The LADDER study was a phase 2 study evaluating the Port Delivery System device (PDS; Genentech) for wet macular degeneration. The study compared the PDS device, which is surgically implanted into the eye, to monthly ranibizumab injections. Patients in the PDS arm were given 1 of 3 doses: 10 mg/mL, 40 mg/mL, or 100 mg/mL. The PDS device gives continuous medication over time. At the Retina Society 2020 Annual Meeting, Glenn Jaffe, MD, presented an analysis of the LADDER data that explored if continuous medication would cause greater macular atrophy (MA) than monthly injections. Below, retina specialists and the senior medical director of US Medical Affairs Ophthalmology for Genentech discuss the results.

Nitish Mehta, MD

New York University, New York, New York

Teasing out whether anti-VEGF accelerates MA in the treatment of neovascular age-related macular degeneration is a question the retina community has wrestled with for the greater part of a decade. Macular atrophy is part of the natural history of macular degeneration; and, when subfoveal, accounts for a meaningful percentage of severe vision loss. The major clinical trials assessing anti-VEGF therapy have all reported progression of existing MA and MA development, perhaps at a rate slightly higher than in nonexudative macular degeneration. Possible mechanisms include accelerated progression of coexisting nonexudative atrophy, de novo atrophy development, or contraction of neovascularization with subsequent atrophy.

To help elucidate whether increased delivery of anti-VEGF itself accelerates MA, post hoc analyses of studies that have compared monthly to pro re nata (HARBOR) or treat and extend (TREX-AMD) anti-VEGF delivery have not demonstrated increased development or progression of MA in the monthly arms. Phase 2 results from the LADDER trial demonstrating no increased incidence, size, and enlargement rate in low-dose continuous delivery vs monthly bolus ranibizumab is welcome news. We anticipate further results from the phase 3 ARCHWAY study.

Michael Singer, MD

Medical Center Ophthalmology Associates, San Antonio, Texas

Glenn Jaffe, MD, presented a very interesting analysis of the LADDER data. The analysis was to determine if continuous exposure to anti-vascular endothelial growth factor (anti-VEGF) medication would result in greater amounts of MA than monthly injection therapy. It turns out that the overall MA percentage was similar across all treatment arms. In terms of new MA development, this was also similar across all treatment arms in patients without MA at baseline. If one looked specifically at the high dose of ranibizumab, the mean area of MA was similar to monthly injections. In addition, the change in area of MA in the high dose was similar to monthly injections as well.

This analysis is comforting in that there was a theoretical possibility based on prior studies that MA increases based on the number of injections. This was seen in the CATT study but not seen in the HARBOR study. Personally, I was not surprised by this analysis, because I think the process of giving bolus injections of medication potentially increases in subclinical inflammation and may contribute to the process of atrophy formation. The reason for my belief is that if one looks at the ongoing studies for the prevention of geographic atrophy enlargement, the majority are focused on the complement cascade. The complement cascade is activated as a result of inflammation.

In the discussion portion of the meeting, Dr. Jaffe explained that it is hard to tell about any trends if continuous delivery causes less atrophy over time vs monthly injections as the numbers are too small. However, the phase 3 ARCHWAY study may give us a better idea, because this study has more patients enrolled.

Shamika Gune, MD, MS

Genentech, South San Francisco, California

The body of evidence on MA in anti-VEGF treated nAMD eyes has mounted over the last few years with the recent publications of CAM criteria-based assessments of SD-OCT datasets of nAMD trials such as HARBOR and TREX-AMD demonstrating no differences in atrophy rates between monthly and less-than-monthly treatment regimens. Additionally, the evidence from HARBOR demonstrates no differences in atrophy incidence or progression between ranibizumab doses of 0.5 mg or 2 mg administered monthly or pro re nata. The question of MA in the context of continuous delivery of ranibizumab via PDS was top of mind in the retina community as well as the team at Genentech ever since the LADDER Phase 2 primary analysis data were reported. The LADDER study population consisted of nAMD patients diagnosed within previous 9 months and treated and responsive to anti-VEGF injections of any agent. There were 3 PDS arms with ranibizumab 10mg/mL (n=58), 40 mg/mL (n=62), and 100 mg/mL (n=59), respectively; and a monthly ranibizumab 0.5mg intravitreal injection (n=41) arm. Given that MA takes time to set in, the LADDER data needed to mature so as to enable a robust MA analysis, which was performed once the LADDER study was completed. At the end of LADDER, all PDS patients had a mean duration of 22.1 months with a range of 10.8 to 37.6 months. Of note, the study population had received a mean of 2.9 injections prior to study baseline. As reported at Retina Society by Dr. Jaffe, the rates of atrophy prevalence, incidence, and progression were comparable among the 4 study arms. Thus, continuous delivery of ranibizumab through the PDS was not associated with an increased incidence or enlargement of MA compared with monthly ranibizumab injections in the LADDER study.

Numbers are small, but these results are encouraging and help to further solidify the potential of continuous ranibizumab delivery via PDS to deliver efficacy equivalent to gold standard monthly anti-VEGF injections with every-6-month refills. We look forward to the MA data from the large ARCHWAY phase 3 trial, which may confirm these observations from LADDER. RP