Clinical Safety of Fospropofol Clinical Safety of Fospropofol Disodium During Diagnostic and Disodium During Diagnostic and

Therapeutic ProceduresTherapeutic Procedures

John B. Leslie MD; Lawrence B. Cohen, MD; Gerard Silvestri, MD; Tong-J Gan, MDJohn B. Leslie MD; Lawrence B. Cohen, MD; Gerard Silvestri, MD; Tong-J Gan, MD

Fospropofol MetabolismFospropofol Metabolism(Enzymatic Liberation of Propofol)(Enzymatic Liberation of Propofol)

Fechner J, et al. Fechner J, et al. Anesthesiology.Anesthesiology. 2003;99:303-1313. 2003;99:303-1313.

• Alkaline phosphatases are widely distributed in bodyAlkaline phosphatases are widely distributed in body• Fospropofol disodium is rapFospropofol disodium is rapidly and completely metabolizedidly and completely metabolized• Phosphate, formaldehyde and formate do not accumulate above endogenous levelsPhosphate, formaldehyde and formate do not accumulate above endogenous levels

Fospropofol Fospropofol disodiumdisodium

alkalinealkaline

phosphatasephosphatase

PropofolPropofol FormaldehydeFormaldehyde PhosphatePhosphate

OHOH OO

HHHH OO

PP

OO

OOOOOO

OO

OO OO

OOPP

FormateFormate

OO

OOHH

FospropofolFospropofol Development Priority Development Priority

• Develop a “propofol experience” without the limitations of Develop a “propofol experience” without the limitations of current propofol administration restrictions and current propofol administration restrictions and minimization of propofol AEsminimization of propofol AEs

• Minimize sedation-related adverse eventsMinimize sedation-related adverse events– Limit peak effects from bolus injectionLimit peak effects from bolus injection

• Respiratory depressionRespiratory depression– Pain on injectionPain on injection– Expertise in dosing and titrationExpertise in dosing and titration

• Define a Dose-Specific routine for sedation routines in Define a Dose-Specific routine for sedation routines in specific clinical scenarios to minimize adverse events but specific clinical scenarios to minimize adverse events but provide “ideal outcomes”provide “ideal outcomes”

Fospropofol Clinical DevelopmentFospropofol Clinical Development

Study 0207 Study 0207 ColonoscopyColonoscopy

N = 164N = 164

Study 0409 BronchoscopyStudy 0409 BronchoscopyN = 40N = 40

Study 0410 ColonoscopyStudy 0410 ColonoscopyN = 210N = 210

Study 0411 Percutaneous Study 0411 Percutaneous Cardiac InterventionsCardiac Interventions

N = 6N = 6

Study 0412 Minor Study 0412 Minor Surgical ProceduresSurgical Procedures

N = 121N = 121

Study 0415 ColonoscopyStudy 0415 ColonoscopyPatients ≥65 yrsPatients ≥65 yrs

N = 15N = 15

Study 0520 Study 0520 ColonoscopyColonoscopy

N = 101N = 101

Study 0522 Study 0522 ColonoscopyColonoscopy

N = 260N = 260

Study 0523 Minor Study 0523 Minor Surgical ProceduresSurgical Procedures

N = 123N = 123

Study 0524 Study 0524 Bronchoscopy Bronchoscopy

N = 252N = 252

Proof ofProof ofConceptConcept

Relatively high initial Relatively high initial bolus (<5 - >14 mg/kg), bolus (<5 - >14 mg/kg), fixed weight rangesfixed weight ranges

DoseDoseResponse:Response:2.0, 5.0, 6.5, 2.0, 5.0, 6.5, 8.0 mg/kg 8.0 mg/kg initial bolus; initial bolus; dose titrationdose titration

6.5 mg/kg initial 6.5 mg/kg initial bolus; dose titrationbolus; dose titration

Fospropofol 6.5 mg/kg Titrated Fospropofol 6.5 mg/kg Titrated Bolus - Metabolism BenefitsBolus - Metabolism Benefits

• Well known, well characterized active moiety -- propofolWell known, well characterized active moiety -- propofol– Predictable PK/PD profile with slower onset & lower Predictable PK/PD profile with slower onset & lower

CCmaxmax compared to IV bolus propofol compared to IV bolus propofol

• Early fixed high-dose (>8 mg/kg) studies produced dose-Early fixed high-dose (>8 mg/kg) studies produced dose-related higher level of sedation-related adverse events related higher level of sedation-related adverse events (primarily respiratory)(primarily respiratory)

