Lucentis (ranibizumab) - 5 indications

Scroll down for information on each indication:

• wet Age-Related Macular Degeneration; approved June 2006
• macular edema following Retinal Vein Occlusion; approved June 2010
• diabetic macular edema; approved August 2012
• diabetic retinopathy in patients with Diabetic Macular Edema; approved February 2015
• all forms of diabetic retinopathy; approved April of 2017
• myopic choroidal neovascularization; approved January 2017

General Information

Lucentis (ranibizumab) is a therapeutic antibody fragment designed to inhibit vascular endothelial growth factor A (VEGF-A), a protein that plays a critical role in ocular angiogenesis. Blocking VEGF-A can decrease abnormal new blood vessel formation and the resultant leaking of serum into the retina.

Lucentis is specifically indicated for the following conditions:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
• Macular Edema Following Retinal Vein Occlusion (RVO)
• Diabetic Macular Edema (DME)
• Diabetic Retinopathy (DR)
• Myopic Choroidal Neovascularization (mCNV)

Lucentis is supplied as a solution for intravitreal injection. Scroll down to see the recommended dosing/administration for each condition.

Mechanism of Action

Lucentis (ranibizumab) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, macular edema following RVO, and DME. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Side Effects

Adverse events associated with the use of Lucentis may include, but are not limited to, the following:

• conjunctival hemorrhage
• eye pain
• vitreous floaters
• increased IOP

Indication 1 - wet Age-Related Macular Degeneration

approved June 2006

Dosing/Administration

Lucentis 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. In the 9 months after three initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly. Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly.

Clinical Trial Results

Approval was based on three controlled clinical trials, which enrolled a total of 1323 subjects.

Studies 1 & 2
These randomized, double-masked, sham- or active-controlled studies enrolled patients with minimally classic or occult (Study 1) or predominantly classic (Study 2) choroidal neovascularization (CNV) associated with wet AMD. In Study 1, subjects received monthly injections of either 0.3 mg or 0.5 mg Lucentis or sham placebo monthly for 24 months. In Study 2, patients received 0.3 mg or 0.5 mg Lucentis monthly plus sham photodynamic therapy (PDT), or monthly sham placebo injections plus active verteporfin PDT for 12 months. Sham or active PDT regimens were administered on with the first injection, then every three months if flourescein angiography revealed persistent or recurrent leakage. The primary efficacy for both studies was maintained visual acuity (loss of <15 letters) at 12 months: trial data met this endpoint for the 0.5 mg dose in both Study 1 (95%, vs. 62% for sham injection) and Study 2 (96% vs. 64% for verteporfin PDT). Both trials also demonstrated significant efficacy in a pair of secondary endpoints: the portion of subjects gaining at least 15 letters of acuity (Study 1: 34% vs. 5%; Study 2: 40% vs. 6%); and mean change in visual acuity (Study 1: +7.2 letters, vs. -10.5 letters; Study 2: +11.3 letters, vs. -9.5 letters). Study 1 showed maintained efficacy through 24 months in the primary (90% vs. 53%) and both secondary endpoints (33% vs. 4%; +6.6 letters vs. -14.9 letters).

Study 3
This randomized, double-masked, sham-controlled study enrolled 184 patients with wet AMD with or without classic CNV, who received 0.3 mg or 0.5 mg Lucentis of sham placebo monthly for 3 months, followed by injections every 3 months through 12 months. Primary efficacy, measured by mean change in visual acuity, indicated that the 3 monthly doses of Lucentis produced improvements in visual acuity; once dosing was transferred to once-every-three-month dosing, visual acuity returned to baseline values, but were maintained without significant worsening, compared to a loss of acuity for sham placebo at 12 months (-0.2 letters vs. -16.3 letters). Almost 90% of subjects maintained their visual acuity.

Indication 2 - macular edema following Retinal Vein Occlusion

approved June 2010

Dosing/Administration

Lucentis 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

Clinical Trial Results

FDA approval was based on two clinical studies, the BRAVO study and the CRUISE study. The BRAVO study assessed the safety and efficacy profile of Lucentis in a total of 397 patients with macular edema following branch-RVO. The CRUISE study assessed the safety and efficacy profile of Lucentis in a total of 392 patients with macular edema following central-RVO. During the first six-month period, patients in both trials received monthly injections of either 0.3 mg or 0.5 mg of Lucentis (n=527) or monthly sham injections (n=262). The primary endpoint of both studies was mean change from baseline in best-corrected visual acuity (BCVA) at six months compared with patients receiving sham injections. The studies were not designed to compare the two doses of Lucentis.

