Long-Term Anti-VEGF Delivery System Draws Closer to Primetime

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world, posing a huge healthcare and societal burden. The impact of AMD will only grow as the population continues to age and the number of patients with AMD increases to an expected 228 million worldwide by 2040.^[1]

Significant strides have been made over the past decade in the treatment of neovascular AMD (nAMD), with intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy proven in numerous studies to be highly effective in preventing further vision loss in most patients and improving vision in many. However, there remains a significant financial and societal burden centered around the frequency of visits needed for continued intravitreal anti-VEGF therapy. For years, researchers have explored the possibility of longer-acting options.

The Port Delivery System (PDS) is a permanent, surgically implanted, refillable intravitreal implant designed to deliver a continuous supply of ranibizumab into the vitreous. The Ladder trial was a phase 2 study that established the efficacy of the 100 mg/mL formulation of ranibizumab as well as an acceptable safety profile of the PDS system.^[2]

Phase 3 Trial Demonstrates Noninferior Outcomes

Recently, the phase 3 Archway trial^[3] evaluated the safety and efficacy of the PDS with ranibizumab compared with traditional monthly intravitreal ranibizumab injections.

Investigators recruited patients with nAMD who had demonstrated response to at least three prior anti-VEGF intravitreal injections within 6 months of screening. Of the 415 patients treated, 248 were randomly assigned to receive PDS with ranibizumab 100 mg/mL with every-24-week refill-exchanges (PDS Q24W) and 167 received intravitreal ranibizumab 0.5 mg injections every 4 weeks, according to a 3:2 randomization ratio.

All patients were monitored monthly to maintain visual acuity examiner masking. Patients in the PDS arm were eligible for supplemental intravitreal ranibizumab injections if they had any of the following signs of increased nAMD activity at a study visit preceding a refill-exchange procedure: an increase in central subfield thickness ≥ 150 μm on spectral-domain optical coherence tomography, a decrease of five or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or an increase ≥ 100 μm in central subfield thickness on spectral-domain optical coherence tomography from the lowest central subfield thickness value in the study associated with a decrease of 10 or more ETDRS letters from the best recorded best corrected visual acuity during the study.

Ultimately, 1.6% of patients in the PDS Q24W group received supplemental intravitreal ranibizumab. Patients in the PDS Q24W group experienced a transient and reversible postsurgical drop of approximately 1 ETDRS line in vision after implant insertion, with vision returning to baseline by week 8. At 36 weeks, mean change in best corrected visual acuity was +0.2 letter (SE, 0.5 letter) in the PDS arm and +0.5 letter (SE, 0.6 letter) in the intravitreal arm (difference, -0.3 letter; 95% CI, -1.7 to 1.1 letters). This difference was not statistically significant. Control of retinal thickness at 36 weeks was also comparable between the PDS and intravitreal arms, with mean central thickness change from baseline of 5.4 μm (SE, 2.9 μm) in the PDS Q24W arm and 2.6 μm (SE, 3.6 μm) in the monthly ranibizumab arm (difference, 2.8 μm; 95% CI, -6.2 to 11.9 μm).

Ocular adverse events of special interest occurred in 19.0% of patients in the PDS Q24W arm and 6.0% of those in the intravitreal injection arm. The most common unique complication in the PDS arm was conjunctival bleb or conjunctival filtering bleb leak, which occurred in 6.5% of patients. Rates of vitreous hemorrhage and cataract formation did not statistically differ between the two groups. Rare but serious complications that were observed in the PDS group included endophthalmitis (1.6%) and retinal detachment (0.8%). The majority of adverse events in the PDS arm occurred within the first month of PDS implantation.

Where Will PDS Fit In?

Although there are limitations to its generalizability, the Archway trial is the first phase 3 study to demonstrate noninferior visual acuity outcomes with a longer-term therapy compared with the current standard of intravitreal injections. The safety profile of the PDS is probably acceptable in patients for whom the burden of returning for monthly intravitreal injections is high.

There is huge potential in decreasing the nAMD treatment burden on patients, families, and the healthcare system. The PDS has the potential to benefit all patients with AMD patients who have proven response to anti-VEGF and have demonstrated the need for a more frequent injection regimen. Specifically, patients with high follow-up visit burden due to financial, logistical, medical, or other challenges could stand to benefit the most. Patients could potentially be seen as few as two times a year for refill-exchanges, although safety data suggest that more frequent follow-up will probably be necessary. Patients will need to be selected carefully and counseled regarding potentially vision-threatening adverse events, which have been shown to occur most often in the postoperative period after PDS implantation. Ultimately, further studies with more patients will need to be pursued before use of the PDS increases, but the Archway study is a big step in the right direction.

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