High Fliers

The treatment of retinal diseases has gone through a dramatic revolution over the past 15 years, since the introduction of anti-vascular endothelial growth factor (VEGF) agents delivered by intravitreal injection. This therapy achieved far better results than those of prior treatment modalities, such as laser or photodynamic therapy (PDT), and also transformed several retinal diseases from uncurable to manageable. Due to their simplicity and excellent efficacy and safety profiles, intravitreal injections of anti-VEGF therapy rapidly gained popularity, and became the most commonly performed procedure in ophthalmology. Today they are considered the first-line of therapy in most retinal diseases, and specifically in the most common ones: age-related macular degeneration (AMD), diabetic macular edema (DME) and macular edema secondary to retinal vein occlusions (RVO). There are three available anti-VEGF agents – ranibizumab, bevacizumab and aflibercept – all of which are delivered in the same manner of intravitreal injection and require close monitoring with frequent repeated injections.

Significant research attention has been devoted to developing a longer-acting anti-VEGF agent to reduce the treatment burden; however, no new drugs have become available in the past few years, and the number of intravitreal injections continues to rise steadily. The promising results with brolucizumab, a new anti-VEGF agent, reported in 2018, signpost it becoming a prominent component of treating retinal diseases in the very near future.

Brolucizumab is a humanized single-chain antibody fragment. It is the smallest active unit of an antibody, with a low molecular weight of only 26 kDa (compared to 48 kDa, ~100 kDa and 148 kDa of ranibizumab, aflibercept and bevacizumab, respectively). The low molecular weight allows for a significantly higher molar concentration of anti-VEGF active molecules (approximately 10 times higher than that achieved with other agents), which may enable it to act for a longer period of time following intravitreal injection. Phase I/II studies (SEE and OSPERY) have shown that brolucizumab achieved significant resolution of intra- and sub-retinal fluids in AMD patients with a longer duration of action (delivered every eight weeks). A larger phase II study has shown that a significant proportion of eyes with neovascular AMD could be treated every 12 weeks with brolucizumab, with comparable results to those achieved with aflibercept.

These results led to larger phase III clinical trials (HAWK and HARRIER), designed to compare two dosages of brolucizumab (3 mg and 6 mg) with aflibercept over two years of treatment for neovascular AMD. Following three-monthly injections, aflibercept is administered every eight weeks and brolucizumab every 12 weeks, with earlier intervention if disease activity is detected in monthly monitoring visits.

The two-years results of these trials were reported in 2018 (by Jaffe at ARVO and Dugel at AAO), highlighting comparable visual improvements and safety profiles in all three treatment groups. However, a significantly greater proportion of patients treated with brolucizumab achieved complete resolution of intra-retinal, sub-retinal and sub-RPE fluids at months 4, 12 and 24. There was also a greater reduction on central macular thickness on OCT in all timepoints in patients treated with brolucizumab. Over half (55 percent) of the patients treated with brolucizumab did not need earlier repeated injections and maintained the 12-week schedule throughout the study period. Moreover, it was shown that over 80 percent of patients who successfully reached the first 12-week interval without needing earlier treatment maintained this success over the first year; 75 percent maintained it over two years, indicating that early observation has a predictive value for individual patients.

These results have demonstrated non-inferiority of brolucizumab therapy for neovascular AMD compared with aflibercept, and have also shown that, in most cases, the desired results can be achieved and maintained with 12-week intervals. The findings represent an important step forward in the direction of longer-term treatment, which could reduce the burden of injections and patient visits. Future studies will be required to evaluate its long-term effects, efficacy in other retinal diseases and possibly even its use with larger treatment intervals. Looking forward, it appears that brolucizumab will soon join the other commonly used anti-VEGF agents in clinical practice, and will hopefully benefit patients, physicians and healthcare systems in the management of retinal diseases.