Division of Anti-inflammatory, Analgesic and Ophthalmic Drug Products

Advisory Committee Meeting

Briefing Package

 

For

 

Macugen (pegaptanib sodium injection) for the Treatment of Neovascular Age-Related Macular Degeneration

 

 

 

 

 

 

 

 

 

 

 

Sponsor:                                                          Eyetech Pharmaceuticals, Inc

                                                                        500 Seventh Avenue, 18th floor

                                                                        New York, New York 10018

 


 

Table of Contents[Note1] 

 

Table of Contents......................................................................... 2

I.          Introduction and Background............................................... 3

A.        Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose, Regimens, Age Groups................................................. 3

B.        State of Armamentarium for Indication(s)................... 4

II.        Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews.................................................................................... 4

III.       Human Pharmacokinetics..................................................... 5

IV.       Description of Clinical Data and Sources............................ 6

VI.       Integrated Review of Efficacy............................................... 8

A.        General Approach to Review of the Efficacy of the Drug.............................................................................. 8

B.        Detailed Review of Trials by Indication...................... 8

VII.     Integrated Review of Safety................................................. 39

A.        Description of Patient Exposure................................ 39

B.        Methods and Specific Findings of Safety Review...... 40

 

                   VIII.     Appendix

Advisory Committee Questions………………………………………………….55

 


 

 

I.        Introduction and Background[IntroBack2] 

 

AMD is the leading cause of blindness in developed countries with approximately 15 million people with the disease in the United States. AMD is characterized as a progressive degenerative disease of the macula. There are two forms of AMD: neovascular and non-neovascular.  The non-neovascular form of AMD is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years.  The neovascular form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina.  These blood vessels leak blood and fluid into the retina, which results in visual abnormalities. The development of these abnormal blood vessels is due in part to the activity of VEGF (vascular endothelial growth factor) and its inhibition is expected to impact on the onset and/or severity of vision loss associated with the proliferation of abnormal blood vessels.

 

Macugen (pegaptanib sodium injection) has been developed for the treatment of the neovascular form of age-related macular degeneration (AMD). In vitro studies have suggested that pegaptanib binds to VEGF and inhibits its binding to cellular receptors.  Macugen’s anti-VEGF activity is expected to inhibit abnormal blood vessel proliferation and therefore decrease the vision loss associated with the neovascular form of AMD.

 

 

A.        Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose, Regimens, Age Groups[IntroPt13] 

 


 

Proprietary Name:                  Macugen

Established name:                   pegaptanib sodium injection

Sponsor:                                  Eyetech Pharmaceuticals

                                                500 Seventh Avenue, 18th Floor

                                                New York, New York 10018

NDA Drug Classification:       1P

Pharmacologic Category         Vascular Endothelial Growth Factor (VEGF) Inhibitor

Proposed Indication:               The treatment of the neovascular form of age-related macular degeneration.

Dosage Form and Route        

of Administration                    Intravitreal Injection

 


 

 

 

 

B.        State of Armamentarium for Indication(s) [ArmInd4] 

 

Macugen (pegaptanib sodium) has been developed for the treatment of the neovascular form of age-related macular degeneration (AMD). Currently, there is only one treatment approved for use in AMD.  Photodynamic therapy (PDT) with verteporfin is approved for patients with the predominantly classic form of AMD. 


 


 


 

II.      Chemical Composition and Specifications

 


Composition of Macugen (pegaptanib sodium injection) 0.3 mg/90 µLa

 

Name of Ingredients

Reference to

Standards

Function

Solution

Composition

mg/mL

Unit Dosage

Composition

0.3 mg/90

µL

Percent

(w/v)

Pegaptanib Sodium

In-house

standard

Drug substance

3.47b

0.3 mgb

0.3b

Monobasic Sodium

Phosphate

Monohydrate

USP

pH buffering

agent

0.77

0.069 mg

0.077

Dibasic Sodium

Phosphate

Heptahydrate

USP

pH buffering

agent

1.2

0.11 mg

0.12

Sodium Chloride

USP

Tonicity

adjuster

9.0

0.8 mg

0.9

Hydrochloric Acid

NF

pH adjuster

As neededc

As neededc

 

Sodium Hydroxide

NF

pH adjuster

As neededc

As neededc

--

Water for Injection

USP

Diluent

q.s.

q.s.

--

Nitrogen

NF

Processing

aid/inert

atmosphere

q.s.

q.s.

--

Total Volume

 

 

1 mL

90 µL

 

a Quantities are calculated

b Based on a theoretical potency of 100% for pegaptanib sodium with no overage. The actual weight varies according to the actual potency of pegaptanib sodium used. Compositions calculated based on oligonucleotide moiety

c For pH adjustment


Proposed analytical specifications for pegaptanib sodium are presented below.  Final specifications are currently undergoing revisions to meet the Agency’s acceptance criteria.

