Clinical Results for Wet AMD

Studied extensively in patients with wet AMD^1-3

LUCENTIS is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (wAMD).

Side Effects

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MARINA and ANCHOR

HARBOR

VIEW 1 and 2

Safety

LUCENTIS Monthly Dosing

MARINA^1,2

Randomized, double-masked, 2-year study of LUCENTIS 0.5 mg (n=240) vs sham (n=238) in patients with minimally classic or occult CNV lesions and BCVA ≤20/320.

PRIMARY OUTCOME: 1 YEAR

% losing <15 ETDRS letters.

ANCHOR^1,3

Randomized, double-masked, 2-year study of LUCENTIS 0.5 mg (n=139) vs active control (vPDT, n=143) in patients with predominantly classic CNV lesions.

PRIMARY OUTCOME: 1 YEAR

% losing <15 ETDRS letters.

PRIMARY OUTCOMES¹

“Maintained” was defined as losing <15 ETDRS letters from baseline.

^*Adjusted estimate based on the stratified model; P<0.01.¹

Rapid & sustained vision gains^1-4
MARINA & ANCHOR: MEAN CHANGE IN BCVA FROM BASELINE

BCVA, best corrected visual acuity; CI, confidence interval; CNV, choroidal neovascularization; ETDRS, Early Treatment Diabetic Retinopathy Scale; vPDT, verteporfin photodynamic therapy.

A STUDY INCLUDING LESS-THAN-MONTHLY DOSING

The only anti-VEGF approved for PRN dosing in patients with wAMD after 3 monthly loading doses.

HARBOR^1,5,6

Randomized, double-masked, active treatment–controlled, 2-year study of LUCENTIS 0.5 mg (N=550) monthly or less frequently in patients with wAMD.

Less-frequent regimens were 3 monthly doses followed by PRN schedules guided by assessment and prespecified retreatment criteria
The patient population was similar to MARINA and ANCHOR, and patients with PEDs were included

PRIMARY OUTCOME – 1 YEAR: Mean change in BCVA from baseline at year 1 with a prespecified noninferiority comparison of LUCENTIS monthly and less-frequent dosing (margin of 4 letters).⁵

THE PRIMARY END POINT WAS NOT MET. AT YEAR 1, THE LESS-FREQUENT DOSING ARM DID NOT MEET THE NONINFERIORITY COMPARISON.⁵

PATIENTS REQUIRED DIFFERENT DOSING REGIMENS^1,6

In HARBOR, patients received 3 initial monthly doses followed by PRN dosing with regular monthly assessment through 2 years. Monthly dosing is more effective. Patients should be regularly assessed to evaluate treatment need.

9.9 Weeks: Average Treatment Interval for LUCENTIS

9.9 weeks=average treatment interval^†
^†This analysis calculated the average interval between injections for study participants after 3 initial monthly doses, and included only patients in the less-frequent dosing arm who completed 24 months of the study (n=232).⁶

Mean change in BCVA from baseline

HARBOR: 2-YEAR RESULTS⁶

Compared to the less-frequent dosing arm, patients in the monthly treatment arm gained 1 to 2 additional letters on average. After 3 initial monthly doses, patients in the less-frequent dosing arm maintained clinically meaningful VA gains through year 1 and year 2.^1,6

^‡Among patients who completed the 2-year study.

Post hoc analysis of HARBOR patients with and without PED at baseline⁷

Limitations of this analysis include that it is post hoc (ie, not prespecified). The statistical significance of these results cannot be determined, and the clinical significance of these results is unknown.

MEAN CHANGE IN BCVA FROM BASELINE AT 2 YEARS

+8.4	with PED (n=598)
+7.9	without PED (n=499)

A post hoc analysis of HARBOR examined the effect of a baseline PED on visual outcomes

At baseline, 54.5% (598/1097) of patients presented with PED
At 2 years, the number of injections was similar in patients with and without PED at baseline (14.0 vs 12.5, respectively)

PED, pigment epithelial detachment; PRN, pro re nata; VA, visual acuity; VEGF, vascular endothelial growth factor.

