AAO Media Briefing ABDHISH R. BHAVSAR, M.D. Chair 1 AMD Trials and Treatments: An Evolving Landscape.

AAO Media BriefingAAO Media Briefing

ABDHISH R. BHAVSAR, M.D.Chair

1

AMD Trials and Treatments:An Evolving Landscape

2

Financial DisclosuresFinancial Disclosures Abdhish R. Bhavsar, MD Research support - clinical trials: DRCR, Regeneron,

Genentech

3

AgendaAgenda Abdhish R. Bhavsar, MD: Welcome/Introductions Pravin Dugel, MD: Fovista 2b clinical trial results

• Q/A

Abdhish R. Bhavsar, MD: Update CATT and Eylea Susan Bressler, MD: Cataract sugery/AMD - no inc risk Paul Mitchell, MD: Cataract surgery/AMD – inc risk Edwin Stone, MD: Update on genetic testing for AMD Media Q & A

• This study does include research conducted on human subjects

• IRB approval has been obtained for each of the studies discussed.

Study Disclosures

V 2.0; Oct 2012

VIEW 1 Integrated

Investigation of Efficacy and Safety of Intravitreal Aflibercept Injection in Wet Age-Related Macular Degeneration (AMD)

Investigation of Efficacy and Safety of Intravitreal Aflibercept Injection in Wet Age-Related Macular Degeneration (AMD)

ABDHISH R. BHAVSAR, MD

7

8

Dosing through Week 52Modified quarterly dosing

through Week 96

Multi-center, active controlled, double masked trial

VIEW 1 N=1217; VIEW 2 N=1240

0.5 mg q4 wks2 mg q4 wks 0.5 mg q4 wks

Patients randomized 1:1:1:1

Primary endpoint: Maintenance of Vision

Secondary endpoint: Mean change in BCVA

Intravitreal Aflibercept

Ranibizumab

2 mg q8 wks

*After 3 initial monthly doses

Study DesignStudy Design

Study EndpointsStudy Endpoints

• Proportion of patients who maintained BCVA (%) (losing <15 ETDRS letters from baseline)

• Mean change in BCVA as measured by ETDRS letter score from baseline

• Proportion of patients who gained at least 15 letters of BCVA from baseline

• Central Retinal Thickness

PRIMARYENDPOINT

KEYSECONDARYENDPOINTS

BCVA: Best-Corrected Visual AcuityETDRS: Early Treatment Diabetic Retinopathy Study

V 2.0; Oct 2012

ResultsWeek 52ResultsWeek 52

VIEW 1 Integrated

16

17

18

20

V 2.0; Oct 2012

ResultsWeek 52 – Week 96ResultsWeek 52 – Week 96

VIEW 1 Integrated

Treatment ScheduleTreatment Schedule

Solid = InjectionOutline = ShamHatched = Modified Quarterly Dosing

Re-treatment Criteria –• 12 weeks since previous injection• New or persistent fluid on OCT • Increase in CRT of ≥100 μm compared to the lowest previous value • Loss of ≥5 ETDRS letters from the best previous score in

conjunction with recurrent fluid on OCT• New onset classic neovascularization• New or persistent leak on FA• New macular hemorrhage

V 2.0; Oct 2012

SafetySafetyVIEW 1 Integrated

41

SummarySummary Aflibercept noninferior to ranibizumab Safety and efficacy was similar amongst the

treatment groups

46

Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS

Comparison of AMD Treatments Trials (CATT): Two Year ResultsComparison of AMD Treatments Trials (CATT): Two Year Results

Abdhish R. Bhavsar, MDfor the Comparison of AMD Treatments Trials

(CATT) Research Group

Abdhish R. Bhavsar, MDfor the Comparison of AMD Treatments Trials

(CATT) Research Group

ObjectivesObjectives

To determine the relative efficacy and safety of intravitreal ranibizumab and bevacizumab for treatment of neovascular AMD

To determine if less than monthly dosing of either drug compromises long term visual outcomes

- Designed as two-year study with primary outcome at one year

47

CATT Clinical SitesCATT Clinical Sites

48

1185 patients with neovascular AMD enrolled at 43 sites in the United States

Enrollment Criteria More Inclusive than Previous AMD Trials

Enrollment Criteria More Inclusive than Previous AMD Trials

CNV not required to be subfoveal as long as center involved by some component such as SRF, PED, or blood.