 

 

Analytical Specification for Macugen Injection, 0.3 mg

 

Test

Method

Method

Reference

Acceptance Criteria

 

TABLE  REMOVED

 

 

III.     Human Pharmacokinetics

 

The pharmacokinetic profile of pegaptanib has been studied in a total of five trials: one single dose study and four repeated dose studies.  The repeated dose studies were conducted with the 3 mg dose injected every 4 weeks or every 6 weeks.  The results of these trials show that maximum plasma concentrations of pegaptanib sodium are approximately 90 ng/mL and are reached within 1 to 4 days after injection.  These levels declined over 4 weeks. Low circulating levels of pegaptanib are seen 4 to 6 weeks after an intravitreous dose of 3 mg.  These levels approach the lower limit of quantification in the majority of patients.  The “terminal” half-life of pegaptanib in the plasma after dosing 3mg is 10±4 days. This “terminal” half-life represents the exit of pegaptanib out of the eye into the systemic circulation. 

 

 

 


 

IV.     Description of Clinical Data and Sources  [CDdesc5] 

 

 

Protocol

Design

Dose

Patients Treated

Study Assessments

Studies in Age-related Macular Degeneration (AMD)

 

Controlled AMD Trials

EOP1003

Phase 2/3 multi-

center, randomized, sham-injection controlled, double masked, dose finding

Intravitreous injections

of either 0.3, 1 or 3 mg pegaptanib sodium/eye

or sham every 6 weeks

for 54 weeks

622 patients   50 years

of age active subfoveal CNV secondary to exudative AMD

BCVA, Fluorescein angiography and fundus photography, AEs, IOP, laboratory parameters, vital signs, PDT administration, local ocular events

EOP1004

Phase 2/3 multi-

center, randomized, sham-injection controlled, double masked, dose finding

Intravitreous injections

of either 0.3, 1 or 3 mg pegaptanib sodium/eye

or sham every 6 weeks

for 54 weeks

586 patients   50 years

of age active subfoveal CNV secondary to exudative AMD

BCVA, Fluorescein angiography and fundus photography, AEs, IOP, laboratory parameters, vital signs, PDT administration, local ocular events, PK, QOL

Uncontrolled AMD Trials

NX109-01

Phase 1, multi-

center, open label escalating dose, dose finding

Single intravitreous injection of either 0.25,

 0.5, 1, 2 or 3 mg pegaptanib sodium/ eye

15 patients   50 years

 of age with exudative AMD

DLT, AEs, vital signs, BCVA, IOP, laboratory parameters, immune response, PK parameters, local ocular events

EOP1000

Phase 1/2, multi-

center, open label, multiple dose in patients without PDT

Total of 3 consecutive intravitreous injections

of 3 mg pegaptanib sodium/eye, 28 days

apart

10 patients   50 years

of age with subfoveal CNV secondary to exudative AMD

BCVA, AEs, IOP, laboratory parameters, vital signs, DLT, PK parameters, immune response, local ocular events

EOP1001

Phase 1/2, multi-

center, open label, multiple dose in patients following PDT administration

Total of 3 intravitreous injections of 3 mg pegaptanib sodium/ eye,

28 days apart

11 patients   50 years

of age with predominantly classic subfoveal CNV secondary to exudative AMD

BCVA, AEs, IOP, laboratory parameters, vital signs, DLT, PK parameters, immune response, requirement for PDT administration, local ocular events

EOP1006

Phase 2 multi-center, randomized, multiple dose, open label

cohort

Intravitreous injections

of 3 mg pegaptanib sodium/ eye every 6

weeks for 54 weeks

37 patients   50 years

of age with subfoveal CNV secondary to exudative AMD

(Study is ongoing in

147 patients)

AE, local ocular events, IOP, laboratory parameters, vital signs, PK parameters, immune response

Development Trials for Additional Indications

 

Studies in Diabetic Macular Edema (DME)

EOP1002

Phase 1/2, multi- center, multiple dose open label,

Intravitreous injections

of 3 mg pegaptanib sodium/ eye every 6

weeks for 12 to 30 weeks

10 patients   18 years

of age with clinically significant DME

AEs, BCVA, laboratory parameters, IOP, retinal thickening, local ocular events

EOP1005

Phase 2, multi-

center, randomized, sham-injection controlled, double masked, dose

finding

Intravitreous injections

of either 0.3, 1.0 and

3 mg pegaptanib

sodium/ eye or sham

every 6 weeks for 12 to

30 weeks

169 patients   18

years of age with clinically significant DME

(Study is ongoing)

Retinal thickening, BCVA, AEs, IOP, laboratory parameters, local ocular events, need for laser at   12 weeks

Studies in Von Hippel-Lindau Disease (VHL)

EOP1007

Phase 1/2, open-

label, non-

 randomized, pilot

Intravitreous injections

of 3 mg pegaptanib sodium/ eye every 6

weeks for 30 to 54 weeks

5 patients   18 years of age with severe ocular VHL tumors

BCVA, macular thickening, fluorescein leakage, disease progression, AEs, local ocular events, IOP.

CNV = Choroidal neovascularization; PDT = Photodynamic therapy with verteporfin; DLT = Dose limiting toxicity; AE = Adverse event;

BCVA = Best corrected visual acuity; IOP = Intraocular pressure; PK = Pharmacokinetics; QOL = quality of life.

 

 



 



Each of the submitted phase 3 studies (EOP1003 and EOP1004) are presented independently to determine if the results of each trial demonstrated efficacy for the primary efficacy endpoint.  The primary efficacy end point for each trial was a responder analysis of the proportion of patients who loss less than 15 letters of visual acuity from baseline (doubling of the visual angle) at 54 weeks.  This analyses was done for two populations which represent the extreme ends of the spectrum to evaluate the robustness of the results; an all randomized patient population with last-observation-carried-forward (LOCF) and the per-protocol population with observed cased only.


