us nda no. 21-272 remodulin injection 1 nda 21-272 remodulin™ (treprostinil sodium) injection...

US NDA No. 21-272Remodulin Injection

1

NDA 21-272Remodulin™ (treprostinil sodium) Injection

United Therapeutics CorporationResearch Triangle Park, NC


2

Presentation and Speakers

Efficacy of treprostinil Stuart Rich, MD

Professor of MedicineDirector, Rush Heart InstituteCenter for Pulmonary Heart DiseaseRush Presbyterian-St. Lukes Medical Center

Safety of treprostinil Robyn Barst, MD

& Professor of Pediatric CardiologyBenefit to Risk Director, Pulmonary Hypertension Center

Columbia Presbyterian Medical Center


3

Gary Koch, Ph.D.Professor, Department of Biostatistics University of North Carolina

Tom Wenger, M.D.Consultant Cardiologist

Allen Lai, Ph.D.Pharmacokinetic Consultant

Shelley Ching, D.V.M., Ph.D.Toxicology Consultant

Additional Representatives for Treprostinil


4

Pulmonary Arterial Hypertension

Primary Pulmonary Hypertension (PPH)– Sporadic– Familial

Pulmonary Hypertension Associated with:– Collagen Vascular Disease– Congenital Systemic to Pulmonary Shunts– Drugs/Toxins– Portal Hypertension– HIV Infection


5

Symptoms of PAH

Initial (%) Eventual (%)

Dyspnea 60 98

Fatigue 19 73

Chest Pain 7 47

Near Syncope 5 41

Syncope 8 36

Edema 3 37


6

Commonly Used Treatments for PAH

Digitalis

Diuretics

Vasodilators

Anticoagulants

Epoprostenol


7

Epoprostenol

Indication• Intravenous treatment of NYHA Class III/IV PPH and

PAH associated with scleroderma

Risks• Trauma and pneumothorax with catheter placement• Local site infection & sepsis• Thromboembolic events related to catheter• Cardiovascular collapse


8

Treprostinil Sodium

Generic Name: Treprostinil SodiumBrand Name: RemodulinTM

Other Names: UT-15, Uniprost, treprostinol

O CH2CO 2

H

H

O H

O H

N a


9

Development Rationale

• Prostaglandin family– Potent vasodilator– Inhibitor of platelet aggregation

• Clinical Pharmacology– Acute hemodynamic effects in PPH similar to

those of epoprostenol

• Chemically Stable at Neutral pH/Room Temp

• Apparent Plasma Half-Life – IV: 45 minutes – SC: 3 hours


10

Epoprostenol Delivery System


11

Treprostinil Delivery System


12

Epoprostenol vs. Treprostinil

Characteristic Epoprostenol TreprostinilDelivery of Drug Intravenous Subcutaneous

Implant of catheter Surgical Patient

Thrombus Yes No

Sterile conditions for frequent drug constitution required

Yes No

Risk of cardiovascular collapse High Low

Risk of serious infections, including sepsis

High None

Bulky pump Yes No


13

Clinical Development

Controlled Trials Open Label Studies

P01:03(n=26)

P01:04P01:05(n=470)

Pivotal Studies

P01:06(n= 631)

Pilot

Direct Enrollment(n=208)


14

Pilot Study P01:03 Efficacy Results - Change from Baseline

Assessment Treprostinil (n=17)

Placebo (n=9)

Median 6-min Walk (m) +24 -6

Borg Dyspnea Score 0.00 +0.97

Dyspnea-Fatigue Rating +0.57 -0.25

Hemodynamics CI (L/min/m2) PAPm (mmHg) PVRI (mmHg/L/min/m2)

+0.420.0-4.8

-0.03-2.4+0.2


15

P01:04 and P01:05International, Multicenter, Double-Blind,

Placebo-Controlled Trial Program(40 Centers)


16

Entry Criteria

Age: 8 to 75 years

Etiology: Primary pulmonary hypertensionCollagen vascular diseaseCongenital heart disease

