Article

The Port Delivery System With Ranibizumab

A new treatment strategy for patients with nAMD enters a phase 3 clinical trial.

By DANTE J. PIERAMICI, MD

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Anti-VEGF therapies have had an enormous impact on the management of neovascular AMD (nAMD). Retina specialists who treated patients with nAMD prior to anti-VEGF agents can remember the many disappointing outcomes with photodynamic therapy (PDT) and laser photocoagulation treatments. Patients with nAMD had reason to be discouraged by their prognosis; many were, and it was palpable in the waiting room.

Today, the waiting room mood is noticeability uplifted. In large part, we have anti-VEGF therapy to thank. However, the burden of anti-VEGF therapy remains a problem that needs to be addressed, despite the efficacy and safety of current anti-VEGF intravitreal injection therapies. The burden of therapy is not merely the inconveniences of monthly or bimonthly therapy and repeat evaluation. More importantly, it is likely that the burden of therapy leads to undertreatment in noninvestigational or “real-world” patient populations. This undertreatment is associated with inferior visual outcomes over time.1-4 Improving efficacy of anti-VEGF therapies is currently a high bar to achieve. However, there is much room to improve on the effectiveness of anti-VEGF by addressing the burden of treatment. One obvious solution would be a long-term drug-delivery device. Such a device could reduce or eliminate the burden of repeat intravitreal injections and the burden of frequent monitoring visits. The Port Delivery System with ranibizumab (PDS; Genentech) is such a device, and it is currently being tested in a phase 3 registration study (ARCHWAY).

Dante J. Pieramici, MD, is a retina specialist with California Retina Consultants in Santa Barbara, California. Dr. Pieramici reports consultancy to and research fees from Genentech. Reach him at dpieramici@yahoo.com.

THE DEVICE

The PDS is designed as a permanent, reusable, surgically placed, office-refilled drug reservoir. The device is placed through a 3.5-mm scleral incision in the pars plana (Figure 1). It is composed of polysulfone and includes a silicone septum that can be entered with a special needle many times to refill the device. The device currently holds 20 microliters of customized formulation of ranibizumab (100 mg/mL). At the distal end, there is a semipermeable titanium membrane that permits continuous passive diffusion of the drug from the higher concentration in the reservoir into the vitreous, a process that follows Fick’s law of diffusion.

Figure 1. The PDS implant in position, viewed externally (top). The small circular silicone septum can be seen with magnification. A close-up of the implant is shown in the bottom image.

The device is refilled in the office with a specialized refill needle that flushes out the device while at the same time recharging it with fresh ranibizumab (Figure 2; video). Currently, the device is being tested with 100 mg/mL of ranibizumab in the phase 3 trial, which was the most effective dose demonstrated in the phase 2 LADDER trial. In my opinion, the genius of this device over others that are being investigated is its simplicity in design. To quote an often-used adage, “Simplicity is the ultimate sophistication.”

Figure 2. The refill needle in position. The older contents are flushed out and the device is refilled with new drug.

TESTING THE DEVICE

Following positive experience with preclinical and phase 1 testing in about 20 patients, a phase 2 study, the LADDER trial, was designed to test the safety and efficacy of the PDS with ranibizumab in the treatment of patients with nAMD who had demonstrated previous efficacy to intravitreal ranibizumab injections. The LADDER trial was a multicenter phase 2 clinical trial testing 3 doses of ranibizumab (10 mg/mL, 40 mg/mL, 100 mg/mL) vs monthly intravitreal injections of 0.5 mg ranibizumab. The primary endpoint of this trail was the time to first refill of the PDS. The need for refill was mandated based on specific visual and/or anatomic criteria. Secondary endpoints included visual and anatomic outcomes and safety. The main question was, could the device safely deliver drug effectively over an extended time period while providing similar or superior visual and anatomical outcomes as the monthly injection arm?

Patients included in this trial were not naïve to anti-VEGF therapy; instead, they had to have demonstrated prior anatomic or visual response to intravitreal anti-VEGF therapy. In addition, the patients had to have been diagnosed with nAMD within the previous 9 months and had at least 2 or more anti-VEGF prior to screening. The design was to include anti-VEGF responsive patients, but ones with relatively new choroidal neovascular lesions and visual acuity between 20/20 and 20/200. Surgical training was a priority and the procedure and equipment were customized to facilitate the procedures. Surgical liaisons were present prior to and during the procedures and refills to maximize the surgical outcomes with this new procedure. Investigators went through rigorous training, and various supplemental educational materials were available, including step-by-step videos and a practice mannequin.