 

B.             Detailed Review of Trials by Indication[Note7] 

 

Proposed Indication: The treatment of the neovascular form of age-related macular degeneration.


Study 1 – Study EOP1003

 

Title:  A Phase 2/3 Randomized, Double-Masked, Controlled, Dose-Ranging, Multi-Center Comparative Trial, in Parallel Groups, to Establish the Safety and Efficacy of Intravitreous Injections of Pegaptanib Sodium (Anti-Vascular Endothelial Growth Factor [VEGF] Pegylated Aptamer) Given Every 6 Weeks for 54 Weeks, in Patients with Exudative Age- Related Macular Degeneration (AMD)

 

Objective:  The objective of this study was to establish the safe and efficacious dose of pegaptanib sodium when given as an intravitreous injection (0.3 mg, 1 mg or 3 mg/eye) compared with control sham injections every 6 weeks over a 54-week period (9 treatments) in patients with subfoveal choroidal neovascularization (CNV) secondary to AMD.

 

Study Design:  This was a randomized, double-masked, controlled, dose-ranging, multi-center, comparative, Phase 2/3 trial, in parallel groups. The study was conducted internationally in Europe, Israel, Australia, South America and North America. The study has a 2 year duration with two randomization steps and is ongoing. Data from the first year on study are included in this report.

 

 

Clinical sites – Study EOP1003

 

Center Number

Principal Investigator

Center Location

Number of Subjects

Australia

 

 

 

114

Andrew Chang, MD

Syndey

7

64

Jennifer Arnold, MD

Parramatta

34

65

Ian Constable, MD

St. Nedlands

12

66

Paul Mitchell, MD

Westmead

5

73

Robyn Guymer, MD

East Melbourne

16

131

Mark Gillies, MD

Sydney

12

Austria

 

 

 

67

Michael Stur, MD

Vienna

11

116

Anton Haas, MD

Graz

4

Belgium

 

 

 

113

Anita Leys, MD

Leuven

38

Brazil

 

 

 

70

Michel Fara, MD

Sao Paulo

7

108

Marcos de Avila, MD

Sector Bureno

6

112

Carlos Moreira, MD

Curitiba

3

134

Jaco Lavinsky

Poro Alegre

5

Chile

 

 

 

71

Jose Manuel Lopez, MD

Satiago

7

Colombia

 

 

 

104

Franciso Rodriguez, MD

Colombia

18

Czech Republic

 

 

 

119

Ivan Fiser, MD

Prague

11

Denmark

 

 

 

72

Michael Larsen, MD

Herlev

9

France

 

 

 

74

Francois Koenig, MD

Lyon

2

75

Gisele Soubrane, MD

Creteil

25

76

Jean-Francois Korobelnik, MD

Bordeau

5

78

Alain Gaudric, MD

Paris

3

Germany

 

 

 

79

Stefan Dithmar, MD

Heidelberg

10

80

Daniel Pauleikhoff, MD

Munstser

1

81

Ulrike Schneider, MD

Tubingen

6

82

Peter Wiedemann, MD

Leipzig

14

83

B Kirchhof, MD

Koln

8

Hungary

 

 

 

122

Ildiko Suveges, MD

Budapest

3

137

Jozsef Gyory, MD

Veszprem Korhaz

3

Israel

 

 

 

84

Anat Loewenstein, MD

Tel-Aviv

11

85

Irit Rosenblatt, MD

Petach Tikva

11

103

Ayala Pollack, MD

Rehovot

7

Italy

 

 

 

86

Rosario Brancato, MD

Milano

6

87

Francesco Bandello, MD

Udine

16

88

Felice Cardillo Piccolino, MD

Torino

10

89

Lfonso Giovannini, MD

Torrette Ancona

18

123

Ugo Menchini

Firenze

8

Poland

 

 

 

127

Krystna Pecold, MD

Poznan

5

128

Jozef Kaluzny, MD

Bydgoszcz

5

Portugal

 

 

 

93

Jose Cunha-Vaz, MD

Coimbra

25

Spain

 

 

 

94

Marta Figueroa, MD

Madrid

7

136

Jose Ruiz Moreno, MD

Alicante

10

95

Jordi Mones, MD

Barcelona

14

Switzerland

 

 

 

98

Constantin Pournaras, MD

Geneva

2

99

Leonides Zografos, MD

Lausanne

1

The Netherlands

 

 

 

91

August Deutman, MD

Nijmegen

7

92

Reiner Schlingemann, MD

Amsterdam

15

United Kingdom

 

 

 

100

Iain Chisholm, MD

Southampton

14

101

Noemi Lois, MD

Scotland

9

102

Usha Chakravarthy, MD

Belfast

18

130

Phil Hykin, MD

London

15

United States

 

 

 

143

David Chow, MD

Illinois

4

144

K. Bailey Freund, MD

New York

4

145

Alexander Eaton, MD

Florida

15

146

Philip M. Falcone, MD

Connecticut

4

147

Patrick Higgins, MD

New Jersey

9

148

Keye Wong, MD

Florida

9

149

Matthew Thomas, MD

Missouri

-

153

Leonard Joffe, MD

Arizona

16

154

Jeffrey Heier, MD

Massachusetts

21

156

John Thompson, MD

Maryland

-

Canada

 