NYHA class: II, III and IV

Hemodynamics: PAPm 25 mmHgPVR > 3 Wood unitsPCWP 15 mmHg

Walk distance: 50 to 450 meters


17

Study Design

Phase: Screen/Baseline TreatmentWeek 1 Week 6 Week 12

Treprostinil

PlaceboRandomization

(1:1)

Exercise Symptoms QOL Clinical Labs Catheterization Initiate Study Drug

ExerciseSymptoms

ExerciseSymptoms QOL

ExerciseSymptomsQOLClinical LabsCatheterization

Assessments:


18

Efficacy Measures

• Exercise tolerance (6-minute walk)

• Signs and symptoms of PAH

• Dyspnea-fatigue rating

• Clinical deterioration – Death, transplant or worsening

requiring IV therapy

• Borg dyspnea score

• Hemodynamics

• Quality of life


19

6-Minute Walk Test

• Unencouraged test

• Practice test (within 6 weeks)

• Independent assessor– No involvement in study or patient care– Blinded to patient treatment– Was not aware of clinical course– Results not communicated to study staff– Separate CRFs kept in locked & secure files

• Borg dyspnea score at end of test


20

Symptoms and Signs

• 8 symptoms and 8 signs of PAH

• Symptoms and Signs were noted by the physician as either being “present” or “absent”

• A change score thus represented either first development of a new symptom/sign or complete resolution of a pre-existing symptom/sign


21

Symptoms and Signs

Symptoms SignsDyspnea Loud P2 sound

Fatigue RV S3 sound

Chest Pain RV S4 sound

Dizziness RV heave

Syncope Tricuspid murmur

Edema Pulmonic murmur

Orthopnea Hepatomegaly

Palpitations JVD at 45 degrees


22

Dyspnea-Fatigue Rating

• Physician-based assessment

• Rated symptoms and their clinical impact

• Consisted of three components, each rated 0-4:– Magnitude of task (at normal pace)– Magnitude of pace– Functional impairment in general activities

• Composite score was derived

• Lower scores reflected more symptomatic patient


23

Dyspnea Fatigue RatingMagnitude of Task

Symptomatic with:

4 = Extraordinary activity

3 = Major activities

2 = Moderate or average tasks

1 = Light activities

0 = At rest


24

Hemodynamic Measurements

• Hemodynamic measurements were measured by right heart catheterization at baseline and after 12 weeks.

• To minimize bias, other efficacy parameters were completed prior to invasive measurements


25

Quality of Life(Minnesota Questionnaire)

• Added at the request of the FDA after start of the study and thus assessed only in subgroup

• Included evaluation of physical, emotional, and global dimensions

• 21 questions were answered using a 0-5 response scale (a lower score was “better”)


26

Prespecified Endpoints

Primary endpoints – Exercise tolerance (6-minute walk distance)

Secondary endpoints– Signs and symptoms of disease*– Dyspnea-fatigue rating*– Clinical deterioration (deaths, transplants or

worsening of the underlying disease necessitating intravenous rescue therapy)*

– Borg dyspnea score

– Hemodynamics


27

Statistical Analysis

• Prespecified and finalized with the FDA prior to randomization code-break

• Efficacy population– 469 of 470 randomized patients– Excluded 1 placebo patient who did not receive study drug

• Analysis of non-completers (primary endpoint)– Death, transplant, worsening disease: worst rank– Adverse effects: last value carried forward

