1. Clinical Safety of Fospropofol Disodium During Diagnostic and Therapeutic Procedures John B. Leslie MD; Lawrence B. Cohen, MD; Gerard Silvestri, MD; Tong-J Gan, MD

2. Fospropofol Metabolism (Enzymatic Liberation of Propofol) Fechner J, et al. Anesthesiology. 2003;99:303-1313. Alkaline phosphatases are widely distributed in body Alkaline phosphatases are widely distributed in body Fospropofol disodium is rapidly and completely metabolized Fospropofol disodium is rapidly and completely metabolized Phosphate, formaldehyde and formate do not accumulate above endogenous levels Phosphate, formaldehyde and formate do not accumulate above endogenous levels Fospropofoldisodium alkaline phosphatase Propofol Formaldehyde Phosphate OH O HH O POOO O O O O O P FormateOOH

3. Fospropofol Development Priority Develop a “propofol experience” without the limitations of current propofol administration restrictions and minimization of propofol AEsDevelop a “propofol experience” without the limitations of current propofol administration restrictions and minimization of propofol AEs Minimize sedation-related adverse eventsMinimize sedation-related adverse events –Limit peak effects from bolus injection Respiratory depressionRespiratory depression –Pain on injection –Expertise in dosing and titration Define a Dose-Specific routine for sedation routines in specific clinical scenarios to minimize adverse events but provide “ideal outcomes”Define a Dose-Specific routine for sedation routines in specific clinical scenarios to minimize adverse events but provide “ideal outcomes”

4. Fospropofol Clinical Development Study 0207 Colonoscopy N = 164 Study 0409 Bronchoscopy N = 40 Study 0410 Colonoscopy N = 210 Study 0411 Percutaneous Cardiac Interventions N = 6 Study 0412 Minor Surgical Procedures N = 121 Study 0415 Colonoscopy Patients ≥65 yrs N = 15 Study 0520 Colonoscopy N = 101 Study 0522 Colonoscopy N = 260 Study 0523 Minor Surgical Procedures N = 123 Study 0524 Bronchoscopy N = 252 Proof of Concept Relatively high initial bolus ( 14 mg/kg), fixed weight ranges DoseResponse: 2.0, 5.0, 6.5, 8.0 mg/kg initial bolus; dose titration 6.5 mg/kg initial bolus; dose titration

5. Fospropofol 6.5 mg/kg Titrated Bolus - Metabolism Benefits Well known, well characterized active moiety -- propofolWell known, well characterized active moiety -- propofol –Predictable PK/PD profile with slower onset & lower C max compared to IV bolus propofol Early fixed high-dose (>8 mg/kg) studies produced dose- related higher level of sedation-related adverse events (primarily respiratory)Early fixed high-dose (>8 mg/kg) studies produced dose- related higher level of sedation-related adverse events (primarily respiratory) Modified dose-titration routine with initial 6.5 mg/kg dose and adjustments based on age, weight, and ASA status implemented to minimize sedation-related AEs with optimal outcomesModified dose-titration routine with initial 6.5 mg/kg dose and adjustments based on age, weight, and ASA status implemented to minimize sedation-related AEs with optimal outcomes

6. Pharmacokinetics of Propofol Formulations 0 1000 2000 3000 4000 5000 6000 700080000102030405060708090100110120 Time post dose (min) Plasma Propofol Concentration (ng/mL) PK625 Fospropofol – 10 mg/kg Shah A, et al. Anesthesiology. 2007;107:A46. Lipid Emulsion Propofol 50 mg/min (3-4 minutes)

7. Metabolic Products of Fospropofol (Enzymatic Liberation of Propofol) The metabolic products of Fospropofol breakdown: Formaldehyde, Formate, and Phosphate levels produced are not clinically significant nor do they produce drug or sedation-related adverse eventsThe metabolic products of Fospropofol breakdown: Formaldehyde, Formate, and Phosphate levels produced are not clinically significant nor do they produce drug or sedation-related adverse events

8. Formate Plasma Concentrations Predose Fospropofol, mg/kg Mean ± SD (N = 6 subjects per dose) 5 10 15 25 20 30 Time, min Plasma formate concentration, mcg/mL PK103

9. Pivotal Program Study Design Purposeful response and MOAA/S score measured every 2 min Supplemental doses administered as needed (no closer than 4 min apart) to initiate and maintain sedationSupplemental doses administered as needed (no closer than 4 min apart) to initiate and maintain sedation MOAA/S ≤4 scope inserted Procedure complete scope removed Sedation Initiation Sedation Maintenance 50 mcg Fentanyl -5 min Initial dose sedative 0 min Up to 3 supplemental doses as needed Supplemental Recovery Period Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S)