 

 

151

Murray Ersmus, MD

Saskatoon

-

155

Raul Garcia, MD

Saskatchewan

8

 

 

First Randomization

The trial had a parallel group design. At study entry, patients were allocated to one of the four treatment arms according to a stratified randomization system. The treatment groups were:

Arm A: pegaptanib sodium 0.3 mg intravitreous injection every 6 weeks for 48 weeks

Arm B: pegaptanib sodium 1 mg intravitreous injection every 6 weeks for 48 weeks

Arm C: pegaptanib sodium 3 mg intravitreous injection every 6 weeks for 48 weeks

Arm D: sham intravitreous injection every 6 weeks for 48 weeks

 

Patients were stratified by center and the following factors:

  • Type of lesion (visible classic CNV area divided by total lesion area); defined as predominantly classic (>50% classic CNV), minimally classic (1-49% classic CNV), or occult with no classic (0% classic CNV)
  • Whether the patient had received prior PDT therapy (one treatment maximum)

 

Second Randomization

At one year (54 weeks), patients were re-randomized for a total study period of 102 weeks.

 

Patients who were treated with pegaptanib sodium during the first year were re-randomized

at week 54 in a ratio of 1:1 to either stop therapy (no further treatment) or to continue with the same dose and dosing regimen of pegaptanib sodium.

 

Patients who were receiving sham injections during the first year were re-randomized at week 54 in a ratio of 1:1:1:1:1 to either stop therapy, continue with sham injections or to continue on study receiving one of the three pegaptanib sodium doses.

 

 

Study Population – Inclusion and Exclusion Criteria

 

Inclusion Criteria

Ophthalmic Inclusion Criteria

 

  1. BCVA in the study eye between 20/40 and 20/320, and better than or equal to 20/800 in the fellow eye.
  2. Subfoveal CNV, secondary to AMD, with a total lesion size (including blood, scar/atrophy and neovascularization) of <12 total disc areas, of which at least 50% had to be active CNV.
  3. Any subretinal hemorrhage could comprise no more than 50% of total lesion size.
  4. For patients with minimally classic and occult with no classic CNV, there had to be the presence of subretinal hemorrhage (but comprising no more than 50% of the lesion) and/or lipid and/or documented evidence of 3 or more lines of vision loss (ETDRS or equivalent) during the previous 12 weeks.
  5. Clear ocular media and adequate pupillary dilatation to permit good-quality stereoscopic fundus photography.
  6. Intraocular pressure (IOP) of 23 mmHg or less.
  7. PDT with verteporfin was permitted in this protocol only for patients with predominantly classic lesions determined by the investigator, and additionally they had to meet the criteria described in the product label (eligibility for PDT was confirmed retrospectively by the IRC). All PDT therapies given during the study were scheduled to occur within a 5- to 10-day window prior to treatment so that the study injection occurred after the period of photosensitivity, and any angiograms required by this protocol would be used to confirm eligibility for any subsequent PDT treatments wherever possible in order to minimize the number of additional angiograms required.

 

General Inclusion Criteria

  1. Patients of either gender, aged >50 years.
  2. Performance status ≤ 2 according to Eastern Cooperative Oncology Group (ECOG) scale.
  3. Normal electrocardiogram (ECG) or clinically non-significant changes.
  4. Women had to be using two forms of effective contraception, be post-menopausal for at least 12 months prior to study entry, or be surgically sterile. If the woman was of child-bearing potential, a serum pregnancy test was performed within 48 hours prior to treatment and the result made available prior to treatment initiation. The two forms of effective contraception had to be implemented during the study and continue for at least 60 days following the last dose of test medication.
  5. Adequate hematological function: hemoglobin >10g/dL, platelet count >130 x 109/L and white blood cell count (WBC) >3.8 x 109/L.
  6. Adequate renal function: serum creatinine and blood urea nitrogen (BUN) within 2 x the upper limit of normal (ULN) of the institution.
  7. Adequate liver function: serum bilirubin < 1.5 mg/dL, and gamma glutamyl transferase (GGT), alanine amino transferase (ALT/SGOT), aspartame amino transferase (AST/SGPT), and alkaline phosphatase within 2 x ULN of the institution.
  8. Written informed consent.
  9. Ability to return for all study visits.

 

Exclusion Criteria:

