Gene Transfer for Neovascular Age-Gene Transfer for Neovascular Age-Related Macular DegenerationRelated Macular Degeneration

Peter A. CampochiaroPeter A. Campochiaro

The Wilmer Eye InstituteThe Wilmer Eye Institute

The Johns Hopkins University School of The Johns Hopkins University School of MedicineMedicine

Baltimore, MDBaltimore, MD

Financial DisclosureFinancial Disclosure

Research SupportResearch Support• GenzymeGenzyme• Oxford BioMedicaOxford BioMedica• AskBioAskBio

TopicsTopics

Neovascular AMD BackgroundNeovascular AMD BackgroundCurrent TreatmentCurrent TreatmentWhy Consider Gene Transfer?Why Consider Gene Transfer?

Endpoints for Clinical TrialsEndpoints for Clinical Trials

Targeted DeliveryTargeted Delivery

Repeat AdministrationRepeat Administration

Age-Related Macular Degeneration (AMD)

Early Intermediate Advanced

Multiple small or a few intermediate

drusen

Extensive intermediate

drusen

Choroidal Neovascularization

Geographic Atrophy

SubretinalFibrosis

Advanced AMDMajor Public Health Problem

1.75

2.95

0

1

2

3

4

No

. of

ind

ivid

ua

ls (

mill

ion

s)

Number of Individuals With Neovascular AMD or Geographic Atrophy

(millions)

2000 2020

Ranibizumab for NVAMDMean Change in Visual Acuity Over Time

17.7 letter benefit *

17.0 letter benefit *

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

Visit (months)

-10

-8

-6

-4

-2

0

2

4

6

8

10

ET

DR

S le

tte

rs

Sham (n=238)Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)

-10.5

+6.5+7.2

* P < 0.0001 vs. sham

Subjects Gaining ≥15 Letters from Baseline Marina Trial

25%34%

26%33%

4%5%

0

20

40

60

80

100

1-year outcomes 2-year outcomes

% o

f p

atie

nts

Ranibizumab 0.3 mg (n = 238)

Ranibizumab 0.5 mg (n = 238)

Sham (n = 240)

Why Consider Gene Transfer?

Monthly intraocular injections provide best results

Burden on patients and physiciansSocietal burden- expenseNot feasible throughout most of the world

Treatment as neededIncreased risk of visual loss

GradualCatastrophic

AAV2.CBA-sFLT01

sFLT01 – contains domain 2 of Flt-1 coupled by 9Gly linker to human IgG1 Fc

- high affinity VEGF binding protein

CBA promoter

Packaged in rAAV2

Retinostat

Endostatin and Angiostatin

CMV promoter

Packaged in Equine Infectious Anemia Viral (EIAV) Vector

11

Study Populations

Subjects with AMD, aged 50 years or more with active CNV that shows evidence of active leaking on fluorescein angiography

BCVA less than or equal to 20/200 in the study eye

BCVA in the fellow eye of 20/200 or better

Subjects unlikely to benefit from standard of care – subfoveal fibrosis

12

Endpoints

Primary Endpoint

• The incidence of adverse events • Changes in best corrected visual acuity (BCVA)• Evidence of ocular inflammation • Intraocular pressure

Secondary Endpoints

• The change from baseline in the amount of subretinal and intraretinal fluid measured by optical coherence tomography (OCT)

• Change in size of active choroidal neovascularisation measured on fluorescein angiography

• The change from baseline in BCVA at all time points • Transgene product levels in aqueous fluid

sFlt01 Trial

Two phases• Dose escalation• MTD evaluation

Dose escalation (Patients with limited visual potential due to macular scarring)

• Four doses to be tested 2x108, 2x109, 6x109, 2x1010 vp• Minimum three patients per cohort• Patients enrolled to show safety and biological activity

MTD evaluation (Patients without scarring)• Two doses to be tested (MTD and one dose below)• Five patients per cohort• Patients enrolled to show safety, biological activity,

possible efficacy

14

Retinostat Trial

Cohort Dose level # of Patients Volume

1 1 3 300 µl

2 2 3 300 µl

3 3 3 300 µl

4 MTD 9 300 µl

Key information to be gained

MTD

Can vector cause reduction in amount of fluid within and under retina- measured by OCT?

Level and duration of transgene product expression- measured in aqueous humor.

Intravitreous vs subretinal injections

Advantages of Gene Transfer in NVAMD

1) OCT provides a good quantitative outcome measure that allows us to assess biological activity even with poor visual potential

2) We know what a good outcome should look like

3) Secreted transgenes allow us to measure expression level over time- we should learn what levels are needed and if they are maintained long term.

Phase III Study Design and Endpoints

0

2

4

6

8

10

12

0 4 8 12 16 20 24 28 32 36 40 44 48 52

ET

DR

S l

ett

ers

VIEW 1VIEW 1

0

2

4

6

8

10

12

14

0 4 8 12 16 20 24 28 32 36 40 44 48 52

RQ4 2q4 0.5q4 2q8

ET

DR

S l

ette

rs

10.9 2q4

6.9 0.5q47.9 2q8

8.1 Rq4

Week

Phase III Study Design

Visits q4wks- BCVA, eye exam, SD-OCTPrimary Endpoint 52 weeks

Group 1 Injection of vector dose 1 at baseline f/u visits- injection of RBZ if intraretinal or subretinal fluidGroup 2

Injection of vector dose 2 at baselinef/u visits- injection of RBZ if intraretinal or subretinal fluid

Group 3Injection of RBZ at baselinef/u visits- injection of RBZ if intraretinal or subretinal fluid

Group 4Injection of RBZ at baselinef/u visits- injection of RBZ q visit

Phase III Endpoints

Mean change in BCVA from baselineNumber of injections of RBZ

Need non-inferiority regarding BCVANeed superiority regarding # of injections of

RBZ

Secondary endpointsIntraretinal and subretinal fluid by OCTSize of active NV lesion by FA

Targeted Delivery

Secreted transgene products so not necessary to deliver to diseased cell type

However must target cells that are capable of robust and prolonged expression

Vector, promoter, and route of injection are important

AAV2

Subretinal injectionTransduction of retinal pigmented epithelium (RPE) and photoreceptors

RPE-specific promoters can be used to exclude photoreceptors and other cells

Very consistent among species including primates

Intravitreous injectionGanglion cells, but differences among species

Lentiviral vectors

Subretinal injection

Transduction of retinal pigmented epithelium (RPE) and photoreceptors

RPE-specific promoters can be used to exclude photoreceptors and other cells

Very consistent among species including primates

Repeat Administration

Long term expression after intraocular injection of AAV or lentiviral vectors in animals

Determination of duration of expression in man is major objective of early phase trials

Fluocinolone Acetonide levels in the aqueous after single injection of sustained delivery pellet

0 100 200 300 4000

1

2

3

4

5

Low Dose

High Dose

Time (Days)

FA

(n

g/m

l

SE

M)

Repeat Administration

Treatment of fellow eye with gene transfer

Since other treatments exist, not an urgent need

Subretinal injection route has theoretical advantages

Gene Delivery for NVAMDConclusions

Early phase trials will provide valuable information relevant to all ocular gene therapyLevel and duration of expression with various vectors and routes of administrationQuantitative endpoints (OCT) allow assessment of biological activity even in small trials and even when visual potential is limited

Incorporating reduced injection burden into primary endpoint for phase III trials would be a major benefit