“Doc- just how many of these injections do I have to have?” a frequent refrain in my retina clinic, is usually followed by “Do I really have to come in every month?” For patients with diabetic macular edema, I emphasize that to maximize vision gains, it is important to comply with monthly or near-monthly visits in the first year of treatment.  However, I tell them that there is a light at the end of the tunnel: at least for diabetic macular edema, we usually can maintain their early vision gains with markedly fewer intravitreous injections over time.  On average, the number of injections decreases by half each year, and by 4 and 5 years after the start of anti–vascular endothelial growth factor therapy (anti-VEGF) therapy, many patients with diabetic macular edema no longer need injections.

However, it is a different story for patients with neovascular age-related macular degeneration.  I use a treat and extend approach, trying to extend visit intervals whenever I can while keeping vision stable and minimizing subretinal and intraretinal fluid.  Nonetheless, on average, patients require injections about every 2 months for what seems to be (and has literally been for some patients) the rest of their lives.  This long-term and continued need for injections is also apparent in some retinal vein occlusion patients with macular edema.

The high frequency of anti-VEGF injections for retinal vascular diseases is a major issue not just because of patient inconvenience. Higher injection numbers mean increases in risk for endophthalmitis and other injection-related complications. The public health implications of monthly intravitreous injections are high, with exploding costs within the last decade related to injection procedures and drugs.  Frequent visits have additional economic consequences in lost work hours and potential loss of pay for working patients.  Unfortunately, patients who are unable to comply with recommended visit schedules and treatments may not have optimal vision results.

Many of us hold out the promise of extended-duration anti-VEGF agents to our patients as a possible solution for some of these woes.  The grail of extended duration anti-VEGF therapy in clinical care is yet to be achieved, although multiple approaches are being investigated.  The diversity of reported methods has included drug conjugation or encapsulation in biodegradable vehicles, drug reservoirs, genetic therapy, iontophoresis, electro-osmosis, hydrogel contact lenses, elution from intracapsular rings, and encapsulated cell techniques.

Longer-duration dosing may be on the horizon with new anti-VEGF agents.  In the HAWK and HARRIER trials of brolucizumab for neovascular age-related macular degeneration, 87% and 83% of patients, respectively, who were assessed as appropriate for 12-week treatment frequency after an initial loading interval, were able to maintain quarterly dosing through week 48.

Even longer dosing intervals may be achievable with alternative approaches.  Phase 2 study results of an investigational, refillable port delivery system loaded with ranibizumab in patients with neovascular age-related macular degeneration were reported at the 2018 American Society of Retina Specialists annual meeting.  LADDER study patients underwent surgical implantation of the device and were randomized to 1 of 3 ranibizumab concentrations:  10 mg/mL, 40 mg/mL, or 100 mg/mL.  Approximately 80% of patients in the 100-mg/mL group were able to go 6 months or longer before requiring their first refill of medication.  In the 10-mg/mL and 40-mg/mL groups, more than 60% and 70% of study participants were able to go 6 months or more before requiring a refill.  Similar vision gains and reductions in central retinal thickness were achieved by the 100 mg/mL dose group as compared with a control group receiving monthly ranibizumab, 0.5 mg, intravitreous injections.  Although vitreous hemorrhage was a potential issue identified in early device users, no major safety issues were identified in this study.

I am thrilled to know that the port delivery system is moving into phase 3 trials later this year.  Data from these larger, longer-term studies are needed to answer critical questions as to whether and how it will change clinical care.  In the context of chronic diseases, such as age-related macular degeneration and diabetic retinopathy, we need to know how long patients can go between refills over the span of multiple years.  The long-term safety profile is also important to understand.  The landscape of available therapies also continues to evolve. If other approaches prove successful over time, their relative risks and benefits may change the calculus of whether advantages accrued from this device warrant a surgical procedure with its associated cost and risks. Despite these questions, it is heartening to know that with the LADDER study, the field has ascended another rung in the search for extended dosing anti-VEGF therapy!

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