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Lucentis

"June 29, 2011 (San Diego) -- Lucentis, a drug used to treat people with vision problems from age-related macular degeneration, may help to restore vision among people with eye complications caused by diabetes, two studies suggest.

The"...

Lucentis

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. 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.

Pharmacodynamics

Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as assessed by optical coherence tomography (OCT) is associated with neovascular AMD, macular edema following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD.

Neovascular (Wet) Age-Related Macular Degeneration

In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with LUCENTIS, CPT decreased, on average, more than in the sham group from baseline through Month 12. CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies].

In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT reductions were observed beginning at Day 7 following the first LUCENTIS injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results [see Clinical Studies].

In patients treated with LUCENTIS, the area of CNV leakage, on average, decreased by Month 3 as assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual acuity.

Macular Edema Following Retinal Vein Occlusion

On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first LUCENTIS injection through Month 6. CPT was not evaluated as a means to guide treatment decisions [see Clinical Studies].

Diabetic Macular Edema

On average, CPT reductions were observed in Studies DME-1 and DME-2 beginning at Day 7 following the first LUCENTIS injection through Month 36. CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies].

Pharmacokinetics

In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal studies, systemic exposure of ranibizumab was more than 2000-fold lower than in the vitreous.

In patients with neovascular AMD, following monthly intravitreal administration, maximum ranibizumab serum concentrations were low (0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab concentrations in RVO and DME patients were similar to those observed in neovascular AMD patients.

Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations of 1.5 ng/mL are predicted to be reached at approximately 1 day after monthly intravitreal administration of LUCENTIS 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations.

In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status.

Clinical Studies

Unless otherwise noted, visual acuity was measured at a distance of 4 meters.

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of LUCENTIS were assessed in three randomized, double-masked, sham-or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (LUCENTIS 879, control 444) were enrolled in the three studies.

Studies AMD-1 and AMD-2

In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with LUCENTIS in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24.

In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly LUCENTIS 0.3 mg intravitreal injections and sham PDT; 2) monthly LUCENTIS 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial LUCENTIS (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with LUCENTIS in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all LUCENTIS-treated patients (approximately 95%) maintained their visual acuity. Among LUCENTIS-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in Table 3, Table 4, and Figure 1 below.

Table 3 : Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-1

Outcome Measure Month Sham
n=229
LUCENTIS 0.5 mg
n=230
Estimated Difference (95% CI)a
Loss of < 15 letters in visual acuity (%) 12 60% 91% 30% (23%, 37%)
24 56% 89% 33% (26%, 41%)
Gain of ≥ 15 letters in visual acuity (%) 12 6% 31% 25% (18%, 31%)
24 4% 30% 25% (18%, 31%)
Mean change in visual acuity (letters) (SD) 12 -11.0(17.9) +6.3 ( 14.1) 17.1 (14.2, 20.0)
24 -15.0(19.7) +5.5 ( 15.9) 20.1 (16.9, 23.4)
aAdjusted estimate based on the stratified model; p < 0.01

Table 4 :Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-2

Outcome Measure Month Sham
n=229
LUCENTIS 0.5 mg
n=230
Estimated Difference (95% CI)a
Loss of < 15 letters in visual acuity (%) 12 60% 91% 30% (23%, 37%)
24 56% 89% 33% (26%, 41%)
Gain of ≥ 15 letters in visual acuity (%) 12 6% 31% 25% (18%, 31%)
24 4% 30% 25% (18%, 31%)
Mean change in visual acuity (letters) (SD) 12 -11.0(17.9) +6.3 ( 14.1) 17.1 (14.2, 20.0)
24 -15.0(19.7) +5.5 ( 15.9) 20.1 (16.9, 23.4)
aAdjusted estimate based on the stratified model; p < 0.01

Figure 1 :Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-1 and Study AMD-2 sBLA 125156/S-094 Page 10

Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-1 and Study AMD-2 - Illustration

Visual acuity was measured at a distance of 2 meters

Patients in the group treated with LUCENTIS had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas (DA) for LUCENTIS versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for LUCENTIS versus 2.9-3.1 DA for the control arms.

Study AMD-3

Study AMD-3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months for 9 months. A total of 184 patients were enrolled in this study (LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with LUCENTIS in Study AMD-3 received a mean of 6 total treatments out of a possible 6 from Day 0 through Month 12.

In Study AMD-3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every 3 months with LUCENTIS lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all LUCENTIS-treated patients (90%) lost fewer than 15 letters of visual acuity at Month 12.