• Nonparametric analysis of primary endpoint


28

Pre-specified Primary Analysis Plan

Combined studiesP 0.01

andone study P 0.049

Supported by effects on principal reinforcing and

secondary endpoints

Individual studiesboth P 0.049OR

Treatment effect demonstrated if


29

Baseline CharacteristicsStudy 04/05

Treprostiniln=233

Placebon=236

Age Years (mean±SE) 45 ± 1 44 ± 1

Race Caucasian 85% 84%

Gender Female 85% 78%

PAH Etiology PPHConnective TissueCongenital Heart

58%17%25%

58%20%22%

NYHA Class IIClass IIIClass IV

11%82%8%

12%81%7%


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Treprostiniln=233

Placebon=236

Six-Minute Walk (m) 326 ± 5 327 ± 6

Borg Scale 4.3 ± 0.13 4.4 ± 0.13

Dyspnea–Fatigue Rating 4.3 ± 0.15 4.4 ± 0.17

Signs and Symptoms Score 7.6 ± 2.5 7.5 ± 2.4

Quality of LifeGlobalPhysicalEmotional

54 ± 1.625 ± 0.712 ± 0.6

55 ± 1.625 ± 0.712 ± 0.5

Baseline CharacteristicsStudy 04/05

Mean ± SEM


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Baseline HemodynamicsStudy 04/05

Treprostiniln=233

Placebon=236

RAPm (mmHg) 10 ± 0.4 10 ± 0.4

PAPm (mmHg) 62 ± 1 60 ± 1

PCWPm (mmHg) 10 ± 0.2 9 ± 0.2

CI (L/min/m2) 2.4 ± 0.1 2.2 ± 0.1

PVRI (mmHg/L/min/m2) 27 ± 1.0 25 ± 0.9

SBP (mmHg) 119 ± 2 123 ± 2

SvO2 (%) 62 ± 1 60 ± 1

HR (bpm) 82 ± 1 82 ± 1Mean ± SEM


32

Baseline Treatment Study 04/05

Treprostiniln (%)

Placebon (%)

Anticoagulants 149 (64) 160 (68)

Ca++ Channel Blockers 97 (42) 99 (42)

Other Vasodilators 33 (14) 35 (15)

Digoxin 56 (24) 59 (25)

Diuretics 136 (58) 129 (55)


33

Dosing Principles Study 04/05

Initiate at 1.25 ng/kg/min

Increase dose if symptoms persist or worsen

Reduce dose if side effects unacceptable

Week 1 2 3 4 5 6 7 8 9 10 11 12

Dose 1.25 2.5 3.75 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 22.5


34

Patient DispositionStudy 04/05

Treprostiniln (%)

Placebon (%)

Randomized 233 (100) 237 (100)

Received drug 233 (100) 236 (>99)

Completed 12 weeks 200 (86) 221 (93)

Withdrawn consent 2 (1) 1 (< 1)

Withdrawn due todeath, transplant, rescue

13 (6) 14 (6)

Withdrawn due to AE 18 (8) 1 (< 1)


35

Effect of Treprostinil on 6-Minute Walk Distance at Weeks 1, 6, 12

(Placebo-Corrected; Study 04/05)

Tre

atm

en

t Eff

ect

(m

ete

rs) P=0.03

P=0.0064

P=0.3


36

Change in 6-Minute Walk DistanceWeek 12

Median Change FromBaseline (m)

Median Difference

Between Groups (m)* P-value

Study P01:04

Treprostinil (n=113) 3.013.0 0.0607

Placebo (n=111) 1.0

Study P01:05

Treprostinil (n=119) 16.018.5 0.0550

Placebo (n=125) -3.0

Pooled 04/05

Treprostinil (n=232) 10.016.0 0.0064

Placebo (n=236) 0.0*Hodges Lehmann estimate


37

FDA Review of Primary Endpoint

Agreement that data supported the finding of a treatment effect, but FDA has questioned the

• Robustness of the finding

• Clinical meaningfulness of the treatment effect


38

Patient DispositionStudy 04/05

Treprostiniln (%)

Placebon (%)

Randomized 233 (100) 237 (100)

Received Drug 233 (100) 236 (>99)

Completed 12 Weeks 200 (86) 221 (93)

Withdrawn Consent 2 (1) 1 (< 1)

Withdrawn due todeath, transplant, rescue

13 (6) 14 (6)

Withdrawn due to AE 18 (8) 1 (< 1)