Allowed RAP lesions, juxtafoveal, and extrafoveal CNV

Allowed eyes with VA 20/25-20/320 No limit on size of lesion

49

Enrollment Criteria More Inclusive than Previous AMD Trials

Enrollment Criteria More Inclusive than Previous AMD Trials

Allowed eyes with >50% blood. All other entry criteria had to be met (VA 20/320 or better and can identify CNV on FA and fluid on OCT)

5050

CATT TreatmentCATT Treatment

51

(Months)

ranibizumabMonthly

0 1 2 3 4 5 6 7 8 9 10 11 12

bevacizumabMonthly

ranibizumabPRNbevacizumabPRN

Finalvisit

PrimaryEndpoint

Retreat if fluid on OCT orother signs of active CNV

13 14 15 16 17 18 19 20 21 22 23 24

Year 1 Year 2

}

Treatment in PRN ArmsTreatment in PRN Arms

52

Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.

May also treat if there is other evidence of CNV activity New subretinal or intraretinal hemorrhage Leakage or increased lesion size on FA Unexplained decrease in visual acuity with no

obvious atrophy or subretinal fibrosis. No retinal thickness threshold (100 microns) as

used in many neovascular AMD treatment studies.

Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.

May also treat if there is other evidence of CNV activity New subretinal or intraretinal hemorrhage Leakage or increased lesion size on FA Unexplained decrease in visual acuity with no

obvious atrophy or subretinal fibrosis. No retinal thickness threshold (100 microns) as

used in many neovascular AMD treatment studies.

CATT Study DrugsCATT Study Drugs

Ranibizumab supplied locallysimilar to patients outside of the study

Bevacizumab supplied by CATT repackaged in glass vials under IND

Mean Change in Visual AcuityMean Change in Visual Acuity

54

All Groups

All GroupsMean Change in Total Retinal Thickness Over Time

57

Percent with No Fluid at 1 Year

43.7%

26.0% 23.9%19.2%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pe

rce

nta

ge

of

Pa

tie

nts

Lucentis Monthly (n=284)

Avastin Monthly (n=265)

Lucentis PRN (n=285)

Avastin PRN (n=271) P < 0.001

Year 1 Adverse EventsYear 1 Adverse Events No difference between drugs in rates of death,

stroke, or myocardial infarction Imbalance in total SAE’s (mostly hospitalizations):

24% bevacizumab vs 19% ranibizumab (p=0.04) SAEs broadly distributed across all organ systems

with differences present in areas not previously identified as areas of concern in systemic bevacizumab trials.

58

Questions at End of Year 1Questions at End of Year 1 Would ranibizumab and bevacizumab remain

equivalent for visual acuity in Year 2? Would wider visual acuity differences emerge

between monthly and PRN dosing in Year 2? Would the fluid differences between treatments

noted in year 1 impact visual acuity with longer follow-up?

Would switching to PRN dosing after one year of monthly treatment maintain or adversely effect vision?

Would important safety differences emerge with longer follow-up?

59

Two Year ResultsTwo Year Results

60

PatientsPatients 1107 patients alive who continued in Year 2 All available monthly treated patients in

Year 1 (n=549) were successfully randomized to monthly or PRN treatment in Year 2

Masking remained robust in Year 2 with identity of assigned drug known to ophthalmologist in only 66 of 12,645 evaluations (11 patients) 62

Visual Acuity ResultsSame Regimen for Two Years

Visual Acuity ResultsSame Regimen for Two Years

64

Mean Change in Visual AcuityMean Change in Visual AcuitySame Regimen for Two years

Patients Without 15 Letter DecreaseSame Regimen for 2 Years

Patients Without 15 Letter DecreaseSame Regimen for 2 Years

66

Anatomical ResultsSame Regimen for Two Years

Anatomical ResultsSame Regimen for Two Years

69

71

Percent with No Fluid on OCTSame Regimen for 2 Years

Typical Amount of Residual FluidTypical Amount of Residual Fluid

72

73

Percent with Geographic AtrophySame Regimen for 2 Years

Effect of Switching to PRN after One Year of Monthly Dosing

Effect of Switching to PRN after One Year of Monthly Dosing

77

Mean Change in Visual Acuity after Week 52Mean Change in Visual Acuity after Week 52Monthly Always and Switched to PRN

81

Percent with No Fluid on OCTMonthly Always and Switched to PRN

82

Percent with Geographic AtrophyMonthly Always and Switched to PRN

Adverse EventsAdverse Events

89

Death and APTC EventsDeath and APTC Events

90

ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI P

Death 32 (5.3%) 36 (6.1%) 0.8% (-1.9%, 3.5%) 0.62

APTC* 28 (4.7%) 29 (5.0%) 0.3% (-2.2%, 2.8%) 0.89

*Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths

ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI P

Death 32 (5.3%) 36 (6.1%) 0.8% (-1.9%, 3.5%) 0.62

APTC* 28 (4.7%) 29 (5.0%) 0.3% (-2.2%, 2.8%) 0.89

*Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths

Cumulative Proportion with a Systemic Serious Adverse Event

Cumulative Proportion with a Systemic Serious Adverse Event

91

Any Systemic Serious Adverse EventAny Systemic Serious Adverse Event

92

Drug Difference 95% CI P

Unadjusted 2-year rates ranibizumab 190 /599 (31.7%) bevacizumab 234 /586 (39.9%) 8.2% (2.8%, 13.6%) 0.004

