MARINA Trial: Ranibizumab for Neovascular Age-Related Macular Degeneration
Primary Efficacy Outcomes
The MARINA trial demonstrated that monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) prevented vision loss in approximately 95% of patients with minimally classic or occult neovascular AMD at 12 months, compared to only 62% with sham injections, establishing ranibizumab as a highly effective treatment that not only prevents vision loss but actively improves visual acuity. 1
Vision Preservation and Improvement
At 12 months, 94.5% of patients receiving 0.3 mg ranibizumab and 94.6% receiving 0.5 mg lost fewer than 15 letters from baseline visual acuity, compared to 62.2% in the sham injection group (P<0.001 for both comparisons). 1
Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, compared with only 5.0% of the sham-injection group (P<0.001 for both doses). 1
Mean visual acuity increased by 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, while the sham-injection group experienced a mean decrease of 10.4 letters (P<0.001 for both comparisons). 1
Sustained Long-Term Benefit
At 24 months, the visual acuity benefit was maintained, with 92.0% of the 0.3-mg group and 90.0% of the 0.5-mg group losing fewer than 15 letters, compared to 52.9% in the sham group (P<0.001). 1, 2
The proportion of patients gaining ≥15 letters increased over time, with 45% of patients continuing on ranibizumab achieving this milestone by day 210 in earlier phase studies. 3
Safety Profile
The MARINA trial demonstrated that ranibizumab had low rates of serious adverse events over 24 months, with the most significant risks being endophthalmitis (1.0%) and serious uveitis (1.3%). 1
Ocular Adverse Events
Presumed endophthalmitis occurred in five patients (1.0%) and serious uveitis in six patients (1.3%) among ranibizumab-treated patients during the 24-month study period. 1
The most common adverse events were reversible inflammation and minor injection-site hemorrhages, which were generally well-tolerated. 3
Transient increases in intraocular pressure occurred post-injection in 22.6% of ranibizumab-treated eyes, but these were typically self-limited. 3
Rare serious adverse events included iridocyclitis, central retinal vein occlusion, and retinal detachment (one subject each in phase I/II studies). 3
Subgroup Analysis: Predictors of Treatment Response
Subgroup analysis revealed that ranibizumab was superior to sham treatment across all patient subgroups, with the most important predictors of visual acuity outcomes being baseline visual acuity score, CNV lesion size, and age (in decreasing order of importance). 4
Key Prognostic Factors
All subgroups of ranibizumab-treated patients performed better than sham-treated patients regardless of gender, age, baseline visual acuity, CNV lesion size, lesion type, or duration of neovascular AMD. 4
Patients with higher baseline visual acuity scores experienced greater net benefit from ranibizumab versus sham treatment, emphasizing the importance of early treatment initiation. 4
Increasing age, larger CNV lesion size at baseline, and higher baseline visual acuity were associated with greater letter loss in the sham group or less letter gain in ranibizumab groups, but ranibizumab still provided substantial benefit across all these subgroups. 4
Fellow Eye Outcomes
Monthly ranibizumab injections in the study eye did not reduce the rate of new CNV development in untreated fellow eyes, with conversion rates of 30-38% by 24 months in ranibizumab-treated patients versus 36% in sham-treated patients (not statistically significant). 5
In MARINA, new CNV developed in fellow eyes in 20.3% of the 0.3-mg group and 21.1% of the 0.5-mg group by 12 months, compared to 26.4% in the sham group (differences not statistically significant). 5
By 24 months, fellow eye conversion rates were 30.4% (0.3 mg), 38.0% (0.5 mg), and 36.3% (sham), indicating no protective effect of systemic ranibizumab absorption on the untreated eye. 5
This finding underscores that fellow eyes remain at exceptionally high risk (up to 36% over 10 years) and require close monitoring every 6-12 months even without symptoms, as AREDS2 supplementation can reduce this risk. 6, 7
Clinical Implications and Current Treatment Standards
Based on MARINA and subsequent trials, the American Academy of Ophthalmology now recommends initiating intravitreal anti-VEGF therapy immediately upon diagnosis of neovascular AMD with three loading doses at 4-week intervals, as early treatment within 2 years significantly reduces legal blindness and visual impairment. 6, 7
Modern Treatment Algorithm
Administer three loading doses of ranibizumab (0.5 mg), aflibercept, or bevacizumab at exactly 4-week intervals as the initial treatment phase. 7
After loading, maintenance regimens include monthly injections, treat-and-extend protocols, or PRN (as-needed) dosing for ranibizumab, though aflibercept offers the advantage of every-8-week dosing after loading with equivalent efficacy to monthly ranibizumab. 7
Perform OCT imaging at every visit to assess for subretinal or intraretinal fluid, as this guides treatment decisions and monitoring for disease activity. 7
Critical Pitfalls to Avoid
Do not delay treatment initiation while awaiting "optimal" timing—early treatment is associated with better visual outcomes, and the MARINA trial demonstrated that even patients with minimally classic or occult lesions benefit substantially from immediate treatment. 1, 4
Patients must be counseled that monthly injections are required for optimal outcomes based on the MARINA protocol, though newer agents like aflibercept allow for less frequent maintenance dosing. 7, 1
Ensure patients understand that anti-VEGF therapy should be combined with AREDS2 supplementation (vitamin C, vitamin E, zinc, copper, lutein 10mg, zeaxanthin 2mg) to reduce progression risk in the fellow eye by up to 36% over 10 years. 6, 7
Long-Term Visual Outcomes
At 5-year follow-up from subsequent studies, 50% of patients maintained visual acuity of 20/40 despite initial vision gains not being fully maintained, demonstrating that while ranibizumab provides substantial long-term benefit, ongoing treatment and monitoring are essential. 7
The MARINA trial established that the visual acuity benefit was maintained through 24 months with continued monthly treatment, supporting the need for long-term therapy rather than short-term intervention. 1
Patients can be reassured that while central visual loss may occur, total blindness is extremely rare, as peripheral vision is typically preserved even in advanced disease. 6