39

0 20 40 60 80 100 120 140 160 180

Time to Initiation of epoprostenolDiscontinuation due to AE vs Deterioration

Since discontinuation

100

90

80

70

60

50

40

30

20

10

0

AE Deterioration

Type of Discontinuation

Days since Discontinuations

% o

f Pati

en

ts N

ot

on

Flo

lan


40

Survival DistributionSince Discontinuation

% o

f Pati

en

ts

Days since Discontinuations

AE Deterioration

Type of Discontinuation

0 100 200 300 400 500 600 700 800 900 1000

100

90

80

70

60

50

40

30

20

10

0


41

Three Alternate Approaches Suggested by the FDA

Approach #1– Patients who died or were transplanted after withdrawal but within

100 days of randomization were reassigned to the deterioration group

• 2 active + 1 placebo patients reclassified to worst rank

Approach #2– Patients who died or were transplanted after withdrawal but within

100 days of randomization plus patients who received epoprostenol within 30 days of discontinuation were reassigned to the deterioration group

• 8 active + 1 placebo patients reclassified to worst rank

Approach #3– Patients who died, were transplanted or received epoprostenol after

withdrawal but within 100 days of randomization were reassigned to the deterioration group

• 10 active + 1 placebo reclassified to worst rank


42

P-Values for Analyses of Prespecified Endpoints (FDA-Requested Post Hoc Reassignment of Patients

Who Discontinued Treatment)

Pre-specified

Approach#1

Approach#2

Approach#3

6-Min Walk 0.0064 0.0075 0.038 0.047

Borg Score 0.000007 0.00002 0.0001 0.0002

Signs & Symptoms 0.00002 0.00003 0.00004 0.0005

Dyspnea-Fatigue Rating

<0.000001 <0.000001 <0.000001 <0.000001


43

FDA Review of Primary Endpoint

Agreement that data supported the finding of a treatment effect, but FDA has questioned the

• Robustness of the finding

• Clinical meaningfulness of the treatment effect


44

Distribution of Exercise Responses at Week 12

Study 04/05

Change from Baseline (meters)

TrepnlPlacebo

Treatment 90

80

70

60

50

40

30

20

10

-50 -40 -30 -20 -10 0 +10 +20 +30 +40 +50

% A

chie

vin

g a

t Le

ast

Outc

om

e


45

Influence of Baseline Walk on 6-Minute Walk Distance at Week 12

Study 04/05

Covariate Analysis Treatment Effect*Baseline Walk

150m +51 m

250m +33 m

350m +16 m

450m -2 m*Mean change predicted from linear regression model


46

Influence of NYHA Class on 6-Minute Walk Distance

Study 04/05

Covariate Analysis Treatment Effect*

NYHA ClassificationIV (n=34) +54 m

III (n=382) +17 m

II (n=53) +2 m*Hodges-Lehmann estimate at Week 12


47

Severity of Dyspnea During ExerciseBorg Dyspnea Score

Baseline(m)

Change atWeek 12*

(m)P-value

Study P01:04Treprostinil (n=97) 4.4 ± 0.2 -0.89 ± 0.18 0.0006

Placebo (n=100) 4.3 ± 0.2 +0.10 ± 0.22

Study P01:05Treprostinil (n=104) 4.2 ± 0.2 -0.88 ± 0.22

0.0010Placebo (n=112) 4.4 ± 0.2 +0.13 ± 0.27

Pooled 04/05

Treprostinil (n=201) 4.3 ± 0.1 -0.88 ± 0.14<0.0001

Placebo (n=212) 4.4 ± 0.1 +0.11 ± 0.17Mean ± SEM *Lower is improved


48

Effect of Treprostinil on Distance and Symptoms During 6-Minute Walk Test

(Placebo-Corrected, Study 04/05)

