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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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slide1

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

slide2

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.

fospropofol development priority
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”
fospropofol clinical development
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

fospropofol 6 5 mg kg titrated bolus metabolism benefits
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

slide6

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.

metabolic products of fospropofol enzymatic liberation of propofol
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

formate plasma concentrations
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

pivotal program study design
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
patient demographics by procedure
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

exposure to fospropofol by procedure and total dose all patients all studies
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)

treatment emergent adverse events
Treatment-Emergent Adverse Events

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

sedation related adverse events
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

incidence of airway assistance
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

slide16
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

deaths all patients
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.

safety summary
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

efficacy with fospropofol
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

efficacy with fospropofol cont
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

the future of fospropofol
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?
the future of fospropofol22
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?