The Port Delivery System with ranibizumab, or PDS (Genentech/Roche), has the potential to reduce the treatment burden for patients with neovascular AMD (nAMD) through continuous delivery of a customized formulation of ranibizumab. It has been tested in the LADDER clinical trial (NCT02510794), a phase 2 randomized controlled study, and recently the end-of-study results have been released.

TRIAL DESIGN

The LADDER phase 2 trial was designed to characterize the treatment effect, durability, and safety of the PDS in patients with nAMD responsive to at least 2 prior injections with any of the anti-VEGF agents available during study enrollment. Two hundred twenty nAMD patients were randomized to 1 of 4 groups: PDS with ranibizumab 10 mg/mL, PDS with ranibizumab 40 mg/mL, PDS with ranibizumab 100 mg/mL, or monthly intravitreal ranibizumab 0.5 mg injections.

The primary endpoint of the LADDER trial was the time to first PDS refill, assessed when the last patient completed the month 9 visit. Refill criteria included an increase in central foveal thickness (CFT) ≥75 microns compared with the average of the prior 2 visits; an increase in CFT ≥100 microns compared to the lowest measurement on study; a loss of ≥5 letters in best-corrected visual acuity (BCVA) compared to the average of the prior 2 visits; or a loss of ≥10 letters in BCVA compared with the best recorded BCVA on study. Key secondary endpoints were change from baseline in BCVA, change from baseline in CFT on spectral-domain OCT, and safety.

RESULTS FROM PHASE 2 STUDY

Baseline demographics and ocular characteristics were well balanced among the 4 groups at the start of the study. It is important to note that mean BCVA in all groups was good at 20/40, because each patient had received anti-VEGF treatment before entering the LADDER study. In fact, patients received between 2 and 8 prior anti-VEGF injections and were known to have VEGF-responsive nAMD.

Figure 1 shows the median time to first refill, assessed at LADDER trial completion. There are 3 important points to glean from these data. First, there appears to be a dose response demonstrated by the 3 different concentrations of ranibizumab delivered via the PDS. Second, the median time to first refill in the PDS 100 mg/mL group was 15.8 months. Third, 80% of PDS 100 mg/mL patients went at least 6 months without requiring a refill.

Patients remained on study for a mean time of 21 to 22 months (range 11-38 months). What happened to BCVA and CFT during this time? Essentially, the mean change in visual acuity from baseline remained flat, showing minimal improvement in the PDS 100 mg/mL arm that was comparable to the visual acuity results for the monthly intravitreal ranibizumab 0.5 mg arm. It is important to remember that vision was relatively good at baseline and that this study represents a long-term maintenance strategy. Large visual acuity gains were not expected. Similarly, the change from baseline in CFT was minimal, with the PDS 100 mg/mL arm behaving in an identical manner to the monthly intravitreal ranibizumab 0.5 mg arm. As this is a maintenance strategy, large improvements in CFT were not expected.

During the 21 to 22 months’ median time that patients in the LADDER trial were followed (range 10.8 to 37.6 months), the PDS groups received more than 7-fold fewer ranibizumab treatments (whether an initial fill, refill-exchange procedure, or a rescue ranibizumab 0.5 mg injection) compared to the monthly intravitreal ranibizumab 0.5 mg injection group. Although this finding requires replication in a larger study, it suggests PDS continuous delivery of ranibizumab may have the potential to significantly reduce the treatment burden in patients with nAMD.

Durability is the other side of the treatment-burden coin. Figure 2 demonstrates the potential for durability of PDS-delivered ranibizumab in the LADDER trial. Again, there appears to be a dose response observed across the 3 different PDS arms of the LADDER trial. Assessing the PDS 100 mg/mL arm alone, the patients not meeting refill criteria were just under 80%, 70%, and 60% at months 6, 9, and 12, respectively. This finding has biologic plausibility given that diffusion governs the rate of drug release from the PDS.

Through the end of study, only 31 of 59 LADDER patients who were randomized to the PDS 100 mg/mL arm met refill criteria. Thus, 28 patients never required a refill-exchange procedure through, on average, 21 to 22 months. Of the 31 patients who met refill criteria, the median time to first refill was 8.8 months. Of the 19 patients who met refill criteria a second time, the median time to second refill was also 8.8 months. Therefore, in the LADDER trial, in patients requiring refills the median time to refill was consistently 8.8 months.

PHASE 3 STUDY UNDER WAY

Given the information gleaned from the LADDER phase 2 clinical trial, the Archway (NCT03677934) phase 3 clinical trial was designated to move forward with only the PDS 100 mg/mL arm and was designed to include mandatory 6-month refills in all patients. In Archway, 360 patients with nAMD responsive to any anti-VEGF treatment are randomized to the PDS 100 mg/mL refilled Q24 weeks, or to monthly intravitreal ranibizumab 0.5 mg injections. The primary endpoint is mean change in BCVA from baseline averaged at weeks 36 and 40. Key secondary endpoints include other visual acuity endpoints, anatomic findings, and safety.

Safety will be a critical part of the Archway clinical trial results. The PDS introduces a surgical procedure to a disease state that has always been managed in the office, and that management has been characterized by an excellent safety profile. While surgical complications are likely to occur in Archway, they must be infrequent and easily managed.

The LADDER trial suggests a few important safety metrics to scrutinize in the Archway trial. First, the incidence of postsurgical and delayed vitreous hemorrhage must be examined. Early in the LADDER clinical trial, the vitreous hemorrhage rate was 50% due to bleeding associated with the surgical implantation of the PDS. The trial was paused, the surgical steps were revised, and later the vitreous hemorrhage rate declined to 4.5%. It is important for the Archway trial to replicate or even further reduce this finding. In addition, the rate of endophthalmitis in the LADDER trial was 1.7% (3/179), significantly higher than the low rate of endophthalmitis associated with in-office intravitreal injections. The Archway trial will provide key safety data regarding endophthalmitis. Finally, conjunctival complications (either blebs or erosions) occurred in 6.8% of patients. Additional conjunctival events (retraction or filtering bleb leaks) occurred in 2.3% of patients. While these issues were mitigated with relevant interventions, the Archway trial results will provide clarifying information on conjunctiva-associated complications.

Even if efficacy is demonstrated, the attainment of safe surgical outcomes will be key to successful future adoption of this method of treating nAMD. The Archway clinical trial is fully enrolled and top-line results are expected soon. RP