• Modified dose-titration routine with initial 6.5 mg/kg dose Modified dose-titration routine with initial 6.5 mg/kg dose and adjustments based on age, weight, and ASA status and adjustments based on age, weight, and ASA status implemented to minimize sedation-related AEs with implemented to minimize sedation-related AEs with optimal outcomesoptimal outcomes

Pharmacokinetics of Propofol Pharmacokinetics of Propofol FormulationsFormulations

00

10001000

20002000

30003000

40004000

50005000

60006000

70007000

80008000

00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 110110 120120

Time post dose (min)Time post dose (min)

Pla

sma

Pro

po

fol

Co

nce

ntr

atio

n (

ng

/mL

)P

lasm

a P

rop

ofo

l C

on

cen

trat

ion

(n

g/m

L)

PK625PK625

Fospropofol – 10 mg/kgFospropofol – 10 mg/kg

Shah A, et al. Shah A, et al. Anesthesiology.Anesthesiology. 2007;107:A46. 2007;107:A46.

Lipid Emulsion Propofol Lipid Emulsion Propofol 50 mg/min (3-4 minutes) 50 mg/min (3-4 minutes)

Metabolic Products of FospropofolMetabolic Products of Fospropofol(Enzymatic Liberation of Propofol)(Enzymatic Liberation of Propofol)

• The metabolic products of Fospropofol The metabolic products of Fospropofol breakdown: Formaldehyde, Formate, and breakdown: Formaldehyde, Formate, and Phosphate levels produced are not Phosphate levels produced are not clinically significant nor do they produce clinically significant nor do they produce drug or sedation-related adverse eventsdrug or sedation-related adverse events

Formate Plasma ConcentrationsFormate Plasma Concentrations

PredosePredose

Fospropofol, Fospropofol, mg/kgmg/kg

Mean ±Mean ± SD (N = 6 subjects per dose)SD (N = 6 subjects per dose)

-60-60 00 6060 120120 180180 240240 300300 360360 420420 48048000

1010

2020

3030

4040

5050

6060

5510101515

25252020

3030

Time, minTime, min

Pla

sm

a fo

rmat

eP

las

ma

form

ate

co

nc

en

trat

ion

, mc

g/m

Lc

on

ce

ntr

atio

n, m

cg

/mL

PK103PK103

Pivotal Program Study DesignPivotal Program Study Design

Purposeful response and MOAA/S score measured every 2 minPurposeful response and MOAA/S score measured every 2 min• Supplemental doses administered as needed (no closer than 4 min apart) to initiate and Supplemental doses administered as needed (no closer than 4 min apart) to initiate and

maintain sedationmaintain sedation

MOAA/S MOAA/S ≤4≤4scope insertedscope inserted

Procedure completeProcedure completescope removedscope removed

SedationSedationInitiationInitiation

SedationSedationMaintenanceMaintenance

50 mcg50 mcgFentanylFentanyl

-5-5minmin

InitialInitialdosedose

sedativesedative

00minmin

Up to 3 supplementalUp to 3 supplementaldoses as neededdoses as needed

SupplementalSupplementaldoses as neededdoses as needed

RecoveryRecoveryPeriodPeriod

Modified Observer’s AssessmentModified Observer’s Assessmentof Alertness/Sedation Scale (MOAA/S)of Alertness/Sedation Scale (MOAA/S)

Patient Demographics by ProcedurePatient Demographics by Procedure

ColonoscopyColonoscopyN=183N=183

Minor Surgical Minor Surgical ProceduresProcedures

N=123N=123BronchoscopyBronchoscopy

N=149N=149

AgeAge 18 - 64 yrs18 - 64 yrs 157 (85.5)157 (85.5) 99 (80.5)99 (80.5) 89 (59.7)89 (59.7) ≥ ≥65 yrs65 yrs 26 (14.2)26 (14.2) 24 (19.5)24 (19.5) 60 (40.0)60 (40.0) ≥ ≥75 yrs**75 yrs** 4 (2.2)4 (2.2) 11 (8.9)11 (8.9) 19 (12.8)19 (12.8)GenderGender

MaleMale 87 (47.5)87 (47.5) 56 (45.5)56 (45.5) 85 (57.1)85 (57.1)WeightWeight <60 kg<60 kg 15 (8.2)15 (8.2) 18 (14.6)18 (14.6) 27 (18.1)27 (18.1) 60 - <90 kg60 - <90 kg 99 (54.1)99 (54.1) 69 (56.1)69 (56.1) 81 (54.4)81 (54.4)