In the BRAVO study, the percentage of patients in the Lucentis 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month six was 61 percent (compared with 29 percent in the sham injection arm). In the CRUISE study, the percentage of patients in the Lucentis 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month six was 48 percent (compared with 17 percent in the sham injection arm). At month six, patients in BRAVO who received 0.5 mg of Lucentis had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections). In the CRUISE study, at month six, patients who received 0.5 mg of Lucentis had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).

Indication 3 - diabetic macular edema

approved August 2012

Dosing/Administration

Lucentis 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days)

Clinical Trial Results

The FDA approval of Lucentis for diabetic macular edema was based on two randomized, double-masked, three-year studies, DME1 and DME2. A total of 759 subjects were enrolled and received Lucentis 0.3 mg (n=250); Lucentis 0.5 mg (n=252) or placebo (n=257); 582 (77%) subjects completed through Month 36. The studies were placebo controlled through Month 24. From Months 25 through 36, subjects who previously received placebo were eligible to receive monthly Lucentis 0.5 mg and subjects originally randomized to monthly Lucentis 0.3 mg or 0.5 mg continued to receive their assigned dose. The study was not designed to compare the two doses of Lucentis, but each dose against the control group. Compared to monthly Lucentis 0.3 mg, no additional benefit was observed with monthly treatment with Lucentis 0.5 mg. The data are from the 0.3 mg arm and were measured at Month 24. The results are as follows:
DME1
Gain of >15 letters in visual acuity: Lucentis 34%; placebo 12%
Loss of <15 letters in visual acuity: Lucentis 98%; placebo 92%
Mean change in visual acuity (letters): Lucentis 10.9; placebo 2.3
DME2
Gain of >15 letters in visual acuity: Luncentis 45%; placebo 18%
Loss of <15 letters in visual acuity: Lucentis 98%; placebo 90%
Mean change in visual acuity (letters): Lucentis 12.5; placebo 2.6

Visual acuity outcomes observed at Month 24 in subjects treated with Lucentis 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Subjects in the placebo arms who received Lucentis 0.5 mg beginning at Month 25 achieved lesser visual acuity gains compared to subjects who began treatment with Lucentis at the beginning of the studies.

Indication 4 - diabetic retinopathy

initially approved February 2015

Dosing/Administration

Lucentis 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days)

Clinical Trial Results

FDA approval was based on The Diabetic Retinopathy Clinical Research Network’s Protocol S study, a randomized, active-controlled study comparing Lucentis to panretinal or scatter photocoagulation (PRP) laser therapy in 305 patients with proliferative diabetic retinopathy, including those with and without diabetic macular edema (DME). In the Lucentis group, patients received a baseline 0.5 mg intravitreal injection followed by three monthly intravitreal injections, after which treatment was guided by pre-specified re-treatment criteria.

Data showed that 37.8 percent (n=56/148) of patients in the Lucentis group without baseline DME had a two-step or better improvement in their diabetic retinopathy and 28.4 percent (n=42/148) had a three-step or better improvement at two years, according to the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS). In Lucentis-treated patients with baseline DME, 58.5 percent (n=24/41) had a two-step or better improvement in their diabetic retinopathy and 31.7 percent (n=13/41) had a three-step or better improvement at two years. Adverse events were similar to those seen in other Lucentis trials.

Indication 5 - myopic choroidal neovascularization

approved January 2017

Dosing/Administration

Lucentis 0.5 mg (0.05 mL of 10 mg/mL Lucentis solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to 3 months. Patients may be retreated if needed.

Clinical Trial Results

FDA approval was based on results of the Phase III RADIANCE study. The randomized, double-masked, active-controlled study compared the efficacy and safety of Lucentis (0.5 mg) versus verteporfin photodynamic therapy (vPDT) in 276 patients with visual impairment due to myopic choroidal neovascularization (mCNV). Patients were randomized into three treatment groups: two groups of patients randomized to Lucentis received injections guided by pre-specified retreatment criteria and the third group received treatment with vPDT. At month 3, the Lucentis groups I and II had a mean change in best-corrected visual acuity (BCVA) of +12.1 and +12.5 letters from baseline, respectively, demonstrating a statistically significant improvement over the vPDT group III, which had a mean BCVA change of +1.4 letters from baseline.