  1. Previous subfoveal thermal laser therapy.
  2. Any subfoveal scarring or atrophy, and no more than 25% of the total lesion size could be made up of scarring or atrophy.
  3. More than one prior PDT with verteporfin was not permitted. In addition, patients could not have received their one prior PDT within less than eight weeks or more than 13 weeks prior to the baseline angiography/photography for the study. Patients could have their first "on study" PDT (if eligible) after baseline angiography/photography, but at least 5 days prior to the first study treatment.
  4. Significant media opacities, including cataract, that might interfere with visual acuity, assessment of toxicity or fundus photography. Patients could not be entered if there was a likelihood that they would require cataract surgery within the following 2 years.
  5. Presence of other causes of CNV, including pathologic myopia (spherical equivalent of -8 diopters or more, or axial length of 25mm or more), the ocular histoplasmosis syndrome, angioid streaks, choroidal rupture and multifocal choroiditis.
  6. Any intraocular surgery within 3 months, or extrafoveal/juxtafoveal laser within 2 weeks, of study entry.
  7. Previous posterior vitrectomy or scleral buckling surgery.
  8. Previous or concomitant therapy with another investigational agent, including PDT with verteporfin for lesions other than predominantly classic (i.e., currently not approved in the majority of participating countries) to treat AMD, except multivitamins and trace minerals.
  9. Presence of pigment epithelial tears or rips.
  10. Any of the following underlying diseases:
    • Diabetic retinopathy
    • History or evidence of severe cardiac disease, e.g., New York Heart Association (NYHA) Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrythmias requiring ongoing treatment or unstable angina
    • History or evidence of peripheral vascular disease
    • Clinically significant impaired renal or hepatic function
    • Stroke (within 12 months of study entry)
    • Acute ocular or periocular infection
  11. Previous therapeutic radiation to the eye, head, or neck.
  12. Any treatment with an investigational agent in the past 60 days for any condition.
  13. Known serious allergies to the fluorescein dye used in angiography (and indocyanine green if used) or to the components of the pegaptanib sodium formulation.

 

 

Primary Efficacy Variable

The primary efficacy endpoint was the proportion of patients losing <15 letters of VA from baseline to 54 weeks (responders).

 

Secondary Efficacy Endpoints:

  • Proportion of patients gaining >15 letters of VA from baseline to 54 weeks
  • Proportion of patients gaining >0 letter of VA from baseline to 54 weeks
  • Mean change in VA from baseline to 6, 12 and 54 weeks

 

 

 

Other Planned Efficacy Endpoints:

  • Change in VA from baseline, prior to every treatment from baseline to 54 weeks
  • Proportion of patients with Snellen Equivalent equal to or worse than 20/200 in the study eye at baseline, 6 weeks, 12 weeks and 54 weeks post baseline
  • Change in total lesion size in disc areas from baseline to 30 weeks and 54 weeks
  • Change in total CNV size in disc areas from baseline to 30 weeks and 54 weeks
  • Change in CNV leak size in disc areas from baseline to 30 weeks and 54 weeks
  • Proportion of patients with progression in lesion subtype from baseline to 54 weeks (pure occult to minimally classic or predominantly classic, and minimally classic to predominantly classic)
  • Proportion of patients receiving PDT at any time during the course of the study.

 

Safety Endpoints

  • All AEs, whether deemed related to treatment or not
  • All serious adverse events (SAEs), whether deemed related to treatment or not
  • All laboratory abnormalities, whether deemed clinically relevant or not
  • A loss of 20 letters of vision on the ETDRS chart between consecutive treatments

 

Safety assessments included documentation of local ocular events in the study eye such as diffuse retinal hemorrhage; acute cataract; increase in IOP; retinal detachment, acute retinal arterial or venous occlusions; and sterile or infectious endophthalmitis. If there was an adverse event relating to the fellow eye, it was captured on the AE page of the CRF.

 

Protocol Defined Analysis Populations

 

Safety Population: consisted of all patients who received at least one treatment, regardless of their eligibility for the study.

Intent-To-Treat Population: all randomized patients who received double-masked treatment and who had complete baseline vision assessments.

Per-Protocol Population: patients in the ITT population who did not experience any major violations of the protocol or of ophthalmic inclusion/exclusion criteria which could have had an impact on VA, for example cataract removal, were included in the per-protocol population. Additionally patients without post-baseline VA assessments were excluded.

All-randomized Population:  Included all patients randomized to take part in the study, regardless of whether they received the study treatment or not.

Week 54 observed patient population: included patients from the ITT population who also had week 54 VA data (whether or not they were still receiving study treatment).

 

Note:  The Intent-To- Treat population as defined in the protocol is not a “true” ITT population that is accepted by the Agency.  The “true” ITT population is defined as all patients randomized to the study regardless of whether they received an study treatments.  The primary efficacy results presented are based on the all-randomized patient population.

 


Study Flow Chart - Assessments and Timing – Study EOP1003

 

 

BL

Randomization 1

Randomization 2

Week

-1

0

6

12

18

24

30

36

42

48

54

60

66

72

78

84

90

96

Treatment number

 

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

7

8

Informed consent

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Medical history

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ophthalmic history

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pregnancy test

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Randomization

X

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

Pegaptanib sodium or sham injection

 

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Efficacy

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Refraction and VA (ETDRS)

B

 

S

S

S

S

B

S

S

S

B

S

S

S

B

S

S

S

Color fundus photographs1

B2

 

 

 

 

 

B

 

 

 

B

 

 

 

B

 

 

 

Fluorescein angiogram1

B2

 

 

 

 

 

B

 

 

 

B

 

 

 

B

 

 

 

ICG/OCT3

B

 

 

 

 

 

 

 

 

 

B

 

 

 

 

 

 

 

Safety

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Physical examination4

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Adverse events / serious adverse events

 

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Intraocular pressure5

B

S6

S6

S6

S6

S6

B6

S6

S6

S6

B6

S6

S6

S6

B6

S6

S6

S6

Ophthalmic examination

B

S6

S6

S6

S6

S6

B6

S6

S6

S6

B6

S6

S6

S6

B6

S6

S6

S6

Vital signs

X

 

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Laboratory tests

X

 

X

X

X

X

X

X

X

X

X8

X8

X8

X8

X8

X8

X8

X8

ECG

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Telephone safety check7

 