Early on in the clinical trial, the rate of vitreous hemorrhage following the surgical procedure were quite high at 50%. As a result, a modification to the procedure was developed, which required scleral dissection to the pars plana followed by careful cauterization of the exposed uvea with laser coagulation prior to entering into the vitreous with a 3.2-mm blade. The prior procedure was a simple one-pass stab incision with the blade and no choroidal cautery. The modification had a huge positive effect, and the rate of postprocedure vitreous hemorrhage declined to less than 5%.

RESULTS OF THE TEST

The LADDER study analysis population included 220 patients, and the treatment groups were well balanced at baseline, with average baseline BCVA of 20/40. Most of the patients had been diagnosed with nAMD in the prior 4 months (range 3.2 to 3.9 months) and had on average 3 previous injections. The primary endpoint, the time to first required PDS refill, was 15 months, 13 months, and 8.7 months in the 100 mg/mL, 40 mg/mL, and 10 mg/mL groups, respectively. Visual results and anatomic results were comparable between the 100 mg/mL and monthly intravitreal injection groups at month 9. The procedures were relatively safe, although there were a few cases of endophthalmitis and retinal detachment. No obvious systemic safety signals were identified. The procedures, performed on an outpatient basis under local anesthesia with sedation, were well tolerated by the patients.5-7

THE NEXT TEST

Following the positive results of the LADDER study, Genentech has decided to proceed with a phase 3 registration trial of the PDS device with 100 mg/mL ranibizumab vs monthly intravitreal ranibizumab treatment, called the ARCHWAY trial. In a separate trial, patients from the LADDER trial were offered enrollment in the PORTAL extension study that included implantation of the PDS for the LADDER control group and continued PDS refill of those who received the implant in the LADDER trial.

In the ARCHWAY trial, the implant group will undergo mandatory refills every 6 months. There will also be opportunity for supplemental ranibizumab if criteria are met at other timepoints. The primary endpoint of this study is the mean change in BCVA averaged between weeks 36 and 40. The design is a noninferiority and equivalence study of the PDS 100 mg/mL ranibizumab Q24 weeks vs monthly intravitreal ranibizumab. Patients will be enrolled 3:2 PDS vs intravitreal ranibizumab for a total of 360 patients. Like the LADDER trial, in ARCHWAY, investigators will undergo rigorous training including virtual reality training of the implant and refill procedures. It is an essential goal that all surgeons will be comfortable and well trained prior to their first study patient surgery.

In this trial, extra attention is being directed toward meticulous surgical technique, such as conjunctival and tenons dissection and hemostasis, so as to reduce the immediate and long-term potential complications of this permanent device.

Some of the techniques used during the PDS implant are not frequently called for with many of our current vitreoretinal procedures. Highlighting these steps with additional training will benefit the patients and the study. The ARCHWAY trial is under way and continues to recruit patients. Positive results from the ARCHWAY trial and FDA approval of this device will provide us with an option of extended delivery for some of our patients with nAMD. By eliminating the burden of current therapy, such extended delivery could make long-term visual results of the “real world” populations similar to the investigational outcomes and will be another major advancement in the care of our patients. RP

REFERENCES

  1. Cohen SY, Mimoun G, Oubraham H, et al; LUMIERE Study Group. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study. Retina. 2013;33(3):474-481.
  2. Finger RP, Wiedemann P, Blumhagen F, Pohl K, Holz FG. Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study - a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol. 2013;91(6):540-546.
  3. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99(2):220-226.
  4. Rao P, Lum F, Wood K, et al. Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry. Ophthalmology. 2018;125(4):522-525.
  5. Awh C. LADDER trial of the Port Delivery System for ranibizumab: preliminary study results. Presented at the 36th Annual Meeting of the American Society of Retina Specialists; Vancouver, British Columbia, Canada; July 25, 2018.
  6. Pieramici D. LADDER trial of the Port Delivery System with ranibizumab: initial study results. Presented at the Retina Society 2018 annual meeting; San Francisco, California; September 14, 2018.
  7. Pieramici D. Port Delivery System with ranibizumab (PDS): from dose ranging in LADDER phase 2 to ARCHWAY phase 3 study design. Presented at the 2018 American Academy of Ophthalmology Annual Meeting; Chicago, Illinois; 2018 Oct 27.