Lucentis (ranibizumab) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular administration. The drug is designed to inhibit macular angiogenesis, the growth of new blood vessels in the eye, which can rupture and cause vision loss.

Lucentis is specifically indicated for the treatment of neovascular ("wet") age-related macular degeneration (AMD).

Lucentis is supplied as a clear, colorless to pale yellow liquid for intravitreal injection. The recommended initial dosing is 0.5 mg once monthly. If monthly dosing is infeasible, administration may be reduced to one injection every three months for the first four injections, though this dose has been shown to be less efficacious in clinical trials.

FDA Approval
Approval of Lucentis 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; p<0.01) and Study 2 (96% vs. 64% for verteporfin PDT; p<0.01). 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%, p<0.01; Study 2: 40% vs. 6%, p<0.01); and mean change in visual acuity (Study 1: +7.2 letters, vs. -10.5 letters, p<0.01; Study 2: +11.3 letters, vs. -9.5 letters, p<0.01). Study 1 showed maintained efficacy through 24 months in the primary (90% vs. 53%, p<0.01) and both secondary endpoints (33% vs. 4%, p<0.01; +6.6 letters vs. -14.9 letters, p<0.01).

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.

Ongoing Study Commitments

• Submit the final Clinical Study Report from Study FVF3689g
  Final Report Submission: by June 30, 2008
• Provide safety and efficacy data from a 2-year adequate and well-controlled clinical trial of a mutually acceptable design exploring multiple dosing frequencies of Lucentis.
  Date of Submission of Protocol: November 14, 2008
  Date of Start of Study: September 21, 2009
  Date of Final Clinical Study Report: April 1, 2013
• To detect and characterize immune responses to ranibizumab:
  a. Develop and validate a confirmatory assay capable of detecting both IgG and IgM isotype responses.
  b. Develop and validate an assay to detect neutralizing anti-ranibizumab antibodies.
  Assay Methodology and Validation Reports: September 28, 2007

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

• Conjunctival Hemorrhage
• Eye Pain
• Vitreous Floaters
• Retinal Hemorrhage
• Increased Intraocular Pressure
• Hypertension
• Vitreous Detachment
• Intraocular Inflammation
• Cataract
• Sensation of Foreign Body Presence
• Lacrimation
• Nasopharyngitis
• Arthralgia
• Headache
• Bronchitis

In addition, use of Lucentis has been associated with incidence of endophthalmitis and retinal detachment. Porper sterile injection technique should be observed, and patients should be monitored for signs of infection during the week following injection.

Administration of Lucentis has also been associated with increased intraocular pressure within 60 minutes of injection. Signs of increased pressure or optic nerve perfusion should be carefully monitored.

Finally, though risk in clinical trials was low (<4%), administration of VEGF inhibitors like Luncentis has been associated with increased risk of serious arterial thromboembolic events. Patients should be monitored for signs and symptoms of these events, as appropriate.

Lucentis binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. This binding activity prevents the interaction of VEGF-A and its angiogenic receptor targets VEGFR1 and VEGFR2. Lowering VEGFR1 & VEGFR2 activation reduces endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Eter N, Krohne TU, Holz FG New pharmacologic approaches to therapy for age-related macular degeneration. BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy 2006;20(3):167-79

Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology 2006 Apr;113(4):632.e1

Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology 2006 Apr;113(4):642.e1-4. Epub 2006 Feb 14

Kim IK, Husain D, Michaud N, Connolly E, Lane AM, Durrani K, Hafezi-Moghadam A, Gragoudas ES, O'Neill CA, Beyer JC, Miller JW Effect of intravitreal injection of ranibizumab in combination with verteporfin PDT on normal primate retina and choroid. Investigative Ophthalmology & Visual Science 2006 Jan;47(1):357-63

For additional information regarding Lucentis or wet age-related macular degeneration, please visit the Lucentis web page.