-20

-15

-10

-5

0

+5

+10

+15

+20

-1.2

-0.8

-0.4

+0.0

+0.4

+0.8

+1.2

Week 1 Week 6 Week 12

P=0.0002

P<0.0001

P=0.3

P=0.0064

P=0.03

P=0.11

Borg

Wa

lk (

m)


49

Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test

(Study 04/05, Week 1)

TrepnlPlacebo

Treatment 100

90

80

70

60

50

40

30

20

10

00.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Standardized Combined Rank

%

Ach

ievin

g a

t Le

ast

this

Rank


50



100

90

80

70

60

50

40

30

20

10

0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0


%

Ach

ievin

g a

t Le

ast

this

Rank

TrepnlPlacebo

Treatment


51



TrepnlPlacebo

Treatment 100

90

80

70

60

50

40

30

20

10

00.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0


% A

chie

vin

g a

t Le

ast

this

Rank


52

Prespecified Endpoints

Primary endpoints – Exercise tolerance (6-minute walk distance)

Secondary endpoints– Signs and symptoms of disease*– Dyspnea-fatigue rating*– Clinical deterioration (deaths, transplants or

worsening of the underlying disease necessitating intravenous rescue therapy)*

– Hemodynamics

Other assessments– Quality of life


53

Signs and Symptoms of PAH Composite Score

Baseline(m)

Change atWeek 12*

(m)P-value

Study P01:04Treprostinil (n=97) 4.3 ±0.2 0.9 ±0.26

0.0107Placebo (n=103) 4.7 ±0.2 -0.1 ±0.22


<0.0001Placebo (n=114) 4.2 ±0.2 0.0 ±0.20

Pooled 04/05

Treprostinil (n=201) 4.3 ±0.2 0.9 ±0.16<0.0001

Placebo (n=217) 4.4 ±0.2 -0.1 ±0.15Mean ± SEM *Higher is improved


54

Individual Symptoms Any Time During Double-Blind Therapy

Compared With 4 Weeks Prior to Randomization

# ResolvedCompletely

# Newly Developed

Trepnl Placebo Trepnl Placebo

Dyspnea 1 2 0 2

Fatigue 0 2 12 17

Chest Pain 25 17 24 50

Dizziness 18 10 38 50

Syncope 13 8 3 9

Orthopnea 8 6 31 47

Palpitations 20 8 46 34

Edema 13 12 34 41


55

Individual Symptoms Last 6 Weeks of Double-Blind Therapy

Compared With 4 Weeks Prior to Randomization


# Newly Developed

Trepnl Placebo Trepnl Placebo

Dyspnea 8 4 0 1

Fatigue 17 12 5 12

Chest Pain 48 37 8 30

Dizziness 55 35 27 33

Syncope 15 11 1 7

Orthopnea 29 14 17 30

Palpitations 46 25 27 22

Edema 36 25 18 29


56

Syncope


# Newly Developed

Last 6 weeks of double-blind therapy Last 6 weeks of double-blind therapy

compared with 4 weeks prior to randomizationcompared with 4 weeks prior to randomization

Treprostinil15

Placebo11

Treprostinil1

Placebo7

P Value0.062

Any time during double-blind therapy Any time during double-blind therapy

compared with 4 weeks prior to randomizationcompared with 4 weeks prior to randomization

Treprostinil13

Placebo8

Treprostinil3

Placebo9

P Value0.047

Any time during double-blind therapy Any time during double-blind therapy

compared with any time in the pastcompared with any time in the past

Treprostinil57

Placebo49

Treprostinil2

Placebo4

P Value0.121


57

Dyspnea Fatigue Score

Baseline(m)

Change at Week 12*(m) P-value


<0.0001Placebo (n=102) 4.7 ±0.2 -0.24 ±0.21


<0.0001Placebo (n=114) 4.2 ±0.2 -0.06 ±0.15

Pooled 04/05

Treprostinil (n=201) 4.3 ±0.2 1.23 ±0.13<0.0001

Placebo (n=216) 4.4 ±0.2 -0.14 ±0.13Mean ±SEM *Higher is better


58

Magnitude of Task Change from BaselinePercent of Patients

Study 04/05

Change in Magnitude of Task Scale


59

Patients Experiencing Clinical Deterioration(Prespecified Analysis)