LUCENTIS MONTHLY DOSING

Head-to-head studies
VIEW 1 and 2 (non-Genentech-sponsored studies)^8,9

VIEW 1 & 2 were two randomized, double-masked, 96-week, active treatment–controlled studies of LUCENTIS 0.5 mg monthly vs aflibercept 2.0 mg monthly or every 8 weeks, or aflibercept 0.5 mg monthly in patients with wAMD (N=2457).

PRIMARY OUTCOME: MAINTENANCE^§ OF VISION AT 52 WEEKS

Noninferiority of aflibercept arms to LUCENTIS (margin of 10%) in the proportion of eyes maintaining vision.

^§“Maintained” was defined as losing <15 ETDRS letters from baseline.

LUCENTIS was clinically equivalent to aflibercept at year 1^8,9

PRIMARY OUTCOMES^8,9

LUCENTIS 0.5 mg was the active control in the VIEW 1 and 2 trials. Prespecified primary and secondary end points were assessed at week 52.^8,9

^||Percentages reflect a combination of aflibercept 2Q4 (2.0 mg every 4 weeks) and 2Q8 (2.0 mg every 8 weeks) treatment groups. Last observation carried forward: full analysis set.^8.9

VIEW 1 AND 2: MEAN CHANGE IN BCVA FROM BASELINE⁸

VIEW 1 STUDY

LUCENTIS wAMD View 1 & View 2 Mean Change in BCVA From Baseline

VIEW 2 STUDY

TWO STUDIES INCLUDING LESS-THAN-MONTHLY DOSING

ADDITIONAL EVIDENCE

VIEW 1 AND 2 (non-Genentech-sponsored studies)^9,10

PRIMARY OUTCOME: MAINTENANCE^¶ OF VISION AT 52 WEEKS

Comparison of aflibercept arms to LUCENTIS (margin of 10%) in the proportion of eyes maintaining vision.

^¶“Maintained” was defined as losing <15 ETDRS letters from baseline.

Exploratory analysis: less-than-monthly dosing 52 to 96 weeks^#

VIEW 1 AND 2 DOSING SCHEDULE^8,9

0-52 WEEKS	52-96 WEEKS
LUCENTIS 0.5 mg monthly (n=609)	Dosed at Least Every 12 Weeks, Additional Doses as Needed.
Aflibercept 2.0 mg every 8 weeks (n=616)
Aflibercept 2.0 mg monthly (n=617)
Aflibercept 0.5 mg monthly (n=615)
Patients continued on their initially randomized dosing through 96 weeks.

VIEW 1 AND 2 DOSING SCHEDULE^8,9

0-52 WEEKS
LUCENTIS 0.5 mg monthly (n=609)
Aflibercept 2.0 mg every 8 weeks (n=616)
Aflibercept 2.0 mg monthly (n=617)
Aflibercept 0.5 mg monthly (n=615)
52-96 WEEKS
Dosed at Least Every 12 Weeks, Additional Doses as Needed.



Patients continued on their initially randomized dosing through 96 weeks.

^#A total of 2412 patients were treated and evaluated for efficacy in VIEW 1 and VIEW 2 studies.⁹

Mean change in BCVA from baseline to 96 weeks^{9**††‡‡}

^**LUCENTIS 0.5 mg was the active control in the VIEW 1 and 2 trials for the prespecified primary and secondary end points at week 52.^9,10
^††During weeks 52-96, patients were evaluated every 4 weeks and treated at least every 12 weeks. Patient dosing schedules were individualized from weeks 52 to 96 using a modified 12-week dosing regimen.^9,10
^‡‡The primary outcome of VIEW 1 and 2 was the noninferiority of aflibercept to LUCENTIS in the proportion of patients maintaining VA at 52 weeks (losing <15 letters) with exploratory end points at week 96.^9,10

VIEW 1

VIEW 2

IN YEAR 2

4.7	Average Injections With LUCENTIS in the VIEW 1 and 2 Pooled Analysis¹⁰

Q4W, every 4 weeks; Q8W, every 8 weeks.

Select safety at 2 years in wAMD pivotal trials^§§

MOST COMMON OCULAR REACTIONS¹

ADVERSE REACTIONS		LUCENTIS 0.5 mg MONTHLY (n=379), %		CONTROL (n=379), %

Conjunctival Hemorrhage	74%	60%
Eye Pain	35%	30%
Vitreous Floaters	27%	8%
Increased Intraocular Pressure	24%	7%
Vitreous Detachment	21%	19%
Intraocular Inflammation	18%	8%

LUCENTIS 0.5 mg MONTHLY (n=379), %	CONTROL (n=379), %
ADVERSE REACTIONS

Conjunctival Hemorrhage
74%	60%
Eye Pain
35%	30%
Vitreous Floaters
27%	8%
Increased Intraocular Pressure
24%	7%
Vitreous Detachment
21%	19%
Intraocular Inflammation
18%	8%

COMMON NON-OCULAR REACTIONS¹

ADVERSE REACTIONS		LUCENTIS 0.5 mg MONTHLY (n=379), %		CONTROL (n=379), %

Nasopharyngitis	16%	13%
Headache	12%	9%
Arthralgia	11%	9%
Bronchitis	11%	9%

LUCENTIS 0.5 mg MONTHLY (n=379), %	CONTROL (n=379), %
ADVERSE REACTIONS

Nasopharyngitis
16%	13%
Headache
12%	9%
Arthralgia
11%	9%
Bronchitis
11%	9%

SERIOUS ADVERSE REACTIONS RELATED TO THE INJECTION PROCEDURE IN <0.1% OF INTRAVITREAL INJECTIONS¹

Endophthalmitis

Rhegmatogenous Detachment

Iatrogenic Traumatic Cataract

SERIOUS ADVERSE REACTIONS RELATED TO THE INJECTION PROCEDURE IN <0.1% OF INTRAVITREAL INJECTIONS¹

Endophthalmitis
Rhegmatogenous Detachment
Iatrogenic Traumatic Cataract

ANTIPLATELET TRIALISTS’ COLLABORATION (APTC)-DEFINED ATEs^2,3,6

MARINA 2-YEAR

SERIOUS ADVERSE EVENTS	LUCENTIS 0.5 mg MONTHLY (n=239), % (n)	SHAM (n=236), % (n)

APTC ATEs^\|\|\|\|	4.6% (11)	3.8% (9)
Nonfatal Myocardial Infarction (MI)	1.3% (3)	1.7% (4)
Nonfatal Stroke	2.5% (6)	0.8% (2)
Vascular Death	1.3% (3)	1.7% (4)
Death of Unknown Cause	1.3% (3)	0.8% (2)

LUCENTIS 0.5 mg MONTHLY (n=239), % (n)	SHAM (n=236), % (n)
SERIOUS ADVERSE EVENTS

APTC ATEs^\|\|\|\|
4.6% (11)	3.8% (9)
Nonfatal Myocardial Infarction (MI)
1.3% (3)	1.7% (4)
Nonfatal Stroke
2.5% (6)	0.8% (2)
Vascular Death
1.3% (3)	1.7% (4)
Death of Unknown Cause
1.3% (3)	0.8% (2)

ANCHOR 2-YEAR

SERIOUS ADVERSE EVENTS	LUCENTIS 0.5 mg MONTHLY (n=140), % (n)	VERTEPORFIN PDT (n=143), % (n)

APTC ATEs^\|\|\|\|	5.0% (7)	4.2% (6)
Nonfatal Myocardial Infarction (MI)	3.6% (5)	1.4% (2)
Nonfatal Stroke	0	1.4% (2)
Vascular Death	1.4% (2)	2.1% (3)
Death of Unknown Cause	0.7% (1)	1.4% (2)

LUCENTIS 0.5 mg MONTHLY (n=140), % (n)	VERTEPORFIN PDT (n=143), % (n)
SERIOUS ADVERSE EVENTS

APTC ATEs^\|\|\|\|
5.0% (7)	4.2% (6)
Nonfatal Myocardial Infarction (MI)
3.6% (5)	1.4% (2)
Nonfatal Stroke
0	1.4% (2)
Vascular Death
1.4% (2)	2.1% (3)
Death of Unknown Cause
0.7% (1)	1.4% (2)

HARBOR 2-YEAR

SERIOUS ADVERSE EVENTS	LUCENTIS 0.5 mg MONTHLY (n=274), % (n)	LUCENTIS 0.5 mg LESS FREQUENT (n=275), % (n)

APTC ATEs^\|\|\|\|	6.6% (18)	4.7% (13)
Nonfatal Myocardial Infarction (MI)	2.6% (7)	1.8% (5)
Nonfatal Stroke	0.7% (2)	0.4% (1)
Vascular Death	3.3% (9)	2.5% (7)
Death of Unknown Cause	0.7% (2)	0.4% (1)

LUCENTIS 0.5 mg MONTHLY (n=274), % (n)	LUCENTIS 0.5 mg LESS FREQUENT (n=275), % (n)
SERIOUS ADVERSE EVENTS

APTC ATEs^\|\|\|\|
6.6% (18)	4.7% (13)
Nonfatal Myocardial Infarction (MI)
2.6% (7)	1.8% (5)
Nonfatal Stroke
0.7% (2)	0.4% (1)
Vascular Death
3.3% (9)	2.5% (7)
Death of Unknown Cause
0.7% (2)	0.4% (1)

ATE, arterial thromboembolic event; PDT, photodynamic therapy.
^§§Data derived from LUCENTIS package insert and safety data from MARINA, ANCHOR, PIER, and HARBOR pivotal trials.
^||||APTC ATEs were defined as nonfatal myocardial infarction (MI), nonfatal stroke, vascular death, and death of unknown cause. Some patients may have experienced multiple events.²

NEXT: Peer Perspectives

INDICATIONS

Wet age-related macular degeneration (wAMD)

LUCENTIS^® (ranibizumab injection) is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (wAMD).

Diabetic retinopathy (DR)

LUCENTIS^® (ranibizumab injection) is indicated for the treatment of patients with diabetic retinopathy (DR).

Diabetic macular edema (DME)

LUCENTIS^® (ranibizumab injection) is indicated for the treatment of patients with diabetic macular edema (DME).

Macular edema following retinal vein occlusion (RVO)

LUCENTIS^® (ranibizumab injection) is indicated for the treatment of patients with macular edema following retinal vein occlusion (RVO).

Myopic choroidal neovascularization (mCNV)

LUCENTIS^® (ranibizumab injection) is indicated for the treatment of patients with myopic choroidal neovascularization (mCNV).

CONTRAINDICATIONS

LUCENTIS is contraindicated in patients with ocular or periocular infections or known hypersensitivity to ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular inflammation.

WARNINGS AND PRECAUTIONS

Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis, retinal detachment, and iatrogenic traumatic cataract. Proper aseptic injection technique should always be utilized when administering LUCENTIS. Patients should be monitored following the injection to permit early treatment, should an infection occur.

Increases in intraocular pressure (IOP) have been noted both pre-injection and post-injection (at 60 minutes) with LUCENTIS. Monitor intraocular pressure prior to and following intravitreal injection with LUCENTIS and manage appropriately.

Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LUCENTIS clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).

Neovascular (wet) age-related macular degeneration

The ATE rate in the 3 controlled neovascular AMD studies during the first year was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 of 441) in patients from the control arms. In the second year of Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the study during the first year were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3.