≥ ≥90 kg90 kg 69 (37.7)69 (37.7) 36 (29.3)36 (29.3) 41 (27.5)41 (27.5)ASA statusASA status P1P1 68 (37.2)68 (37.2) 33 (26.8)33 (26.8) 7 (4.7)7 (4.7) P2P2 110 (60.1)110 (60.1) 67 (54.5)67 (54.5) 74 (49.6)74 (49.6) P3P3 5 (2.7)5 (2.7) 22 (17.9)22 (17.9) 61 (41.0)61 (41.0) P4P4 0 (0.0)0 (0.0) 1 (0.8)1 (0.8) 7 (4.7)7 (4.7)

Patients*, n (%)Patients*, n (%)

*6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524*6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524**Patients ≥ 75 yr are also included in ≥ 65 yr category**Patients ≥ 75 yr are also included in ≥ 65 yr category

Types of Minor Surgical Procedures at ProposedTypes of Minor Surgical Procedures at Proposed Dosage Regimen Dosage Regimen

Study 0523 Minor ProceduresStudy 0523 Minor Procedures

Fospropofol Fospropofol 6.5 mg/kg6.5 mg/kg

Duration of Duration of procedure, minprocedure, min

Procedure

Patients, n Patients, n (%)(%)

N = 123N = 123 MedianMedian MinMin MaxMax

EsophagogastroduodenoscopyEsophagogastroduodenoscopy 27 (22.0)27 (22.0) 44 22 2525

ArthroscopyArthroscopy 22 (17.9)22 (17.9) 17.517.5 1212 2626

HysteroscopyHysteroscopy 21 (17.1)21 (17.1) 1212 33 3131

BunionectomyBunionectomy 18 (14.6)18 (14.6) 43.543.5 2626 105105

Transesophageal Transesophageal echocardiogramechocardiogram

13 (10.6)13 (10.6) 1414 44 2626

UreteroscopyUreteroscopy 10 (8.1)10 (8.1) 1212 88 3232

LithotripsyLithotripsy 8 (6.5)8 (6.5) 29.529.5 2424 5656

Dilatation & CurettageDilatation & Curettage 3 (2.4)3 (2.4) 88 77 2626

Arteriovenous shuntArteriovenous shunt 1 (0.8)1 (0.8) 4545 –– ––

Exposure to fospropofol by Procedure Exposure to fospropofol by Procedure and Total Dose and Total Dose

(All Patients—All Studies)(All Patients—All Studies)Patients, n (%)Patients, n (%)

ProcedureProcedure ≤≤ 450 mg450 mg > 450 - 700 mg> 450 - 700 mg > 700 - 950 mg> 700 - 950 mg > 950 - 1200 mg> 950 - 1200 mg > 1200 mg> 1200 mg

Colonoscopy Colonoscopy (N = 750)(N = 750)

151 (20.1)151 (20.1) 116 (15.5)116 (15.5) 242 (32.3)242 (32.3) 194 (25.9)194 (25.9) 47 (6.3)47 (6.3)

Bronchoscopy Bronchoscopy (N = 292)(N = 292)

144 (49.3)144 (49.3) 73 (25.0)73 (25.0) 50 (17.1)50 (17.1) 19 (6.5)19 (6.5) 6 (2.1)6 (2.1)

Minor Minor procedures procedures (N = 250)(N = 250)

12 (4.8)12 (4.8) 51 (20.4)51 (20.4) 88 (35.2)88 (35.2) 75 (30.0)75 (30.0) 24 (9.6)24 (9.6)

Prolonged Prolonged exposure exposure (N = 46)(N = 46)

10 (21.7)10 (21.7) 5 (10.9)5 (10.9) 2 (4.3)2 (4.3) 3 (6.5)3 (6.5) 26 (56.5)26 (56.5)

Healthy Healthy volunteers volunteers (N = 273)(N = 273)

70 (25.6)70 (25.6) 38 (13.9)38 (13.9) 45 (16.5) 45 (16.5) 36 (13.2)36 (13.2) 84 (30.8)84 (30.8)

Total (N = 1611)Total (N = 1611) 387 (24.0)387 (24.0) 283 (17.6)283 (17.6) 427 (26.5)427 (26.5) 327 (20.3)327 (20.3) 187 (11.6)187 (11.6)

Treatment-Emergent Adverse EventsTreatment-Emergent Adverse Events

Patients*, n (%)Patients*, n (%)

ColonoscopyColonoscopyN=183N=183

Minor Surgical Minor Surgical ProceduresProcedures

N=123N=123BronchoscopyBronchoscopy

N=149N=149Event Event >>5% Pts5% Pts

ParesthesiaParesthesia 122 (66.6)122 (66.6) 66 (53.7)66 (53.7) 74 (49.7)74 (49.7)

