Dennis M. Marcus, MD: Phase 3 Updates on the Port Delivery System

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Presented at ASRS 2023, additional results from the Pagoda and Pavilion trials suggest a potential benefit of PDS for patients with DME and diabetic retinopathy.

The phase 3 Pagoda and Pavilion trials investigating the Port Delivery System with ranibizumab (PDS) in patients with diabetic macular edema (DME) and diabetic retinopathy (DR), respectively, met their primary endpoints, according to new findings.

The data, presented at the American Society of Retina Specialists (ASRS) 41st Annual Meeting, suggests the PDS could have the potential to provide functional and anatomical benefits without the need for frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections.

“There’s no doubt in my mind that with regard to treatment burden trials that the PDS is the most advanced platform and good proof that it’s equivalent to monthly intravitreal injections and significantly decreases treatment burden,” Dennis M. Marcus, MD, Southeast Retina Center, told HCPLive at ASRS 2023. “I think that it has a potential applicability for some patients that require reduced treatment burden which has been the dogma of anti-VEGF intravitreal therapy.”

The PDS was approved by the US Food and Drug Administration (FDA) in October 2021, as a drug-device combination with 2 refills of ranibizumab per year for the maintenance of vision and retinal anatomy in patients with nAMD. It additionally offered a treatment strategy in DME and DR designed to maintain the clinical benefit of intravitreal anti-VEGF therapy while reducing the treatment burden. By October 2022, Roche Genentech voluntarily recalled the PDS, after laboratory testing revealed suboptimal implant performance.

In the phase 3 Pagoda trial for DME and the Pavilion trial for nonproliferative DR without center-involved DME, the PDS with ranibizumab 100 mg/mL was investigated with fixed refill-exchanges every 24 weeks (Q24W) or 36 weeks (Q36W), respectively. In Pagoda, PDS Q24W was compared to intravitreal ranibizumab 0.5mg every 4 weeks (Q4W); in Pavilion, PDS Q36W was compared to control, with supplemental intravitreal ranibizumab injections as needed.

The primary endpoint in Pagoda was noninferiority of PDS Q24W based on best-corrected visual acuity (BCVA) change from baseline average over weeks 60 - 64. For Pavilion, the primary endpoint was the superiority of PDS Q36W based on ≥2-step ETDRS-DRSS improvement from baseline at week 52. Other endpoints included the maintenance of driving vision (BCVA Snellen ≥20/40), stable vision (avoiding ≥3-line BCVA loss), and the absence of protocol-defined DME.

Results from Pagoda suggest PDS Q24W was non-inferior to ranibizumab Q4W in BCVA change from baseline (+9.4 letters versus +9.6 letters, respectively: difference, 0.2 [95% CI, –1.2 to 1.6]). At Week 64, the analysis showed 77.5% of PDS Q24W patients had BCVA ≥20/40 (vs. 71.1%), 98.9% avoided ≥3-line BCVA loss (vs. 97.5%), and 82.6% had DME absence (vs. 78.3%).

Analyses of Pavilion showed PDS Q36W was superior to control, as 80.1% of patients versus 9.0% of patients achieved ≥2-step ETDRS-DRSS improvement from baseline at week 52 (difference, 71.1% [95% CI, 61.0–81.2]).

At week 52, 93.7% of PDS Q36W patients (vs. 89.3%) maintained BCVA ≥20/40 and 98.9% (vs. 92.9%) avoided ≥3-line BCVA loss. Additionally, the rate of patients who did not develop center-involved DME was significantly greater with PDS Q36W (92.9%) vs. control (71.0%) (HR, 0.2 [95% CI, <0.1 - 0.5]; P = .0001).

The results indicated the PDS was generally well-tolerated across both trials, with no new safety signals observed and no cases of endophthalmitis reported in patients with PDS. The safety data was indicated to show a trend toward a reduction in ocular adverse events compared with a similar study period in neovascular age-related macular degeneration (nAMD).

Since the recall, Marcus noted there has been testing of improvements in the manufacturing processes, particularly regarding the potential for septum dislodgement, as well as changes made to optimize the performance of the implant. Robust accelerated age testing has been performed to simulate the lifespan of the PDS beyond the expected product lifespan.

“The anticipation is to be able to implant patients in clinical trials and then testing by the end of 2023,” Marcus said. “With the goal of engaging the FDA with also reimplanting patients with the hope of bringing the commercial product (Susvimo) back to patients and doctors for further options. So far, the testing indicates that the manufacturing has improved both the implant and the refill needles.”

Relevant disclosures for Dr. Marcus include Apellis, Genentech/Roche, Iveric Bio, Kodiak, Novartis, Regeneron, and others.