Figure 2 : Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3

Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3 - Illustration

Study AMD-4

Study AMD-4 was a randomized, double-masked, active treatment-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS 0.5 mg administered monthly or less frequently than monthly in patients with neovascular AMD. Patients randomized to the LUCENTIS 0.5 mg less frequent dosing arm received 3 monthly doses followed by monthly assessments where patients were eligible to receive LUCENTIS injections guided by pre-specified re-treatment criteria. A total of 550 patients were enrolled in the two 0.5 mg treatment groups with 467 (85%) completing through Month 24. Data are available through Month 24. Clinical results at Month 24 remain similar to that observed at Month 12.

From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm (see Figure 3). Over this 21 month period, patients in the 0.5 mg less frequent dosing and the 0.5 mg monthly arms averaged 10.3 and 18.5 injections, respectively. The distribution of injections received in the less frequent dosing arm is shown in Figure 4.

Figure 3 : Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-4

Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-4 - Illustration

Figure 4 : Distribution of Injections from Month 3 to Month 24 in the Less Frequent Dosing Arm in Study AMD-4

Distribution of Injections from Month 3 to Month 24 in the Less Frequent Dosing Arm in Study AMD-4 - Illustration

Macular Edema Following Retinal Vein Occlusion (RVO)

The safety and efficacy of LUCENTIS were assessed in two randomized, double-masked, 1-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (LUCENTIS 0.3 mg, 266 patients; LUCENTIS 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive LUCENTIS injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12.

In Study RVO-1, patients with macular edema following branch or hemi-RVO, received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 6-month treatment period. Macular focal/grid laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg LUCENTIS and 71 of 132 (54%) patients treated with sham.

In Study RVO-2, patients with macular edema following central RVO received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months.

At Month 6, after monthly treatment with 0.5 mg LUCENTIS, the following clinical results were observed:

Table 5 : Visual Acuity Outcomes at Month 6 in Study RVO-1 and Study RVO-2

Outcome Measure Studya Sham LUCENTIS 0.5 mg Estimated Difference (95% CI) b
Gain of ≥ 15 letters in visual acuity (%) RVO-1 29% 61% 31% (20%, 43%)
Gain of ≥ 15 letters in visual acuity (%) RVO-2 17% 48% 30% (20%, 41%)
aRVO-1: Sham, n=131; LUCENTIS 0.5 mg, n=132 RVO-2: Sham, n=130; LUCENTIS 0.5 mg, n=130
bAdjusted estimate based on stratified model; p < 0.01

Figure 5 : Mean Change in Visual Acuity from Baseline to Month 6 in Study RVO-1 and Study RVO-2

Mean Change in Visual Acuity from Baseline to Month 6 in Study RVO-1 and Study RVO-2 - Illustration

p < 0.01 for all time points

Diabetic Macular Edema (DME)

The safety and efficacy of LUCENTIS were assessed in two randomized, double-masked, 3-year studies in patients with DME. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (LUCENTIS 0.3 mg, 250 patients; LUCENTIS 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36.

In Studies DME-1 and DME-2, patients received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly LUCENTIS 0.5 mg and patients originally randomized to monthly LUCENTIS 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with LUCENTIS 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with LUCENTIS 0.3 mg and 30 of 257 (12%) patients treated with sham.

Compared to monthly LUCENTIS 0.3 mg, no additional benefit was observed with monthly treatment with LUCENTIS 0.5 mg. At Month 24, after monthly treatment with LUCENTIS 0.3 mg, the following clinical results were observed:

Table 6 : Visual Acuity Outcomes at Month 24 in Study DME-1 and Study DME-2

Outcome Measure Studya Sham LUCENTIS 0.3 mg Estimated Difference (95% CI)b
Gain of ≥ 15 letters in visual DME-1 12% 34% 21% (11%, 30%)
acuity (%) DME-2 18% 45% 24% (14%, 35%)
Loss of < 15 letters in visual DME-1 92% 98% 7% (2%, 13%)
acuity (%) DME-2 90% 98% 8% (2%, 14%)
Mean change in visual DME-1 2.3 10.9 8.5 (5.4, 11.5)
acuity (letters) DME-2 2.6 12.5 9.6 (6.1, 13.0)
a DME-1: Sham, n=130; LUCENTIS 0.3 mg, n=125 DME-2: Sham, n=127; LUCENTIS 0.3 mg, n=125
b Adjusted estimate based on stratified model; p ≤ 0.01

Figure 6 : Mean Change in Visual Acuity from Baseline to Month 36 in Study DME-1 and Study DME-2

Mean Change in Visual Acuity from Baseline to Month 36 in Study DME-1 and Study DME-2 - Illustration

p < 0.01 for all time points comparing LUCENTIS 0.3 mg to sham through Month 24

VA outcomes observed at Month 24 in patients treated with LUCENTIS 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received LUCENTIS 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with LUCENTIS at the beginning of the studies.

Last reviewed on RxList: 3/17/2014
This monograph has been modified to include the generic and brand name in many instances.

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