PruritusPruritus 27 (14.8)27 (14.8) 32 (26.0)32 (26.0) 22 (14.8)22 (14.8)

Procedural painProcedural pain 83 (45.4)83 (45.4) 62 (50.4)62 (50.4) 18 (12.1)18 (12.1)

NauseaNausea 00 10 (8.1)10 (8.1) 00

Inadequate analgesiaInadequate analgesia 8 (4.8)8 (4.8) 00 00

VomitingVomiting 00 7 (5.7)7 (5.7) 00

CoughCough 00 00 13 (8.7)13 (8.7)

HypoxemiaHypoxemia 3 (1.6)3 (1.6) 1 (0.8)1 (0.8) 26 (17.4)26 (17.4)

HypotensionHypotension 4 (2.2)4 (2.2) 5 (4.1)5 (4.1) 12 (8.1)12 (8.1)

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

Sedation-Related Adverse EventsSedation-Related Adverse Events

Patients*, n (%)Patients*, n (%)

ColonoscopyColonoscopyN=183N=183

Minor Surgical Minor Surgical ProceduresProcedures

N=123N=123BronchoscopyBronchoscopy

N=149N=149

Patients with Patients with ≥≥ 1 SRAE 1 SRAE 6 (3.3)6 (3.3) 5 (4.1)5 (4.1) 30 (20.1)30 (20.1)††

ApneaApnea 00 00 1 (0.7)1 (0.7)

HypoxemiaHypoxemia 3 (1.6)3 (1.6) 1 (0.8)1 (0.8) 23 (15.4)23 (15.4)

HypotensionHypotension 3 (1.6)3 (1.6) 4 (3.3)4 (3.3) 8 (5.4)8 (5.4)‡‡

BradycardiaBradycardia 00 1 (0.8)1 (0.8) 00

*6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524*6.5 mg/kg Dosage Regimen; COLO520, COLO522, MSURG523, BRONCH524† † 1 patient experienced apnea, hypoxemia, and hypotension1 patient experienced apnea, hypoxemia, and hypotension‡ ‡ 2 of 8 treated with airway assistance; 6 of 8 treated with IV fluids2 of 8 treated with airway assistance; 6 of 8 treated with IV fluids

Incidence of Airway AssistanceIncidence of Airway Assistance

BronchoscopyBronchoscopy

N = 149N = 149

Minor surgical Minor surgical proceduresprocedures

N = 123N = 123

ColonoscopyColonoscopy

N = 183N = 183Type of Type of Airway AssistanceAirway Assistance

000000Mechanical ventilation Mechanical ventilation (intubation)(intubation)

1 (0.7)1 (0.7)0000Manual ventilation Manual ventilation (bag-valve-mask)(bag-valve-mask)

2 (1.3)2 (1.3)0000SuctionSuction000000Oral airwayOral airway000000Nasal trumpetNasal trumpet

3 (2.0)3 (2.0)1 (0.8)1 (0.8)00Chin liftChin lift2 (1.3)2 (1.3)0000Jaw thrustJaw thrust1 (0.7)1 (0.7)0000Face maskFace mask3 (2.0)3 (2.0)0000Tactile stimulationTactile stimulation5 (3.4)5 (3.4)1 (0.8)1 (0.8)2 (1.1)2 (1.1)Verbal stimulationVerbal stimulation2 (1.3)2 (1.3)0000Patient repositioningPatient repositioning

21 (14.1)21 (14.1)0000Increased oxygen flowIncreased oxygen flow

Patients*, n (%)Patients*, n (%)

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

Propofol Plasma Concentrations with the Proposed Propofol Plasma Concentrations with the Proposed Dose Titration RegimenDose Titration Regimen

Population PK (0522, 0523, 0524)Population PK (0522, 0523, 0524)

00

Pro

po

fol

Pro

po

fol

con

cen

trat

ion

, co

nce

ntr

atio

n,

µg

/mL

µg

/mL

2020 4040 6060 8080 100100 120120Time, minTime, min

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5 95% of observed propofol plasma 95% of observed propofol plasma concentrations < 2 µg/mLconcentrations < 2 µg/mL

DeathsDeathsAll PatientsAll Patients

• No deaths were considered to be related No deaths were considered to be related to fospropofolto fospropofol

• No deaths occurred within 24 hr of exposure No deaths occurred within 24 hr of exposure to fospropofolto fospropofol

• 10 deaths occurred during the clinical program10 deaths occurred during the clinical program– 5 patients in phase 3 bronchoscopy study5 patients in phase 3 bronchoscopy study– 55†† patients in prolonged exposure (ICU) study patients in prolonged exposure (ICU) study

† † 1 patient received Diprivan only.1 patient received Diprivan only.

