J. Varon, MD, FCCP , W.F. Peacock, MD, N. Garrison, MD, R. Ebrahimi, MD, L. Dunbar, MD, P. Acosta, MD, and C. Pollack, M

1. Prolonged Infusion of Clevidipine Results in Safe and Predictable Blood Pressure Control in Patients with Acute Severe Hypertension Results from the VELOCITY Trial J. Varon, MD, FCCP, W.F. Peacock, MD, N. Garrison, MD, R. Ebrahimi, MD, L. Dunbar, MD, P. Acosta, MD, and C. Pollack, MD

2. Disclosures This study was conducted with the support of a research grant by The Medicines Company Dr. Varon was a PI in this trial and has served as a consultant for The Medicines Company.

3. 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 US Department of Heath and Human Services. Bethesda, Md: National Institutes of Health. NIH Publication No. 04-5230. August 2004.

4. Cl Cl H CH3OOC COOCH2OOCC3H7 H3C N CH3 H Clevidipine A rationally designed dihydropyridine calcium channel blocker characterized by its rapid onset and offset of BP lowering effect t ½ ~1 min Steady state achieved in ~2 mins Protein binding >99.5% High clearance rate (independent of dosing rate) Arterial Selective Small Vd = 0.17 L/kg

5. Cl Cl Cl O O Cl O O O O H O Esterases O * O H O H H O O O N N H H Primary metabolite Clevidipine Clevidipine: Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite + + *The chiral center of clevidipine. Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67. Bailey JM, et al. Anesthesiology. 2002;96:1086-1094. Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564. Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

6. VELOCITY: Rationale Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hr Phase III safety and efficacy study • Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight based dosing algorithm • Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline

7. VELOCITY: Objectives Primary Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension • Efficacy: percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion • Safety: percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion

8. VELOCITY: Objectives Secondary Efficacy: • Time to attainment of 30-min SBP target range Safety: • Change in heart rate during the 30-min period from initiation of infusion • Dose of clevidipine during the treatment period • Of the patients converted to oral antihypertensive therapy, the proportion of those with successful transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusion • Safety of prolonged infusion of clevidipine (≥18 hr)

9. VELOCITY: Enrollment Criteria Inclusion Criteria • Age 18 years and older • Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on 2 successive occasions, 15 min apart • Provide written informed consent before initiation of any study-related procedures Exclusion Criteria • SBP ≤180 mmHg and DBP ≤115 mmHg • Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hr • Known or suspected aortic dissection

10. VELOCITY: Treatment Clevidipine • Selection of SBP Initial Target Range (ITR) was determined prior to the initiation of clevidipine • ITR was determined for each individual patient • The difference between the upper and lower ITR was between 20 mmHg and 40 mmHg • BP monitoring was done with a BP cuff • Clevidipine initiated at 2 mg/hr via peripheral vein • Titrated in doubling increments Q3 min, not to exceed 32 mg/hr, to achieve pre-specified ITR • Infusion rate could have been decreased at the investigators discretion in order to achieve the target SBP • Infusion was maintained or further titrated after the first 30 min to achieve the desired long-term reduction in SBP • Treatment duration for at least 18 hr and not exceeding 96 hr

11. VELOCITY: Treatment – Transition to Oral Therapy If transition to an oral antihypertensive agent was required, the agent could be given 1 hr prior to the anticipated cessation of clevidipine infusion but not before the 18 hr time point At any time following the administration of the oral agent, the 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 upon cessation of the infusion, additional oral therapy may have been added or clevidipine infusion may have been restarted Successful transition to oral therapy was defined as achieving a target BP within 6 hours of cessation of clevidipine infusion

12. VELOCITY: Patient Disposition Total patients enrolled N=131 SBP ≤UL of target range n=14 No clevidipine n=5 mITT Population (patients with SBP >UL of target range) N=117 Safety Population (patients who received at least 1 dose) N=126 <18 hr treatment n=9 ≥18 hr continuous infusion n=117 DNC=did not complete.

13. VELOCITY: Results – Patient Demographics Safety Population, N=126. Mean ± SD

14. VELOCITY: Results – Medical History, Comorbidity, and End-Organ Dysfunction Safety Population, N=126.

15. VELOCITY: Efficacy Results Initial infusion rate 2 mg/hr (4 mL/hr) Time to first achievement to Initial Target Range (ITR) • 10.9 min (95% CI 9.0, 15.0) • Median dose rate 4 mg/hr (mean 6 mg/hr) mITT population

16. VELOCITY: Efficacy Results 89% of patients achieved pre-specified ITR within 30 min • An additional 7% of patients achieved ITR after 30 min • Of the 96% of patients who did not have protocol violations with selection of ITR, 90% achieved the ITR within 30 min From drug initiation to 30 min • Median infusion rate 7 mg/hr (mean 9.5mg/hr) Time to a 15% drop in blood pressure 9.5 min

17. 91% VELOCITY: Probability of Having Attained SBP Initial Target Range 100 90 80 70 60 Percent of Patients 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Minutes K-M Analysis

18. -6% -21% -16.5% VELOCITY: Efficacy Results – Change in BP (30 min) 0 -5 -10 % Reduction from Baseline SBP (Mean ± SE) -15 -20 -25 3 6 9 12 15 18 21 24 27 30 Time after start of infusion (min.) mITT population

19. VELOCITY: Results – Long-term Infusion 92.9% of patients were administered clevidipine for ≥18 hours • The infusion rate was maintained or further titrated after 30 min to the desired long-term (≥18 h) SBP target • SBP reduction at 18 hours was -27% (-55 mmHg) from baseline • Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation

20. 30 min. Titration to ITR Additional Titration BP Adjustment and Maintenance VELOCITY: Efficacy Results – Change in BP (18 hour) 0 -5 -10 % SBP Reduction from Baseline (Mean ± SE) -15 -20 -25 -30 0 3 6 9 12 15 18 Time after start of infusion (hours)

21. VELOCITY: Results – Long-term Infusion 92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours) 118 patients were eligible for transition to oral antihypertensive therapy • 97.5% did so to a defined target BP within 6 hr of cessation of clevidipine infusion

22. VELOCITY: Safety Results 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion • One patient had a narrower than specified ITR (205-195 mmHg), SBP was 15 mmHg below the lower limit • One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this • Both patients continued clevidipine infusion beyond 18 hr without AEs No hypotensive events related to clevidipine were reported throughout the study • One patient was reported to have a hypotensive event not related to clevidipine 17 hours after infusion initiation mITT population

23. VELOCITY: Safety Results Clevidipine is formulated and administered in a lipid emulsion Changes in serum triglyceride concentrations were assessed: • Median percent change in serum triglyceride concentrations was zero • Additional analyses were conducted to evaluate the relationship of triglycerides to total lipid dose exposure • No relationship was observed when triglyceride concentrations at baseline and 6 hours post infusion were examined based on the total clevidipine dose received (Pearson’s correlation coefficient = -0.0269)

24. Conclusion:What We Learned From VELOCITY Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 min Patients reached target BP without overshoot in a median 10.9 min Clevidipine was easy to administer and well tolerated • Peripheral venous administration • BP monitoring via a cuff • Non-weight based dosing regimen Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension