The First FDA-approved Anti-VEGF for Diabetic Retinopathy (DR) With or Without DME7

Significant regression in diabetic retinopathy

LUCENTIS is indicated for the treatment of patients with diabetic retinopathy and for treatment of patients with diabetic macular edema (DME).

RISE & RIDE study design8,9

RISE and RIDE (N=759) were 2 methodologically identical, randomized, double-masked, sham injection–controlled, Phase III pivotal trials that studied the efficacy and safety of LUCENTIS 0.3 mg and 0.5 mg administered monthly to patients with DR and DME at baseline. The mean age was 62 years (range: 21–91). The primary outcome was the proportion of patients gaining ≥15 letters at 2 years. Following 3 years of study participation, patients could enroll in an open-label extension study. 

LUCENTIS 0.3 mg is recommended to be administered by intravitreal injection once a month (~28 days).7

DME STATUS AT BASELINE8

RISE & RIDE patient population: 100% of patients had DME at baseline; DR severity at baseline ranged from absent to high-risk PDR

DR SEVERITY AT BASELINE1

RISE & RIDE patient population: 100% of patients had DME at baseline; DR severity at baseline ranged from absent to high-risk PDR
OVER 80% OF PATIENTS
COMPLETED RISE & RIDE AT 2 YEARS9

≥2- AND ≥3-STEP ETDRS-DRSS IMPROVEMENTS AT 2 YEARS7

RISE & RIDE: Vision gains through 2 years, sustained at 3 years

Estimated differences (95% CI)7:

  • ≥2-step: 31% (21%, 40%) in RISE and 35% (26%, 44%) in RIDE
    • P<0.05 for all time points comparing LUCENTIS 0.3 mg to sham from month 3 through month 24 
  • ≥3-step: 9% (4%, 14%) in RISE and 15% (7%, 22%) in RIDE 
    • P<0.05 for all time points comparing LUCENTIS 0.3 mg to sham from month 12 through month 24

VISION IMPROVEMENT IN RISE & RIDE4,7,8

Vision gains through 2 years, sustained at 3 years

Primary end point: Proportion of patients gaining ≥15 letters at 2 years.9

RISE & RIDE: Vision gains through 2 years, sustained at 3 years

OPEN-LABEL EXTENSION (OLE): 36 THROUGH 48 MONTHS

4.5 mean injections for the total study during OLE (n=298).10

~20% of patients maintained vision with no further injections through year 4, following 3 years of therapy (n=58).7

  • ETDRS, Early Treatment Diabetic Retinopathy Scale; ETDRS-DRSS, Early Treatment Diabetic Retinopathy Scale Diabetic Retinopathy Severity Score; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; VA, visual acuity; VEGF, vascular endothelial growth factor.
  • *At least 12 months of follow-up. Crossover to LUCENTIS (0.5 mg) was optional.
  • P<0.01 for all time points comparing LUCENTIS 0.3 mg vs sham through 2 years.7

Protocol S7,11

A randomized, active-controlled study that evaluated LUCENTIS 0.5 mg vs panretinal photocoagulation (PRP) in DR patients with and without DME. The mean age was 51 years (range: 20–83). Baseline ETDRS-DRSS ranged from 20 to 85. The primary outcome was mean change in visual acuity letter score from baseline to 2 years.

  • All eyes in the LUCENTIS group (n=191) received a baseline 0.5 mg intravitreal injection followed by 3 monthly injections. Further treatments were guided by prespecified retreatment criteria. FDA approval was based on an analysis of the LUCENTIS arm of Protocol S

  • All eyes in the PRP group (n=203) received initial PRP. After completion of PRP, 45% received additional PRP—median time from baseline to additional PRP was approximately 7 months. Of patients in the PRP group, 53% (n=90) received LUCENTIS treatment during the study (35% from baseline [n=72]). Initiation and retreatment with LUCENTIS for DME was at investigator discretion11

Efficacy and safety data for DR were derived from RISE, RIDE, and Protocol S.7

LUCENTIS 0.3 mg is recommended to be administered by intravitreal injection once a month (~28 days).7

DR STATUS AT BASELINE7

Protocol S patient population: 78% of patients had DR, and 22% had DR with DME. Disease severity ranged from very mild NPDR to high-risk PDR.

DR SEVERITY AT BASELINE11

Protocol S patient population: 78% of patients had DR, and 22% had DR with DME. Disease severity ranged from very mild NPDR to high-risk PDR.
~90% OF PATIENTS COMPLETED 2 YEARS OF PROTOCOL S
IN THE LUCENTIS ARM (EXCLUDING 10 DEATHS)11

≥2- AND ≥3-STEP ETDRS-DRSS IMPROVEMENTS AT 2 YEARS7

LUCENTIS 0.5 mg WITH DME (n=41) improvements over time
LUCENTIS 0.5 mg WITH DME (n=41) improvements over time

Error bars represent 95% confidence intervals.

Estimated differences (95% CI) for percentage at 2 years7:

  • ≥2-step: 58.5% (43.5%, 73.6%) for eyes with baseline DME and 37.8% (30%, 45.7%) for eyes without baseline DME
  • ≥3-step: 31.7% (17.5%, 46%) for eyes with baseline DME and 28.4% (21.1%, 35.6%) for eyes without baseline DME

OVERALL, 48% OF ALL EYES
TREATED WITH LUCENTIS IMPROVED BY ≥2 STEPS7

CHANGES IN VISUAL ACUITY OVER TIME11

All eyes in the LUCENTIS group (n=191) received a baseline 0.5 mg intravitreal injection followed by 3 monthly injections. Further treatments were guided by prespecified retreatment criteria.

LUCENTIS 0.3 mg is recommended to be administered by intravitreal injection once a month (~28 days).7

Primary outcome: Mean change in visual acuity letter score from baseline to 2 years.

OVERALL COHORT (n=191)11

CHANGES IN VISUAL ACUITY OVER TIME: OVERALL COHORT (n=191), +2.8 ETDRS letters at 2 years

Error bars represent 95% confidence intervals.

LUCENTIS MET THE PRIMARY OUTCOME
FOR VA CHANGE FROM BASELINE AT 2 YEARS11

In line with the overall cohort, a prespecified subgroup analysis evaluated VA change in patients with and without baseline DME. Protocol S subgroup analyses were not powered to show differences between subgroups.11

EYES WITHOUT BASELINE DME (n=148)11

Changes in visual acuity over time: eyes without baseline DME (n=148) at 2 years

EYES WITH BASELINE DME (n=41)11

Changes in visual acuity over time: eyes with baseline DME (n=41) at 2 years

Error bars represent 95% confidence intervals.

SAFETY DATA OBSERVED IN PROTOCOL S
WERE CONSISTENT WITH OTHER LUCENTIS PIVOTAL TRIALS7

CI, confidence interval.

INDICATIONS
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).

Wet age-related macular degeneration (wAMD)

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

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.

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