint (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

27. ECLIPSE SNP: Primary Endpoint (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

28. ECLIPSE NIC: Primary Endpoint (Safety Population) Aronson S et al. Anesth Analg 2008 (in press)

29. ECLIPSE Secondary Endpoint: SBP Control Within Predefined Range Over 24 Hours 145 SBP 75 Time (24 hrs) • Schematic illustration for an individual patient • Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op)

30. 12 24 18 0 6 ECLIPSE Secondary Endpoint AUC: Schematic Illustration for an Individual Patient SBP Upper Lower Time (hours) Aronson S et al. Anesth Analg 2008 (in press)

31. ECLIPSE: Blood Pressure Control Aronson S et al. Anesth Analg 2008 (in press)

32. Post-Hoc Analysis: Total AUC Outside Targeted BP Range Median AUC p=0.0002 n=751 n=756 mm Hg x min/h p<0.0001 p<0.0001 p=0.0004 85-145 pre-/post-op 75-135 intra-op 105-145 pre-/post-op 95-135 intra-op 95-145 pre-/post-op 85-135 intra-op 75-145 pre-/post-op 65-135 intra-op SBP Ranges: Aronson S et al. Anesth Analg 2008 (in press)

33. Post-hoc Analysis: Perioperative BP Control - Clevidipine vs SNP Median AUC P=0.0068 140 127.9 Clevidipine n=295 120 100.2 Sodium Nitroprusside n=284 100 mm Hg x min/h 80 P=0.0003 60 41.5 P=0.0009 40 P=0.0027 23.6 17.3 20 10.5 8.9 4.4 0 85-145 pre-/post-op 75-135 intra-op 105-145 pre-/post-op 95-135 intra-op 95-145 pre-/post-op 85-135 intra-op 75-145 pre-/post-op 65-135 intra-op SBP Ranges: Aronson S et al. Anesth Analg 2008 (in press)

34. Post-hoc Analysis: Perioperative BP Control - Clevidipine vs NTG Median AUC P=0.0556 120 108.6 Clevidipine n=269 100 Nitroglycerin n=278 83.7 80 mm Hg x min/h 60 P=0.0016 34.2 P=0.0002 40 P=0.0006 23.4 14.9 20 8.9 6.0 4.1 0 85-145 pre-/post-op 75-135 intra-op 105-145 pre-/post-op 95-135 intra-op 95-145 pre-/post-op 85-135 intra-op 75-145 pre-/post-op 65-135 intra-op SBP Ranges: Aronson S et al. Anesth Analg 2008 (in press)

35. Post-hoc Analysis:Postoperative BP Control - Clevidipine vs NIC Median AUC 120 P=0.0231 101.6 n=187 Clevidipine 100 n=194 Nicardipine 77.0 80 mm Hg x min/h 60 P=0.3086 40 P=0.8949 P=0.8508 22.8 21.6 20 5.7 5.3 1.8 1.7 0 SBP Ranges: 85-145 post-op 105-145 post-op 95-145 post-op 75-145 post-op Aronson S et al. Anesth Analg 2008 (in press)

36. Post-Hoc Logistic Regression Results:Predictors of Mortality Aronson S et al. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA

37. Post-hoc Analysis: 30-Day Mortality by Magnitude of AUC I mm Hg x 60 min 2 mm Hg x 60 min 3 mm Hg x 60 min 4 mm Hg x 60 min 5 mm Hg x 60 min Aronson S et al. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA

38. Post-Hoc Logistic Regression Results: Predictors of 30-day Renal Dysfunction *Total AUC of the magnitude and duration of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg intraoperatively; patients with AUC ≥75th percentile analyzed. Aronson S et al. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA

39. Serious Adverse Events Aronson S et al. Anesth Analg 2008 (in press)

40. Primary Endpoint Conclusions • Clevidipine demonstrated similar 30 day outcomes (Death, MI, Stroke, Renal Dysfunction) in a pooled analysis with comparator treatments (NTG, SNP, NIC). • Clevidipine demonstrated similar 30 day outcomes when compared individually with NTG and NIC in all components of the primary endpoint • When compared with SNP, Clevidipine demonstrated a significant mortality advantage, with similar outcomes in the remaining endpoint components • In post hoc analyses, clevidipine demonstrated improved blood pressure control compared to NTG and SNP as measured by 24 hour median AUC • BP control with clevidipine was comparable to nicardipine as measured by AUC • Excursions outside a targeted BP range are correlated with 30-day mortality and renal dysfunction • Future analysis of this post-hoc finding is warranted

