LUCENTIS™ (ranibizumab injection) 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). Ranibizumab has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.
LUCENTIS is a sterile, colorless to pale yellow solution in a single‑use glass vial. LUCENTIS is supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL LUCENTIS aqueous solution with 10 mM histidine HCl, 10% α,α‑trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
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 is thought to contribute to the progression of the neovascular form of age‑related macular degeneration (AMD). 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.
Neovascular AMD is associated with foveal retinal thickening as assessed by optical coherence tomography (OCT) and leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography.
In Study 3, foveal retinal thickness was assessed by OCT in 118/184 patients. OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with LUCENTIS, foveal retinal thickness decreased, on average, more than the sham group from baseline through Month 12. Retinal thickness decreased by Month 1 and decreased further at Month 3, on average. Foveal retinal thickness data did not provide information useful in influencing treatment decisions [see Clinical Studies].
In patients treated with LUCENTIS, the area of vascular leakage, on average, decreased by Month 3 as assessed by fluorescein angiography. The area of vascular leakage for an individual patient was not correlated with visual acuity.
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 vitreous concentration. In these animal studies, systemic exposure of ranibizumab is 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 1.0 mg/eye. Based on a population pharmacokinetic analysis, 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or mutagenicity data are available for ranibizumab injection in animals or humans.
No studies on the effects of ranibizumab on fertility have been conducted.
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.
Study 1 and Study 2
In Study 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 1 received a mean of 22 total treaments out of a possible 24 from Day 0 to Month 24.
In Study 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 12. Patients treated with LUCENTIS in Study 2 received a mean of 12 total treatments out of a possible 13 from Day 0 through Month 12.
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. 34%–40% of LUCENTIS‑treated patients 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 the tables below.
Table 3: Outcomes at Month 12 and Month 24 in Study 1
Difference Adjusted estimate based on the stratified model.
| Loss of<15 letters in visual acuity (%)
||Month 12||62%||95%||32% (26%, 39%)|
|Month 24||53%||90%||37% (29%, 44%)|
|Gain of≥15 letters in visual acuity (%)||Month 12||5%||34%||29% (22%, 35%)|
|Month 24||4%||33%||29% (23%, 35%)|
| Mean change in visual acuity(letters) (SD)||Month 12||–10.5 (16.6)||+7.2 (14.4)||17.5 (14.8, 20.2)|
|Month 24||–14.9 (18.7)||+6.6 (16.5)||21.1 (18.1, 24.2)|
Table 4: Outcomes at Month 12 in Study 2
|Outcome Measure||Verteporfin PDT|
Difference Adjusted estimate based on the stratified model.
|Loss of <15 letters in visual acuity (%)
||64%||96%||33% (25%, 41%)|
|Gain of ≥15 letters in visual acuity (%) ||6%||40%||35% (26%, 44%)|
|Mean change in visual acuity(letters) (SD) ||–9.5 (16.4)||+11.3 (14.6)||21.1 (17.5, 24.6)|
Figure 1: Mean Change in Visual Acuity from Baseline to Month 24 in Study 1 and to Month 12 in Study 2
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 DA for LUCENTIS versus 2.3–2.6 DA for the control arms
The use of LUCENTIS beyond 24 months has not been studied.
Study 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. 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 3 received a mean of 6 total treatments out of possible 6 from Day 0 through Month 12.
In Study 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 three months with LUCENTIS lost visual acuity, returning to baseline at Month 12. In Study 3, almost all LUCENTIS treated patients (90%) maintained their visual acuity at Month 12.
Figure 2: Mean Change in Visual Acuity from Baseline to Month 12 in Study 3
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