10. Patient Demographics by Procedure ColonoscopyN=183 Minor Surgical Procedures N=123BronchoscopyN=149 Age 18 - 64 yrs 18 - 64 yrs 157 (85.5) 99 (80.5) 89 (59.7) ≥65 yrs ≥65 yrs 26 (14.2) 24 (19.5) 60 (40.0) ≥75 yrs** ≥75 yrs** 4 (2.2) 11 (8.9) 19 (12.8) Gender Male Male 87 (47.5) 56 (45.5) 85 (57.1) Weight <60 kg <60 kg 15 (8.2) 18 (14.6) 27 (18.1) 60 - <90 kg 60 - <90 kg 99 (54.1) 69 (56.1) 81 (54.4) ≥90 kg ≥90 kg 69 (37.7) 36 (29.3) 41 (27.5) ASA status P1 P1 68 (37.2) 33 (26.8) 7 (4.7) P2 P2 110 (60.1) 67 (54.5) 74 (49.6) P3 P3 5 (2.7) 22 (17.9) 61 (41.0) P4 P4 0 (0.0) 1 (0.8) 7 (4.7) Patients*, n (%) *6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524 **Patients ≥ 75 yr are also included in ≥ 65 yr category

11. Types of Minor Surgical Procedures at Proposed Dosage Regimen Study 0523 Minor Procedures Fospropofol 6.5 mg/kg Duration of procedure, min Procedure Patients, n (%) N = 123 MedianMinMax Esophagogastroduodenoscopy 27 (22.0) 4225 Arthroscopy 22 (17.9) 17.51226 Hysteroscopy 21 (17.1) 12331 Bunionectomy 18 (14.6) 43.526105 Transesophageal echocardiogram 13 (10.6) 14426 Ureteroscopy 10 (8.1) 12832 Lithotripsy 8 (6.5) 29.52456 Dilatation & Curettage 3 (2.4) 8726 Arteriovenous shunt 1 (0.8) 45––

12. Exposure to fospropofol by Procedure and Total Dose (All Patients—All Studies) Patients, n (%) Procedure ≤ 450 mg > 450 - 700 mg > 700 - 950 mg > 950 - 1200 mg > 1200 mg Colonoscopy (N = 750) 151 (20.1) 116 (15.5) 242 (32.3) 194 (25.9) 47 (6.3) Bronchoscopy (N = 292) 144 (49.3) 73 (25.0) 50 (17.1) 19 (6.5) 6 (2.1) Minor procedures (N = 250) 12 (4.8) 51 (20.4) 88 (35.2) 75 (30.0) 24 (9.6) Prolonged exposure (N = 46) 10 (21.7) 5 (10.9) 2 (4.3) 3 (6.5) 26 (56.5) Healthy volunteers (N = 273) 70 (25.6) 38 (13.9) 45 (16.5) 36 (13.2) 84 (30.8) Total (N = 1611) 387 (24.0) 283 (17.6) 427 (26.5) 327 (20.3) 187 (11.6)

13. Treatment-Emergent Adverse Events Patients*, n (%) ColonoscopyN=183 Minor Surgical Procedures N=123BronchoscopyN=149 Event >5% Pts Paresthesia 122 (66.6) 66 (53.7) 74 (49.7) Pruritus 27 (14.8) 32 (26.0) 22 (14.8) Procedural pain 83 (45.4) 62 (50.4) 18 (12.1) Nausea0 10 (8.1) 0 Inadequate analgesia 8 (4.8) 00 Vomiting0 7 (5.7) 0 Cough00 13 (8.7) Hypoxemia 3 (1.6) 1 (0.8) 26 (17.4) Hypotension 4 (2.2) 5 (4.1) 12 (8.1) *6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524

14. Sedation-Related Adverse Events Patients*, n (%) ColonoscopyN=183 Minor Surgical Procedures N=123BronchoscopyN=149 Patients with ≥ 1 SRAE 6 (3.3) 5 (4.1) 30 (20.1) † Apnea Apnea00 1 (0.7) Hypoxemia Hypoxemia 3 (1.6) 1 (0.8) 23 (15.4) Hypotension Hypotension 3 (1.6) 4 (3.3) 8 (5.4) ‡ Bradycardia Bradycardia0 1 (0.8) 0 *6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524 † 1 patient experienced apnea, hypoxemia, and hypotension ‡ 2 of 8 treated with airway assistance; 6 of 8 treated with IV fluids