X

X

X

X

X

X

X

X

X

X8

X8

X8

X8

X8

X8

X8

X8

B = Assessment on both eyes

BL = Baseline, performed within 7 days of first treatment

S = Assessment on study eye only

EW = Early withdrawal (prior to Week 102)

1 Sent to Independent Reading Center (IRC) for efficacy and safety assessments

2 Reviewed by Eligibility and Classification Quality Assurance Team (ECQAT) for eligibility and randomization stratification

3 Some selected sites performed optional indocyanine green angiograms (ICG) or optical coherence tomography (OCT), but no analyses of data were performed

4 Physical examination performed post baseline only if indicated

5 Applanation tonometry at baseline and for confirmation of IOP>30 mmHg

6 Before treatment, at least 30 minutes after treatment and 1 week after treatment

7 Telephone safety check carried out 3 days post treatment

8 Treated (active or sham) patients only


Subject Disposition and Demographics – Study EOP1003

 

Treatment

Patients Randomized and Treated (N=612)

Patients Discontinued (n=53)

0.3 mg

151

11

1 mg

155

13

3 mg

153

17

Sham

153

12

 

 

Discontinued Patients and Reason – Study EOP1003

 

Patient

Treatment

Reason

Study day

064-012

Sham

Died

342

064-019

Sham

Patient request/frustrated with vision

376

084-010

Sham

Patient request/requested other treatment options

68

085-007

Sham

Patient request/pain on injection

332

087-014

Sham

Worsening macular hemorrhage

391

089-016

Sham

Personal/economic problems-noncompliant with visits

428

093-018

Sham

Osteoarticular pain

355

102-009

Sham

Patient request/refused further injections

294

098-002

Sham

Died

35

130-013

Sham

Died

273

145-018

Sham

Died

350

154-026

Sham

Adverse event/colon cancer

137

075-005

0.3 mg

Patient request/pain on injection

130

081-005

0.3 mg

Patient request/refused further injections

378

087-010

0.3 mg

Patient request/palpitations prior to injection

57

089-019

0.3 mg

Endophthalmitis

385

100-002

0.3 mg

Investigator decision/Transient ischemic attack

39

108-007

0.3 mg

Died

312

123-002

0.3 mg

Protocol deviation/noncompliant with visits

404

123-010

0.3 mg

Patient request/cannot attend follow-up visits

248

136-011

0.3 mg

Died

130

154-001

0.3 mg

Patient request/refused further injections

35

154-017

0.3 mg

Patient request/poor health-unable to make visits

213

064-014

1 mg

Patient request/frustrated with vision

377

065-010

1 mg

Patient request/frustrated with vision

217

070-001

1 mg

Patient request/refused further injections

376

073-008

1 mg

Patient request/visit schedule too rigorous

27

073-014

1 mg

Patient request/developed cataract 2ş to injection/had surgery

344

075-028

1 mg

Pulmonary embolism

260

083-002

1 mg

Poor health/pneumonia

137

084-009

1 mg

Patient request/refused further injections

76

101-010

1 mg

Adverse event/shortness of breath-suspected pulmonary embolism

252

102-026

1 mg

Adverse event/ refused further injections(watery eyes)

90

104-001

1 mg

Panuveitis

217

130-001

1 mg

Died

358

136-005

1 mg

Died

281

075-006

3 mg

Patient request/travel problems

453

082-006

3 mg

Cerebrovascular accident

271

085-001

3 mg

Died

202

089-015

3 mg

Metastatic lung cancer

248

089-018

3 mg

Patient request/no improvement in vision

419

092-012

3 mg

Angina pectoris

294

093-028

3 mg

Investigator/sponsor decision-worsening AMD

214

095-003

3 mg

Adverse event/worsening general condition

475

104-011

3 mg

Died

195

108-004

3 mg

Patient request/refused further injections

169

113-015

3 mg

Patient request/refused further participation

134

119-012

3 mg

Died

341

122-002

3 mg

Adverse event/lung cancer

260

123-005

3 mg

Patient request/refused further treatment

440

147-003

3 mg

Investigator/sponsor decision/abnormal EKG

48

155-004

3 mg

Patient request/spouse died

135

 

Demographics – Safety Population – Study EOP1003

 

 

0.3 mg

(N=151)

1 mg

(N=155)

3 mg

(N=153)

Sham

(N=153)

Gender

 

 

 

 

Male

69 (46%)

68 (44%)

60 (39%)

57 (37%)

Female

82 (54%)

87 (56%)

93 (61%)

96 (63%)

Race

 

 

 

 

White

143 (95%)

148 (95%)

145 (95%)

144 (94%)

Asian

0

1 (1%)

1 (1%)

1 (1%)

Black

0

1 (1%)

0

1 (1%)

Hispanic

7 (5%)

5 (3%)

7 (5%)

5 (3%)

Other

1 (1%)

0

0

2 (1%)

Age

 

 

 

 

Mean

74.9

74.5

75.4

74.9

Range

53-90

53-90

53-89

52-92

Smoking status

 

 

 

 

Yes

24 (16%)

15 (10%)

15 (10%)

14 (9%)

% Classic AMD

≥ 50%

35 (23%)

40 (26%)

39 (25%)

39 (25%)

 

1% - 49%

60 (40%)

57 (37%)

55 (36%)

52 (34%)

 

0%

56 (37%)

58 (37%)

59 (39%)

62 (41%)

Prior PDT with verteporfin

6 (4%)

10 (6%)

6 (4%)

4 (3%)

ETDRS Vision

 

 

 

 

Mean

53

50.9

50.1

51.3

Range

11-75

22-77

22-76

21-75

                       

Efficacy Analysis

 

The primary efficacy results are presented below. The statistically significant findings are highlighted in the table. Statistical significance was determined by the protocol defined Hochberg procedure to correct for multiple dose comparisons. The bolded entries indicate a trend for efficacy although formal statistical testing was not performed.