In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of LUCENTIS used adjunctively with verteporfin photodynamic therapy), the stroke rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in patients in the control arms (odds ratio 2.2 [95% confidence interval (0.8-7.1)]).

Macular edema following retinal vein occlusion

The ATE rate in the 2 controlled RVO studies during the first 6 months was 0.8% in both the LUCENTIS and control arms of the studies (4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS and 2 of 260 in the control arms). The stroke rate was 0.2% (1 of 525) in the combined group of LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms.

Diabetic macular edema and Diabetic Retinopathy

In a pooled analysis of Studies DME-1 and DME-2, the ATE rate at 2 years was 7.2% (18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS.

Fatal events occurred more frequently in patients with DME and DR at baseline treated monthly with LUCENTIS compared with control. A pooled analysis of Studies D-1 and D-2, showed that fatalities in the first 2 years occurred in 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250) of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 mg LUCENTIS. Although the rate of fatal events was low and included causes of death typical of patients with advanced diabetic complications, a potential relationship between these events and intravitreal use of VEGF inhibitors cannot be excluded.

ADVERSE EVENTS

Serious adverse events related to the injection procedure that occurred in <0.1% of intravitreal injections included endophthalmitis, rhegmatogenous retinal detachment, and iatrogenic traumatic cataract.

In the LUCENTIS Phase III clinical trials, the most common ocular side effects included conjunctival hemorrhage, eye pain, vitreous floaters, and increased intraocular pressure. The most common non-ocular side effects included nasopharyngitis, anemia, nausea, and cough.

As with all therapeutic proteins, there is the potential for an immune response in patients treated with LUCENTIS. The clinical significance of immunoreactivity to LUCENTIS is unclear at this time.

FOR ADDITIONAL SAFETY INFORMATION, PLEASE SEE LUCENTIS FULL PRESCRIBING INFORMATION.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

- LUCENTIS [package insert]. South San Francisco, CA: Genentech, Inc; 2018.
  
  LUCENTIS [package insert]. South San Francisco, CA: Genentech, Inc; 2018.
- Rosenfeld PJ, et al; MARINA Study Group. N Engl J Med. 2006;355:1419-1431.
  
  Rosenfeld PJ, et al; MARINA Study Group. N Engl J Med. 2006;355:1419-1431.
- Brown DM, et al; ANCHOR Study Group. Ophthalmology. 2009;116:57-65.
  
  Brown DM, et al; ANCHOR Study Group. Ophthalmology. 2009;116:57-65.
- Data on file. South San Francisco, CA: Genentech, Inc.
  
  Data on file. South San Francisco, CA: Genentech, Inc.
- Busbee BG, et al; HARBOR Study Group. Ophthalmology. 2013;120:1046-1056.
  
  Busbee BG, et al; HARBOR Study Group. Ophthalmology. 2013;120:1046-1056.
- Ho AC, et al; HARBOR Study Group. Ophthalmology. 2014;121:2181-2192.
  
  Ho AC, et al; HARBOR Study Group. Ophthalmology. 2014;121:2181-2192.
- Sarraf D, et al. Ophthalmology. 2016;123(10):2213-2224.
  
  Sarraf D, et al. Ophthalmology. 2016;123(10):2213-2224.
- Heier JS, et al; VIEW 1 and VIEW 2 Study Groups. Ophthalmology. 2012;119(12):2537-2548.
  
  Heier JS, et al; VIEW 1 and VIEW 2 Study Groups. Ophthalmology. 2012;119(12):2537-2548.
- Eylea [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2019.
  
  Eylea [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2019.
- Schmidt-Erfurth U, et al. Ophthalmology. 2014;121:193-201.
  
  Schmidt-Erfurth U, et al. Ophthalmology. 2014;121:193-201.

Clinical Results for Wet AMD

Studied extensively in patients with wet AMD1-3