Study 04/05

Treprostinil(n=233)

Placebo(n=236)

Death within 12 weeks or discontinuation due to transplant or clinical worsening requiring rescue therapy

13 (6%) 16 (7%)

Death 7 9

Transplant 0 1

Clinical worsening requiring rescue 6 6


60

Patients Experiencing Clinical Deterioration(Expanded Analysis)

Study 04/05

Treprostinil(n=233)

Placebo(n=236)

Odds Ratio(CI)

Death within 12 weeks or discontinuation due to transplant or clinical worsening requiring rescue therapy

13 16 0.81(0.38-1.73)

Clinical worsening (PH/RHF) leading to hospitalization* 1 6

Clinical worsening (too ill to walk)* 2 6

Total 16 28 0.55(0.29-1.04)

*Not included in the first row


61

HospitalizationsStudy 04/05

Number of Patients Number of Events

Treprostinil(n=233)

Placebo(n=236)

Treprostinil(n=233)

Placebo(n=236)

Any hospitalization 37 40 53 56

Due to worsening pulmonary hypertensionor right heart failure

7 18 8 22

Other reason 33 26 45 34


62

Hemodynamic EffectWeek 12

Study 04/05

Treprostinil(n=163-199)

Placebo(n=182-215) P-value

RAPm (mmHg) -0.5 ± 0.4 +1.4 ± 0.3 0.0002

PAPm (mmHg) -2.3 ± 0.5 +0.7 ± 0.6 0.0004

CI (L/min/m2) +0.12 ± 0.04 -0.06 ± 0.04 <0.0001

PVRI (mmHg/L/min/m2) -3.5 ± 0.6 +1.2 ± 0.6 <0.0001

SvO2 (%) +2.0 ± 0.8 -1.4 ± 0.7 <0.0001

SBP (mmHg) -2.3 ± 1.1 -0.2 ± 1.2 0.08

HR (bpm) -0.5 ± 0.8 -0.8 ± 0.7 0.6Mean ± SEM


63

Quality of Life (Minnesota Scale)

Study 04/05

Baseline Change at Week 12* P-value

Global TreprostinilaPlacebob

54 ± 255 ± 2

-6.6 ± 1.6-1.9 ± 1.4

0.17

PhysicalTreprostinilPlacebo

25 ± 125 ± 1

-4.5 ± 0.7-1.8 ± 0.6

0.006

Emotional TreprostinilPlacebo

12 ± 112 ± 1

-1.3 ± 0.5-0.3 ± 0.5

0.37

Mean ± SEMa n=157b n=173

*Lower is improved


64

Study 06

Controlled Trials Open Label Studies

P01:03(n=26)

P01:04P01:05(n=470)

Pivotal Studies

P01:06(n= 631)

Pilot

Direct Enrollment(n=208)


65

Long-term Effects on 6-minute Walk (Study P01:06)

Months

No. Patients (% of patients with specified

duration of exposure)Dose

(ng/kg/min)

Exercise Change from

Baseline(meters)

3 235 (47) 10 ± 0.4 +15 ± 4

6 156 (38) 16 ± 0.7 +34 ± 6

9 112 (34) 19 ± 1.3 +34 ± 8

12 102 (37) 25 ± 1.7 +33 ± 7

15 63 (35) 24 ± 2.1 +37 ± 12

18 46 (43) 31 ± 3.1 +46 ± 13

21 15 (38) 38 ± 7.1 +55 ± 17Mean ± SEM


66

Efficacy Conclusions

In patients with PAH, treprostinil produced clinically meaningful improvements in:

• exercise tolerance (distance and symptoms)

• symptoms of PAH

• dyspnea-fatigue rating

• hemodynamic variables

• quality of life (physical domain)