 

Primary Efficacy Results – All Randomized Patients LOCF – Study 1003

 

Number of Patients (%)

0.3 mg

N= 153

1 mg

N= 158

3 mg

N= 155

Sham

N= 156

Responders1

Month 3

134 (87.6%)

146 (92.4%)

136 (87.7%)

130 (83.3%)

Month 6

127 (83%)

137 (86.7%)

128 (82.6%)

112 (71.8%)

Month 9

117 (76.5%)

126 (79.8%)

125 (80.7%)

105 (67.3%)

Month 12

112 (73.2%)

p=0.01

119 (75.3%)

p=0.002

108 (69.7%)

p=0.06

93 (59.6%)

1 Patients who lost < 15 letters of vision.  Note:  Patients who lost < 15 letters of vision from baseline to 54 weeks is the primary efficacy endpoint

 

 

Primary Efficacy Results – PP population observed cases only– Study 1003

 

Number of Patients (%)

0.3 mg

 

1 mg

 

3 mg

 

Sham

 

Responders1

Month 3

122 (87.8%)

N=139

131 (92.9%)

N= 141

122 (86.5%)

N= 141

120 (82.8%)

N= 145

Month 6

110 (85.3%)

N= 129

125 (86.8%)

N= 144

116 (82.3%)

N= 141

101 (69.7%)

N= 145

Month 9

103 (78.3%)

N= 131

115 (78.9%)

N= 144

110 (79.1%)

N= 139

93 (66%)

N= 141

Month 12

98 (73.7%)

p=0.01

N= 133

105 (75.5%)

0.005

N= 139

90 (66.7%)

p=0.26

N= 135

82 (58.6%)

N= 140

1 Patients who lost < 15 letters of vision.  Note:  Patients who lost < 15 letters of vision from baseline to 54 weeks is the primary efficacy endpoint

2  3 mg dose was omitted from statistical analysis prior to unmasking data

 

 

 

 

 

 

 

 

 

 

 

 

Primary Efficacy Results – Sensitivity Analyses – Study 1003

 

Worst Case Analysis*

N=153

N=158

N=155

N=156

Responders1

104 (68%)

109 (69%)

93 (60%)

96 (61.5%)

p-value

0.15

0.11

-

-

Week 54 Observed population

N=139

N=144

N=139

N=142

Responders1

103 (74%)

109 (76%)

93 (67%)

82 (58%)

p-value

0.005

0.003

-

-

1 Patients who lost < 15 letters of vision from baseline to 54 weeks – primary efficacy endpoint

2  3 mg dose was omitted from statistical analysis prior to unmasking data

 

* In the worst case analysis, all patients in the sham group with missing VA measurements are assumed to be Responders and all patients in the pegaptanib group with missing VA measurements are assumed to be Non-Responders. 

 

 

Number of Patients Receiving On-Study PDT Treatment in the Study Eye – ITT Population – Study EOP1003

 

Number of patients

 

0.3 mg

N=150

1 mg

N=154

3 mg

N=153

Sham

N=152

All patients

 

 

 

 

 

PDT treatment

Yes

17 (11%)

19 (12%)

20 (13%)

19 (13%)

Predominantly Classic CNV

 

n=35

n=39

n=39

n=39

PDT Treatment

Yes

14 (40%)

15 (38%)

16 (41%)

13 (33%)

Minimally Classic CNV

 

n=59

n=57

n=55

n=52

PDT Treatment

Yes

2 (3%)

3 (5%)

3 (5%)

5 (10%)

Occult CNV

 

n=56

n=58

n=59

n=61

PDT Treatment

Yes

1 (2%)

1 (2%)

1 (2%)

1 (2%)

Pairwise Comparison

 

0.3 mg vs. sham

1 mg vs. sham

3 mg vs. sham

 

 

 

p=0.68

p=1.0

p=0.92

 

 

 

Number of On-Study PDT Treatments Received in The Study Eye – ITT population – Study EOP1003

 

Number of patients

0.3 mg

N=150

1 mg

N=154

3 mg

N=153

Sham

N=152

Total number of PDT treatments

n=28

n=36

n=41

n=32

Predominantly classic CNV

23 (82%)

30 (83%)

35 (85%)

20 (63%)

Minimally classic CNV

3 (11%)

4 (11%)

5 (12%)

10 (31%)

Occult CNV

2 (7%)

2 (6%)

1 (2%)

2 (6%)

 

 

Responder Analysis for PDT Treatment Interaction– Study 1003

 

Number of Patients (%) who never received PDT before or during the study

0.3 mg

N= 131

1 mg

N= 132

3 mg

N= 127

Sham

N= 127

Responders1

Month 3

116 (88.6%)

123 (93.2%)