Safety SummarySafety Summary

• Safety of fospropofol evaluated in: Safety of fospropofol evaluated in: – Wide range of patient age and ASA status Wide range of patient age and ASA status – Proposed dose and higher dose regimens (more than Proposed dose and higher dose regimens (more than

twice the proposed label dose)twice the proposed label dose)– Considerable clinical trial experience with fospropofol at Considerable clinical trial experience with fospropofol at

wide range of procedureswide range of procedures• Simple airway maneuvers support patients with sedation-Simple airway maneuvers support patients with sedation-

related adverse eventsrelated adverse events• All patients with sedation-related events recovered without All patients with sedation-related events recovered without

sequelae sequelae

Efficacy with Fospropofol*Efficacy with Fospropofol*• Successful procedural sedation experienceSuccessful procedural sedation experience

– Sedation Success: 87 – 89%Sedation Success: 87 – 89%

– Treatment success: 88 - 91%Treatment success: 88 - 91%

– Few procedure or drug discontinuations Few procedure or drug discontinuations

– Rate of sedation related adverse events that is in line with the Rate of sedation related adverse events that is in line with the experience and expectations of those performing procedural sedationexperience and expectations of those performing procedural sedation

• Rapid recovery experience Rapid recovery experience

– Median time to fully alert: 5 minutesMedian time to fully alert: 5 minutes

– Median time to Aldrete Median time to Aldrete >>9: <10 minutes9: <10 minutes

– Potential for reduced duration of monitoring and burden on patient Potential for reduced duration of monitoring and burden on patient care teamcare team

*6.5 mg/kg Dosage Regimen COLO522, *6.5 mg/kg Dosage Regimen COLO522, BRONCH524BRONCH524

• Most patients did not recallMost patients did not recall– Being awake during the procedureBeing awake during the procedure– Pain or discomfortPain or discomfort– Disagreeable aspects of the procedureDisagreeable aspects of the procedure

• High level of patient and physician satisfaction High level of patient and physician satisfaction with the drug and sedation experience using the with the drug and sedation experience using the proposed dosing regimenproposed dosing regimen– 95% of patients would receive fospropofol again95% of patients would receive fospropofol again– Physicians rated it 9 out of 10 on satisfaction scalePhysicians rated it 9 out of 10 on satisfaction scale

• Supplemental doses of sedative and analgesia Supplemental doses of sedative and analgesia – Fospropofol initiation period: 0.9 – 1.6 doses Fospropofol initiation period: 0.9 – 1.6 doses – Total supplemental doses of fospropofol: 1.7 – 2.3Total supplemental doses of fospropofol: 1.7 – 2.3– Patients receiving supplemental analgesia: 17% - 55%Patients receiving supplemental analgesia: 17% - 55%

Efficacy with Fospropofol*Efficacy with Fospropofol*(cont)(cont)

*6.5 mg/kg Dosage Regimen COLO522, *6.5 mg/kg Dosage Regimen COLO522, BRONCH524BRONCH524

• No burning on injectionNo burning on injection– Paresthesia and Pruritus better tolerated by patientsParesthesia and Pruritus better tolerated by patients

• Reduced CReduced Cmaxmax with less interpatient variability with less interpatient variability– Minimal sedation-related adverse eventsMinimal sedation-related adverse events– Effectively tested bolus dose adjustments for higher risk Effectively tested bolus dose adjustments for higher risk

patients patients

• Delayed onset due to metabolic conversion Delayed onset due to metabolic conversion to propofolto propofol

– Time to pre-oxygenate - position patient – refine protocolsTime to pre-oxygenate - position patient – refine protocols

The Future of Fospropofol?The Future of Fospropofol?

• Longer duration of effect from single bolus doses Longer duration of effect from single bolus doses vs. propofolvs. propofol

– Less frequent re-dosing or inadequate sedation intervals Less frequent re-dosing or inadequate sedation intervals • Rapid recovery to fully alert and discharge Rapid recovery to fully alert and discharge

readinessreadiness– ““Propofol Experience” with reduced variability and titration Propofol Experience” with reduced variability and titration

issuesissues– Improved post-procedure patient alertness and instruction Improved post-procedure patient alertness and instruction

recallrecall• Improved patient outcomes with reduced overall Improved patient outcomes with reduced overall

procedure costsprocedure costs– Reduced opioids & sedation-related adverse events, Reduced opioids & sedation-related adverse events,

reduced PONV, faster dischargereduced PONV, faster discharge

The Future of Fospropofol?The Future of Fospropofol?