67

Treprostinil Safety Experience/Exposure

Overall Experience843 Subjects

PAH Trial Experience743 Patients

Controlled TrialsStudies 03/04/05

496 Patients

Open Label Study 06Direct Enrollment

208 Patients

Open-Label StudyStudy 06

631 Patients

423 of 445 eligible (95%)

Acute Trials Studies 01/02

39 Patients

Treprostinil Exposure679 Patients


68

Duration of Exposure(As of Oct. 1, 2000)

Time (months)

Nu

mb

er

of

Pati

en

ts


69

Doses of Treprostinil Used During Long-term Treatment

Dose

(n

g/k

g/m

in)

0 1 2 3 6 9 12 15 18Months


70

Adverse Events Reported by >10% of Patients

Percent of Patients03/04/05Placebo(n=242)

03/04/05Treprostinil

(n=253)

P01:06Treprostinil

(n=631)Infusion Site Pain 26 85 83

Infusion Site Reaction 26 84 76

Infusion Site Bleed/Bruise 43 33 26

Diarrhea 15 27 29

Headache 24 31 21

Nausea 17 25 23

Jaw Pain 5 15 16

Vasodilatation 5 13 9

Pain 10 14 15

Dizziness 8 9 11

Rash 11 13 11

Pharyngitis 9 6 12


71




(n=253)

P01:06Treprostinil




Diarrhea 15 27 29

Headache 24 31 21

Nausea 17 25 23

Jaw Pain 5 15 16


Pain 10 14 15

Dizziness 8 9 11

Rash 11 13 11

Pharyngitis 9 6 12


72




(n=253)

P01:06Treprostinil




Diarrhea 15 27 29

Headache 24 31 21

Nausea 17 25 23

Jaw Pain 5 15 16


Pain 10 14 15

Dizziness 8 9 11

Rash 11 13 11

Pharyngitis 9 6 12


73

Adverse Events by Dose at First Onset

Doses (ng/kg/min)2.5

>2.5-5.0

>5.0- 10.0

>10.0- 20.0

>20.0- 40.0

>40.0- 60.0

Infusion Site Pain 52 15 17 14 2 <1

Infusion Site Reaction 48 15 19 14 4 <1

Diarrhea 20 11 21 30 15 3

Nausea 27 12 27 23 7 3

Headache 39 17 12 20 10 3

Jaw Pain 14 11 29 25 17 3

Vasodilatation 16 18 23 26 13 3Numbers denote percent of patients who reported a specific adverse event who experienced that event for the first time at a specific dose. All rows add up to 100%.


74

Adverse Events by Duration of Treatment

Percent of PatientsDay

1Day 2-

Week 12Weeks 13-24

Weeks 25-48

Weeks 48-72

Infusion Site Pain 12 88 54 43 39

Infusion Site Reaction 10 83 57 47 43

Diarrhea 2 18 15 16 12

Headache 6 21 10 12 7

Nausea 3 15 11 11 7

Jaw Pain 1 11 9 9 6

Pain 1 13 7 7 6

Infusion Site Bleed/Bruise 6 16 7 7 5

Vasodilatation 2 11 6 4 5

Rash 2 11 4 4 3Data expressed as percent of the 254 patients treated for at least 72 weeks (May 01)


75

Serious Adverse Events

03/04/05Placebo(n=242)

n (%)


(n=253) n (%)

P01:06Treprostinil

(n=631) n (%)

Serious adverse event 38 (16) 44 (17) 170 (27)

Deaths during study 10 (4) 9 (4) 36 (6)


76

Adverse Events Leading to Discontinuation

Number of Patients (%)

03/04/05Placebo(n=242)


(n=253)

P01:06Treprostinil

(n=631)

Any Event 7 (3) 26 (10) 96 (15)

Infusion Site Pain 0 (0) 18 (7) 88 (14)

Infusion Site Reaction 0 (0) 8 (3) 22 (3)

Heart Failure 0 (0) 2 (1) 11 (2)

