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Clinical Safety of Fospropofol Disodium During Diagnostic and Therapeutic Procedures

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. O. O. OH. O. P. O. H. H. O. O. H. O. Fospropofol Metabolism (Enzymatic Liberation of Propofol). O. O. P. O. O.

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Clinical Safety of Fospropofol Disodium During Diagnostic and Therapeutic Procedures

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

  3. Fospropofol Development Priority • Develop a “propofol experience” without the limitations of current propofol administration restrictions and minimization of propofol AEs • Minimize sedation-related adverse events • Limit peak effects from bolus injection • Respiratory 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”

  4. Fospropofol Clinical Development Study 0409 Bronchoscopy N = 40 Study 0522 ColonoscopyN = 260 Study 0410 Colonoscopy N = 210 Study 0523 Minor Surgical ProceduresN = 123 Study 0411 Percutaneous Cardiac Interventions N = 6 Study 0524 Bronchoscopy N = 252 Study 0412 Minor Surgical Procedures N = 121 Study 0415 ColonoscopyPatients ≥65 yrs N = 15 Dose Response: 2.0, 5.0, 6.5, 8.0 mg/kg initial bolus; dose titration Relatively high initial bolus (<5 - >14 mg/kg), fixed weight ranges 6.5 mg/kg initial bolus; dose titration Proof ofConcept Study 0207 Colonoscopy N = 164 Study 0520 ColonoscopyN = 101

  5. Fospropofol 6.5 mg/kg Titrated Bolus - Metabolism Benefits Well known, well characterized active moiety -- propofol Predictable PK/PD profile with slower onset & lower Cmax 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) 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 outcomes

  6. 8000 7000 6000 5000 4000 3000 2000 1000 0 Pharmacokinetics of Propofol Formulations Fospropofol – 10 mg/kg Lipid Emulsion Propofol 50 mg/min (3-4 minutes) Plasma Propofol Concentration (ng/mL) 0 10 20 30 40 50 60 70 80 90 100 110 120 Time post dose (min) PK625 Shah A, et al. Anesthesiology. 2007;107:A46.

  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 events

  8. Formate Plasma Concentrations 60 50 40 30 20 10 0 -60 0 60 120 180 240 300 360 420 480 Predose Fospropofol, mg/kg 5 concentration, mcg/mL 10 Plasma formate 15 20 25 30 Time, min Mean ±SD (N = 6 subjects per dose) PK103

  9. Pivotal Program Study Design -5min 0min Initialdosesedative 50 mcgFentanyl Modified Observer’s Assessmentof Alertness/Sedation Scale (MOAA/S) Procedure completescope removed MOAA/S ≤4scope inserted RecoveryPeriod SedationInitiation SedationMaintenance Supplemental doses as needed Up to 3 supplemental doses as needed • 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 sedation

  10. Patient Demographics by Procedure 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 RegimenStudy 0523 Minor Procedures

  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 *6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524

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

  16. Propofol Plasma Concentrations with the Proposed Dose Titration RegimenPopulation PK (0522, 0523, 0524) 3.5 95% of observed propofol plasma concentrations < 2 µg/mL 3.0 2.5 Propofol concentration, µg/mL 2.0 1.5 1.0 0.5 0 0 20 40 60 80 100 120 Time, min

  17. DeathsAll Patients No deaths were considered to be related to fospropofol No deaths occurred within 24 hr of exposure to fospropofol 10 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: 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 events All patients with sedation-related events recovered without sequelae

  19. Efficacy with Fospropofol* Successful 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 experience Median time to fully alert: 5 minutes Median time to Aldrete >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 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 regimen 95% of patients would receive fospropofol again Physicians rated it 9 out of 10 on satisfaction scale Supplemental 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 injection Paresthesia and Pruritus better tolerated by patients Reduced Cmax 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 propofol Time to pre-oxygenate - position patient – refine protocols The Future of Fospropofol?

  22. Longer duration of effect from single bolus doses vs. propofol Less frequent re-dosing or inadequate sedation intervals Rapid 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 costs Reduced opioids & sedation-related adverse events, reduced PONV, faster discharge The Future of Fospropofol?

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