114 (89.8%)

106 (83.5%)

Month 6

110 (84%)

117 (88.6%)

109 (85.8%)

92 (72.4%)

Month 9

102 (78%)

109 (82.6%)

105 (82.7%)

85 (67%)

Month 12

97 (74%)

103 (78%)

92 (72.4%)

78 (61.4%)

1 Patients who lost < 15 letters of vision. 

 

 

Number of Patients (%) who only received PDT before the study

0.3 mg

N= 2

1 mg

N= 5

3 mg

N= 6

Sham

N= 4

Responders1

Month 3

1 (50%)

5 (100%)

6 (100%)

3 (75%)

Month 6

2 (100%)

5 (100%)

4 (66.7%)

3 (75%)

Month 9

2 (100%)

5 (100%)

5 (83.3%)

3 (75%)

Month 12

2 (100%)

3 (60%)

5 (83.3%)

3 (75%)

1 Patients who lost < 15 letters of vision. 

 

 

Number of Patients (%) who only received PDT during the study

0.3 mg

N= 16

1 mg

N= 17

3 mg

N= 20

Sham

N= 25

Responders1

Month 3

13 (81.3%)

15 (88.2%)

14 (70%)

21 (84%)

Month 6

12 (75%)

11 (64.7%)

13 (65%)

17 (68%)

Month 9

9 (56.3%)

8 (47%)

13 (65%)

17 (68%)

Month 12

9 (56.3%)

9 (53%)

10 (50%)

12 (48%)

1 Patients who lost < 15 letters of vision. 

 

 

Number of Patients (%) who received PDT before and during the study

0.3 mg

N= 4

1 mg

N= 4

3 mg

N= 2

Sham

N= 0

Responders1

Month 3

4 (100%)

3 (75%)

2 (100%)

0

Month 6

3 (75%)

4 (100%)

2 (100%)

0

Month 9

4 (100%)

4 (100%)

2 (100%)

0

Month 12

4 (100%)

4 (100%)

1 (50%)

0

1 Patients who lost < 15 letters of vision. 


 

Additional Efficacy Analyses

 

 

 


 

Mean Total Lesion Size, CNV Size and Leak Size – Study 1003

 

 

0.3 mg

n=150

1 mg

n=154

3 mg

n=153

Sham

N=152

Total Lesion size1

 

 

 

 

Baseline

3.9

3.7

3.7

4.0

Week 30

4.9

4.7

5.1

5.5

Week 54

5.6

5.6

6.0

6.4

Total CNV Size1

 

 

 

 

Baseline

3.1

3.2

3.2

3.5

Week 30

3.9

3.9

4.3

4.8

Week 54

4.7

4.6

5.0

5.7

Total Leak Size1

 

 

 

 

Baseline

3.4

3.3

3.3

3.5

Week 30

4.1

3.4

4.2

4.9

Week 54

4.5

3.9

4.4

5.1

1 size given in DA (disc area)

 

 

Vision Gain – Study EOP1003

 

 

0.3 mg

n=150

1 mg

n=154

3 mg

n=153

Sham

N=152

Number of Patients (%)

 

 

 

 

 

Vision gain ≥ 15 letters1

Yes

6 (4%)

10 (6%)

7 (5%)

5 (3%)

 

p-value

0.93

0.49

-3

-

Vision gain ≥ 0 letters2

Yes

49 (33%)

59 (38%)

60 (39%)

42 (28%)

 

p-value

0.38

0.08

-3

-

1patients who gained ≥ 15 letters of vision from baseline to 54 weeks

2patients who gained ≥ 0 letters of vision from baseline to 54 weeks

33 mg dose was omitted from statistical analyses prior to unmasking data

 

 


Responder analyses based on baseline characteristics for study EOP1003

 

 

 

 

 

 

 

 


Study 2 – Study EOP1004

 

Title:   Same as Study EOP1003

Objective:      Same as Study EOP1003

Study Design: Same as Study EOP1003.  This study was conducted in North America.

 

Clinical sites – Study EOP1004

 

Center Number

Principal Investigator

Center Location

Number of Patients

01

Julia Haller, MD

Baltimore, MD

4

02

Michael Klein, MD

Portland, OR

6

03

Daniel F. Martin, MD

Atlanta, GA

-

04

Gary Fish, MD

Dallas TX

6

05

Allen Ho, MD

Philadelphia, PA

11

06

Scott D. Pendergast, MD

Lakewood, OH

33

07

Christine Gonzales, MD

Los Angeles, CA

30

08

Antonia Capone, MD

Royal Oak, MI

23

09

Jorge Arroyo, MD

Boston, MA

8

10

Steve Sanislo, MD

Menlo Park, CA

9

12

Richard Rosen, MD

New York, NY

6

13

Dean Eliot, MD

Detroit, MI

1

14

Jean Daniel Arbour, MD

Montreal, Quebec

-

15

Robert Avery, MD

Santa Barbara, CA

3

17

Paul Bernstein, MD

Salt Lake City, UT

7

18

Francis Cangemi, MD

Belleville, NJ

6

19

David Boyer, MD

Beverly Hills, CA

22

20

Sandy Brucker, MD

Philadelphia, PA

12

21

Herbert Cantrill, MD

Minneapolis, MN

20

22

Gaetano Barille, MD

New York, NY

-

23

Steven Charles, MD