15. Incidence of Airway Assistance Bronchoscopy N = 149 Minor surgical procedures N = 123 Colonoscopy N = 183 Type of Airway Assistance 000 Mechanical ventilation (intubation) 1 (0.7) 00 Manual ventilation (bag-valve-mask) 2 (1.3) 00Suction 000 Oral airway 000 Nasal trumpet 3 (2.0) 1 (0.8) 0 Chin lift 2 (1.3) 00 Jaw thrust 1 (0.7) 00 Face mask 3 (2.0) 00 Tactile stimulation 5 (3.4) 1 (0.8) 2 (1.1) Verbal stimulation 2 (1.3) 00 Patient repositioning 21 (14.1) 00 Increased oxygen flow Patients*, n (%) *6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524

16. Propofol Plasma Concentrations with the Proposed Dose Titration Regimen Population PK (0522, 0523, 0524) 0 Propofol concentration, µg/mL 20406080100120 Time, min 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 95% of observed propofol plasma concentrations < 2 µg/mL

17. Deaths All Patients No deaths were considered to be related to fospropofolNo deaths were considered to be related to fospropofol No deaths occurred within 24 hr of exposure to fospropofolNo deaths occurred within 24 hr of exposure to fospropofol 10 deaths occurred during the clinical program10 deaths occurred during the clinical program –5 patients in phase 3 bronchoscopy study –5 † patients in prolonged exposure (ICU) study † 1 patient received Diprivan only.

18. Safety Summary Safety of fospropofol evaluated in:Safety of fospropofol evaluated in: –Wide range of patient age and ASA status –Proposed dose and higher dose regimens (more than twice the proposed label dose) –Considerable clinical trial experience with fospropofol at wide range of procedures Simple airway maneuvers support patients with sedation- related adverse eventsSimple airway maneuvers support patients with sedation- related adverse events All patients with sedation-related events recovered without sequelaeAll patients with sedation-related events recovered without sequelae

19. Efficacy with Fospropofol* Successful procedural sedation experienceSuccessful procedural sedation experience –Sedation Success: 87 – 89% –Treatment success: 88 - 91% –Few procedure or drug discontinuations –Rate of sedation related adverse events that is in line with the experience and expectations of those performing procedural sedation Rapid recovery experienceRapid recovery experience –Median time to fully alert: 5 minutes –Median time to Aldrete >9: 9: <10 minutes –Potential for reduced duration of monitoring and burden on patient care team *6.5 mg/kg Dosage Regimen COLO522, BRONCH524

20. Most patients did not recallMost patients did not recall –Being awake during the procedure –Pain or discomfort –Disagreeable aspects of the procedure High level of patient and physician satisfaction with the drug and sedation experience using the proposed dosing regimenHigh level of patient and physician satisfaction with the drug and sedation experience using the proposed dosing regimen –95% of patients would receive fospropofol again –Physicians rated it 9 out of 10 on satisfaction scale Supplemental doses of sedative and analgesiaSupplemental doses of sedative and analgesia –Fospropofol initiation period: 0.9 – 1.6 doses –Total supplemental doses of fospropofol: 1.7 – 2.3 –Patients receiving supplemental analgesia: 17% - 55% Efficacy with Fospropofol* (cont) *6.5 mg/kg Dosage Regimen COLO522, BRONCH524

21. No burning on injectionNo burning on injection –Paresthesia and Pruritus better tolerated by patients Reduced C max with less interpatient variabilityReduced C max with less interpatient variability –Minimal sedation-related adverse events –Effectively tested bolus dose adjustments for higher risk patients Delayed onset due to metabolic conversion to propofolDelayed onset due to metabolic conversion to propofol –Time to pre-oxygenate - position patient – refine protocols The Future of Fospropofol?

22. Longer duration of effect from single bolus doses vs. propofolLonger duration of effect from single bolus doses vs. propofol –Less frequent re-dosing or inadequate sedation intervals Rapid recovery to fully alert and discharge readinessRapid recovery to fully alert and discharge readiness –“Propofol Experience” with reduced variability and titration issues –Improved post-procedure patient alertness and instruction recall Improved patient outcomes with reduced overall procedure costsImproved patient outcomes with reduced overall procedure costs –Reduced opioids & sedation-related adverse events, reduced PONV, faster discharge The Future of Fospropofol?