Pulmonary Hypertension 4 (2) 1 (<1) 6 (<1)

Infusion Site Bleed/Bruise 0 (0) 2 (1) 1 (<1)

Chest Pain 1 (<1) 2 (1) 1 (<1)

Pain 0 (0) 0 (0) 2 (<1)

Shock 1 (<1) 2 (1) 0 (0)

Anxiety 0 (0) 2 (1) 0 (0)


77

Local Infusion Site Pain and Reaction

• Characterized by pain, erythema, induration

• Varies from patient to patient and infusion site to infusion site

• Primarily related to initiation of infusion

• Improves after several months

• Generally not dose-limiting

• Manageable in majority of patients– By relocation of the infusion site– By use of hot/cold compresses– By OTC and/or prescription meds, if needed


78

Infusion Site TreatmentsPrescribed to >20% Patients

Study 04/05

Prescribed Medications236 Patients

n (%)

Other Analgesics and Antipyretics 96 (41)

Anti-inflammatory/Antirheumatic (non steroid) 83 (35)

Topicals (non steroid) 76 (32)

Corticosteroids, topical 67 (29)

Narcotic Analgesics 64 (27)

Antiinflammatory 60 (25)

Antihemorrhoidals 51 (22)

Antipruritics 48 (20)


79

Prescribing of Narcotic Analgesics

• Prescribed for PRN use– Actual use not captured

• Center-specific– Approximately 40% of centers did not

prescribe for treatment of infusion site pain

• Prescription rate lower in long-term study


80

Infusion Site Pain TreatmentPrescribed Narcotic Analgesics

Percent of PatientsStudy 04/05

n=236Study 06

n=631

All Opioids 27 21

Schedule IV 8 6

Schedule III 13 11

Schedule II 6 5

Schedule I 0 <1**Tilidine/Naloxone used in non-US center


81

Use of Narcotic AnalgesicsStudy 06 Survey

(535 of 545 patients)

Percent of Patientswith Use in:

Past Day Past Week

All Opioids 8 15

Schedule IV 3 5

Schedule III 4 8

Schedule II 1 2

Schedule I 0 0


82

Other Safety Considerations

• Treprostinil was not associated with adverse changes in:– serum electrolytes– renal and hepatic function– hemoglobin/hematocrit– platelet count– coagulation parameters– ECG intervals

• There were no clinically important drug interactions or idiosyncratic events


83

Safety Conclusions

• The adverse effects of treprostinil were related to its pharmacologic properties and were generally not serious. Serious AEs occurred with similar frequency in the placebo and treprostinil groups.

• Localized infusion site pain and reactions were common, but generally were manageable and did not limit increases in dose or require the withdrawal of treatment.

• Treprostinil was not associated with any significant changes in laboratory parameters or end-organ toxicity.


84

Risks of Epoprostenol Therapy

• Risk of sepsis

• Risk of thrombosis

• Risk of stroke

• Risk of trauma and pneumothorax

• Risk of cardiovascular collapse


85

Treprostinil

• Microinfusion delivery device

• Self-insertion of subcutaneous catheter at home

• No reconstitution; ready for infusion

• Stable at ambient temperature; no cold packs

• Addresses unmet medical need


86

Benefits of Treprostinil

In patients with pulmonary arterial hypertension, treprostinil produced clinically meaningful improvements in:

• exercise tolerance (distance and symptoms)

• symptoms of PAH

• hemodynamics


87

Relation of Benefits to Risks of Treprostinil

Since treprostinil produces clinically meaningful effects without potentially life-threatening risks, both patients and physicians can weigh on an ongoing and individual basis the severity of infusion site pain against the magnitude of improvement in symptoms.

As a result, the benefits of treprostinil can be expected to outweigh the risks of treatment in each patient who continues to receive treatment with the drug.


88

Proposed Indication

Treprostinil is indicated for the treatment of symptoms in patients with pulmonary arterial hypertension.

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