Adjusted Risk Ratio 1.30 (1.07, 1.57) 0.009

Regimen

Unadjusted 2-year rates* Monthly 199 /587 (33.9%) PRN 225 /598 (37.6%) 3.7% (-1.7%, 9.1%) 0.18

Adjusted Risk Ratio§ 1.20 (0.98, 1.47) 0.08

*Regimen as originally assigned§PRN a time dependent covariate in Cox model

Drug Difference 95% CI P

Unadjusted 2-year rates ranibizumab 190 /599 (31.7%) bevacizumab 234 /586 (39.9%) 8.2% (2.8%, 13.6%) 0.004

Adjusted Risk Ratio 1.30 (1.07, 1.57) 0.009

Regimen

Unadjusted 2-year rates* Monthly 199 /587 (33.9%) PRN 225 /598 (37.6%) 3.7% (-1.7%, 9.1%) 0.18

Adjusted Risk Ratio§ 1.20 (0.98, 1.47) 0.08

*Regimen as originally assigned§PRN a time dependent covariate in Cox model

Systemic Serious Adverse EventsSystemic Serious Adverse Events

93

ranibizumab bevacizumab (N=599) (N=586) Difference (95% CI) P

Associatedw/ Anti-VEGF* Yes 45 ( 7.5%) 62 ( 10.6%) 3.1% (-0.2%, 6.4%) 0.07

No 170 (28.4%) 202 (34.5%) 6.1% (0.8%,11.3%) 0.02

* Arteriothrombotic events (myocardial infarction, stroke), systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension, vascular death.

ranibizumab bevacizumab (N=599) (N=586) Difference (95% CI) P

Associatedw/ Anti-VEGF* Yes 45 ( 7.5%) 62 ( 10.6%) 3.1% (-0.2%, 6.4%) 0.07

No 170 (28.4%) 202 (34.5%) 6.1% (0.8%,11.3%) 0.02

* Arteriothrombotic events (myocardial infarction, stroke), systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension, vascular death.

Ocular Adverse EventsOcular Adverse Events Endophthalmitis – 0.06% (11 /18,509 injections)

- 11 cases (4 ranibizumab, 7 bevacizumab)- 10 of 11 cases in monthly treatment group; PRN case had received 22 injections

Pseudo-endophthalmitis

Ocular HTN or Glaucoma

94

ranibizumab 1 bevacizumab - 1

ranibizumab - 15 bevacizumab - 14

2-Year Drug Cost Per Patient2-Year Drug Cost Per Patient

Lucentis Monthly

Avastin Monthly

Lucentis PRN Avastin PRN0

5,00010,00015,00020,00025,00030,00035,00040,00045,00050,000

Dollars

95

SummarySummary Ranibizumab and bevacizumab were equivalent for visual acuity at

all time points over a 2-year period. PRN treatment resulted in less gain in visual acuity (-2.4 letters) at

2 years but vision for all groups was similar at end of 2 years. PRN dosing resulted in mean of 10 fewer injections over 2 years

than monthly dosing. Bevacizumab patients received mean 1.5 more injections than ranibizumab.

More eyes were completely dry on OCT with monthly dosing with the highest rate in eyes receiving ranibizumab monthly.

More eyes developed geographic atrophy with monthly dosing with the highest rate in eyes receiving ranibizumab monthly.

97

SummarySummary

PRN groups had more leakage on FA and more lesion growth than monthly groups.

Switching to PRN after one year of monthly treatment produced visual and anatomical results that were similar to PRN-always.

There were no differences between drugs in rates of death or arteriothrombotic events.

Bevacizumab treated patients had higher rates of systemic SAEs than ranibizumab treated patients.

The reason for this difference remains unclear given the lack of specificity to conditions associated with inhibition of VEGF. 98

110

FutureFuture Improved drug delivery systems Treatments for non-exudative AMD Targeted treatments with combinations of drugs Better prevention strategies

111

Additional QuestionsAdditional Questions Mary Wade, Academy Science and International PR

Manager [email protected] Cell: 510-725-5677

112

Thank You!Thank You!