41. Post-Hoc Analyses Conclusions • Clevidipine demonstrated improved blood pressure control compared to NTG and SNP as measured by 24 hour median AUC • BP control with clevidipine was comparable to nicardipine as measured by AUC • Excursions outside a targeted BP range are correlated with 30-day mortality and renal dysfunction • Future analysis of this post-hoc finding is warranted

42. Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

43. VELOCITY: Rationale Common Hypertensive Emergencies1,2 • Acute coronary syndromes • Heart failure, pulmonary edema • Acute cerebrovascular syndromes (Stroke) • subarachnoid hemorrhage • cerebral bleeding • cerebral infarction • Hypertensive encephalopathy and retinopathy • Renal Crisis • Varon J, Marik PE. Chest. 2000;118:214-227. • Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371.

44. VELOCITY: Rationale Treatment Goals for Hypertensive Emergency • Prompt, but smooth reduction in BP • Reduce BP by ≤ 25% during the first minute to 1 hour • If stable, reduce BP in next 2-6 hours • Gradual reductions toward normal BP over next 24-48 hours • Exceptions requiring special care: ischemic stroke, stroke eligible for thrombolytic agents, aortic dissection • Avoid excessive drops in BP • May cause renal, cerebral or coronary ischemia • Need careful and close monitoring • Use of an arterial catheter for monitoring BP routinely required • Choice of pharmacologic agent should be tailored to patient • Based on risks, comorbidities and type of end-organ damage Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

45. VELOCITY: Objective • To assess the safety and efficacy of IV clevidipine for the treatment of acute, severe hypertension: • A predetermined, patient-specific SBP target range (TR) • Prespecified, non-weight-based titration dosing • Continuous maintenance infusion for 18 hours or longer Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

46. VELOCITY: Design and Methods • Prospective, open-label, single-arm evaluation • Population: patients 18 years or older presenting to ED or ICU with severe hypertension (SBP >180 mm Hg or DBP >115 mm Hg) assessed at 2 successive occasions 15 min apart at baseline • Selection of SBP Target Range (TR) was determined prior to the initiation of clevidipine for each individual patient, with a range of 20-40 mm Hg from upper to lower limit • Dosing: clevidipine was initiated at 2 mg/hr and titrated to achieve TR: • during initial 30 min in doubling increments every 3 min to a maximum of 32 mg/hr • continued for a total duration of 18-96 hrs. • If TR not achieved in first 30 min, use of additional IV anti-hypertensives permitted Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

47. VELOCITY: Methods – Transition to Oral Therapy • Transition to an oral antihypertensive agent could be initiated after 18 hours of clevidipine infusion, starting 1 hr prior to stopping the infusion • During transition to oral therapy: • Clevidipine infusion could have been down-titrated or terminated in order to achieve the desired BP level • If the BP rose to an undesirable level after stopping the infusion, additional oral therapy may have been added or clevidipine infusion may have been restarted • Successful transition to oral therapy was defined as transition with SBP remaining within the last identified TR within 6 hours of stopping the clevidipine infusion Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

48. VELOCITY: Outcome Measures – Efficacy • Primary: percentage of patients in whom SBP decreased to within the SBP target range within 30 min of initiating infusion • Secondary: Time to achieve SBP target range within the initial 30 minute treatment period Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

49. VELOCITY: Outcome Measures – SAFETY • Primary: percentage of patients in whom SBP decreased below the lower limit of the initial SBP target range within 3 min of initiating infusion • Secondary • Change in pulse rate during initial 30 min treatment period • Dose of clevidipine during treatment period • Percentage of patients meeting criteria of “successful transition to oral antihypertensive” • In TR of last specified SBP 6 hrs after cessation of clevidipine infusion Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)

50. VELOCITY: Enrollment Criteria Exclusion Criteria • SBP ≤180 mm Hg and DBP ≤115 mm Hg • Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hrs • Known or suspected aortic dissection, liver failure or cirrhosis • Acute hypertension precipitated by the use or withdrawal from alcohol, illicit drugs, or by intentional overdose • Positive pregnancy test result • Intolerance/allergy to Ca channel blockers, soybean oil, or egg lecithin • Any antihypertensive drug within 2 hrs before enrollment • Participation in another study in previous 30 days Inclusion Criteria • Age 18 years and older • Systolic BP >180 mm Hg and/or diastolic BP >115 mm Hg, assessed on 2 successive occasions, 15 minutes apart • Provide written informed consent before initiation of any study-related procedures Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)